nitroarginine and Liver-Cirrhosis

In liver cirrhosis/portal hypertension, collaterals as varices may bleed and are influenced by vasoresponsiveness. An angiotensin blockade ameliorates portal hypertension but the influence on collaterals is unknown.. Portal hypertension and cirrhosis were induced by portal vein (PVL) and common bile duct ligation (BDL). Hemodynamics, real-time PCR of angiotensin II receptors (AT(1)R, AT(2)R) in the left adrenal vein (LAV, sham) and splenorenal shunt derived from LAV (PVL, BDL) were performed. With an in situcollateral perfusion model, angiotensin II vasoresponsiveness with different preincubations was evaluated: (1) vehicle; (2) AT(1)R blocker losartan; (3) losartan plus nonselective nitric oxide synthase (NOS) inhibitor (N(ω)-nitro-L-arginine); (4) AT(2)R blocker PD123319; (5) PD123319 plus N(ω)-nitro-L-arginine; (6) N(ω)-nitro-L-arginine, and (7) losartan plus inducible NOS inhibitor aminoguanidine.. LAV AT(1)R and AT(2)R expression decreased in PVL and BDL rats. Losartan attenuated angiotensin II-elicited vasoconstriction but PD123319 had no effect. N(ω)-nitro-L-arginine but not aminoguanidine reversed the losartan effect.. Angiotensin receptors are downregulated in the collateral vessel of portal hypertensive and cirrhotic rats. The AT(1)R blockade attenuates the angiotensin II vasoconstrictive effect, suggesting AT(1)R mediates collateral vasoconstriction and the influence of AT(2)R is negligible. The lack of aminoguanidine influence indicates that endothelial NOS participates in the losartan effect.

Topics: Animals; Collateral Circulation; Down-Regulation; Guanidines; Hypertension, Portal; Imidazoles; Ligation; Liver Cirrhosis; Losartan; Male; Nitric Oxide Synthase; Nitroarginine; Portal Vein; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Vasoconstriction

Clonidine, an alpha2-agonist, has been shown to be useful in the treatment of hepatic portal hypertension in cirrhosis. The mechanism has been attributed to a clonidine-induced decrease in sympathetic activity. While clonidine has been shown to stimulate the alpha2-adrenoceptors of blood vessels, there is limited knowledge of the effects of clonidine on the circular muscle of the hepatic portal vein which regulates its blood flow. To investigate clonidine-induced contraction of the circular muscle of the hepatic portal vein and to clarify the possible role of the endothelium in the contraction, we examined the effects of clonidine on the isometric contraction of endothelium-intact and -removed ring preparations of the rat hepatic portal vein. In endothelium-intact preparations, clonidine caused a concentration-dependent increase in the amplitude of contractions. Inhibition of NO synthesis with Nomega-nitro-L-arginine (L-NNA) elevated the resting tone, and increased the amplitude of the clonidine-induced contractions. Inhibition of cyclooxygenase by diclofenac did not change the amplitude of the clonidine-induced contractions observed both in the presence and absence of L-NNA. Application of a single concentration of clonidine induced a clear increase in amplitude of both twitch and tonic contractions. Twitch and tonic contractions induced by clonidine were inhibited by yohimbine. When the endothelium was damaged by sodium deoxycholate, tonic contractions induced by clonidine were completely suppressed, whereas the increase in twitch contractions was not influenced by chemical damage of the endothelium. Neither SKF-96365, a nonselective cation channel blocker, nor superoxide dismutase, a free radical scavenger, in the presence of catalase, changed the tonic contraction induced by clonidine. These results indicate that stimulation of alpha2-adrenoceptors enhanced twitch contractions and induced tonic contractions in the circular muscle of the rat hepatic portal vein, especially in the absence of NO. The latter, but not the former, occurs through an endothelium-dependent pathway.

Topics: Adrenergic alpha-Agonists; Animals; Clonidine; Diclofenac; Endothelium, Vascular; Humans; Hypertension, Portal; In Vitro Techniques; Isometric Contraction; Liver Cirrhosis; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Nitroarginine; Portal Vein; Rats; Rats, Wistar

The mechanisms responsible for mesenteric vasodilatation in cirrhosis have not been fully elucidated. The aim of the present study was to examine whether there is altered intrinsic vascular reactivity of human mesenteric vessels in cirrhosis, which might contribute to vasodilatation in vivo.. Ten mesenteric arteries from six cirrhosis patients undergoing liver transplantation were compared with 11 arteries from six control patients. Vasoconstrictor responses to potassium, norepinephrine and methoxamine were determined. Endothelium-dependent vasodilatation responses to acetylcholine and substance P were determined both before and after inhibition of nitric oxide (NO) and prostanoid synthesis.. Cirrhotic vessels responded normally to potassium depolarization and did not differ to control vessels with respect to sensitivity and maximal response to norepinephrine. In cirrhotic vessels, inhibition of NO synthesis had significantly less effect on substance P-induced vasorelaxation than in controls (% Relaxation: cirrhosis 70.3 +/- 9.6; control 34.9 +/- 9.5; P = 0.03). However, after inhibition of both NO and prostanoid synthesis, vasodilatory responses were eliminated in both groups.. The findings of the present study indicate that intrinsic hyporesponsiveness to vasoconstrictors does not play a pathogenetic role in the mesenteric vasodilatation in human cirrhosis. Furthermore, vasodilator prostanoids might make a significant contribution in mediating enhanced endothelium-dependent vasorelaxation in the mesenteric circulation.

Topics: Cardiovascular Agents; Endothelium, Vascular; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Indomethacin; Liver Cirrhosis; Liver Transplantation; Male; Mesenteric Arteries; Middle Aged; Nitric Oxide; Nitroarginine; Prostaglandins; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Intrahepatic nitric oxide (NO) production is decreased in cirrhotic livers. Our objective was to identify, in cirrhotic rat livers, intrahepatic vascular segments where the deficit of NO facilitates the effect of vasoconstrictors. By using a modified rat liver perfusion system with measurement of both the perfusion and sinusoidal (wedged hepatic vein) pressures, we studied the effect of the NO synthase blocker N(omega)-nitro-l-arginine (l-NNA) on the response to methoxamine (alpha(1)-adrenoreceptor agonist) in different segments of the intrahepatic circulation of normal and cirrhotic rat livers. l-NNA enhanced the presinusoidal, sinusoidal, and postsinusoidal responses to methoxamine in normal livers as well as the presinusoidal response in cirrhotic livers. However, l-NNA did not change the already enhanced sinusoidal/postsinusoidal response to methoxamine in cirrhotic livers. The postsinusoidal response to methoxamine was higher in cirrhotic rats with ascites than in those without ascites. We concluded that NO modulates the presinusoidal, sinusoidal, and postsinusoidal vascular tone in normal livers. NO production in cirrhotic rat livers is severely impaired in the sinusoidal and postsinusoidal areas but is preserved in the presinusoidal area, as evidenced by its normal response to l-NNA. We speculate that an increased postsinusoidal response to catecholamines may participate in the genesis of ascites in cirrhosis.

Topics: Adrenergic alpha-Agonists; Animals; Enzyme Inhibitors; Liver Circulation; Liver Cirrhosis; Male; Methoxamine; Microcirculation; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Vasoconstriction

We examined the functional role of nitric oxide (NO) and nitric oxide synthase (NOS) isoforms in the pulmonary dysfunction seen in cirrhosis. Lungs were isolated from control and carbon tetrachloride (CCl(4))-induced cirrhotic rats and perfused at constant flow with a whole blood mixture. Ventilation with hypoxic gas resulted in attenuated hypoxic pulmonary vasoconstriction (HPV) in lungs from cirrhotic animals. Administration of the non-selective NOS inhibitor N-omega-Nitro-L-Arginine (L-NNA) resulted in HPV responses that were not different between groups. However, inhibition of inducible nitric oxide synthase (iNOS) did not restore cirrhotic HPV responses. Lungs from cirrhotic rats demonstrated enhanced endothelial-dependent vasodilation to vasopressin when preconstricted with hypoxia but not when preconstricted with thromboxane mimetic. Western blot analysis failed to demonstrate differences in pulmonary endothelial NOS (eNOS) or iNOS levels between groups. Our data suggest that, while NO may play a role in mediating the reduced pulmonary vasoreactivity observed in cirrhosis, other vasoactive factors are likely also important modulators of the pulmonary dysfunction seen in this disease.

Topics: Animals; Blotting, Western; Carbon Tetrachloride; Endothelium, Vascular; Enzyme Inhibitors; Liver Cirrhosis; Lung; Male; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Pulmonary Circulation; Rats; Rats, Wistar; Vasoconstriction; Vasodilation

In cirrhosis, in splanchnic arteries, endothelium-dependent relaxation may persist even if overactive nitric oxide synthase (NOS) and cyclooxygenase (COX) are inhibited. In normal arteries, a significant endothelium-dependent relaxation to acetylcholine persists after NOS/COX inhibition. This relaxation is caused by smooth muscle cell (SMC) membrane hyperpolarization, which is sensitive to a combination of the potassium channel blockers apamin and charybdotoxin, and is mediated by an endothelium-derived hyperpolarizing factor (EDHF). The aim of this study was to detect EDHF and evaluate its pathophysiologic role in isolated superior mesenteric arteries from cirrhotic rats. Arterial rings were obtained and exposed to N(w)-nitro-L-arginine (L-NNA, a NOS inhibitor) and indomethacin (a COX inhibitor). Acetylcholine-induced membrane potential responses and concentration-response curves to the relaxant of acetylcholine were obtained with and without apamin plus charybdotoxin. Acetylcholine-induced responses were measured in certain rings from endothelium-denuded arteries. Contractions caused by the alpha(1)-adrenoceptor agonist phenylephrine were obtained in cirrhotic and normal rings with and without apamin and charybdotoxin. Significant acetylcholine-induced, endothelium-dependent, apamin- and charybdotoxin-sensitive, SMC membrane hyperpolarization and relaxation were found. An apamin- and charybdotoxin-sensitive hyporesponsiveness to the contractile action of phenylephrine was found in cirrhotic rings. In conclusion, in cirrhotic rats, in the superior mesenteric artery exposed to NOS/COX-inhibitors, an EDHF exists that may replace NOS/COX products to induce endothelium-dependent arterial relaxation.

Topics: Acetylcholine; Animals; Apamin; Barium; Biological Factors; Charybdotoxin; Cyclooxygenase Inhibitors; Drug Combinations; Enzyme Inhibitors; In Vitro Techniques; Indomethacin; Liver Cirrhosis; Male; Mesenteric Arteries; Nitroarginine; Ouabain; Rats; Rats, Sprague-Dawley; Reference Values; Vasodilation; Vasodilator Agents