The role of a cAMP-dependent pathway in the uterine relaxant action of relaxin in rats.
The aim of this study was to investigate the role of the adenylyl cyclase pathway, and in particular cyclic AMP-dependent protein kinase A, in the relaxant action of relaxin in the isolated uterus of the nonpregnant rat. The purportedly selective inhibitor of cAMP-dependent protein kinase A N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8) (at 100 mumol l-7) antagonized relaxin, salbutamol (an agonist at beta-adrenoceptors) and levcromakalim (a K+ channel opener) to a similar extent (by factors of 3.1, 1.9 and 2.8, respectively), demonstrating that it is not a selective inhibitor. Relaxin and levcromakalim were less potent and had smaller, maximal, relaxant effects in longitudinal myometrium than in intact uterus cut in the longitudinal plane. By contrast, nifedipine (a Ca2+ channel blocker) was equipotent in the two preparations and salbutamol only slightly less potent in the longitudinal myometrium. Relaxin did not alter the cyclic AMP-dependent protein kinase A activity ratio in longitudinal myometrium, but did increase the activity ratio by a factor of 2.0 +/- 0.2 in the intact uterus. Salbutamol, the positive control, increased this activity ratio in both longitudinal myometrium (by 1.9 +/- 0.3 times) and in the intact uterus (by 3.8 +/- 0.3 times), whereas the negative control levcromakalim had no effect. Relaxin seems to act as a relaxant of longitudinal myometrium by a cyclic AMP-independent mechanism but possibly interacts with the circular myometrium or endometrium to release a relaxant factor via a cyclic-AMP-dependent mechanism.
Hughes
S J
SJ
Smooth Muscle Pharmacology Group, School of Biological Sciences, University of Manchester, UK.
Hollingsworth
M
M
Elliott
K R
KR
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019806:Cromakalim; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D009215:Myometrium / Q000187:drug effects / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012065:Relaxin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014590:Uterine Contraction / Q000187:drug effects*; D014599:Uterus / Q000187:drug effects / Q000201:enzymology
D000318:Adrenergic beta-Agonists; D001578:Benzopyrans; D002121:Calcium Channel Blockers; D007546:Isoquinolines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D012065:Relaxin; D019001:Nitric Oxide Synthase; D017868:Cyclic AMP-Dependent Protein Kinases; D009543:Nifedipine; D000420:Albuterol; D019331:NG-Nitroarginine Methyl Ester