Defective intracellular calcium handling in monocrotaline-induced right ventricular hypertrophy: protective effect of long-term endothelin-A receptor blockade with 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080).
We studied the effect of long-term treatment with the oral endothelin (ET) ET(A) antagonist 2-benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)-4-oxobut-2-enoate-sodium (PD 155080; PD) on right ventricular intracellular calcium (Ca(2+)(i)) handling and cardiac and pulmonary artery function in control rats and rats with monocrotaline (MCT)-induced right-heart hypertrophy. Rats were given an intraperitoneal injection of either saline (controls; n = 9) or MCT (50 mg/kg; n = 12), resulting in pulmonary hypertension-induced myocardial hypertrophy, or MCT followed by the daily administration of PD (50 mg/kg) for 9 weeks (n = 9). After 9 weeks, right ventricular pressure was measured, and the hearts were removed and perfused in vitro. Right ventricular function and Ca(2+)(i) transients were recorded simultaneously on a beat-to-beat basis using aequorin. Surviving animals in the MCT group (58%) developed significant hypertrophy and had 2-fold higher right ventricular pressure and a prolonged duration of isovolumic contraction that correlated with a similar prolongation of the Ca(2+)(i) transient, indicating a reduced rate of Ca(2+) sequestration in hypertrophy (P < 0.05 versus control). In the PD group, all animals survived, and right ventricular pressure, diastolic relaxation, Ca(2+) transport kinetics, and peak systolic and end-diastolic wall stress were all normalized (P > 0.05 versus control); and pulmonary artery endothelial function was partly restored (P < 0.05 versus MCT and control groups). These results demonstrate for the first time that long-term ET(A) receptor antagonism normalizes myocardial cytosolic Ca(2+) modulation, which may contribute to the antihypertrophic and cardioprotective effect of ET(A) receptor therapy in this model.
Brunner
Friedrich
F
Institut für Pharmakologie und Toxikologie, Universität Graz, Graz, Austria. friedrich.brunner@kfunigraz.ac.at
Wölkart
Gerald
G
Haleen
Stephen
S
D000331:Aequorin / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D004149:Dioxoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D016686:Monocrotaline / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000502:physiology; D010477:Perfusion; D011042:Poisons / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D016278:Ventricular Function, Right / Q000502:physiology
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C093322:PD 155080; D011042:Poisons; D044022:Receptor, Endothelin A; D000331:Aequorin; D016686:Monocrotaline; D002118:Calcium