Role of endothelial carbon monoxide in attenuated vasoreactivity following chronic hypoxia

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 275; no. 4; pp. 1025 - R1030
• Main Authors: Caudill, Timothy K, Resta, Thomas C, Kanagy, Nancy L, Walker, Benjimen R
• Format: Journal Article
• Language: English
• Published: United States 01.10.1998
• Subjects: Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiology; Aorta, Thoracic - physiopathology; Arsenites - pharmacology; Carbon Monoxide - physiology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Guanylate Cyclase - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - biosynthesis; Hypoxia - physiopathology; In Vitro Techniques; Kinetics; Male; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Muscle, Smooth, Vascular - physiopathology; Nitric Oxide Donors - pharmacology; Nitroarginine - pharmacology; Oxadiazoles - pharmacology; Penicillamine - analogs & derivatives; Penicillamine - pharmacology; Phenylephrine - pharmacology; Protoporphyrins - pharmacology; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; Reference Values; S-Nitroso-N-Acetylpenicillamine; Sodium Compounds - pharmacology
• ISSN: 0363-6119; 0002-9513; 1522-1490
• DOI: 10.1152/ajpregu.1998.275.4.r1025

Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-5218 Chronic hypoxic exposure has been previously demonstrated to attenuate systemic vasoconstrictor activity to a variety of agents. This attenuated responsiveness is observed not only in conscious animals but in isolated vascular preparations as well. Because hypoxia has been documented to increase heme oxygenase (HO) levels and the subsequent production of the vasodilator CO in vitro, we hypothesized that the blunted reactivity observed with chronic hypoxia (CH) may be in part due to increased HO activity. In thoracic aortic rings from CH rats, cumulative dose-response curves to phenylephrine (PE) in the presence of the nitric oxide (NO) synthase inhibitor N -nitro- L -arginine ( L -NNA) and the HO inhibitor zinc protoporphyrin 9 (ZnPPIX) elicited increased contractility compared with CH rings treated with only L -NNA. Similar results were observed in rings incubated overnight with the HO-inducing agent sodium m -arsenite. In contrast, contractile responses in rings from control rats were unaffected by the HO inhibitor. Furthermore, endothelium-denuded rings from either control or CH rats did not exhibit an increase in reactivity to PE following ZnPPIX incubation. ZnPPIX had no effect on relaxant responses to the NO donor S -nitroso- N -penicillamine, suggesting that its actions were specific to HO inhibition. Finally, aortic rings exhibited dose-dependent relaxant responses to exogenous CO that were endothelium independent and blocked by an inhibitor of soluble guanylyl cyclase. The other products of HO enzyme activity, iron and biliverdin, were without effect on vasoreactivity. Thus we conclude that the attenuated vasoreactivity to PE following CH is likely to involve the induction of endothelial HO and the subsequent enhanced production of CO. rat; thoracic aorta; heme oxygenase; nitric oxide synthase; endothelium