Inhibition by calcium antagonism of circulating and renal endothelin in experimental congestive heart failure

Endothelin (ET) is a potent vasoconstrictor and sodium-regulating peptide w hose tissue and:plasma concentrations are increased in congestive heart fai lure (CHF). ET may mediate its vasoconstrictor and sodium-regulatory action s secondary to an increase in intracellular calcium. Calcium influx may aug ment ET synthesis. Although felodieine, a dihydropyridine calcium-channel a ntagonist, is effective in reducing vascular resistance in generalized vaso constriction, its actions in CHF on circulating and local tissue ET remain undefined. The current studies were designed to determine the modulating ac tions of felodipine (oral, 40 mg/day for 7 days; n = 6) in an experimental canine model of CHF produced by chronic thoracic inferior vena caval constr iction (TIVCC) compared with normal(n = 7) and TIVCC-alone (n = 7) dogs. We hypothesized that felodipine would decrease circulating and renal ET. Plas ma ET was significantly increased in TIVCC compared with normal dogs (26 +/ - 0.5 vs. 12 +/- 0.7 pg/ml, P < 0.05) and was markedly decreased by felodip ine compared with TIVCC alone (14 +/- 3 vs. 26 +/- 0.5 pg/ml, P < 0.05). Re nal ET immunohistochemical staining demonstrated the presence of ET in norm al kidney, which was:markedly increased in renal cortex and medulla in TIVC C dogs; Renal cortical and medullary ET staining densities were markedly de creased with felodipine compared with those with TIVCC alone. In the TIVCC + felodipine group,cardiovascular hemodynamics also was markedly improved c ompared with the TIVCC-alone group [systemic vascular resistance: 27 +/- 2 vs. 44 +/-: 3 resistance units (RU), P < 0.05; pulmonary vascular resistanc e: 3.3 +/- 0.1 vs. 5.7 +/- 0.4 RU, P < 0.05; cardiac output: 2.9 +/- 0.2 vs . 1.7 +/- 0.1 l/min, P < 0.05].: This study demonstrates important modulati ng inhibitory actions of felodipine on renal and plasma ET in an experiment al model of CHF.