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

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 μg/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.