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CARDIOVASCULAR

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

Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas

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 precontracted with norepinephrine at a concentration required to produce 70% of maximal response (ED₇₀). The concentration-response curve of adrenomedullin was shifted to the right by adrenomedullin receptor antagonist adrenomedullin_22–52 (10 µM) or calcitonin gene-related peptide_8–37 (1 µM). Inhibition of adenylate cyclase by 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536) (10 µM) or protein kinase A [Rp-cyclic adenosine monophosphorothioate (Rp-cAMP); 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 ATP-sensitive, voltage-gated, or inward rectifier 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, whereas there was no additional inhibition by SQ22536 or Rp-cAMP when K_Ca channels were already inhibited. In conclusion, this study provides evidence that cAMP-dependent protein kinase A and K_Ca channels seem to mediate as the cellular pathways in the adrenomedullin-induced endothelium-independent relaxation of mesenteric artery from pregnant rats.

Address correspondence to: Dr. Chandra Yallampalli, Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd., MRB, 11.138, Rt. 1062, Galveston, TX 77555-1062. E-mail: chyallam{at}utmb.edu

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