title: Vascular smooth muscle cell membrane depolarization after NOS inhibition hypertension.
abstract: Nitric oxide (NO) synthase (NOS) inhibition with N(omega)-nitro-L-arginine (L-NNA) produces L-NNA hypertensive rats (LHR), which exhibit increased sensitivity to voltage-dependent Ca(2+) channel-mediated vasoconstriction. We hypothesized that enhanced contractile responsiveness after NOS inhibition is mediated by depolarization of membrane potential (E(m)) through attenuated K(+) channel conductance. E(m) measurements demonstrated that LHR vascular smooth muscle cells (VSMCs) are depolarized in open, nonpressurized (-44.5 +/- 1.0 mV in control vs. -36.8 +/- 0.8 mV in LHR) and pressurized mesenteric artery segments (-41.8 +/- 1.0 mV in control vs. -32.6 +/- 1.4 mV in LHR). Endothelium removal or exogenous L-NNA depolarized control VSMCs but not LHR VSMCs. Superfused L-arginine hyperpolarized VSMCs from both the control and LHR groups and reversed L-NNA-induced depolarization (-44.5 +/- 1.0 vs. -45.8 +/- 2.1 mV). A Ca(2+)-activated K(+) channel agonist, NS-1619 (10 microM), hyperpolarized both groups of arteries to a similar extent (from -50.8 +/- 1.0 to -62.5 +/- 1.2 mV in control and from -43.7 +/- 1.1 to -55.6 +/- 1.2 mV in LHR), although E(m) was still different in the presence of NS-1619. In addition, superfused iberiotoxin (50 nM) depolarized both groups similarly. Increasing the extracellular K(+) concentration from 1.2 to 45 mM depolarized E(m), as predicted by the Goldman-Hodgkin-Katz equation. These data support the hypothesis that loss of NO activation of K(+) channels contributes to VSMC depolarization in L-NNA-induced hypertension without a change in the number of functional large conductance Ca(2+)-activated K(+) channels.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-5218, USA. ibratz@salud.unm.edu
authors.forename: Ian N
authors.initials: IN
authors.lastname: Bratz
authors.forename: Ricardo
authors.initials: R
authors.lastname: Falcon
authors.forename: L Donald
authors.initials: LD
authors.lastname: Partridge
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Kanagy
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000502:physiology*; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000648:ultrastructure*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000819:agonists / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D010455:Peptides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C110881:S-nitro-N-acetylpenicillamine; C086491:NS 1619; D019335:Nitroarginine; C064719:iberiotoxin; D001120:Arginine; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D011188:Potassium; D002118:Calcium