ADRENERGIC DESENSITIZATION IN LEFT-VENTRICLE FROM STREPTOZOTOCIN-DIABETIC SWINE

Patients with diabetes mellitus that exhibit cardiac pump failure display compromised stroke volume, ejection fraction, and slower rates of rise and fall of left ventricular (LV) dP/dt in the absence of ischemic injury. We hypothesized that diabetic cardiomyopathy may involve decrements in adrenergic sensitivity, with specific molecular alterations in the beta-adrenergic receptor (beta AR)- G protein- adenylyl cyclase (AC) signal transduction system, We assessed the effects of 3 months of streptozotocin-induced diabetes (125 mg/kg i.v.; DIAB, n = 10) on myocardial signal transduction in mini-pigs. DIAB were hyperglycemic compared to controls (CON, n = 10; 20.92 +/- 2.64 v 5.24 +/- 0.35 mM glucose), and had lower fasting insulin levels (6.46 +/- 0.97 v 13.68 +/- 3.91 mu U/ml). Transmural LV free wall homogenates from DIAB exhibited similar beta AR density as CON, but decreased cAMP production (pmol cAMP/mg prot.min) using these pharmacological stimulators: 10 mu M Isoproterenol plus 100 mu M GTP (74 +/- 5 v 97 +/- 11); 100 mu M Gpp(NH)p (116 +/- 7 v 161 +/- 17); 10 mM fluoride ion (266 +/- 16 v 324 +/- 25). No differences between DIAB and CON were observed when stimulated by 100 mu M forskolin (440 +/- 20 v 429 +/- 33), suggesting no alterations in the catalytic subunit of AC. In DIAB, quantitative immunoblotting indicated slightly depressed levels of Gs (552 +/- 44 v 630 +/- 59 pmol/g ww; NS), but a significant redistribution of as from the sarcolemma to the cytosol (32.7 +/- 0.82% v 25.9 +/- 1.7%). Significantly elevated levels of cardiac Gi were seen in DIAB homogenates compared to CON ventricles (2326 +/- 145 v 1522 +/- 181 pmol/g ww), with no alpha i subunit redistribution. We conclude that despite maintained PAR density, receptor-dependent and G protein-dependent stimulation of AC is depressed so that streptozotocin-induced diabetic LV is affected by increased cardiac Gi, redistribution of Gsa to the cytosol, and an increase in the Gi/Gs ratio. These results help explain depressed catecholamine responsiveness and cardiac performance exhibited by diabetic patients. (C) 1995 Academic Press Limited