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Adenovirus-Mediated Gene Transfer of Angiopoietin-1 Induces Angiogenesis in the Chronic Ischemic Myocardium

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Adenovirus-Mediated Gene Transfer of Angiopoietin-1 Induces Angiogenesis in the Chronic Ischemic Myocardium
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  FIRST INTERNATIONAL SYMPOSIUM ON CARDIOVASCULAR SCIENCE: SELECTED ABSTRACTS  561 01Adenovirus-Mediated Gene Transfer of Angiopoietin-1 InducesAngiogenesis in the Chronic Ischemic Myocardium Li Zhang 1 , Akanksha Bapna 2 , Winston Shim, Oakley Reida El 1 , YeanTeng Lim 3 , Tai Tian Lim 4 , Ming Teh 5 , Ruowen Ge 2 , Eugene Sim 1 . 1 Department of Surgery, Faculty of Medicine, National University ofSingapore, 2 DepartmentofBiologicalScience,FacultyofScience,NationalUniversityofSingapore, 3 CardiacDepartment,NationalUniversityHospital, 4 Department of Cardiology, National Heart Center,  5 Department of Pathol-ogy, National University Hospital, Singapore. Objective:  Overexpression of Angiopoietin-1 (Ang-1), a newly identifiedangiogenic mediator, was shown to enhance angiogenesis in vitro, andaugment collateral vessel development in animal model of limb ischemia.However, its potential effect on myocardium remains unclear. We testedthehypothesisthatadenovirus-mediatedgenetransferofAng-1(AdAng-1)may stimulate revascularization in the ischemic myocardium.  Methods: Ameroid constrictors were placed around the proximal left circumflex ar-teries of porcine hearts to induce chronic myocardial ischemia. Six weekslater, animals were randomized to three groups (ischemic control (withoutfurtherinterventions),AdNull(nulladenoviralvector),andAdAng-1).AdNulland AdAng-1 were injected directly into the ischemic myocardium alongthefreewallofleftventricle,10 9 pfuperinjection,10injectionsperanimal.Regional blood flow measurement was performed by fluorescence micro-spheres, in the AdAng-1 group at the time of administration and 3 monthslater. Animals were then sacrificed. Collateral development was assessedby ex vivo angiography after treatment. Anti-Factor VIII serum was ap-plied to stain vascular endothelium, for quantifying the vascular density oftreated areas.  Results:  Ex vivo angiography showed collateral formationin most of the animals. The average grade by quantitative assessment ofangiograms in the AdAng-1 group was higher, compared with the othertwo groups. Immunohistological studies (Fig. 1) demonstrated that the av-erage of vascular density of AdAng-1 group was significantly higher thanthose of the other two groups. Most of the vessels developed were capil-laries.Thevectoradministrationdidn’tcauseadditionalinflammationinthemyocardium.  Conclusion:  Administration of adenoviral vector coding forAng-1 might enhance angiogenesis, especially the formation of sustainedcollaterals in the ischemic myocardium. Figure 1.  Immunohistochemistry (srcinal magnification 200  × ) staining with anti-Factor VIII for (A) ischemic control, (B) AdNull treated and (c) AdAng-1 treated. Increased number of capillaries is demonstrated in the AdAng-1 injection region. 02ContributionofNitricOxideSynthasetoImprovedEarlyGraftPatencyin Human Saphenous Vein Graft Harvested by a Novel ‘No-Touch’Technique JCS Tsui 1 , D Souza 3 , D Filbey 4 , MR Dashwood 1 , 2 .  1 Departments of Sur-gery and  2 Molecular Pathology and Clinical Biochemistry, Royal Free &University College Medical School, Royal Free Campus, Pond Street,London NW3 2QG, U.K.,  3 Departments of Cardiothoracic Surgery and 4 Transfusion Medicine, Orebro Medical Centre, Orebro, Sweden. Aim:  Saphenous vein (SV) is the most commonly used conduit in bypassprocedures but has a one-year occlusion rate of 15-30%. A new ‘no-touch’technique where the SV is harvested with a cushion of surrounding tis-sue with no distension has led to improved early patency rates of 5% at18-months. Nitric oxide (NO), synthesised by nitric oxide synthase (NOS)has properties beneficial to graft patency. Our aim was to study the distri-bution of NOS in SV harvested by this technique and the effect of disten-sion and removal of perivascular tissue on NOS content of SV.  Methods: Following ethical committee approval and patients’ informed consent,SVs were harvested from ten patients undergoing coronary artery bypassgrafting. A segment of vein was harvested by the conventional technique(surrounding tissue stripped and vein distended with saline); another partwas stripped but not distended (‘control’) and the remaining parts har-vested by the ‘no-touch’ technique. Samples of each segment were takenand transverse sections prepared for NOS identification using  3 [H]L-N G ni-troarginine (NO Arg) autoradiography and NADPH-diaphorase histochem-istry. NOS isoforms were studied using standard immunohistochemistry.Endothelial cells and nerves were also identified using immunohistochem-istry with CD31 and NF200 respecitvely, to confirm sources of NOS. Mor-phometric analysis of NADPH-diaphorase staining was carried out to studytissue NOS content.  Results:  NO Arg binding representing NOS was pre-served on the lumen of ‘no-touch’ vessels whilst that on conventional andcontrolvesselswasreduced.NOSwasalsolocalisedtothemedialsmoothmuscle cells of all vein segments and to the intact adventitia of ‘no-touch’segments. This was confirmed by NADPH-diaphorase staining, which re-vealed a mean reduction of NOS by 19.5% (p < 0.05, ANOVA) in controlsegments due to stripping of surrounding tissue alone and a reduction of35.5% (p  <  0.01, AVNOVA) in conventional segments due to stripping anddistension, compared to ‘no-touch’ segments. Adventitial NOS sources in‘no-touch’vesselscorrespondedtovasavasorumandparavascularnerves.AllthreeNOSisoformscontributedtothepreservedNOSin‘no-touch’ves-sels.  Conclusions:  Apart from preserved lumenal NOS, NOS sourcesare also located in the media and adventitia of SV grafts. These are re-duced by both adventitial damage and vein distension during conventionalvein harvesting. The ‘no-touch’ technique avoids these procedures, pre-serving NOS sources. This may result in improved NO availability in SVharvested by this technique, contributing to the improved patency ratesreported. 03Influence of Body Size on Clinical Outcome in Patients UndergoingCoronary Surgery with or Without Cardiopulmonary Bypass RAscione,KRees,MHChamberlain,FCiulli,AJBryan,GDAngelini.BristolHeart Institute, University of Bristol, UK. Objective:  Coronary artery bypass grafting (CABG) in overweight patientscarries significant morbidity. We compare the effectiveness of off-pumpcoronary artery bypass (OPCAB) surgery versus conventional CABG us-ing cardiopulmonary bypass and cardioplegic arrest, in a consecutive se-ries of overweight patients.  Methods:  From April 1996 to April 2001, datafrom 4321 patients undergoing coronary revascularisation (mortality 1.4%)were prospectively entered into the Patients Analysis and Tracking Sys-tem. Data were extracted for all patients with a body mass index (BMI) ≥ 25. In hospital mortality and early morbidity were compared between pa-tients undergoing on- and off-pump coronary surgery. A risk-adjusted anal-ysis was also carried out to assess the influence of surgery on outcomes. Results:  2844 overweight patients with BMI  ≥  25 were identified, andof these 674 (23.7%) were operated on with off-pump surgery. On-pumppatients were less likely to have unstable angina, hypercholesterolaemia,to have coronary disease involving the left main stem, or to have a BMI ≥ 30. However, they had more extensive coronary disease, were more likelyto have suffered previous myocardial infarction, and received more graftsthan those undergoing off-pump surgery. Intra- and post-operative arrhyth-mias, inotropic use, and post-operative low cardiac output, use of IABP,blood loss, transfusion requirement, chest infections, neurological com-plications including permanent stroke, ICU and hospital stay all were sig-nificantly reduced in the off-pump group (all p  <  0.05). After adjustmentfor age, gender, ejection fraction, extent of coronary disease, and degreeof urgency, odd ratios (ORs) for most of the adverse outcomes investi-gated, confirmed significant benefit of off-pump surgery (table). The pointestimate of the adjusted effect size for in-hospital mortality also indicatedbenefit from off-pump surgery (table). On-Pump Off-Pump OR/MeanVariable (2169) (674) Difference 95% CI p Death 20 (0.92%) 2 (0.29%) 0.37 0.08, 1.59 0.18Postoperative MI 35 (1.6%) 14 (2.0%) 1.37 0.72, 2.62 0.337New Inotropes 879 (40.5%) 219 (32.5%) 0.8 0.66, 0.97 0.02New IABP 54 (2.5%) 5 (0.7%) 0.32 0.12, 0.8 0.015Ward arrhythmia 320 (14.8%) 65 (9.6%) 0.63 0.47, 0.84 0.002Chest Infection 106 (4.9%) 14 (2.1%) 0.43 0.24, 0.76 0.004Neurolog. Complic. 59 (2.7%) 6 (0.9%) 0.36 0.15, 0.85 0.02Blood Loss (ml) 939.9 (512.3) 856.2 (582.1)  − 60.8  − 111.7, − 9.87 0.019Total RBCs (unit) 1.05 (1.51) 0.436 (1.52)  − 0.51  − 0.65, − 0.37 0.0001Total Platelets (unit) 0.24 (0.81) 0.08 (0.455)  − 0.157  − 0.23, − 0.08 0.0001Total FFP (unit) 0.49 (1.48) 0.126 (0.72)  − 0.38  − 0.5, − 0.25 0.0001Sternal rewiring 17 (0.78%) 1 (0.14%)  − 0.22 0.03, 1.7 0.15Renal complications 98 (4.5%) 24 (3.56%)  − 0.74 0.44, 1.25 0.265Hospital stay (day) 7.76 (4.26) 6.64 (3.04)  − 0.94  − 1.39, − 0.49 0.0001 Conclusions:  These results suggest that off-pump surgery is safe, eff-ective and associated with reduced morbidity in overweight patients.  562  FIRST INTERNATIONAL SYMPOSIUM ON CARDIOVASCULAR SCIENCE: SELECTED ABSTRACTS 04The Prognosis of Patients with Ventricular Septal Defect Accompa-nied by Mitral Insufficiency Feng Sheng, Zipu Li, Yuyang Liu, Zhanggen Chen. Children’s Hospital ofFudan University, Shanghai 200032, PR China. Aim: Ventricularseptaldefect(VSD)isthemostfrequentlycongenitalheartdisease. Some patients with VSD are accompanied by mitral insufficiency(MI). The post-operative MI is a much more important cause resulting incongestive heart failure. But it is still unclear whether MI will disappearedafter VSD closure procedure. The purpose is to study the relationship be-tween early VSD closure and the post-operative MI.  Methods:  295 caseswithVSD,MIwerechosenforstudyfromFeb.1990toFeb.1998.Patientsaged from 10 day to 12 year old, mean age was 2.6 year old. There were223patientswithcongestiveheartfailure(CHF). Results: MIwasrelatedtothe severity of CHF, the more severe MI, the more severe CHF. The morelarge size VSD and left to right shunt, the more severe MI. 126 patientswere performed surgical VSD close and 169 patients received medicinetherapyincludingdigoxinandcaptopril.Therearenosignificantdifferencesbetween two groups in age, sex, sevirity of MI before surgery. The follow-up period varied from 6 months to 34 months. After surgical VSD closure,MI disappeared in 99 patients, diminished in 5 patients, MI unchangedin 22 patients. After medicine therapy, MI disappeared in 69 patients, di-minished in 13 patients, unchanged in 83 patients, and deteriorated in12 patients.  Conclusion:  After surgical VSD closure in patients with VSD,MI, MI in most patients disappeared or diminished, but MI disappeared ordiminished only in about half patients without surgical VSD closure, MI re-mainedunchangedinahalfpatientsandevenworsein12patients.SoearlyVSDclosureisnecessaryforpatientswithVSD,MI. 05Effect of the Contractile Properties of the Aortic Root on ValveCompetence  In Vitro  Adrian H Chester, Martin Misfeld, Hans-Hinrich Sievers, Magdi H Yacoub.Department of Cardiothoracic Surgery, Heart Science Centre, HarefieldHospital,NHLI,ImperialCollegeofScienceTechnologyandMedicine,UK&Clinic of Cardiac Surgery, University Clinic of Luebeck, Luebeck, Germany. Aim of the study:  Contraction of the aortic root in response to a varietyof stimuli has been implicated to influence the function of the aortic valve.We aimed to assess the contractile capacity of different parts of the aorticroot and determine the ability of vasoactive agents to affect valve compe-tence.  Methods:  Cusp, annular, sinus and sinotubular junction tissue wasisolated from porcine aortic roots and set-up in in vitro organ baths andtested for their response to 90 mM KCl or increasing concentrations of5-HT (10-7–10-5M). In a separate seris of experiments isolated porcineaortic roots were pressurised through the aortic arch with Kreb’s solution.5-HTwasaddedinincreasingconcentrations(10-7–10-5M)andtheamountofleakagethroughthevalvewasmeasuredovertime. Results: Additionof90 mM KCl to isolated valve structures gave a mean contractile responseof 0.8  ±  0.1 mN for cusp, 19  ±  11.0 mN for annular, 29  ±  8.0 mN for si-nus and 23 ± 8.0 mN for sinotubular junction tissue (n = 4). The responsefor cusp tissue was significantly less than that of all the other structures.Out of all the different aortic root structures tested only cusp tissue con-tracted in response to 5-HT, with a maximum response of 105.5 ± 17.2%of the response to 90mM KCl (n  =  4). The response to 5-HT could beblocked by 10 − 6 M of the 5-HT 2A -receptor antagonist ketanserin (n  =  4).The rate of leakage from intact aortic roots increased significantly in aconcentration-dependent manner when 5-HT was added. The maximumeffect observed at 10 − 5 M 5-HT, was equal to an increase of 61.8 ± 23.0%above control (p  <  0.05). The perfusion pressure at each concentration of5-HT was unaltered. This response was also inhibited by the 5-HT 2A  recep-tor antagonist ketanserin.  Conclusions:  These results demonstrate thatcontractile mechanisms in the aortic root have the capacity to influencevalve competence  in vitro  . These effects appear to be principally medi-ated via an action on cusp tissue. Contractility of cusp tissue may be animportant mechanism by which optimal performance of the aortic valve isregulated. 06Pathology-Related Differences in Cardiac Troponin I and ClinicalOutcome After Paediatric Open-Heart Surgery P Modi, H Imura, M Caputo, AJ Parry ∗ , A Pawade ∗ , M-S Suleiman, GDAngelini. Bristol Heart Institute, University of Bristol and ∗ The Royal Hos-pital for Children, Bristol, UK. Objectives:  A prospective study to evaluate pathology-related differencesin cardiac troponin I (TnI) release and its relation to clinical outcome af-ter paediatric open-heart surgery.  Backgound:  The degree of periopera-tive myocardial injury is determined by the ischaemic duration but also bythe pathology and preoperative state of the heart (acidosis or cyanosis).Cardiac TnI is a marker of myocardial injury but little is known about thedifferences in TnI release between different pathologies.  Methods:  Tro-ponin I was measured in 133 consecutive children undergoing repair ofatrial (ASD, n = 41) and ventricular septal defects (VSD, n = 46) and Tetral-ogy of Fallot (TOF, n = 46). The length of the right ventricular outflow tract(RVOT) incision in the latter was classified as either  minimum  (n = 33) or extended   (n = 13)accordingtothenormaldiameterofthepulmonaryvalveto body weight.  Results:  There was no mortality. Postoperative TnI levelswere lesion-specific and did not correlate with clinical outcome for ASDs(Table1).ForVSDs,peakTnIcorrelatedwiththedurationsofinotropicsup-port (r = 0.69, p = 0.0001), ventilation (r = 0.64, p  <  0.0001) and intensivecare unit (ICU) stay (r = 0.60, p  <  0.0001) with infants ( < 1 year old, n = 29)showing higher peak TnI (4.11 ± 0.46 vs 2.49 ± 0.33ng / ml, p = 0.02) andworseclinicaloutcomethanchildren.ForTOF,peakTnIcorrelatedwiththedurationofinotropicsupport(r = 0.51,p = 0.0004),ventilation(r = 0.36,p = 0.02)andICUstay(r = 0.55,p = 0.0001)whereasarterialoxygensaturationshowed a negative correlation with these (r =− 0.39 to − 0.49, p  <  0.05).Those undergoing an  extended   RVOT incision had greater peak TnI andworseclincialoutcomethanthosewitha minimum RVOTincision(Table2). Conclusions:  TnI is a reliable marker of early post-operative recovery af-ter repair of VSDs and TOF. Age ( < 1 year) for patients with VSDs andright ventriculotomy length in TOF are important determinants of clinicaloutcome. TABLE 1Patient CharacteristicsASD VSD TOF(n = 41) (n = 46) (n = 46) Age (months) 71.4 ± 6.9 25.3 ± 6.2 18.0 ± 2.9ACC time (min) 26.4 ± 2.7 ∗ 39.2 ± 2.9 49.1 ± 3.6Inotrope duration (hours) 9.5 ± 1.4 ∗ 37.2 ± 6.5 71.6 ± 9.0 † Ventilation time (hours) 6.9 ± 1.1 ‡  28.5 ± 5.9 54.8 ± 8.4 † ICU stay (days) 1.4 ± 0.1 ∗ 3.0 ± 0.4 5.2 ± 0.6 † Hospital stay (days) 5.3 ± 0.1 ∗ 9.3 ± 0.8 11.5 ± 1.0Peak TnI (ng/ml) 2.2 ± 0.2 ∗ 3.5 ± 0.3 7.3 ± 0.7p  <  0.05  versus   other pathologies,  † p  <  0.05  versus   VSD,  ‡ p  <  0.0001 versus   TOF. TABLE 2Minimum Versus Extended Incision in TOFMinimum Extended(n = 33) (n = 13) P value O 2 sat (%) 84.2 ± 1.1 76.7 ± 2.5 0.003ACC time 46.9 ± 4.1 54.8 ± 7.3 0.32Inotrope duration (hours) 46.4 ± 6.2 131.8 ± 18.1  < 0.0001Ventilation time (hours) 33.1 ± 5.2 106.6 ± 19.5  < 0.0001ICU stay (days) 3.5 ± 0.3 9.3 ± 1.1  < 0.0001Hospital stay (days) 9.6 ± 0.7 15.7 ± 2.4 0.0023Peak TnI 5.0 ± 0.4 12.9 ± 1.1  < 0.0001 07Impaired EDHF-Mediated Relaxation in Porcine Pulmonary Micro-Arteries by Cold Storage with University of Wisconsin and Euro-Collins Solutions Wei Zou, Qin Yang, Anthony P. C. Yim, Afmed Arifi, & Guo-Wei He. Cardio-vascular Research Laboratory, Department of Surgery, The Chinese Uni-versity of Hong Kong, Hong Kong SAR, China & Providence Heart Institute& Albert Star Academic Center, OR ,  U.S.A. Background: Vascularendotheliumplaysakeyroleinregulationofvasculartone. Hyperkalemia has been demonstrated to impair the EDHF-mediatedendothelial function in coronary circulation. University of Wisconsin (UW)and Eruo-collins (EC) solutions are used for organ preservation in trans-plantation surgery. The potassium concentration in UW or EC solutionsis as high as 125 mmol/L or 115 mmol/L, respectively. This study wasdesigned to examine whether hyperkalemia or storage with UW and ECsolutionsaffectstherelaxationmediatedbyEDHFintheporcinepulmonarymicro-arteries.  Methods:  Porcine pulmonary micro-artery rings (diameter200–450  µ m) were studied in myograph (n  =  8 in each group). After in-cubation with hyperkalemia (K + 125 mmol/L, at 37 ◦ C), UW or EC solu-tions(at4 ◦ Cfor4hours),EDHF-mediatedrelaxationinducedbybradykinin  FIRST INTERNATIONAL SYMPOSIUM ON CARDIOVASCULAR SCIENCE: SELECTED ABSTRACTS  563 (BK, − 10 to − 6.5 log M) in the presence of inhibitors for cyclooxygenase(Indomethacin, 7  µ M), nitric oxide synthase ( N  G -nitro- L -arginine, 300  µ M),and oxyhemoglobin (20  µ M) was compared with control (Krebs’ solution)in precontraction with U 46619  ( − 7.5 log M).  Results:  The EDHF-mediatedrelaxation to BK was 69.6 ± 6.3% compared with 97.1 ± 1.7% ( p  = 0.003)in control (no inhibitors). After incubation with hyperkalemia, the relaxationsignificantly decreased (38.6 ± 3.0% vs. 59.1 ± 7.4%,  p  = 0.03). StoragewithUWorECsolutionsalsosignificantlydecreasedtherelaxation(49.3 ± 7.3% vs. 65.2  ±  3.5%,  p  =  0.04 and 51.9  ±  8.4% vs. 60.3  ±  6.1%,  p  = 0.02, respectively).  Conclusions:  In porcine pulmonary micro-arteries, ex-posure to hyperkalemia or storage with UW or EC solutions at 4 ◦ C for4 hours impairs the EDHF-mediated endothelial function. The clinicalsignificanceofthiseffectshouldbefurtherstudied. 08The Effect of Ischaemic Preconditioning on Cardiac Function AfterPotassium Channel Opener (Pinacidil) Cardioplegia at Hypothermiaand Normothermia CAJurisevic ∗ ,JOliver,RABaker. FlindersUniversity,BedfordPark,SouthAustralia. Objectives:  To determine the effect of ischaemic preconditioning on post-ischemic myocardial recovery in hearts arrested with Pinacidil at both hy-pothermia and normothermia; and to assess the efficacy of Pinacidil as acardioplegic agent.  Methods:  Isolated ejecting Porton rat hearts were per-fused at normothermia via a Langendorff apparatus, utilizing retrogradecoronary perfusion at a constant pressure (70cm/H 2 O). All animals un-derwent a 30-min normothermic stabilization phase, thereafter being di-videdintothefollowinggroups.Heartsarrestedwith50mlofhyperkalemic(16mmol/L) Krebs solution at 37 ◦ C (A; n = 15) or 15 ◦ C (B; n = 15); heartsarrested with 50ml of Pinacidil (100umol/L) at 37 ◦ C (C; n  =  15) or 15 ◦ C(D; n  =  15); hearts exposed to two 3 min episodes of 37 ◦ C zero flow is-chaemia(preconditioning)andsubsequentlyarrestedwithPinacidilat37 ◦ C(E; n = 15) or 15 ◦ C (F; n = 15). All hearts then underwent 60 min of globalischaemia at their respective cardioplegic temperatures, and 60 min ofnormothermic perfusion.  Results:  In non-preconditioned groups (A-D) atboth hypo- and normothermia there were no significant differences be-tween Pinacidil and hyperkalemic arrested hearts in reperfusion coronaryflow, percentage recovery of developed pressure, or dP/dT max (systolicand diastolic). At normothermia, time to mechanical and electrical arrestwas significantly longer in the Pinacidil group (C; 16.0 min and 21.0 min)than in the hyperkalemic group (A; 5.0 min and 7.6 min; p  <  0.01). At hy-pothermia the incidence of reperfusion VF was significantly higher in thePinacidil group (D; 40%) than the hyperkalemic group (B; 0%; p  <  0.001).In the preconditioned groups (E & F) reperfusion coronary flow was signif-icantly greater than in non-preconditioned groups (C & D) at both normo-and hypothermia. At hypothermia, preconditioned hearts (F), when com-pared to non- preconditioned hearts (D), displayed a significantly greaterrecovery of developed pressure (D; 84.3% c.f. 70.2% at 60 min; p  <  0.04)and systolic dP/dT max (D; 84.7% c.f. 66.1%; p = 0.01) throughout reper-fusion.  Conclusions:  Pinacidil affords myocardial protection similar to thatof hyperkalemic cardioplegia despite significantly prolonged mechanicaland electrical arrest times. Furthermore, at hypothermia, ischaemic pre-conditioning confers a myocardial protective benefit in addition to that pro-vided by Pinacidil alone. Thus, Pinacidil cardioplegia in combination withhypothermia and ischaemic preconditioning is an effective and promisingcardioprotective strategy. 09Role of Endothelium/Nitric Oxide and Cyclic AMP in IsoproterenolPotentiation of 17ß-Estradiol-Mediated Vasorelaxation HY Chan, XQ Yao, SY Tsang, BP Bourreau, FL Chan, Y Huang. DepartmentofPhysiology,ChineseUniversityofHongKongandHongKongUniversity,Hong Kong, China.Estrogen exerts vasorelaxation and cardiac protection via multiple cellularmechanisms.Estrogenmodifiesvasodilatationinducedbycertainrelaxantssuch as ß-adrenoceptor agonists. However, little is known whether lowconcentrations of ß-adrenoceptor agonists would also influence the acuterelaxant response to estrogen. The present study was designed to inves-tigate the synergistic interaction between isoproterenol and 17ß-estradiol,and to study the role of endothelium and cyclic AMP-dependent path-way in this interaction. Changes in vessel tone of the isolated rat mesen-teric artery rings were measured by force-displacement Grass transducer.In 9,11-dideoxy-11 α , 9 α -epoxy-methanoprostaglandin F 2 α - preconstrictedendothelium-intact rings, 17ß-estradiol induced concentration-dependentrelaxation with pD 2  of 5.074 ± 0.043. Pretreatment of endothelium-intactringswithisoproterenol(1-3 × 10 − 9 M,1-hincubationtime)significantlyen-hanced 17 β -estradiol-induced relaxation. Longer incubation (2.5 h) did notproduce further amplifying effect. This effect was inhibited by Rp-cGMPStriethylamine(3 × 10 − 6 M),anddisappearedinthepresenceof3 × 10 − 5 MN G -nitro-L-arginine methyl ester or in the endothelium-denuded rings. Theeffect of isoproterenol was partially antagonized by propranolol (3 × 10 − 6 M),ICI118,551(3 × 10 − 6 M)butnotbyatenolol(10 − 5 M).Noneofthree β -adrenoceptor antagonists affected 17ß-estradiol-induced relaxation in theabsence of isoproterenol. Rp-cAMPS triethylamine (3 × 10 − 6 M) abolishedthe effect of isoproterenol. Besides, exposure to 3  ×  10 − 9 M forskolinfor 1 h also potentiated the relaxant response to 17 β -estradiol. In sum-mary, this isoproterenol enhancement was dependent on the presenceof endothelium and abolished by L-NAME via a  β 2 -adrenoceptor-mediatedcyclic AMP-dependent mechanism. These data also indicate the possibleexistence of cyclic AMP-dependent nitric oxide-producing pathway in theregulation of the vascular response to vasodilators. (supported by UPGCDirect Grant) 10Exogenous CGRP Improves Coronary Microcirculation After Myocar-dial Reperfusion Associated with Cardiopulmonary Bypass Xin Li, Zhanggen Chen, Bing Jia, Hui Zhong, Ming Ye, Wei Hui, HuimingJin. Cardiovascular Center, Children’s Hospital of Fudan University, 183Fenglin Road, Shanghai 200032, P.R.China. Background:  Calcitonin gene-related peptide (CGRP) is known to have anextremely potent and prolonged vasodilator effect on the coronary arter-ies. Studies have shown that CGRP increased coronary blood flow andalleviated reperfusion injury in vitro. It is still unknown, however, whetherexogenous CGRP has a protective effect on the reperfusion heart asso-ciated with cardiopulmonary bypass (CPB).  Methods:  An in vivo porcinemodel of CPB was established. Twenty pigs, 10 controls and 10 CGRPused animals (CGRP group), were performed a median sternotomy fol-lowed by a standard CPB. All the hearts were arrested for 45 minutes.In the CGRP group, 1mg/kg CGRP was added into the cardioplegia, andanother 1mg/kg was reperfused just before the aortic cross-clamp wasremoved. In both groups, myocardial microvascular perfusion, coronaryarterial microvessel diameter and microvessel blood flow were detectedby a laser doppler flowmeter and a contact microscope with TV monitoron five consecutive time perioperatively.  Result:  Myocardial microvascularperfusion was significantly higher and coronary arterial microvessel diam-eter was larger in the CGRP group on every point of time of reperfusioncompared to those in the control group. In the CGRP group, microvesselblood flow also improved significantly than that in the control group duringreperfusion.  Conclusion:  CGRP improves myocardial microcirculation dur-ing cardiac ischemia-reperfusion associated with CPB and could becomea new, potent myocardial protector. 11Evidence of Apoptosis: Bax and Fas Expression in Acute Phase ofMyocardial Infarction in Rats 1 , 3 Yi Zhun Zhu,  2 , 3 Yi-Chun Zhu,  1 Zhong Jing Wang,  1 Qing Lu,  1 How SungLee,  3 Thomas Unger.  1 Department of Pharmacology, National Universityof Singapore, Singapore,  2 Department of Physiology, Shanghai MedicalUniversity, China,  3 Department of Pharmacology, University of Kiel,Germany.Myocardial infarction (MI) remains the leading cause of death from car-diovascular diseases over the past decades. Apoptosis is ‘programmed’cell death which leads to clearance of ‘unwanted’ cells without disrup-tion of tissue structure or function. Recently, we reported that angiotensinreceptor subtype AT1 and AT2 mRNA levels were time dependently regu-lated after MI. AT1 and AT2 receptor mRNA levels markedly increased at30 min and peaked 24 h post-MI. The time-dependent increase of AT1 andAT2 receptor mRNA is associated with the early remodeling process ofthe non-infarcted myocardium post MI. There is a further question raisedwhethertheup-regulationofAT2receptorislinkedtoapoptosis.Therefore,we investigated the apoptotic development and apoptotic related gene ex-pression after MI at different time points in the current study. MI wasinduced in Wistar rats by ligation of the left anterior descending coronaryartery.Baxgeneexpressionwasfoundtobeincreasedat12hafterMIandpeaked at 24 h (4.3-fold). It declined at 72 h after MI. Fas gene started toover-express at 12 h after MI as well but it reached maximum at 72 h (4.7-fold).ProteinlevelsofBaxandFasexpressionweredetectedinthenecroticarea and area at risk (surrounding area) at different time points after MI.Apoptosis was detected in the infarcted areas. No apoptosis was detectedin the sham operated rats. In the MI groups, strongest staining of apopto-sis was detected in rats 3 days post operation. Weak staining was found1 day, 7 day post MI. Very fewer apoptotic cells were detected in the rats  564  FIRST INTERNATIONAL SYMPOSIUM ON CARDIOVASCULAR SCIENCE: SELECTED ABSTRACTS 2 weeks after MI. Our results demonstrate that apoptotic development af-terMIistimedependentintheischemicareaandtherecouldbesomelink-agewiththeoverexpressionofAT2receptorpostMI. 12Octopus Approach to Cardiovascular Management Zenobia CY Chan. Department of Social Work, The Chinese University ofHong Kong.The  Octopus Approach  to cardiovascular management aims to fill the in-adequaciesofthebiomedicalmodelintheaspectofbothconceptualizationand treatment as well as to place the patients in their specific life contextby offering a holistic humanistic care to them. Each alphabet of the term “Octopus”   stands for a specific facet below: O – ongoing meansthatanycardiovasculartreatmentshouldbealifelongprocess for promoting positive health and preventing relapse. C  –  collaboration is  intrasectorally and intersectorally to achieve a mul-tidisciplinary approach in both prevention and treatment of cardiovasculardiseases. T  –  therapeutic goals  mean that they should be co-constructed betweenthe health professions and the patients. O  –  offering support  is to let the cardiac patients and their families expe-rience a sense of alliance and psychological support from the health careproviders. P  –  participation  is to encourage the patients to exercise their autonomyforselectingtreatmentaswellastoempowerthemtohavetheownershipof their bodies. U  –  understanding  and  unfolding  the experience of patients’ illness byemploying an empathetic counselling and self-help groups. S  –  sociocultural  perspective is to perceive the cardiovascular diseasesof the patients in their unique life context.On the whole, the above approach is to question the necessity of themono-vision and hegemony of the western medicine that is embracedon both the ideology and the intervention for the cardiovascular diseases. 13TheEffectofClopidogrel(Plavix)onPlateletFunctioninPatientswithPeripheral Vascular Disease - Comparison with Aspirin I Anita Jagroop,  ∗ George Geroulakos,  ∗ Miltiadis Matsagas, Dimitri PMikhailidis. Department Clinical Biochemistry, Royal Free University Col-legeSchoolofMedicine,UniversityofLondon,RoyalFreeCampus,LondonNW3 2QG, UK. ∗ Vascular Unit, Ealing Hospital, London, UK. Aims:  To establish if clopidogrel (Plavix) is a more effective platelet in-hibitor than aspirin in patients with peripheral vascular disease (PVD). Introduction:  PVD is a common condition that is associated with a con-siderable increase in the risk of vascular events, like myocardial infarction(MI) and stroke. Aspirin resistance has been reported in PVD patients.These patients tend to have hyperactive platelets. Aspirin is an inhibitor ofthe synthesis of thromboxane A 2  (TXA 2 ), a promoter of platelet aggrega-tion. In contrast, clopidogrel acts at the level of the platelet ADP receptor.ADP is released by activated platelets to further induce aggregation onotherplatelets.Therationalebehindcombinationtherapyisthataspirinandclopidogrel act by different mechanisms.  Methods:  Twenty PVD patients(14 men; 6 women: mean age 70 years) took part in this study. Citratedvenousblood was collectedat baseline(visit 1, n = 20), 10 daysafterclopi-dogrel (75 mg/day) or aspirin (75 mg/day) (visit 2, n  =  10 for each drug),and then 10 days after combination therapy with aspirin plus clopidogrel,(visit 3, n = 20). Platelet aggregation was measured in whole blood usinga MD18 Coulter counter, after adding ADP (5–10  µ mol/l) or 5HT (sero-tonin, 5.0  µ mol/l). Spontaneous platelet aggregation (SPA) was followedfor up to 15 min. Platelet shape change (PSC) was assessed after addingagonists (5-HT, 0.5  µ mol/l; ADP, 0.4-0.8  µ mol/l -in platelet rich plasma)using a high-resolution (0.07 fl) channelyzer (ZM34 coupled to a Coultercounter). Median platelet volume (MPV) was measured at various timepoints.  Results:  There was a significant decrease in platelet aggregation,induced with ADP (measured as% free platelet count, FPC), after takingclopidogrel for 10 days, P = 0.0001. In contrast taking aspirin for 10 daysshowed no significant increase in FPC after adding ADP. The combinationof clopidogrel plus aspirin significantly decreased SPA (P = 0.001) and alsoADP-induced aggregation (P = < 0.0001). SPA was not significantly alteredby either drug used alone. The effect of either drug or both combined on5HT-induced platelet aggregation was not significant. ADP-induced PSC(using% increase in MPV) was more significantly inhibited by clopidogrel(P = 0.004) than by aspirin (P = 0.01). This was also true for 5HT-inducedPSC (clopidogrel P  =  0.01, aspirin P  =  0.03). However, with combinationtherapy the PSC effect was more marked (ADP, P  =  0.0002, 5HT, P  = 0.0006) than with either drug alone.  Conclusions:  In patients with PVD,clopidogrel is a more potent inhibitor of ADP-induced platelet activationthan aspirin. There appears to be a beneficial combined effect of clopido-grel plus aspirin on platelet activation in PVD. 14Influence of Body Size on Clinical Outcome in Patients UndergoingCoronary Surgery with or Without Cardiopulmonary Bypass RAscoine,KRees,MHChamberlain,FCiulli,AJBryan,GDAngelini. BristolHeart Institute, University of Bristol, UK. Objective:  Coronary artery bypass grafting (CABG) in overweight patientscarries significant morbidity. We compare the effectiveness of off-pumpcoronary artery bypass (OPCAB) surgery versus conventional CABG us-ing cardiopulmonary bypass and cardioplegic arrest, in a consecutive se-ries of overweight patients.  Methods:  From April 1996 to April 2001, datafrom 4321 patients undergoing coronary revascularisation (mortality 1.4%)were prospectively entered into the Patients Analysis and Tracking Sys-tem. Data were extracted for all patients with a body mass index (BMI) ≥ 25. In hospital mortality and early morbidity were compared between pa-tients undergoing on- and off-pump coronary surgery. A risk-adjusted anal-ysis was also carried out to assess the influence of surgery on outcomes. Results:  2844 overweight patients with BMI ≥ 25 were identified, and ofthese 674 (23.7%) were operated on with off-pump surgery. On-pump pa-tients were less likely to have unstable angina, hypercholesterolaemia,to have coronary disease involving the left main stem, or to have aBMI ≥ 30.However,theyhadmoreextensivecoronarydisease,weremorelikely to have suffered previous myocardial infarction, and received moregrafts than those undergoing off-pump surgery. Intra- and post-operativearrhythmias, inotropic use, and post-operative low cardiac output, use ofIABP, blood loss, transfusion requirement, chest infections, neurologicalcomplications including permanent stroke, ICU and hospital stay all weresignificantly reduced in the off-pump group (all p  <  0.05). After adjustmentfor age, gender, ejection fraction, extent of coronary disease, and degreeof urgency, odd ratios (ORs) for most of the adverse outcomes investi-gated, confirmed significant benefit of off-pump surgery (table). The pointestimate of the adjusted effect size for in-hospital mortality also indicatedbenefit from off-pump surgery (table). On-Pump Off-Pump OR/MeanVariable (2169) (674) Difference 95% CI p Death 20 (0.92%) 2 (0.29%) 0.37 0.08, 1.59 0.18Postoperative MI 35 (1.6%) 14 (2.0%) 1.37 0.72, 2.62 0.337New Inotropes 879 (40.5%) 219 (32.5%) 0.8 0.66, 0.97 0.02New IABP 54 (2.5%) 5 (0.7%) 0.32 0.12, 0.8 0.015Ward arrhythmia 320 (14.8%) 65 (9.6%) 0.63 0.47, 0.84 0.002Chest Infection 106 (4.9%) 14 (2.1%) 0.43 0.24, 0.76 0.004Neurolog. Complic. 59 (2.7%) 6 (0.9%) 0.36 0.15, 0.85 0.02Blood Loss (ml) 939.9(512.3) 856.2 (582.1)  − 60.8  − 111.7, − 9.87 0.019Total RBCs (unit) 1.05 (1.51) 0.436 (1.52)  − 0.51  − 0.65, − 0.37 0.0001Total Platelets (unit) 0.24 (0.81) 0.08 (0.455)  − 0.157  − 0.23, − 0.08 0.0001Total FFP (unit) 0.49 (1.48) 0.126 (0.72)  − 0.38  − 0.5, − 0.25 0.0001Sternal rewiring 17 (0.78%) 1 (0.14%)  − 0.22 0.03, 1.7 0.15Renal complications 98 (4.5%) 24 (3.56%)  − 0.74 0.44, 1.25 0.265Hospital stay (day) 7.76 (4.26) 6.64 (3.04)  − 0.94  − 1.39, − 0.49 0.0001 Conclusions:  These results suggest that off-pump surgery is safe, eff-ective and associated with reduced morbidity in overweight patients. 15Reduction in the Sodium Currents in Isolated Ventricular Myocytes ofGuinea Pigs Treated by Chronic L-Thyroxin Medication Yu-Ping Ma 1 , Xue-Mei Hao 2 , Guang-Qing Zhang 1 , Pei-Ai Zhang 2 , Cai-HongWu 2 , De-Zai Dai 1 .  1 China Pharmaceutical University, Research Division ofPharmacology, Nanjing, 210009;  2 Key Laboratory of Biological Membrane,College of Life Science, Peking University, Beijing,100871, China. Objective: CardiacremodelinginducedbychronicmedicationofL-thyroxinis manifested by a much more severe cardiac arrhythmias on the occlu-sion/reperfusion of the coronary artery in rats. A pattern of changes inion currents in a diseased heart (L-thyroxin induced cardiac remodeling) ispossibly provided as a basis of promoting malignant cardiac arrhythmias.An enhanced delayed outward rectifier potassium currents the rapid (I Kr )and slow (I KS ) component was found in the remodeled heart by L-thyroxinchronicmedication.Itisinterestedtoinvestigatethechangesinthesodiumcurrents in the L-thyroxin remodeled guinea pig ventricle.  Method:  The re-modeling model in guinea pig was developed by L-thyroxin 4 mg po for10 days. On d 11, the heart was removed and perfused to isolate ven-tricular myocytes with medium of Ca2 +  free medium containing col-lagen. The whole cell holding technique was applied. Results: The I Na  FIRST INTERNATIONAL SYMPOSIUM ON CARDIOVASCULAR SCIENCE: SELECTED ABSTRACTS  565 density in the L-thyroxin caused hypertrophied myocytes was reduced sig-nificantly at holding potential  − 30 mV,  − 53.20  + / − 10.78pA / pF against − 73.78 + / − 14.66pA / pF in the normal. (n = 45, p  <  0.001). No differencein the steady-state inactivation and recovery kinetics between the remod-eled and the normal was found. The recovery constant 37.54 + / − 3.63 msin the remodeled vs 36.57 + / − 2.81 ms in the normal (n  =  18, p  >  0.05).Theaccelerateddeactivationtimeconstant3.67 + / − 0.14oftheremodeled(n  =  39) against the normal 4.14 + / − 0.15 ms (n = 43) (p < 0.05). Conclusion:  There is a reduced I Na  in the L-thyroxin remodeled ventricularmyocytesandthedeactivationofthecurrentisaccelerated.Achangedde-polarizationoftheaffectedmyocardiumislikelyinvolvedinthemechanismof arrhythmogenesis of the remodeled ventricle. 16Short-Term Incubation with Physiological Level of Estrogen Impairsß 1 -Adrenoceptor-Mediated but Enhances ß 2 -Adrenoceptor MediatedCoronary Relaxation HY Chan, XQ Yao, GW He, SY Tsang, CM Wong, Y Huang. Departmentsof Physiology and Surgery, Chinese University of Hong Kong, Hong Kong.Considerable evidence suggests that ß-adrenoceptors are subject to regu-lation by sex steroid hormones. It was reported that estrogen replacementpotentiated the vascular responses mediated by ß-adrenoceptor activationby an endothelium-independent mechanism. ß-Adrenoceptor is presenton both vascular smooth-muscle and endothelial cells. However, no exper-iment has examined the effect of acute exposure to physiological concen-trations of estrogen on ß-adrenoceptor–mediated vasorelaxation in mam-malian arteries. The major observation in this study is that the relaxantresponse to ß 2 -adrenoceptor activation with fenoterol was significantlyenhanced by short-term incubation (1 hr) with 0.3 nM 17ß-estradiol in theisolated porcine coronary circumflex arteries. This effect was abolishedby pretreatment with 10- µ M tamoxifen. Preincubation with 17ß-estradiol(0.3 nM) reduced the relaxant response to dobutamine, a ß 1 -adrenoceptoragonist.Theconcentrationof0.3nMfallsintothereportedcirculatinglevelof estrogen ranging between 0.1 and 1 nM in the body. Low concentra-tions of estrogen appeared to slightly enhance the relaxation induced byisoproterenol, a non-selective ß- (ß 1  and ß 2 ) adrenoceptor agonist, follow-ing 1-hr incubation. Physiological level of estrogen did not influence therelaxation induced by IBMX, an inhibitor of phosphodiesterase. In contrast,20-min exposure to 17ß-estradiol (0.1–1 nM) was without effect on ß 1 -or ß 2 -adrenoceptor-mediated vascular responses. Our data indicate thatacute exposure to physiological concentration of estrogen has differen-tial effect on ß-adrenoceptor-mediated relaxation in porcine coronary ar-teries, increasing ß 2 -adrenergic response but decreasing ß 1 -adrenergic re-sponse. It would therefore be not surprising to observe a marginal effectof estrogen on relaxation induced by isoproterenol, an agonist that acti-vates both ß 1  and ß 2 -adrenoceptors in blood vessels. (supported by UPGCDirect Grant) 17AlteredVascularReactivityoftheCerebralArteriesinOvariectomizedRat S.Y. Tsang, X.Q. Yao, F.L. Chan, C.M. Wong, C.W. Lau, Y. Huang. Depart-ments of Physiology, ChineseUniversity of Hong Kong, Hong Kong, China.Estrogen has received considerable attention recently as a potential ther-apeutic agent in vascular pathophysiological states such as stroke. Themechanisms by which estrogen influences cerebral arteries are incom-pletelyunderstood.Thepresentstudywastoexaminetheeffectofovariec-tomy and chronic estrogen or tamoxifen treatment on vascular reactivityin rat posterior communicating cerebral arteries with intact endothelium.Changes in vascular tension were measured by microvessel myograph.Ovariectomysignificantlyenhancedtheconstrictingresponsestoendothe-lin I, but not to phenylephrine. Chronic treatment with estrogen or tamox-ifen partially reversed or abolished the effect of ovariectomy. The contrac-tion induced by high K + solution was also enhanced in the ovariectomizedrats and this enhancement was abolished by estrogen or tamoxifen treat-ment.OvariectomypotentiatedtherelaxantresponsetonicardipinebutnotNS 1619. Estrogen but not tamoxifen reversed the effect of ovariectomy.The present results indicate that chronic tamoxifen may not act as an an-tagonist of estrogen, instead, chronic treatment with estrogen and tamox-ifen has similar effect in inhibiting the increased vascular tension inducedby ovariectomy. This study suggests the influence of physiological levelof estrogen on vascular contractility. It is at present unknown what mayhavecausedincreasedrelaxanteffectofnicardipine,aL-typeCa 2 + channelblocker. More experiments are needed to show the role of endothelium inthealteredvascularcontractilityintheovariectomizedandestrogen-treatedrats. (supported by UPGC Direct Grant). 18Multiplicity in the Vascular Response to Pinacidil in Rat MesentericArtereies SY Tsang, XQ Yao, CM Wong, CW Lau and Y Huang. Departments ofPhysiology, Chinese University of Hong Kong, Hong Kong, China.Pinacidil is a clinically effective antihypertensive drug that directly relaxesvascular smooth muscle. Pinacidil activates both ATP-sensitive and Ca 2 + -activated K + channels in vascular myocytes. However, it remains con-troversial whether activation of K + channels and subsequent hyperpo-larization mediates pinacidil-induced vasorelaxation, particularly when theconcentration is higher than that reported for pinacidil-induced openingof K ATP  channels. In the present study, attempt was made to investi-gate the possible K ATP  channel-independent relaxant effect of pinacidil inisolated rat mesenteric arteries without endothelium. In phenylephrine-contracted rings, glibenclamide at 10  µ M attenuated pinacidil-induced re-laxation without an effect on the maximum relaxation. Pinacidil relaxed ar-teriescontractedbyU46619and60mMK + withrespectiveIC 50  of0.19and16.7  µ M. Some rings were first contracted by 60 mM K + and then re-laxed totally by 1  µ M nifedipine in order to minimize the influence of bothK + channels and voltage-sensitive Ca 2 + channels. Under this condition,U46619-induced tone was reduced by pinacidil (IC 50  of 20.6  µ M) and max-imumrelaxationcanbeachieved.FollowinginhibitionofK + andCa 2 + chan-nelspinacidil-inducedrelaxationremainedunchangedbypretreatmentwith10  µ M cyclopiazonic acid, the endoplasmic reticulum Ca 2 + -ATPase in-hibitororwith100 µ Mouabain,theNa + -K + -ATPaseinhibitor.Pretreatmentwith30 µ MNi 2 + causedparallelrightwardshiftofconcentration-relaxationcurve for pinacidil without affecting maximal relaxation. Besides, pinacidilalsoconcentration-dependentlyrelaxedringspreconstrictedbyactivephor-bol ester, phorbol 12,13-diacetate (1  µ M). The present results indicate thatthemechanismsbywhichpinacidilmediatesvasorelaxationaremultifacto-rial when its concentration is higher than 1  µ M (supported by UPGC DirectGrant) 19Different Effects of Estrogen and Progesterone on K + Currents Ex-pressed in  Xenopus   Oocytes CMWong,XQYao,SYTsang,YHuang. DepartmentofPhysiology,ChineseUniversity of Hong Kong, Hong Kong, China.Potassium channel plays an active role in the regulation of membrane po-tential in vascular smooth muscle and vascular tone. These channels notonly participate in the physiological responses to endogenously occurringsubstances, but also become the therapeutic targets for many syntheticdrugs. Information regarding the role of K + channels in vascular effectsof female sex steroid hormones is scarce. We previously showed thatK + channel activation contributed in part to the estrogen-mediated va-sorelaxation. In order to examine further whether steroid hormones mayhave direct interaction with K + channels, we have recently expressed twotypes of K + channels, K Ca  and K V  channels in  Xenopus   oocytes. It wasfound that 17ß-estradiol increased the large-conductance K Ca  currents in aconcentration-related manner. Tetraethylammonium ions or iberiotoxin in-hibited the effect of 17ß-estradiol. K Ca  current was increased by NS 1619and inhibited by progesterone. BSA-conjugated estrogen also increasedK Ca  currents. Progesterone reduced the estrogen-stimulated K Ca  currents.K V1 . 5  channels were also expressed in  Xenopus   oocytes and inhibited by4-aminopyridine. Progesterone reduced the K V1 . 5  current, while estrogenhad little effect. These results showed that estrogen could stimulate K Ca channels without an effect on K V1 . 5  channels. Progesterone inhibited theactivity of both K Ca  and K V1 . 5  channels expressed in  Xenopus   oocytes. Pro-gesterone was described to antagonize the vascular action of estrogen. In-hibition of K + channels may be involved in the reported antagonistic effectof progesterone against the estrogen-induced vasorelaxation. (supportedby UPGC Direct Grant) 20Blocking Cyclic GMP Synthesis Enhances the Pro-Apoptotic Actionsof Nitric Oxide (NO) in the NG108-15 Cholinergic Neuronal Cell Line Jessie P.S. Yuen and Ronald R. Fiscus. Department of Physiology, Facultyof Medicine, Epithelial Cell Biology Research Center, and the Center forGerontology & Geriatrics, The Chinese University of Hong Kong, Shatin,New Territories, Hong Kong. Introduction:  Little is known about the regulation of apoptosis in sympa-thetic and parasympathetic nerves that innervate the cardiovascular sys-tem.OurpreviousstudieshaveshownthatPC12cells,acellculturemodelof sympathetic nerves, respond to NO or atrial natriuretic peptide (ANP)with increases in production of cyclic GMP (cGMP), resulting in increasedlevels of cGMP in both the intracellular and extracellular spaces  (Fiscus,
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