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1 Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
2 Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
* To whom correspondence should be addressed. E-mail: dmatteso{at}umaryland.edu.
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 ([Mg2+]o) 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 (Nif, 0.3-1.0 µM) markedly reduced MT as well as vasoconstriction induced by high external K+ concentrations ([K+]o), a measure of LVGC-mediated Ca2+ entry. Block of MT and high [K+]o-induced vasoconstriction by 
1 µM Nif in WT, but not DHPR/R, arteries implies that Ca2+ entry via Cav1.2 LVGCs is obligatory for MT, and that Nif inhibits MT exclusively by blocking LVGCs. We also examined the effect of Mg2+ on MT and LVGCs. High [Mg2+]o (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 effect 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.
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