Background: This stu dy was designed to invest igate the ef· feet s of th e select ive endothelin-Areceptor antagonist BQ123 on myocardial and endothe lial funct ion after rever sible deep hypot hermic ischem ia and reperfusion . Methods: Isogenic intra-abdomina l het erotopic hea rt transplantati on was perfo rmed in l ew is rat s. Afte r one hour of cold ischemic preservation reperfusia n was sta rte d afte r a pplicatio n of either saline vehicle or BQ l23 (l !lmol/l).left-ventricular pressure-volum e relat ions and myocardial blood flow were asse sse d aft er one and 24 hour s of reperfu sion . Responses to endothelium-de pende nt vasodilator acetylcholine and endot helium-inde pende nt vaso dilato r sodium nitropru sside we re also det ermin ed. Results: BQ123 significant ly improved myocardial co ntract ility. as indicated by the leftward shift of the systolic pressure-volume relation and significantly increased myocardial blood flow during ea rly reperfu sion (p < 0.05). Although myocardial functi on and baseline myocardial blood flow were similar in both gro ups after 24 hour s of reperfuslon, endothelium-depende nt vasod ilatation was st ill sig nificantly higher in the BQ 123 group (p < 0.05). Conclusions: These results suggest that endot helin-A receptor antagonists may be useful in reducing ischemia/ reperfusion injury after heart transplanta tion by preservat ion of myocardial and endothelial function.
The aim of this study was to investigate the changes in monophasic action potentials (MAP) from different sites in the heart and to determine MAP dispersion during endothelin-1 (ET-1) infusion. Standard ECG, left ventricular anterior, right ventricular lateral, right ventricular septal, and right ventricular apical MAPs and intra-arterial blood pressure were monitored in seven anesthetized open-chest mongrel dogs. After radiofrequency atrioventricular node ablation, ventricular pacing (70/min) was performed and intracoronary ET-1 (60 pmol/min) was administered into the left anterior descending coronary artery. Both MAPd90 and MAPd90 dispersion increased significant during ET-1 infusion. The onset of spontaneous monomorphic and polymorphic sustained ventricular tachycardias (sVT) was observed in five dogs (around 40 min), and nonsustained VTs (nsVT) developed in another two dogs. The increases in MAP and MAP dispersion lasted until the appearance of polymorphic nsVTs and sVTs, but at the time of these VTs this difference decreased. At the termination of the experiments, ventricular fibrillation occurred in six cases. In four cases third-phase early afterdepolarizations were recorded. Our results suggest that increased MAP dispersion and development of EAD contribute to the arrhythmogenic action of ET-1, and these phenomena might explain the pathogenesis of a wide variety of ventricular arrhythmias with different morphology observed in this study.
The vasodilator capacity of the coronaries was determined by the reactive hyperemia (RH) test in open-chest anesthetized dogs. The myocardial release of adenine nucleosides (adenosine and inosine) was measured by the HPLC-UV method. In group I (n = 9) after the control RH test, a bolus injection of endothelin-1 (ET-1; 1.0 nmol i.c.) was administered and was followed by a second RH test. In group II (n = 9), glibenclamide (GLIB) was infused continuously (1.0 mumol/min i.c.) and RH tests were performed during the control period and then before and after bolus injection of ET-1. In contrast to the significant reduction of the RH response after ET-1 in group I and after GLIB in group II, the nucleoside release into the coronary sinus during the first minute of the RH test was significantly higher (adenosine release 0.05 +/- 0.02 vs. 0.10 +/- 0.04 mumol, and 0.02 +/- 0.00 vs. 0.08 +/- 0.02 mumol; p < 0.05). Injection of ET-1 did not result in further RH reduction in GLIB-pretreated dogs (group II) but significantly increased nucleoside release. High doses of ET-1 activated the metabolic compensatory mechanisms of the myocardium and thereby increased the release of adenine nucleosides into the venous blood of the heart. However, whether these metabolites can exert any significant compensatory vasodilator effects appears doubtful.
These results suggest that activation of the ET-B receptors contributes to reperfusion injury after cardiac preservation in a rat heart transplant model.
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