Defective response to cAMP-dependent protein kinase in non-insulin-dependent diabetic heart

Abstract

Hearts isolated from 1-yr-old non-insulin-dependent diabetic rats exhibited reduced responsiveness to the beta-adrenergic agonist isoproterenol. Over a concentration range of 3 x 10(-9) to 10(-7) M, isoproterenol-mediated stimulation in the rate of left ventricular pressure decline, a measure of myocardial relaxation, and the rate of left ventricular pressure rise, a measure of myocardial contractility, were significantly depressed in the diabetic hearts. To clarify the basis for this defect, individual steps involved in the actions of the beta-adrenergic agonists were examined. Dihydroalprenolol binding assays revealed that neither beta-adrenergic receptor number nor binding affinity was affected by the diabetic condition. Also unaffected by diabetes was isoproterenol-mediated stimulation of adenylate cyclase activity, myocyte accumulation of adenosine 3',5'-cyclic monophosphate (cAMP), or the increase in cAMP-dependent protein kinase activity ratio. However, it was found that both in the presence and absence of cAMP-dependent protein kinase, activity of the sarcolemmal calcium transporter was significantly depressed in the diabetic heart. Also attenuated was protein kinase-induced enhancement of sarcoplasmic reticular calcium transport. The likelihood that these abnormalities contribute to alterations in calcium homeostasis and myocardial contractile function is discussed.

Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

“…This was significant for both heart rate and contractility. This result is consistent with the reduced responsiveness of diabetic hearts to beta adrenergic stimulation that has been established for several decades [35,36]. The reduced isoproterenol response of OVE26 hearts may at least partially explain why basal diabetic cardiac contractility measured by echocardiography appeared unimpaired, while contractility of isolated OVE26 myocytes was significantly impaired.…”

Left Ventricular Mechanoenergetics in Small Animals

“…In non-insulindependent diabetic hearts, no changes in the myocardial β-receptor population could be found, but the reduced responsiveness to a β-adrenergic agonist was reported [175]. The O 2 cost of LV contractility for dobutamine in late DM rat hearts, however, was unchanged.…”

Mechanisms of [Ca2+]i Transient Decrease in Cardiomyopathy of db/db Type 2 Diabetic Mice

“…By contrast, other well-known models of type 2 diabetes such as Otsuka Long Evans Tokushima Fatty rats (10) and db/db mice (11) present defects in both function and expression of SERCA. Streptozotocin injection in neonatal rats induces adult noninsulin-dependent diabetes, and the activities of plasmalemmal Ca 2ϩ ATPase (12,13) and Na ϩ /Ca 2ϩ exchanger (NCX) (13) are both decreased in this model. Thus, a distinct Ca 2ϩ transporter malfunction has been identified in different diabetic models, but an integrated mechanism of altered Ca 2ϩ homeostasis is lacking.…”