Cardiovascular effects of canrenone in patients with preascitic cirrhosis

Abstract

In patients with cirrhosis and portal hypertension, standing induces a reduction in cardiac index (CI) and an increase in systemic vascular resistance index. Our previous studies indicate that this abnormal hemodynamic response to standing is due to an altered myocardial function, because cirrhotic patients are unable to compensate for the reduced preload with an increase in left ventricular (LV) ejection fraction (EF) and stroke volume. To evaluate whether the cardiac dysfunction in cirrhosis is influenced by canrenone, an aldosterone antagonist, 8 patients with preascitic, nonalcoholic cirrhosis, and portal hypertension underwent echocardiographic assessment of LV function and systemic hemodynamics and determinations of plasma volume, urinary sodium excretion, and plasma renin activity T he hemodynamic pattern of cirrhosis with portal hypertension, with high blood volume and cardiac output and low systemic vascular resistance (SVR), is thought to play a major role in the development of sodium retention and ascites. 1 Bernardi et al. [2][3][4] showed that this hemodynamic pattern occurs only in the supine position; standing is associated with a reduction in cardiac output and an increase in SVR, that is, a "normalization" of systemic hemodynamics. This response to standing is quite different from that of healthy subjects, who do not show any appreciable changes in either cardiac output or SVR. 2-4 However, "normalization" of systemic hemodynamics during standing is associated with activation of vasoconstricting and sodium retaining systems. 3,4 In patients with preascitic cirrhosis, sodium retention occurs only during standing, 3 whereas, in those with ascites, it occurs in either position but worsens during standing. 4 We recently evaluated cardiovascular function in healthy subjects and cirrhotic patients with ascites and hyperdynamic circulation. 5 When supine, patients had increased left ventricular ejection fraction (LVEF) and cardiac index (CI) and reduced LV end-systolic volume index (LVESVI) and SVR. On standing, LV end-diastolic volume index (LVEDVI) decreased in all subjects. Healthy subjects maintained CI and stroke volume index (SVI) by decreasing LVESVI. In contrast, cirrhotic patients experienced a fall in SVI and CI and a disproportionate increase in arterial elastance (Ea), despite marked

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

“…However, although there is no clear evidence on the role of [pH] i in the regulation of ECM protein synthesis, it is well established that any derangement in the organization of the actin-containing cytoskeleton has implications for the regulation of ECM synthesis. 59,60 Finally, the observation that canrenone may reduce the contractility of activated HSC in response to a strong vasoconstrictor such as thrombin supports the hypothesis, derived from several clinical and experimental studies, [2][3][4][5] that antialdosteronic drugs may directly exert beneficial effects on portal pressure.…”

“…Because the effects of antialdosteronic drugs on portal pressure have been shown in several clinical and experimental studies, [2][3][4][5] we then explored whether canrenone is able to reduce thrombin-induced intracellular calcium increase and cell contraction in activated human HSC. As previously reported, 26 stimulation of human HSC with thrombin resulted in increased [Ca 2ϩ ] i coupled with a transient reduction of cell area, indicating reversible cell contraction.…”

“…[1][2][3] This beneficial effect has been ascribed to a reduction of the expanded blood volume typical of preascitic cirrhosis and early ascitic cirrhosis. 4,5 However, several lines of evidence suggest that the reduction of portal pressure could also be due to direct effects of spironolactone on factors affecting intrahepatic portal circulation. First, spironolactone and its metabolites potassium canrenoate and canrenone have been shown to induce relaxation of isolated rat aorta rings precontracted by different agonists, 6,7 an effect apparently independent of a possible interference with nongenomic effects of aldosterone or activation of potassium channels.…”

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

“…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. Available literature data are based on animal models [32][33][34] and on autoptic findings [35] overall handling conflicting results.…”

Pathophysiological basis of pharmacotherapy in the hepatorenal syndrome

“…Most studies have focused on defects in the SNS, but several papers have emphasized the importance of vagal impairment for sodium and fluid retention [68,70]. Blood pressure responses to orthostasis are impaired, probably because of a blunted baroreflex function [71,72] and the cardiovascular responses to pharmacological stimulations with angiotensin II, noradrenaline and vasopressin are abnormal [73,74]. Captopril may, to some extent, correct vagal dysfunction in cirrhosis [68] and neuromodulation by the RAAS is also supported by data from Laffi et al, who recently reported that canrenone, an aldosterone antagonist, normalized cardiac responses to postural changes in compensated cirrhotic patients [72].…”