Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats

Abstract

Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade.