Abstract
Endothelin (ET), a coronary vasoconstrictor, mediates its activity through the specific receptors ET-A and ET-B, which may demonstrate different activity under pathophysiological conditions. Thoracic inferior vena cava constriction (TIVCC) is an experimental model of congestive heart failure that is characterized by a decrease in cardiac output and an increase in circulating ET concentrations. The present study was designed to test the hypothesis that experimental heart failure altered coronary vascular responsiveness to ET-A- and ET-B-receptor stimulation in vivo. ET-1 was infused at a rate of 2 ng/kg per minute into the left circumflex coronary artery in normal dogs (n = 5) and in dogs subjected to TIVCC (TIVCC dogs, n = 6). Similarly, sarafotoxin, an ET-B-receptor agonist, was infused at the same dosage in normal (n = 5) and TIVCC (n = 6) dogs. Intracoronary infusion of ET-1 significantly decreased coronary blood flow and increased coronary vascular resistance in normal dogs; this effect was significantly attenuated in TIVCC compared with normal dogs. The percent changes in coronary blood flow and coronary vascular resistance in the TIVCC compared with the normal dogs was -11 +/- 8% versus -48 +/- 7% (P < .01) and 29 +/- 10% versus 105 +/- 23% (P < .01), respectively. There was no significant effect on coronary blood flow, coronary vascular resistance, or coronary artery diameter in normal dogs that received an intracoronary infusion of sarafotoxin. In contrast, the administration of intracoronary sarafotoxin in TIVCC compared with normal dogs resulted in significant percent changes in coronary blood flow and coronary vascular resistance (-31 +/- 4% versus -7 +/- 3% [P < .001] and 53 +/- 12% versus 12 +/- 8% [P < .02], respectively). The present study demonstrates an attenuated coronary vasoconstrictor response to ET-1 with an enhanced vasoconstrictor response to sarafotoxin and suggests an alteration in coronary ET receptor sensitivity in experimental heart failure.
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