Hemodynamic, Renal, and Endocrine Effects of Acute Inhibition of Nitric Oxide Synthase in Compensated Cirrhosis

Abstract

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 ؎ 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N Gmonomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg ⅐ min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (؊13%) and increased systemic vascular resistance (؉26%), arterial pressure (؉9%), renal blood flow (؉12%), glomerular filtration rate (؉12%), and sodium excretion (؉25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves re- Patients with cirrhosis and portal hypertension eventually develop a hyperdynamic circulation, with high cardiac output, reduced systemic vascular resistance, and a trend towards arterial hypotension. 1 This abnormality, that contributes to worsen portal hypertension and plays a major role in the pathogenesis of other complications, including ascites and renal failure, has been related to peripheral arterial vasodilation, mainly occurring in the splanchnic circulation. 2 The cause(s) and mechanism(s) of arterial vasodilation are still unknown, but available evidence suggests that an increased synthesis of nitric oxide (NO) participates in the pathogenesis of the altered systemic hemodynamics in cirrhosis. 3,4 Animals with experimental cirrhosis have increased expression of nitric oxide synthase (NOS) and increased synthesis of NO in the vasculature. 5-9 They also have impaired response to vasoconstrictors in isolated aortic rings or splanchnic vasculature preparations, which is reversed by NOS inhibitors, 10,11 and increased pressor response to systemic administration of NOS inhibitors. 12,13 In addition, normalization of NO production by low-dose N G -nitro-L-arginine methyl ester, a NOS inhibitor, corrected the altered systemic hemodynamics, normalized the activity of the main vasoconstricting and sodiumretaining systems, 14 and improved renal sodium and water excretion in cirrhotic rats with ascites. 15 Evidence of an increased synthesis of NO has also ...

Pulmonary Vascular Complications of Liver Disease

“…Increased nitric oxide (NO) production with resultant vasodilation has been suggested to explain the hyperdynamic systemic circulation observed in patients with cirrhosis (21)(22)(23). In HPS, investigators have documented increased NO production in the lungs (24,25), possibility mediated by endothelin receptor B signaling (26,27).…”

Modulation of Prostaglandin Biosynthesis by Nitric Oxide and Nitric Oxide Donors

“…Therefore, genetic or pharmacological inhibition of iNOS was associated with a dramatic reduction of liver, intestine, and lung injury measured by plasma transaminase levels (Needleman and Manning, 1999). Moreover, recent results indicate that in patients with compensated cirrhosis, portal hypertension, and hyperdynamic circulation, a condition where iNOS is up-regulated (Laffi et al, 1995), acute inhibition of NO synthase corrects the altered systemic hemodynamic and improves renal function and sodium excretion (La Villa et al, 2001). Subsequent studies have revealed a similar protective effect of iNOS inhibition on bowel damage and maintenance of small bowel motility as well as preventing the gut permeability following zymosan shock (Nogawa et al, 1998).…”

Heart Function and Myocardial Tissue Characterization in Patients with HCV Related Cirrhosis: Diastolic Dysfunction and Cardiac Hypertrophy

“…Diastolic dysfunction, characterized by an altered pattern of transmitral flow due to impaired diastolic relaxation of left ventricle, can be easily assessed by echocardiography and accordingly can be considered as a marker of this condition. As far as diastolic dysfunction is concerned, many etiological factors have been reliably advocated as potential pathogenic agents: notably substances as NO [18][19][20][21], TNF [22], reactive nitrogen species [23], neurohormones [24][25][26][27][28] may well affect heart structure and function along with circulatory overload [24,29] and overactivity of the SNS [30]. Thickening of heart parietal walls has been reported [12,14,17,31], nevertheless the nature of the structural changes underlying diastolic dysfunction has not been clarified so far.…”