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 β-adrenergic receptor (βAR)- G protin- 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 nM glucose), and lower fasting insulin levels (6.46 ± 0.97 v 13.68 ± 3.91 μU/ml). Transmural LV free wall homogenates from DIAB exhibited simiar βAR density as CON, but decreased cAMP production (pmol cAMP/mg prot.min) using these pharmacological stimulators: 10 μm Isoproterenol plus 100 μm GTP (74 ± 5 v 97 ± 11); 100 μm Gpp(NH)p (116 ± 7 v 161 ± 17); 10, m fluoride ion (266 ± 16 v 324 ± 25). No differences between DIAB and CON were observed when stimulated by 100 μm 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 of as from the sarcolemma to the cytosol (32.7 ± 0.82% v 25.9 ± 1.7%). Significantly levels of cardiac Gi were seen in DIAB homogenates compared to CON ventricles (2326 ± 145 v 1522 ± 181 pmol/g ww), with no αi subunit redistribution. We conclude that despite maintained βAR 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 Gsα 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.