saralasin and Myocardial-Ischemia

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Captopril; Clinical Trials as Topic; Coronary Circulation; Heart Failure; Hemodynamics; Humans; Hypertension; Male; Myocardial Ischemia; Renin; Renin-Angiotensin System; Saralasin; Teprotide

Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen involved in vascular development and angiogenesis. Recently we have observed increased VEGF expression in the normal myocardium after myocardial infarction in a rat heart. This study was designed to explore the mechanism responsible for this increase in VEGF expression. Induction of myocardial stretch in an isolated perfused Langendorff preparation by inflation of an intraventricular balloon to an end-diastolic load of 35 mmHg for 30 min resulted in a nearly sixfold increase in VEGF message level not only in the chamber subjected to stretch (left ventricle) but also in the unstretched right ventricle, thus raising the possibility of a soluble factor mediating stretch- induced induction of VEGF expression. This was further confirmed by demonstrating that coronary venous effluent collected from the stretched heart and used to perfuse isolated hearts in which no balloon was present was able to induce VEGF expression in these normal hearts. Inhibition of TGF-beta activity using a neutralizing antibody, but not antagonists/inhibitors of endothelin and angiotensin II, eliminated stretch-induced increase in VEGF expression. Staurosporine, a protein kinase C inhibitor, also blocked stretch-induced increase of VEGF expression. Measurement of TGF-beta concentration in the perfusate demonstrated increased amounts of the cytokine after myocardial stretch, and addition of TGF-beta protein to the perfusion buffer resulted in increased VEGF expression in control hearts. These results suggest that stretch-induced increase of VEGF expression in the heart is mediated at least in part by TGF-beta.

Topics: Angiotensin II; Animals; Antibodies; Catheterization; Diastole; Endothelial Growth Factors; Endothelin Receptor Antagonists; Endothelin-1; Heart; In Vitro Techniques; Lymphokines; Male; Myocardial Ischemia; Myocardium; Peptides, Cyclic; Protein Kinase C; Rats; Rats, Sprague-Dawley; RNA, Messenger; Saralasin; Staurosporine; Transcription, Genetic; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The effects of saralasin on electrophysiological changes and arrhythmias induced by simulated ischemia and reperfusion were examined in an isolated tissue model. Segments of guinea pig right ventricles, stimulated regularly, were exposed to simulated ischemia for 15 min and then were reperfused with normal Tyrode's solution for 30 min. Transmembrane electrical activity and a high-gain electrogram were recorded. Arrhythmias and electrophysiological changes accompanying simulated ischemia and reperfusion in control preparations were compared to those in preparations treated with 0.1 or 1 microM saralasin. Simulated ischemia caused abbreviation of action potential duration measured at 90% repolarization, abbreviation of endocardial effective refractory period (ERP) and prolongation of transmural conduction time. Premature ventricular beats, ventricular tachycardia and conduction block were observed in approximately 35% of control preparations during simulated ischemia. Rapid sustained or nonsustained ventricular tachycardia occurred in approximately 60% of control preparations in early reperfusion. The overall incidence of arrhythmias and the incidence of ventricular tachycardia in early reperfusion were significantly decreased by 1 microM but not 0.1 microM saralasin. Saralasin (1 microM) prolonged the ERP in normoxic tissues, but it did not alter changes induced by ischemia or reperfusion in ERP or the action potential duration at 90% repolarization. Prolongation of transmural conduction time during ischemia and early reperfusion was significantly inhibited by both concentrations of saralasin. However, only 1 microM saralasin reduced the ratio of transmural conduction time to ERP enough to prevent arrhythmias. Our observations demonstrate that saralasin exerts antiarrhythmic effects in myocardial reperfusion by a mechanism independent of circulatory and central actions.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Guinea Pigs; Heart Ventricles; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion; Saralasin