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(Circulation. 2001;103:2382.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Paradoxically Enhanced Endothelin-B Receptor–Mediated Vasoconstriction in Conscious Old Monkeys

Kuniya Asai, MD, PhD; Raymond K. Kudej, DVM, PhD; Gen Takagi, MD; Amelia B. Kudej, BSBME; Filipinas Natividad, PhD; You-Tang Shen, MD; Dorothy E. Vatner, MD; Stephen F. Vatner, MD

From the Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, and Hackensack University Medical Center, Hackensack, NJ.

Correspondence to Stephen F. Vatner, MD, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, MSB-I576, 185 S Orange Ave, Newark, NJ 07103. E-mail svatner{at}humed.com

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.

Key Words: aging • endothelin • receptors • nitric oxide synthase • vasoconstriction

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