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Preservation of the Positive Lusitropic Effect of &bgr;-Adrenoceptors Stimulation in Diabetic Cardiomyopathy

BACKGROUND: In diabetic cardiomyopathy, diastolic dysfunction results in part from sarcoplasmic reticulum abnormalities affecting both phospholamban and sarcoplasmic reticulum Ca2+ uptake (SERCA2a). Consequently, the positive lusitropic effect of &bgr;-adrenoceptors stimulation could be altered, and &bgr;3-adrenoceptor over-expression may play a role, as previously demonstrated with an altered positive inotropic effect. In this study, we tested the hypothesis that the &bgr;-adrenergic positive lusitropic effect is altered in diabetic cardiomyopathy, and that &bgr;3-adrenoceptor over-expression is involved. METHODS: &bgr;-adrenergic responses were investigated in vivo (dobutamine-echocardiography) and in vitro (papillary muscle preparation) in healthy and diabetic rats killed 4 (4W) and 12 (12W) wk after IV streptozotocin injection. The effect of &bgr;3-adrenoceptor pathway inhibition by S-cyanopindolol (selective &bgr;3-adrenoceptor antagonist) or by NG-nitro-l-arginine-methyl-ester (nonselective nitric oxide synthase inhibitor) on the lusitropic response to isoproterenol (nonselective &bgr;-adrenoceptors agonist) was studied in vitro. Western blots were performed to quantify the protein expressions of &bgr;1- and &bgr;3-adrenoceptors, phospholamban, and SERCA2a. Data are presented as mean percentages of baseline ± sd. RESULTS: Despite the increased phospholamban/SERCA2a protein ratio and documented diastolic dysfunction, the positive lusitropic effect of &bgr;-adrenoceptors stimulation was preserved in vivo (dobutamine) and in vitro (isoproterenol) in 4W and 12W diabetic, compared with healthy, rats. The &bgr;3-adrenoceptor was up-regulated whereas &bgr;1-adrenoceptor was down-regulated in 4W and 12W diabetic, compared with healthy, rats. Nevertheless, S-cyanopindolol or NG-nitro-l-arginine-methyl-ester had no lusitropic effect. CONCLUSIONS: The positive lusitropic effect of &bgr;-adrenoceptor stimulation was preserved in diabetic cardiomyopathy. &bgr;3-adrenoceptor over-expression does not seem to affect this process.