Abstract 12686: Cariporide, a Selective Na+-H+ Exchange Inhibitor, Improves Cardiac Basal and β-Adrenergic Stimulated Functional Performance in Experimental Hypothyroidism

Abstract

Background: Upregulation of Na + -H + exchanger 1 (NHE1) occurs during pathological insult and contributes to the deleterious consequence on the myocardium. Cariporide (CAR), a NHE1 selective inhibitor, exerts protective actions in various forms of heart disease, including heart failure (HF). Hypothyroidism (Hypo) causes cardiac injury. Recent studies link Hypo to the pathology of cardiomyopathy and HF. However the direct cardiac effects of CAR in Hypo are unknown. We tested the hypothesis that Hypo produces direct depressions in LV and myocyte basal function and β-adrenergic reserve. CAR would improve cardiac [Ca 2+ ] i regulation and enhance myocyte basal and β-adrenergic stimulated contraction and relaxation. Methods: We simultaneously evaluated LV functional performance and compared myocyte contractile and [Ca 2+ ] i transient ([Ca 2+ ] iT ) responses to isoproterenol (ISO) in 12 control (C) and 14 rats with Hypo induced by methimazole (30 mg/kg/day for 8 weeks in the drinking water) in the absence and presence of CAR. Results: Versus controls, Hypo caused LV dysfunction with significantly increased the time constant of LV relaxation (t) and decreased LV contractility (E ES ) accompanied by concomitant significant depressed myocyte contraction (dL/dt max ) (Hypo: 65.6 vs C: 135.9 μm/s), relaxation (dR/dt max ) (52.8 vs 107.4 μm/s), and [Ca 2+ ] iT (0.16 vs 0.25). Versus normal myocytes, in Hypo myocytes, ISO (10 -8 M) caused significantly less increases in dL/dt max (36% vs 65%), dR/dt max (26% vs 52%), and [Ca 2+ ] iT (16% vs 31%). In Hypo, versus Hypo baselines, after CAR (0.5 mg/kg, ip), t (18.0 ms vs 22.8 ms) significantly decreased and the peak rate of mitral flow (4732 vs 3263 μl/s) and E ES (0.86 vs 0.60 mmHg/μl) were significantly augmented. Consistently, in Hypo myocytes, superfusion of CAR (10 -5 M) produced significant increases in dL/dt max (38%, 90.5 vs 65.6 μm/s), dR/dt max (27%, 67.1 vs 53.8 μm/s) and [Ca 2+ ] iT (23%, 0.20 vs 0.16). Importantly, compared with Hypo baselines, with CAR superfusion, ISO also caused significantly greater increases in dL/dt max (57%), dR/dt max (46%), and [Ca 2+ ] iT (29%). Conclusions: In hypothyroidism, clinically relevant dose of cariporide improves LV myocyte contraction, relaxation, [Ca 2+ ] iT and β-adrenergic responsiveness.