Protein kinase A-dependent and -independent effects of isoproterenol in rat isolated mesenteric artery: interactions with levcromakalim.
The effect of beta-adrenoceptor activation on levcromakalim-induced relaxation was investigated in myograph-mounted rat mesenteric arteries. The nonselective beta-adrenoceptor agonist isoproterenol (at a concentration causing approximately 30% relaxation of methoxamine-induced tone) potentiated relaxation to levcromakalim; higher concentrations exerted no additional effect. The modulatory and relaxant effects of isoproterenol were inhibited by the beta(1)-adrenoceptor antagonist atenolol, but the ATP-sensitive K(+) (K(ATP)) channel inhibitor glibenclamide did not inhibit relaxations to isoproterenol. The protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPS) inhibited the ability of isoproterenol to modulate levcromakalim relaxation. However, neither Rp-cAMPS nor N-[2-(p-bromocinnamylamino)ethyl]-6-isoquinolinesulfonamide (H-89) (another protein kinase A inhibitor) markedly reduced isoproterenol-induced relaxation, although Rp-cAMPS inhibited relaxations induced by forskolin (an adenylyl cyclase activator). Iberiotoxin (50 nM), an inhibitor of large conductance Ca(2+)-activated K(+) channels (BK(Ca)), attenuated isoproterenol relaxation. Moreover, both Rp-cAMPS and H-89 caused inhibition of the effects of isoproterenol in the presence of iberiotoxin, whereas glibenclamide did not. We conclude that isoproterenol modulates the actions of levcromakalim through beta(1)-adrenoceptors and protein kinase A, even though K(ATP) channels do not contribute to its relaxant effects. However, the major relaxant mechanism for isoproterenol appears to be protein kinase A-independent activation of BK(Ca), with cyclic AMP-dependent mechanisms only being unmasked when the BK(Ca) mechanism is inhibited. Although direct G protein-mediated activation of BK(Ca) has been demonstrated previously in electrophysiological studies of single smooth muscle cells, this is the first time that such a mechanism has been shown to be functionally important in an intact blood vessel preparation.
White
R
R
Department of Pharmacology, University of Cambridge, Cambridge, England.
Bottrill
F E
FE
Siau
D
D
Hiley
C R
CR
D018528:ATP-Binding Cassette Transporters; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000465:Algorithms; D000818:Animals; D019806:Cromakalim / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D054086:KATP Channels; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D013449:Sulfonamides; D014665:Vasodilator Agents / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D018342:Receptors, Adrenergic, beta-1; D013449:Sulfonamides; D014665:Vasodilator Agents; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide