Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production.
Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)
Simonet
S
S
Servier Research Institute, Department of Angiology, Suresnes, France.
Porro de Bailliencourt
J
J
Descombes
J J
JJ
Mennecier
P
P
Laubie
M
M
Verbeuren
T J
TJ
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001161:Arteriosclerosis / Q000503:physiopathology; D002118:Calcium / Q000502:physiology; D015687:Cell Hypoxia; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D019335:Nitroarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D012701:Serotonin; D001120:Arginine; D006152:Cyclic GMP; D002118:Calcium; D008751:Methylene Blue