Diabetes‐Induced Changes in the Gi‐Modulated Muscarinic Receptor‐Adenylyl Cyclase System in Rat Myocardium^*

Abstract

The inhibitory guanine nucleotide binding regulatory protein (Gi)-mediated muscarinic receptor-adenylyl cyclase system was studied in myocardium from adult male Wistar rats with 10 weeks of diabetes induced by a single intravenous injection of streptozotocin (60 mg/kg). Neither the messenger ribonucleic acid level nor the amount of Gi was changed in the streptozotocin diabetic group as compared to the control group. The activity of the adenylyl cyclase stimulated by guanyliminodiphosphate was decreased by 48% in the streptozotocin diabetic group whereas stimulated activities of adenylyl cyclase by sodium fluoride and forskolin remained unchanged. The inhibition of forskolin-stimulated adenylyl cyclase activity by carbachol was more potent in membranes from the streptozotocin diabetic group than that in membranes from the control group. The competition binding curve between (3H)- quinuclidinyl benzilate and carbachol obtained from the streptozotocin diabetic group was shifted to the left as compared to the control group. These results suggest that the myocardium of streptozotocin-induced diabetic rats exhibited an increase in Gi function as demonstrated by the increased inhibition of guanyliminodiphosphate-mediated adenylyl cyclase and the superhigh affinity for carbachol of the muscarinic receptors. As there were signs, similar to those seen in clinical heart failure, in the streptozotocin diabetic group, these results demonstrate that functional alteration of Gi might underlie, at least in part, the cardiac dysfunction that is associated with diabetes.

Increased expression of Gαq protein in the heart of streptozotocin-induced diabetic rats

“…Our result on the expression of Gαs, not affected by insulin deficiency, was agreeable with the findings of Wichelhaus et al (1994) in the heart ventricles of streptozotocin-induced diabetic rat. The result of no change of Gαi expression in heart of diabetic rat was agreeable with the findings of Fu et al (1994), but differed from the result of Wichelhaus et al (1994). The G protein-coupled signaling pathways initiate a cascade of enzyme activation, such as PKA, PLC, PKC, CaM kinase etc.…”

Functional defects in adenylyl cyclase signaling mechanisms of insulin and relaxin in skeletal muscles of rat with streptozotocin type 1 diabetes

“…This is supported by the decrease of the effects of G protein activators NaF and guanine nucleotides (GppNHp), and a suppression of GppNHp potentiating influence on the hormone effects. The decrease (about 50 %) of the GppNHp stimulating effect on AC in the myocardium of diabetic rats was described earlier [27]. In the present study, isoproterenol stimulation of GTPbinding of heterotrimeric G proteins in the STZ diabetes model is reduced in the skeletal muscles, and in the heart muscle of rats [28].…”

Increased function of inhibitory neuronal M2 muscarinic receptors in diabetic rat lungs

“…The mechanism of increased function of the neuronal M 2 muscarinic receptors in the diabetic rat lungs is unclear. Radioligand bindind studies performed with diabetic heart membranes confirmed a half‐log increase in agonist binding affinity at the M 2 receptor compared to controls (Bergh et al , 1984; Fu et al , 1994), indicating that increased M 2 muscarinic receptor function seen in diabetic rats may be due, in part, to increased agonist binding affinity at the receptor. In diabetic rat hearts, Bergh et al (1984) have suggested increased coupling of muscarinic receptors to G i .…”