Smooth muscle-derived nitric oxide is elevated in isolated forearm veins in human alcoholic cirrhosis.
1. Cirrhosis is often complicated by disturbances in the systemic circulation. We have previously demonstrated decreased vascular responses to vasoconstrictors in forearm resistance arteries in subjects with alcoholic cirrhosis. In the current study we investigate the role of the potent endogenous vasodilator nitric oxide in the peripheral circulation of these patients. 2. Ten patients with alcoholic cirrhosis (Pugh grade A) and 10 age-matched control subjects were studied. The effect of blockade of nitric oxide synthesis was studied both in vivo in forearm resistance arteries using forearm venous occlusion plethysmography and in vitro in veins isolated from the forearm. The role of endothelium-derived nitric oxide was studied in vivo using the endothelium-dependent vasodilator acetylcholine. 3. Mean arterial pressure and forearm basal flow in vivo were similar in the two groups. The constrictor response (percentage decrease in forearm blood flow) to noradrenaline (100 ng/min) was 26% smaller in patients with cirrhosis (31.65 +/- 2.64%) than in control subjects (42.75 +/- 3.87%, P = 0.037). Constrictor responses to the nitric oxide synthase inhibitor NG-monomethyl-L-arginine were not different in the two groups. Dilator responses to acetylcholine were significantly attenuated in cirrhotic patients compared with control subjects. 4. To investigate the role of smooth muscle-derived nitric oxide in vitro, all veins were stripped of their endothelium. Responses to noradrenaline were significantly diminished in veins isolated from patients with cirrhosis compared with control subjects. Incubation with the nitric oxide synthase inhibitor N omega-nitro-L-arginine had no effect on responses to noradrenaline in veins from control subjects but significantly enhanced the maximal response to noradrenaline by 23.95% (range 3.77-100%, P = 0.043) in veins from patients with cirrhosis. 5. Responses to noradrenaline were attenuated in vivo in forearm resistance arteries in patients with alcoholic cirrhosis. This impairment was also apparent in forearm isolated veins, stripped of the endothelium. Our data exclude a major role for endothelium-derived nitric oxide but highlight a possible role for smooth muscle-derived nitric oxide.
Ryan
J
J
Department of Gastroenterology, Baker Medical Research Institute, Melbourne, Victoria, Australia.
Jennings
G
G
Dudley
F
F
Chin-Dusting
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010991:Plethysmography; D051381:Rats; D012039:Regional Blood Flow; D014655:Vascular Resistance / Q000187:drug effects; D014680:Veins / Q000503:physiopathology; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine; D009638:Norepinephrine