Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats With Volume-Overload Congestive Heart Failure

Abstract

Background-The side effects of fluid retention and edema of the thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor-␥ agonists limit their use in patients with congestive heart failure (CHF). The present study aims to explore whether chronic treatment with the TZD compound rosiglitazone (RGZ) is associated with worsening of salt and water retention in male Sprague-Dawley rats with aorto-caval fistula, an experimental model of volume-overload CHF. Methods and Results-The effects of oral RGZ (30 mg/kg per day for 4 weeks) in CHF rats on plasma volume, cumulative sodium excretion, renal expression of Na ϩ channels and transporters, and selected biomarkers of CHF were compared with those in CHF rats and sham-operated control rats treated with vehicle only (nϭ7 to 10). Additionally, the response to acute saline loading (3.5% of body weight) was evaluated after 2 weeks of treatment by renal clearance methodology. Chronic RGZ treatment caused no further increase in plasma volume compared with vehicle-treated CHF rats. Moreover, no increase in renal expression of Na ϩ transport-linked channels/transporters was observed in response to RGZ. Cumulative sodium excretion was enhanced in CHF rats after RGZ and by another TZD compound, pioglitazone. In response to saline loading, RGZ-treated animals displayed a higher natriuretic/diuretic response than did vehicle-treated rats. Chronic RGZ treatment was not associated with any deterioration in selected biomarkers of CHF, whereas indices of cardiac hypertrophy and blood pressure were improved. Conclusions-Chronic RGZ treatment was not associated with worsening of fluid retention or cardiac status in rats with experimental volume-overload CHF. Rather, RGZ appeared to improve renal handling of salt and water in rats with CHF. (Circ Heart Fail. 2011;4:345-354.)Key Words: thiazolidinedione Ⅲ aorto-caval fistula Ⅲ renal sodium excretion Ⅲ ECF volume expansion Ⅲ rat R osiglitazone (RGZ) is a member of the thiazolidinedione (TZD) class of compounds that act as agonists of peroxisome proliferator-activated receptor-gamma (PPAR-␥). 1 Activation of PPAR-␥ exerts important metabolic effects by regulating the expression of genes involved in glucose and lipid metabolism. 2 Oral RGZ is highly effective in improving insulin sensitivity and the metabolic abnormalities of type 2 diabetes mellitus (T2DM). 1 However, the clinical benefits of TZDs are hampered by the concomitant adverse effects of fluid retention and peripheral edema. These were reported in 4% to 7% of TZD-treated patients and in up to 15% in those who receive concurrent insulin therapy. [3][4][5] Moreover, the overall cardiovascular safety of these drugs has been questioned on the basis of observations of increased incidence of heart failure and cardiac ischemic events in RGZ-treated patients. 6 -8 In particular, the increase in cardiac events led recently to more restrictive measures on RGZ use in patients with T2DM. 9,10 Indeed, the original guidelines of the American Heart Association (AHA) prohibit th...

Rosiglitazone treatment restores renal responsiveness to atrial natriuretic peptide in rats with congestive heart failure

“…The present study extends our previous reports 21 In rats with ACF, RGZ did not exacerbate Na+ and water retention or cardiac dysfunction. Rather, it improved renal salt handling and ANP sensitivity, possibly through the enhancement of tubular post-cGMP signalling.…”

“…The present study extends our previous reports and provides novel information on the effects of prolonged RGZ treatment on renal haemodynamics and excretory functions in rats with ‘compensated’ CHF. Previously, we have demonstrated that chronic RGZ treatment caused no further increase in plasma volume compared with vehicle‐treated CHF rats, no increase in renal expression of Na + transport‐linked channels/transporters, no association with any deterioration in selected biomarkers of CHF and did not result in worsening of the cardiac and renal status.…”

“…20 However, a recent study from our laboratory concluded that chronic exposure to RGZ in a rat model of volume overload had actually improved renal and cardiac response to volume overload. 21 The aim of the present study was to explore potential mechanism(s) that may underlie RGZ adverse effects in CHF.…”

Thiazolidinedione-Induced Fluid Retention: Recent Insights into the Molecular Mechanisms

“…Goltsman et al [43] recently examined the effect of rosiglitazone administered at a dose of 30 mg/kg/day for 4 weeks in rats with congestive heart failure (CHF) induced by aortocaval fistula. Surprisingly, rosiglitazone improved sodium excretion which was impaired in CHF rats.…”

Rosiglitazone improves the natriuretic response to atrial natriuretic peptide in rats with experimental congestive heart failure: possible involvement of a post-guanylate cyclase mechanism

“…Recently, we reported that chronic treatment with the PPARγ-agonist rosiglitazone (RGZ) improved the natriuretic and diuretic responses to extracellular fluid volume expansion in rats with aorto-caval fistula, an experimental model of volume-overload CHF [1]. In the present study we explored whether RGZ improves also the natriuretic/diuretic response to ANP in rats with experimental CHF.…”