DEFECTIVE GLOMERULAR BETA-ADRENERGIC SIGNAL TRANSMISSION IN SPONTANEOUSLY DIABETIC RATS

Previous studies in experimental diabetes have demonstrated cardiovasc ular abnormalities of the beta-adrenergic system and reduced adrenergi cally stimulated renal renin secretion. To examine the defect in the b eta-adrenergic signal, glomerular cyclic adenosine monophosphate (cAMP ) levels were measured in response to isoproterenol and other humoral agonists (coincubated with the phosphodiesterase inhibitor isomethylxa nthine) in nondiabetic and diabetic BB/Wor rats. Basal (unstimulated) levels of glomerular cAMP did not differ between control and diabetic BB/Wor rats, nor did cAMP accumulation differ on incubation with the h umoral agonists PGE(2) and histamine. However, on incubation with vari ed concentrations of the nonselective beta-adrenergic agonist isoprote renol, control glomeruli demonstrated a twofold increase in cAMP while a negligible response was observed in diabetic glomeruli. Peak levels of cAMP were higher in control (192 +/- 24 pmol/mg protein) than in d iabetic (141 +/- 8 pmol/mg protein) glomeruli Ip < 0.01). No differenc es were observed on incubation with the adenylate cyclase stimulator f orskolin. Measurement of glomerular beta-adrenoreceptors by coincubati on with iodine 125-labeled cyanopindolol demonstrated no differences i n either receptor number (B-max) or affinity (K-D). These data indicat e that a specific defect in beta-adrenergic signalling exists in glome rular tissue from spontaneously diabetic rats. Because no decrease in forskolin-stimulated adenylate cyclase was observed, defective couplin g of the receptor to its effector, perhaps through the guanine nucleot ide stimulatory protein, may account for these observations.