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Effect of Endothelin Antagonism on Contractility, Intracellular Calcium Regulation and Calcium Regulatory Protein Expression in Right Ventricular Hypertrophy of the Rat
Author(s) -
Stessel Heike,
Brunner Friedrich
Publication year - 2004
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2004.pto_940107.x
Subject(s) - contractility , antagonism , calcium in biology , calcium , endothelin receptor , right ventricular hypertrophy , medicine , muscle hypertrophy , endocrinology , endothelin 1 , intracellular , chemistry , biology , pharmacology , microbiology and biotechnology , pulmonary hypertension , receptor
We have documented the effects of long‐term endothelin receptor antagonism on intracellular Ca 2+ regulation and Ca 2+ regulatory protein expression in rat hearts with right ventricular hypertrophy without signs of heart failure. Rats were given either a single injection of monocrotaline (50 mg/kg, n=9) resulting in pulmonary hypertension‐induced myocardial hypertrophy, or monocrotaline followed by daily administration of the endothelin subtype‐A receptor antagonist 2‐benzo(1,3)dioxol‐5‐yl‐3‐benzyl‐4‐(4‐methoxy‐phenyl‐)‐4‐oxobut‐2‐enoate‐Na (PD 155080, 50 mg/kg) over 9 weeks (n=8). Hearts from saline‐injected rats served as controls (n=9). Monocrotaline‐treated animals developed marked right‐sided hypertrophy without fibrosis as evident from hydroxyproline measurements, systolic contractility was increased, fully compensating for the increased afterload, but diastolic function was impaired as evident from protracted relaxation and slowed diastolic intracellular Ca 2+ handling (measured by aequorin bioluminescence). In hypertrophic hearts, quantitative immunoblotting analyses showed increased levels both of sarco(endo)plasmic reticulum Ca 2+ ‐ATPase (SERCA) and phosphorylated phospholamban, along with decreased levels of total phospholamban, which is in line with strengthened right ventricular systolic function. PD 155080 reversed abnormalities in Ca 2+ handling, although SERCA and phospholamban protein levels were not altered (P=not significant versus monocrotaline group). Thus, endothelin‐A receptor antagonism attenuates right ventricular remodeling and improves myocardial Ca 2+ handling, but has no discernable effect on elevated expression of SERCA and phospholamban observed in hypertrophic hearts. These data indicate that the hypotensive action of PD 155080 is independent of its effects, if any, on SERCA and its regulation.