Paradoxically enhanced endothelin-B receptor-mediated vasoconstriction in conscious old monkeys.

Abstract

BACKGROUND: We investigated the effects of aging on the responses to endothelin (ET) in conscious old (19.8+/-0.6 years) and young adult (6.8+/-0.3 years) monkeys and compared these results with those of other vasoconstrictors, eg, phenylephrine (PE) and angiotensin II (Ang II). METHODS AND RESULTS: The monkeys (Macaca fascicularis) were chronically instrumented. Baseline total peripheral resistance (TPR) was not different between the 2 groups. As expected, TPR rose less (P<0.05) with PE (5 microgram/kg) in old monkeys (34+/-3%) than in young monkeys (57+/-6%); TPR also rose less with Ang II. Surprisingly, TPR rose more (P<0.05) with endothelin-1 (ET-1, 25 ng. kg(-1). min(-1)) in old monkeys (36+/-6%) than in young monkeys (10+/-2%). An ET(B) receptor agonist, sarafotoxin (S6c, 30 ng. kg(-1). min(-1)) was administered in the presence of an ET(A) receptor antagonist, BQ-123 (1 mg/kg). Under these conditions, TPR increased more (P<0.05) in old monkeys (59+/-10%) than in young monkeys (31+/-4%). In the presence of nitric oxide synthase (NOS) inhibition with N(W)-nitro-L-arginine methyl ester (60 mg/kg), vasoconstriction induced by S6c no longer differed with age, because it was enhanced in young monkeys (P<0.05) (68+/-9% versus 31+/-4%) but not in old monkeys (58+/-6% versus 59+/-10%). Thus, after NOS inhibition, vasoconstrictor responses to ET were no longer enhanced in old monkeys. CONCLUSIONS: Peripheral vasoconstriction (PE and Ang II) is reduced in old monkeys, as expected. Paradoxically, vasoconstriction induced by ET-1 was actually enhanced in old monkeys, which appears to be a result of impaired endothelium-dependent vasodilation, which with ET-1 should involve the ET(B) receptor.