Background/Aims: Autonomic neuropathy, as indicated by alterations in standard cardiovascular tests, is frequently encountered in cirrhosis. We investigated the autonomic modulation of the heart in nonalcoholic cirrhosis with ascites by evaluating the 24-hour heart rate variability (HRV), a powerful noninvasive tool to assess the sympathovagal balance of the heart. Methods: Low (LF) and high frequency (HF) components and their ratio, and time domain indexes of HRV were evaluated in 24-hour, daytime and nighttime periods in 12 patients and 12 healthy subjects, together with the conventional and dynamic QT interval. Results: Cirrhotic patients had values of the mean RR interval and frequency domain indexes in the whole 24-hour period similar to those of healthy subjects, despite higher than normal plasma norepinephrine levels. Patients also showed lower LF and higher HF values than controls during the day, a reduction in time domain indexes, and no circadian rhythm of frequency domain indexes. QT parameters were similar in the 2 groups, but patients had a blunted QT rhythm and a reduced QT variability. Conclusions: Patients with nonalcoholic cirrhosis and ascites have an impaired autonomic regulation of the heart, which involves both the sympathetic and the parasympathetic branches of the autonomic nervous system.

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 ...

Abstract-In experimental animals, C-type natriuretic peptide (CNP) has vasodilating, hypotensive, and natriuretic activities.The role of circulating CNP in the overall regulation of cardiac and renal function in humans is less defined, in both health and disease. We measured cardiac volumes, diastolic and systolic functions, systemic (Doppler echocardiography) and renal hemodynamics, intrarenal sodium handling (lithium clearance method), plasma and urinary cGMP, plasma renin concentration, and plasma aldosterone level in six healthy volunteers (mean age, 33Ϯ3 years) receiving CNP (2 and 4 pmol/kg per minute for 1 hour each) in a single-blind, placebo-controlled, random-order, crossover study. During CNP infusion, plasma CNP increased from 1.17Ϯ0.23 to 41.52Ϯ4.61 pmol/L (ie, 4-to 10-fold higher levels than those observed in disease states) without affecting plasma and urinary cGMP, cardiac volumes, dynamics of left and right heart filling, cardiac output, arterial pressure, renal hemodynamics, intrarenal sodium handling, sodium excretion, or plasma levels of renin and aldosterone. The finding that increments in plasma CNP within the pathophysiological range have no effects on systemic hemodynamics, renal function, or the renin-angiotensin system do not support the hypothesis that CNP may act as a circulating hormone in humans. (Hypertension. 1998;31:802-808.)Key Words: echocardiography Ⅲ hemodynamics Ⅲ systole Ⅲ diastole Ⅲ natriuretic peptides T he natriuretic peptide system consists of at least three structurally homologous peptides: ANP, BNP, and CNP. ANP and BNP are cardiac hormones that contribute to the overall regulation of cardiovascular homeostasis and fluid volume due to their natriuretic, vasodilating, and renin-aldosterone-inhibiting actions.1,2 CNP, first isolated in porcine brain, 3 is a 22-amino acid peptide that shares a high homology with ANP and BNP within the ring structure but lacks the carboxyl-terminal extension. 3Outside the central nervous system, CNP is mainly produced by the vascular endothelium, [4][5][6] in which it is thought to act as a local paracrine factor for the control of vascular tone. Endothelial production of CNP is remarkably augmented by various cytokines and growth factors such as transforming growth factor-␤ and tumor necrosis factor-␣, suggesting that CNP may be of pathophysiological relevance in various vascular disorders.7 Like the other natriuretic peptides, CNP is detectable in plasma of healthy subjects, although at much lower concentrations than ANP and BNP. 4,8 -13 Plasma CNP levels are increased in patients with chronic renal failure, 9,10 septic shock, 11 and cor pulmonale, 12 raising the possibility that CNP may be a circulating hormone involved in the regulation of cardiovascular function. CNP exerts its biological effects by selectively activating the NPR-B, 14,15 leading to an increase in cGMP in target cells. In experimental animals, the administration of CNP induces vasodilation of both arteries and veins 16 ; reduces cardiac filling pressures, 17 CO,18,1...

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These data indicate that the elevated cardiac output is adequately maintained in pregnancy during the postural challenge, due to optimisation of the responses of preload and afterload.