Received for publication January 24, 2006.
Revised March 17, 2006.
Accepted for publication March 17, 2006.

Endothelium-Independent Relaxation by Adrenomedullin in Pregnant Rat Mesenteric Artery: Role of cAMP-Dependent Protein Kinase A and Calcium-Activated Potassium Channels

Abstract

The mechanisms of relaxation of adrenomedullin were investigated in isolated mesenteric artery from pregnant rats. Adrenomedullin (1 nM - 0.3 µM) produced concentration-dependent relaxation of endothelium-denuded mesenteric artery rings, pre-contracted with norepinephrine at a concentration required to produce 70% of maximum response (ED₇₀). The concentration-response curve of adrenomedullin was shifted to the right by adrenomedullin receptor antagonists, adrenomedullin_22-52 (10 µM) or CGRP_8-37 (1 µM). Inhibition of adenylate cyclase (SQ22536 (10 µM)) or protein kinase A (Rp-cyclic adenosine monophosphates (Rp-cAMPs) (10 µM)) reduced the adrenomedullin-induced relaxation to the same magnitude. Adrenomedullin increased the intracellular cAMP level from 0.38 ± 0.07 to 2.00 ±0.47 pmol/mg tissues, which was completely inhibited by adrenomedullin_22-52 (100 µM). Extracellular high potassium (80 mM) which inactivates the potassium channels reduced the adrenomedullin-induced relaxation. Blockade of adenosine triphosphate (ATP)-sensitive (K_ATP)-, voltage-gated (K_V)- or inward rectifier (K_IR)- potassium channels did not affect the adrenomedullin-induced relaxation. Blockade of calcium-activated K⁺-channels (K_Ca) by tetraethylammonium (1 mM) or iberiotoxin (100 nM) inhibited the adrenomedullin-induced relaxation while there was no additional inhibition by SQ22536 or Rp-cAMPs when K_Ca channels were already inhibited. In conclusion, this study provides evidence that cAMP-dependent protein kinase A and KCa channels appear to mediate as the cellular pathways in the adrenomedullin-induced endothelium-independent relaxation of mesenteric artery from pregnant rats.

Key words: Adrenomedullin, K+-Channels, Mesenteric Artery, Protein Kinase A, Relaxation, cAMP

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