Endothelium-independent relaxation by adrenomedullin in pregnant rat mesenteric artery: role of cAMP-dependent protein kinase A and calcium-activated potassium channels.
The mechanisms of relaxation of adrenomedullin were investigated in isolated mesenteric artery from pregnant rats. Adrenomedullin (1 nM-0.3 microM) 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 microM) or calcitonin gene-related peptide(8-37) (1 microM). Inhibition of adenylate cyclase by 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536) (10 microM) or protein kinase A [Rp-cyclic adenosine monophosphorothioate (Rp-cAMP); 10 microM] 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 microM). 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.
Ross
Gracious R
GR
Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Blvd., MRB, 11.138, Rt. 1062, Galveston, TX 77555-1062, USA.
Yallampalli
Chandra
C
D053607:Adrenomedullin; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D017538:Mesenteric Artery, Superior / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D010446:Peptide Fragments; D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D047428:Protein Kinase Inhibitors; D053607:Adrenomedullin; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide