title: Nitric oxide synthase inhibition activates L- and T-type Ca2+ channels in afferent and efferent arterioles.
abstract: Previous studies have shown that L-type Ca(2+) channel (LCC) blockers primarily dilate resting and ANG II-constricted afferent arterioles (AA), but do not influence either resting or ANG II-constricted efferent arterioles (EA). In contrast, blockade of T-type Ca(2+) channels (TCC) dilate EA and prevent ANG II-mediated efferent constriction. The present study determined the role of LCC and TCC in mediating the AA and EA constriction following inhibition of nitric oxide synthase (NOS) and tested the hypothesis that inhibition of NOS increases the influence of LCC on EA. With the use of an isolated blood-perfused rat juxtamedullary nephron preparation, single AA or EA were visualized and superfused with a NOS inhibitor, N-nitro-l-arginine (l-NNA), with or without concomitant treatment with an LCC blocker, diltiazem, or a TCC blocker, pimozide. In response to l-NNA (1, 10, and 100 micromol/l), AA and EA diameters decreased significantly by 6.0 +/- 0.3, 13.7 +/- 1.7, and 19.9 +/- 1.4%, and by 6.2 +/- 0.5, 13.3 +/- 1.1, and 19.0 +/- 1.9%, respectively. During TCC blockade with pimozide (10 micromol/l), l-NNA did not significantly constrict afferent (0.9 +/- 0.6, 1.5 +/- 0.5, and 1.7 +/- 0.5%) or efferent (0.4 +/- 0.1, 2.1 +/- 0.7, and 2.5 +/- 1.0%) arterioles. In contrast to the responses with other vasoconstictors, the l-NNA-induced constriction of EA, as well as AA, was reversed by diltiazem (10 micromol/l). The effects were overlapping as pimozide superimposed on diltiazem did not elicit further dilation. When the effects of l-NNA were reversed by superfusion with an NO donor, SNAP (10 micromol/l), diltiazem did not cause significant efferent dilation. As a further test of LCC activity, 55 mmol/l KCl, which depolarizes and constricts AA, caused only a modest constriction in resting EA (8.7 +/- 1.3%), but a stronger EA constriction during concurrent treatment with l-NNA (23.8 +/- 4.8%). In contrast, norepinephrine caused similar constrictions in both l-NNA-treated and nontreated arterioles. These results provide evidence that NO inhibits LCC and TCC activity and that NOS inhibition-mediated arteriolar constriction involves activation of LCC and TCC in both AA and EA. The difference in responses to high KCl between resting and l-NNA-constricted EA and the ability of diltiazem to block EA constriction caused by l-NNA contrasts with the lack of efferent effects in resting and SNAP-treated l-NNA-preconstricted arterioles and during ANG II-mediated vasoconstriction, suggesting a recruitment of LCC in EA when NOS is inhibited. These data help explain how endothelial dysfunction associated with hypertension may lead to enhanced activity of LCC in postglomerular arterioles and increased postglomerular resistance.
authors.affiliation: Department of Physiology and Hypertension and Renal Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA. mfeng@tulane.edu
authors.forename: Ming-Guo
authors.initials: MG
authors.lastname: Feng
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001160:Arterioles / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D004110:Diltiazem / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D010868:Pimozide / Q000494:pharmacology; D051381:Rats; D014655:Vascular Resistance; D014661:Vasoconstriction
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D018492:Dopamine Antagonists; D009603:Nitroso Compounds; C084185:N-nitrosoarginine; D010868:Pimozide; D001120:Arginine; D019001:Nitric Oxide Synthase; D004110:Diltiazem