Address of Corresponding Author

Pharmacology 2004;72:231-239 (DOI: 10.1159/000080378)

  Key Words

• Nitric oxide
• Endothelium-derived hyperpolarizing factor
• Endothelium
• K⁺ channels
• Renal hypertension

  Abstract

Acetylcholine induced relaxation in a concentration-dependent way in isolated phenylephrine-contracted carotid artery rings from normotensive two-kidney (2K) and hypertensive two-kidney one-clip (2K-1C) rats. In the presence of the nitric oxide (NO) synthase inhibitor N^G-nitro-L-arginine (L-NOARG, 100 µmol/l), the relaxation stimulated with acetylcholine was blocked in 2K arteries. However, in 2K-1C arteries, the relaxation was only partially inhibited. Indomethacin (3 µmol/l) had no effect in both groups. In 2K arteries, the combination of L-NOARG and indomethacin had similar effects to L-NOARG alone. On the other hand, in 2K-1C arteries, indomethacin further inhibited the maximum effect induced by acetylcholine. Endothelium-dependent relaxation induced by acetylcholine was markedly reduced in 2K arteries contracted with 90 mmol/l KCl, and it was abolished in 2K-1C arteries. The remaining response to acetylcholine in 2K arteries was blocked by L-NOARG. Thus, in addition to NO, a relaxing factor sensitive to extracellular K⁺ changes in the membrane potential contributes to endothelium-dependent relaxation in 2K-1C rat carotid artery. On the other hand, in arteries from 2K rats, only NO is involved in the relaxation induced by acetylcholine. The combination of 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 3 µmol/l), indomethacin (3 µmol/l) and L-NOARG (100 µmol/l) reduced the relaxation induced by acetylcholine in arteries from 2K-1C rats contracted with phenylephrine. On the other hand, in 2K arteries, the relaxation induced by acetylcholine was abolished. The combination of ODQ and K⁺ channel blockers charybdotoxin (100 nmol/l), apamin (500 nmol/l) and 4-aminopyridine (1 µmol/l) abolished the relaxation induced by acetylcholine in 2K and 2K-1C carotid arteries. These data indicate that the endothelium-derived relaxing factors that contribute to relaxation induced by acetylcholine are different in 2K and 2K-1C arteries. In 2K arteries, the only factor is NO, which involves the activation of K⁺ channels and the cGMP pathway. However, in 2K-1C arteries, the relaxation induced by acetylcholine is dependent on NO in addition to another factor, which is insensitive to indomethacin, but also activates the K⁺ channels and the cGMP pathway, presumably by membrane hyperpolarization through endothelium-derived hyperpolarizing factor.

Copyright © 2004 S. Karger AG, Basel

  Author Contacts

Lusiane M. Bendhack
Laboratório de Farmacologia
Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP
Av. do Café s/no., 14040-903 Ribeirão Preto, SP (Brazil)
Tel. +55 16 602 4165, Fax +55 16 633 2960, E-Mail bendhack@usp.br

  Article Information

Received: October 13, 2003
Accepted: April 20, 2004
Number of Print Pages : 9
Number of Figures : 6, Number of Tables : 0, Number of References : 41