TY - JOUR T1 - Endothelium-Independent Relaxation by Adrenomedullin in Pregnant Rat Mesenteric Artery: Role of cAMP-Dependent Protein Kinase A and Calcium-Activated Potassium Channels JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1269 LP - 1275 DO - 10.1124/jpet.106.101790 VL - 317 IS - 3 AU - Gracious R. Ross AU - Chandra Yallampalli Y1 - 2006/06/01 UR - http://jpet.aspetjournals.org/content/317/3/1269.abstract N2 - 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 adrenomedullin22–52 (10 μM) or calcitonin gene-related peptide8–37 (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 adrenomedullin22–52 (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 (KCa) 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 KCa channels were already inhibited. In conclusion, this study provides evidence that cAMP-dependent protein kinase A and KCa channels seem to mediate as the cellular pathways in the adrenomedullin-induced endothelium-independent relaxation of mesenteric artery from pregnant rats. The American Society for Pharmacology and Experimental Therapeutics ER -