Slow channel calcium blockers attenuate reoxygenation-mediated vascular contraction, but augment anoxia-mediated vascular contraction.
Anoxia and reoxygenation modulate vasomotor tone. To determine the effect of the slow channel calcium blockers verapamil and diltiazem in vascular smooth muscle contraction during states of altered oxygenation, rat aortic rings with intact endothelium were contracted with norepinephrine (NE) or the thromboxane A2 mimic U46,619 and then exposed abruptly to anoxia (switch from 95% O2 to 95% N2) for 30 min and then reoxygenated (switch from 95% N2 to 95% O2). Anoxia caused a transient 40 +/- 9% (mean +/- SE, n = 15) increase in contraction, whereas reoxygenation resulted in an initial decrease followed by a large (83 +/- 21%) increase in contraction. Treatment of vascular rings with verapamil or diltiazem (1 microgram/ml or 2 microM) decreased contractile response to the agonists (p less than 0.01). Both these agents consistently augmented the magnitude and duration of anoxia-induced contraction (p less than 0.01). In other experiments, pretreatment of vascular rings with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of endothelium-derived relaxing factor (EDRF) synthesis, or with oxyhemoglobin, an inhibitor of EDRF activity, or de-endothelialization resulted in marked (p less than 0.01) decrease in anoxic contraction, indicating that anoxia-induced contraction is caused by modulation of EDRF. Treatment of aortic rings with verapamil also reduced acetylcholine-mediated relaxation (from 86 +/- 6% to 45 +/- 5%, p less than 0.02) and cyclic GMP accumulation (from 192 +/- 53 to 111 +/- 35 fmol/mg, p less than 0.02), indicating reduction in EDRF synthesis or activity by verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
Haught
W H
WH
Division of Cardiology, University of Florida College of Medicine, Gainesville.
Yang
B C
BC
Lawson
D L
DL
Mehta
J L
JL
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D004110:Diltiazem / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology*; D010108:Oxyhemoglobins / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014700:Verapamil / Q000494:pharmacology*
D010108:Oxyhemoglobins; D011450:Prostaglandin Endoperoxides, Synthetic; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D014700:Verapamil; D004110:Diltiazem; D000109:Acetylcholine; D010100:Oxygen; D009638:Norepinephrine; D007213:Indomethacin