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 contribute to cardiac remodeling after myocardial infarction (MI). Each of these mechanisms involves different signaling pathways for the cellular hypertrophic response. All three also activate the Na(+)/H(+) exchanger. In the present study we evaluated the hypothesis that activation of the Na(+)/H(+) exchanger is involved in parallel with other signaling mechanisms for ANG II. Three days before coronary artery ligation, rats were randomly allocated to no treatment or treatment with amiloride, losartan, or amiloride and losartan in combination. Four weeks after coronary artery ligation, left ventricular (LV) function was assessed from in vivo resting cardiac pressures, hemodynamic responses to cardiac volume and pressure load, and cardiac remodeling by in vitro pressure-volume curves and LV and right ventricle (RV) weight. Amiloride and losartan given alone to a similar extent attenuated the shift of the pressure-volume curve to the right. This effect was significantly more pronounced with amiloride and losartan in combination. Each drug alone to a minor extent improved LV responses to pressure and volume load. However, with amiloride and losartan in combination, close-to-normal responses to pressure 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 after MI. This finding suggests that, besides ANG II, other mechanisms activating the Na(+)/H(+) exchanger contribute to cardiac remodeling after MI.
Ruzicka
M
M
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
Yuan
B
B
Leenen
F H
FH
D000584:Amiloride / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure; D001810:Blood Volume; D004338:Drug Combinations; D006439:Hemodynamics; D006940:Hyperemia / Q000503:physiopathology; D006973:Hypertension / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D018487:Ventricular Dysfunction, Left / Q000209:etiology*
D057911:Angiotensin Receptor Antagonists; D004338:Drug Combinations; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017923:Sodium-Hydrogen Exchangers; D000584:Amiloride; D019808:Losartan