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Departments of 1Physiology and 3Medicine, University of Maryland School of Medicine, Baltimore, Maryland; and 2Department of Pharmacology and Toxicology; Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
Submitted 16 November 2005 ; accepted in final form 1 September 2006
Ca2+ entry via L-type voltage-gated Ca2+ channels (LVGCs) is a key factor in generating myogenic tone (MT), as dihydropyridines (DHPs) and other LVGC blockers, including Mg2+, markedly reduce MT. Recent reports suggest, however, that elevated external Mg2+ concentration and DHPs may also inhibit other Ca2+-entry pathways. Here, we explore the contribution of LVGCs to MT in intact, pressurized mesenteric small arteries using mutant mice (DHPR/R) expressing functional but DHP-insensitive Cav1.2 channels. In wild-type (WT), but not DHPR/R, mouse arteries, nifedipine (0.3–1.0 µM) markedly reduced MT and vasoconstriction induced by high external K+ concentrations ([K+]o), a measure of LVGC-mediated Ca2+ entry. Blocking MT and high [K+]o-induced vasoconstriction by <1 µM nifedipine in WT but not in DHPR/R arteries implies that Ca2+ entry via Cav1.2 LVGCs is obligatory for MT and that nifedipine inhibits MT exclusively by blocking LVGCs. We also examined the effects of Mg2+ on MT and LVGCs. High external Mg2+ concentration (10 mM) blocked MT, slowed the high [K+]o-induced vasoconstrictions, and decreased their amplitude in WT and DHPR/R arteries. To verify that these effects of Mg2+ are due to block of LVGCs, we characterized the effects of extracellular and intracellular Mg2+ on LVGC currents in isolated mesenteric artery myocytes. DHP-sensitive LVGC currents are inhibited by both external and internal Mg2+. The results indicate that Mg2+ relaxes MT by inhibiting Ca2+ influx through LVGCs. These data provide new information about the central role of Cav1.2 LVGCs in generating and maintaining MT in mouse mesenteric small arteries.
myogenic tone; patch clamp; calcium current; dihydropyridine receptor; arterial smooth muscle
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