title: Adrenergic desensitization in left ventricle from streptozotocin diabetic swine.
abstract: 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 microU/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 microM Isoproterenol plus 100 microM GTP (74 +/- 5 v 97 +/- 11); 100 microM 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 microM 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 alpha s 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 beta AR 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 Gs alpha 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.
authors.affiliation: Department of Kinesiology, University of Colorado, Boulder 80309-0354, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Roth
authors.forename: C D
authors.initials: CD
authors.lastname: White
authors.forename: C D
authors.initials: CD
authors.lastname: Hamilton
authors.forename: J L
authors.initials: JL
authors.lastname: Hall
authors.forename: W C
authors.initials: WC
authors.lastname: Stanley
mesh_terms: D000262:Adenylyl Cyclases / Q000032:analysis*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000535:Aluminum / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000172:deficiency*; D003600:Cytosol / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000172:deficiency*; D006160:Guanosine Triphosphate / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D007328:Insulin / Q000032:analysis; D007545:Isoproterenol / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000032:analysis*; D012508:Sarcolemma / Q000737:chemistry; D015398:Signal Transduction; D013311:Streptozocin; D013552:Swine; D013556:Swine, Miniature
chemical_list: D000318:Adrenergic beta-Agonists; D001786:Blood Glucose; D007328:Insulin; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D013311:Streptozocin; D006160:Guanosine Triphosphate; D000535:Aluminum; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D005459:Fluorides