Mechanism of adrenomedullin-induced relaxation in isolated canine retinal arteries.
OBJECTIVE
To analyze the mechanism of action of adrenomedullin (AM), a peptide recently isolated from human pheochromocytoma, in isolated canine central retinal arteries and to compare the action of calcitonin gene-related peptide (CCRP).


METHODS
Changes in isometric tension were recorded in helical strips of the arteries with and without the endothelium.


RESULTS
Both AM and CGRP produced relaxation: EC50s were 2.62 and 0.71 x 10(-9) mol/l, respectively, and maximal relaxations were 85.1% and 84.3%, respectively. The AM-induced relaxation was endothelium-independent and unaffected by indomethacin, Ng-nitro-L-arginine, methylene blue, and glibencaalmide. Treatment with [8-37] CGRP markedly inhibited the relaxations caused by AM and CGRP. Treatment with a high concentration of sodium nitroprusside abolished the relaxation caused by nitroglycerin and atrial natriuretic peptide and reduced the relaxation caused by AM and CGRP. A high concentration of beraprost, a stable analog of prostaglandin I2, suppressed the response to AM and CGRP but not to nitroglycerin.


CONCLUSIONS
Endothelium-independent relaxations to AM of canine retinal arteries may be mediated primarily by intracellular cyclic adenosine monophosphate by stimulation of CGRP1 receptors and partially by cyclic guanosine monophosphate; cyclic guanosine monophosphate is unlikely ot be produced by methylene blue-sensitive soluble guanylate cyclase. Prostanoids, nitric oxide, and adenosine triphosphate-dependent K+ channel opening do not appear to be involved in the AM-induced relaxation.
Okamura
T
T
Department of Pharmacology, Shiga University of Medical Science, Ohtsu, Japan.
Ayajiki
K
K
Kangawa
K
K
Toda
N
N
D053607:Adrenomedullin; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology* / Q000502:physiology; D012161:Retinal Artery / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; D019335:Nitroarginine; D000242:Cyclic AMP; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide; D005905:Glyburide; D008751:Methylene Blue; D007213:Indomethacin