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.