Defective glomerular beta-adrenergic signal transmission in spontaneously diabetic rats.
Previous studies in experimental diabetes have demonstrated cardiovascular abnormalities of the beta-adrenergic system and reduced adrenergically stimulated renal renin secretion. To examine the defect in the beta-adrenergic signal, glomerular cyclic adenosine monophosphate (cAMP) levels were measured in response to isoproterenol and other humoral agonists (coincubated with the phosphodiesterase inhibitor isomethylxanthine) 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 humoral agonists PGE2 and histamine. However, on incubation with varied concentrations of the nonselective beta-adrenergic agonist isoproterenol, 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 diabetic (141 +/- 8 pmol/mg protein) glomeruli (p < 0.01). No differences were observed on incubation with the adenylate cyclase stimulator forskolin. Measurement of glomerular beta-adrenoreceptors by coincubation with iodine 125-labeled cyanopindolol demonstrated no differences in either receptor number (Bmax) or affinity (KD). These data indicate that a specific defect in beta-adrenergic signalling exists in glomerular tissue from spontaneously diabetic rats. Because no decrease in forskolin-stimulated adenylate cyclase was observed, defective coupling of the receptor to its effector, perhaps through the guanine nucleotide stimulatory protein, may account for these observations.
Silbiger
S R
SR
Department of Medicine (Renal), University of Massachusetts Medical School, Worcester 01655.
Cohen
A J
AJ
Fishman
J B
JB
Stoff
J S
JS
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology*; D015232:Dinoprostone / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D011913:Rats, Inbred BB; D011922:Rats, Mutant Strains; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D001786:Blood Glucose; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D006632:Histamine; D000242:Cyclic AMP; D015232:Dinoprostone; D007545:Isoproterenol