Blockade of AT(1) receptors and Na+/H+ exchanger and LV dysfunction after myocardial infarction in rats

Mechanical stretch, ANG II, and alpha(1)-receptor stimulation may contribut e to cardiac remodeling after myocardial infarction (MI). Each of these mec hanisms involves different signaling pathways for the cellular hypertrophic response. All three also activate the Na+/H+ exchanger. In the present stu dy we evaluated the hypothesis that activation of the Na+/H+ exchanger is i nvolved in parallel with other signaling mechanisms for ANG II. Three days before coronary artery ligation, rats were randomly allocated to no treatme nt or treatment with amiloride, losartan, or amiloride and losartan in comb ination. Four weeks after coronary artery Ligation, left ventricular (LV) f unction was assessed from in vivo resting cardiac pressures, hemodynamic re sponses to cardiac volume and pressure load, and cardiac remodeling by in v itro pressure-volume curves and LV and right ventricle (RV) weight. Amilori de and losartan given alone to a similar extent attenuated the shift; of th e pressure-volume curve to the right;. This effect was significantly more p ronounced with amiloride and losartan in combination. Each drug alone to a minor extent; improved LV responses to pressure and volume load. However, w ith amiloride and losartan in combination, close-to-normal responses to pre ssure and volume load were observed. Losartan and amiloride alone had only a small effect on development of RV hypertrophy after MI but in combination completely prevented the RV hypertrophy. Amiloride and losartan appear to be complementary in prevention of cardiac remodeling and LV dysfunction aft er MI. This finding suggests that, besides ANG II, other mechanisms activat ing the Na+/H+ exchanger contribute to cardiac remodeling after MI.