s6c-sarafotoxin and Coronary-Disease

The aims of this study were to determine if the ETB receptor agonist, sarafotoxin 6c (S6c) reduces myocardial infarct size following myocardial ischemia and reperfusion and to investigate whether any changes in mRNA for endothelin receptors in the injured myocardium were modified by S6c pretreatment. Hypnorm/Hypnovel anesthetized rats were subjected to occlusion of the left main coronary artery for 30 minutes, followed by 120 minutes reperfusion. Animals were administered a bolus dose of S6c (0.24 nmol kg-1 i.v., n = 10) or saline (n = 15) 5 minutes prior to occlusion. At the end of reperfusion, hearts were stained with Evan's Blue dye to delineate area at risk. A 1.5- to 2.0-mm thick slice was cut transmurally 1 mm below the site of ligation for assessment of infarct size by triphenyltetrazolium chloride. A further transmural slice (2.5-3-mm thick) was cut for assessment of receptor mRNA levels by RTPCR. Administration of S6c caused a transient fall in mean arterial blood pressure (MABP) prior to occlusion and attenuated the fall in MABP induced by coronary occlusion. S6c significantly reduced infarct size (13 +/- 4% of area of slice at risk) compared with control hearts (35 +/- 5%; P < 0.05). In control hearts, there was a marked reduction in mRNA content for both ETA (50% reduction) and ETB (70% reduction) receptors in the ischemic zone, compared with non-ischemic tissue. In hearts pre-treated with S6c there was a reduction in ETA, but not ETB receptor mRNA in the ischemic zone. This study has shown that S6c reduces myocardial infarct size and results in preservation of ETB receptor mRNA in ischemic/reperfused tissue.

Topics: Animals; Blood Pressure; Coronary Disease; Disease Models, Animal; Drug Administration Schedule; Evans Blue; Glyceraldehyde-3-Phosphate Dehydrogenases; Injections, Intravenous; Ligation; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazolium Salts; Time Factors; Ventricular Fibrillation; Viper Venoms

Various snake venom peptides have been extensively evaluated for use as antithrombotic agents. Recently, it was determined that the snake venom peptide sarafotoxin S6b (S6b) is structurally similar to the potent vasoactive hormone endothelin-1 (ET-1), which has been shown to inhibit agonist-induced platelet aggregation. The potential in vivo antithrombotic activity of S6b was compared with that of ET-1, a much more potent pressor agent than S6b, by evaluating the effects of S6b and ET-1 (0.5 microgram/kg i.v.) on repetitive platelet thrombus formation (RPTF) in the stenosed canine circumflex coronary artery. In this model platelets adhere to the damaged vessel wall near a mechanically produced stenosis. As platelets aggregate at this site, blood flow gradually declines until the vessel is completely occluded. The thrombus is then physically dislodged, thus restoring flow. The blood flow pattern resulting from RPTF is referred to as cyclic flow reductions (CFRs). Injection of S6b or ET-1 blocked RPTF, as indicated by inhibition of CFRs. On a rating system of 0 (no effect) to 3 (complete inhibition), S6b and ET-1 produced CFR ratings of 1.8 +/- 0.5 (n = 6) and 2.0 +/- 0.4 (n = 6), respectively. This effect was not blocked by pretreatment with aspirin at 5 mg/kg i.v., a dose that abolishes arachidonic acid-induced ex vivo platelet aggregation (CFR scores for S6b and ET-1 were 2.6 +/- 0.2, n = 5 and 2.0 +/- 0.3, n = 5, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Platelets; Blood Pressure; Coronary Circulation; Coronary Disease; Dogs; Endothelins; Epoprostenol; Fibrinolytic Agents; Heart Rate; Vasoconstrictor Agents; Viper Venoms