Renin-angiotensin system and cell communication in the failing heart.
The influence of heart failure on the process of cell communication was investigated in cell pairs isolated from the ventricle of cardiomyopathic hamsters (11 months old) and the results compared with age-matched normal hamsters. The gap junctional conductance (gj) was measured with two voltage-clamp amplifiers. The results showed two major populations of cell pairs with respect to gj values: one with very low values (0.8 to 2.5 nS) and the other with higher values (7 to 35 nS). In normal hamsters, the most frequent gj values were in the range of 40 to 100 nS. Angiotensin II (Ang 11, 1 microg/mL) caused cell uncoupling in myopathic myocytes with low gj but reduced gj by 53 +/- 6.6 percent (+/- SE) in cell pairs with higher gj values (7 to 35 nS). The effect of Ang II on gj of myopathic cell pairs was suppressed by losartan (10(-7) mol/L). In cardiomyopathic cell pairs with low gj (0.8 to 2.5 nS), enalapril (1 microg/mL) caused an appreciable increase in gj (219 +/- 20.3 percent), whereas in cell pairs with higher gj (7 to 35 nS), the gj increment was smaller (80 +/- 10.8 percent) but still larger than that seen in controls (33 +/- 5.4 percent). Intracellular dialysis of Ang I (10(-8) mol/L) abolished cell communication in myopathic cell pairs with low gj (0.8 to 2.5 nS) and reduced gj by 66 +/- 1.7 percent in the other pairs (7 to 35 nS). The effect of Ang I on gj was greatly reduced by enalaprilat (10(-9) mol/L) added to the cytosol. Dialysis of Ang II (10(-8) mol/L) into the myopathic cell reduced gj by 48 +/- 4.2 percent, an effect abolished by losartan (10(-8) mol/L). The results indicate that the decline in gj seen in the ventricle of cardiomyopathic hamsters is in part due to activation of the cardiac renin-angiotensin system.
De Mello
W C
WC
Department of Pharmacology, School of Medicine, University of Puerto Rico, San Juan 00936-5067, USA.
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D006224:Cricetinae; D004656:Enalapril / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D006329:Heart Conduction System / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008647:Mesocricetus; D018408:Patch-Clamp Techniques; D012084:Renin-Angiotensin System / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D004656:Enalapril; D019808:Losartan