Alpha 1-adrenoceptor-mediated phosphoinositide breakdown and inotropic responses in diabetic hearts.
The mechanism(s) involved in diabetes-induced changes in the heart is still unclear, but one defect appears to occur in the alpha 1-adrenoceptor system. We evaluated the possibility that the changes in the inotropic responsiveness to alpha 1-adrenoceptor stimulation in streptozotocin-diabetic rat hearts may be linked to altered phosphoinositide turnover. Stimulation of alpha 1-adrenoceptor by norepinephrine (in the presence of propranolol) in right ventricles resulted in the formation of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] [measured with an Ins(1,4,5)P3 protein binding assay kit] in a time- and concentration-dependent manner in both control and diabetic rats. The increase in Ins(1,4,5)P3 preceded the increase in the norepinephrine-mediated positive inotropic effect. Diabetic hearts showed a greater maximum inotropic response to norepinephrine stimulation and also had higher Ins(1,4,5)P3 levels. These observations suggest that the changes in Ins(1,4,5)P3 levels may be implicated in the increased inotropic responsiveness to alpha 1-adrenoceptor stimulation in diabetic hearts. Ca2+ overload, induced by Ins(1,4,5)P3, could further be involved in the development of diabetic cardiomyopathy.
Xiang
H
H
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
McNeill
J H
JH
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D009994:Osmolar Concentration; D010716:Phosphatidylinositols / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D013997:Time Factors
D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D015544:Inositol 1,4,5-Trisphosphate; D009638:Norepinephrine; D011224:Prazosin