Deficiency of Cardiac β-Adrenergic Receptor in Streptozocin-Induced Diabetic Rats

The number of β-adrenergic receptors in cardiac myocytes isolated from rats made diabetic with streptozocin (STZ) for 10 wk was measured by use of a hydrophilic nonselective antagonist [³H]CGP 12177 and was found to decrease to 59% of the number in control rats (P < .05), without any change in affinity. Similarly, using [¹²⁵I]iodocyanopindolol as a ligand, we found a decrease in the β-adrenergic-receptor number on cardiac plasma membrane isolated from the diabetic rats [29% decrease (P < .05) at 1 wk, 50% (P < .01) at 3 wk, and 49% (P < .01) at 10 wk compared with control rats]. However, the serum triiodothyronine level that had been known to modulate the β-adrenergic-receptor-adenylate cyclase system was decreased in the 1-wk-diabetic rats but not in the 10-wk-diabetic rats compared with each control group. Furthermore, there was no difference in urinary catecholamine excretion between diabetic and control groups. In the 10-wk-diabetic rats, the response of adenylate cyclase to isoproterenol was significantly defective (56% decrease compared with control rats; P < .05), although both the basal and the forskolin-stimulated maximum adenylate cyclase activities and a half-maximum concentration of isoproterenol for the stimulation of adenylate cyclase were similar in control and diabetic rats. On the other hand, both cholera toxin-dependent and islet-activating protein-dependent [³²P]NAD incorporations into cardiac plasma membrane were markedly increased in the diabetic rats. The 2-wk insulin treatment improved not only the number of β-adrenergic receptors but also the response of adenylate cyclase to 10 μM isoproterenol. These results indicate that cardiac unresponsiveness to a β-adrenergic agonist in STZ-induced diabetic rats is specifically associated with a deficiency in the β-adrenergic-receptor concentration in cardiac plasma membrane.