Adrenomedullin-mediated relaxations in veins are endothelium-dependent and distinct from arteries.
In arteries, adrenomedullin (ADM) causes relaxations of rings with and without endothelium by stimulating accumulation of cyclic nucleotides resulting from activation of the ADM and calcitonin gene-related peptide (CGRP) receptors. Experiments were designed to determine the mechanism(s) of relaxation to ADM in veins. Rings of canine femoral vein with and without endothelium were suspended in organ chambers for measurement of isometric force. Rings were contracted with prostaglandin F2alpha (2 x 10(-6) M), and cumulative dose-responses to ADM (10(-11) to 10(-7) M) were obtained in the absence or presence of indomethacin (10(-5) M), indomethacin + N(G)-monomethyl-L-arginine (10(-4) M), methylene blue (10(-5) M), particulate guanylate cyclase inhibitor HS-142-1 (10(-5) M), tetraethylammonium (TEA, 10(-2) M), CGRP-receptor antagonist (CGRP 8-37, 10(-6) M), ADM-receptor antagonist (ADM 26-52, 10(-6) M), diphenhydramine (10(-6) M), 8-phenyltheophylline (3 x 10(-6) M), or superoxide dismutase (150 U/ml) plus catalase (1,200 U/ml). ADM produced concentration-dependent relaxations only in veins with endothelium. Relaxations to ADM in rings with endothelium were significantly inhibited only by methylene blue and HS-142-1. In separate experiments, incubation of rings with ADM (10(-8) M) and 3-isobutyl-1-methyl-xanthine (10(-4) M) for 3 min did not significantly affect the accumulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). These data suggest that ADM-mediated relaxation in veins is endothelium dependent and is not associated with activation of CGRP receptors or currently defined ADM receptors. Further, relaxations are not mediated by nitric oxide, indomethacin-sensitive prostanoids, TEA-sensitive hyperpolarizing factors, oxygen free radicals, or accumulation of cyclic nucleotides.
Barber
D A
DA
Department of Surgery, Surgical Research, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, U.S.A.
Park
Y S
YS
Burnett
J C
JC
Miller
V M
VM
D053607:Adrenomedullin; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D005263:Femoral Artery; D005268:Femoral Vein; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008638:Mesenteric Arteries; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000378:metabolism; D018000:Receptors, Peptide; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D008565:Membrane Proteins; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide; D018000:Receptors, Peptide; D014665:Vasodilator Agents; D053607:Adrenomedullin; D000242:Cyclic AMP; D006152:Cyclic GMP