Vol. 300, Issue 2, 442-449, February 2002

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)

Friedrich Brunner, Gerald Wölkart and Stephen Haleen

Institut für Pharmakologie und Toxikologie, Universität Graz, Graz, Austria (F.B., G.W.); and Pfizer Global R&D, Ann Arbor Laboratories, Ann Arbor, Michigan (S.H.)

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 (Ca²⁺_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 Ca²⁺_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 Ca²⁺_i transient, indicating a reduced rate of Ca²⁺ sequestration in hypertrophy (P < 0.05 versus control). In the PD group, all animals survived, and right ventricular pressure, diastolic relaxation, Ca²⁺ 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 Ca²⁺ modulation, which may contribute to the antihypertrophic and cardioprotective effect of ET_A receptor therapy in this model.