Abstract
The effect of β-adrenoceptor activation on levcromakalim-induced relaxation was investigated in myograph-mounted rat mesenteric arteries. The nonselective β-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 β1-adrenoceptor antagonist atenolol, but the ATP-sensitive K+ (KATP) 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 norN-[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 Ca2+-activated K+ channels (BKCa), 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 β1-adrenoceptors and protein kinase A, even though KATP channels do not contribute to its relaxant effects. However, the major relaxant mechanism for isoproterenol appears to be protein kinase A-independent activation of BKCa, with cyclic AMP-dependent mechanisms only being unmasked when the BKCa mechanism is inhibited. Although direct G protein-mediated activation of BKCa 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.
Footnotes
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A preliminary account of this work was presented to the British Pharmacological Society, Bradford, Yorkshire, September 6–8, 2000 (White et al., 2000). R.W. is a Junior Research Fellow of Sidney Sussex College, Cambridge, England.
- Abbreviations:
- KATP
- ATP-sensitive K+channel
- Rp-cAMPS
- Rp-adenosine 3′,5′-cyclic monophosphothioate triethylamine
- H-89
- N-[2-(p-bromocinnamylamino)ethyl]-6-isoquinolinesulfonamide
- ANOVA
- analysis of variance
- BKCa
- large conductance Ca2+-activated K+ channels
- Received February 26, 2001.
- Accepted May 7, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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