Effects of Varying Doses of Spironolactone Without and With Nitrates on Portal Vein Pressure and Kidney Function in Partial Portal Vein Ligated Rats

Abstract

volume in portal hypertension and hence by reducing the The optimal dose of spironolactone to reduce portal splanchnic flow. 5,6 However, a correlation between the decline vein pressure, alone or in combination with isosorbidein plasma volume and portal pressure could not be shown. 5-7 5-mononitrate (IsMn), has not been identified. We studAcute and chronic administration of nitrovasodilators lowers ied the effects of 8 days oral treatment with spironolac-HVPG 8,9 but a concomitant reduction of the glomerular filtratone, IsMn or both on portal pressure, plasma volume tion rate and activation of the renine-aldosterone system with and renal sodium handling in rats with partial portal reduced water and sodium excretion have been observed. 10,11 vein ligation. At daily doses of 0.33; 0.50; 1, and 1.50 mg/ This might explain the worsening or development of ascites kg, spironolactone reduced portal pressure (all P õ .05) observed in some patients. 12 The combination of nitrates with as compared with placebo. Only the highest dose signifispironolactone might offer the advantage that spironolactone cantly lowered plasma volume (10.1 { 0.7 vs. 13.0 { 0.3 could counteract the activation of the renine-aldosterone sysmL; P õ .03) and enhanced urinary fractional sodium tem and the development of ascites. Furthermore, if spironoexcretion (0.73 { 0.04 vs. 0.58 { 0.03%; P õ .03) and the lactone lowers portal pressure by a reduction in plasma vol-(Na / )/(K / ) ratio in urine (0.43 { 0.04 vs. 0.30 { 0.03; P õ ume, it might enhance the portal pressure lowering effect of .02). IsMn at doses of 0.25; 0.50, and 1 mg/kg decreased nitrates. Therefore, the aim of the present study, using a portal pressure (all P õ .05) without a change in plasma portal hypertensive rat model, was to investigate the effects volume but with a tendency (not significant) to lower of different doses of spironolactone, isosorbide-5-mononitrate fractional sodium excretion. IsMn impaired free water (IsMn), and their combination, on portal pressure, plasma clearance at doses of 0.5 and 1 mg/kg (P õ .05). Combinavolume, water, and sodium household. Male Wistar rats, with a body weight beeffect of spironolactone is opposed. Low doses of spiro-tween 209 and 240 g (mean 226 g) underwent partial portal vein nolactone are as effective as a higher dose to reduce ligation, as described previously. 13 Three weeks postoperatively, aniportal pressure. This reduced portal pressure was inde-mals were randomly assigned to one of the following treatments given by daily gavage: placebo, i.e., 2 mL saline (n Å 8); spironolacpendent of changes in plasma volume and diuretic effect, tone, 0.33 mg/kg body weight (n Å 6), 0.50 mg/kg (n Å 6), 1 mg/kg which suggests that spironolactone might have a direct (n Å 6), and 1.50 mg/kg (n Å 6); IsMn, 0.25 mg/kg (n Å 6), 0.50 mg/ vasoactive effect on the splanchnic circulation. To counkg (n Å 8), and 1 mg/kg (n Å 11); spironolactone, 1 mg/kg in combinateract sodium retention of nitrovasodilators, combination with IsMn, 0.5 mg/kg (n Å 8) and 1...

Cardiovascular effects of canrenone in patients with preascitic cirrhosis

“…Indeed, neither Garcìa-Pagàn et al 7 nor Sugano et al 8 found any correlation between drug-induced reductions in the hepatic venous pressure gradient and changes in plasma volume. In addition, spironolactone inhibits contraction of rat portal vein strips in vitro 24 and reduced portal pressure in experimental cirrhosis at doses that had no effects on plasma volume, renal sodium handling, 9 or systemic hemodynamics. 10 Finally, acute infusion of potassium canrenoate, an aldosterone antagonist suitable for intravenous administration, reduced portal cross-sectional area, portal blood velocity, and portal blood flow in patients with preascitic cirrhosis.…”

“…9,10 The current investigation was aimed at establishing whether canrenone, another aldosterone antagonist, affects the cardiac dysfunction of cirrhosis.…”

Oesophageal varices: Assessment of the risk of bleeding and mortality

“… 81,82 Spironolactone was also shown to decrease portal and variceal pressure, even when added to propranolol. 83 Investigations in animal models seem to indicate that the effect of spironolactone on portal hypertension is independent of its diuretic effect, and is present even at low doses. 84 Further studies are needed to establish the minimal human dosage, and to investigate its mechanisms of action.…”

“…Combination therapy can be advocated because nadolol plus isosorbide‐5‐mononitrate was more effective than nadolol alone, 85 and spironolactone plus propranolol was more effective than propranolol alone. 83 …”

“…All three methods have documented that 25 to 35% of cirrhotic patients are either non‐responders to β‐blockers, 37,47,55,77 or to spironolactone. 83 A follow‐up study has shown that a medication‐induced decrease in HVPG to below 12 mmHg, or at least 20% of the initial value, is needed to be protective. 86 In a prospective follow‐up study of 51 cirrhotic patients with large varices treated with propranolol or the combination propranolol and isosorbide dinitrate, we observed that a VP during treatment of above 14 mmHg was associated with a bleeding incidence of 39%; if the VP was below 14 mmHg only 9% of the patients bled.…”