Abstract
Signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in potassium-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonist bethanechol was given by bolus injection or constant infusion. Perfusion pressure was monitored as an indicator of coronary vascular resistance. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, whereas infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Bethanechol-induced phasic vasoconstriction was eliminated by perfusion with a Ca2+-free buffer. The L-type voltage-operated Ca2+ channel blocker nifedipine decreased the maximal constrictor response to bethanechol by 59 ± 2% (n = 4, P < .001), whereas the putative receptor-operated Ca2+ channel blocker SK&F 96365 converted this vasoconstriction into vasodilation that was not mediated by nitric oxide. The protein kinase C inhibitor chelerythrine reduced the maximal phasic vasoconstrictor response to bethanechol by 78 ± 2% (n = 6, P < .001) Bethanechol-induced tonic vasoconstriction was rapidly converted to a sustained vasodilation during infusion of SK&F 96365 or nifedipine, whereas infusion of chelerythrine gradually attenuated the tonic response to bethanechol. Results from other experiments do not support a role for phospholipase A2-dependent mediators in generating coronary vasoconstrictor responses to bethanechol. It is concluded that voltage-independent receptor-operated Ca2+channels, voltage-operated Ca2+ channels, and protein kinase C are major signaling components for muscarinic receptor-mediated contraction of rat coronary resistance arteries.
Footnotes
-
Send reprint requests to: Dr. Donald B. Hoover, Department of Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0577. E-mail: hoover{at}etsu.edu
-
↵1 This work was supported by National Institutes of Health Grant HL-54633. Preliminary reports of the results were presented at the 8th International Symposium on Subtypes of Muscarinic Receptors and the 28th Annual Meeting of the Society for Neuroscience.
- Abbreviations:
- ACh
- acetylcholine
- A-9-C
- anthracene-9-carboxylic acid
- COX
- cyclooxygenase
- p-BPB
- 2,4′-dibromoacetophenone
- ROCC
- receptor-operated calcium channel
- SK&F 96365
- 1-[β-[3-(4-methoxyphenyl)proxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride
- SQ-29548
- [1S-[1α,2α(Z),3α,4α]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid
- U-46619
- 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α
- VOCC
- voltage-operated calcium channel
- EDRF
- endothelium-derived relaxing factor
- PLA2
- phospholipase A2
- PKC
- protein kinase C
- l-NAME
- NG-nitro-l-arginine methyl ester hydrochloride
- LTD4
- leukotriene D4
- DMSO
- dimethyl sulfoxide
- Received August 26, 1999.
- Accepted December 21, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|