methylatropine and Insulin-Resistance

To determine the time-dependent effects of rosiglitazone (RSG) on blood pressure (MAP) and baroreflex sensitivity (BRS) and the involvement of nitric oxide (NO) in these effects.. Male Sprague-Dawley rats were treated with RSG (8 mg/kg per day, orally) or saline for 4, 8 and 12 weeks. BRS was determined by linear regression method with bolus injections of phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS). Insulin sensitivity (M value) was determined by euglycemic hyperinsulinemic clamp study. Vascular and cardiac responsiveness to isoproterenol, acetylcholine and NP were determined after ganglionic blockade. Effects of endogenous NO were examined by Nomega-nitro-L-arginine-methyl ester (L-NAME) administration.. RSG treatment time-dependently decreased circulating lipids, insulin, glucose levels and insulin resistance (HOMA-IR) but increased plasma NOx levels. M values were progressively decreased in control rats, but remained unchanged in RSG-treated rats. Chronic RSG treatment progressively lowered MAP but reciprocally increased heart rate (HR). In addition, chronic RSG treatment significantly attenuated HR changes to methylatropine but enhanced HR changes to propranolol. Twelve-week RSG treatment enhanced PE-BRS which was suppressed by methylatropine but not propranolol, and attenuated NP-BRS which was sustained after methylatropine or propranolol. Moreover, 12-week RSG treatment also diminished cardiac responsiveness to isoproterenol and augmented vascular responsiveness to acetylcholine, but not to NP. L-NAME eliminated the differences in MAP and HR between groups, and reversed both RSG-induced enhanced PE-BRS and attenuated NP-BRS. Plasma NOx levels were highly correlated with RSG-mediated changes in the baseline MAP, HR and BRS.. These data suggest that RSG-induced NO production is important for the time-dependent effects of RSG on MAP and BRS in rats.

Topics: Administration, Oral; Animals; Arteries; Atropine Derivatives; Autonomic Nervous System; Baroreflex; Blood Glucose; Blood Pressure; Body Weight; Heart Rate; Insulin; Insulin Resistance; Linear Models; Lipids; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Propranolol; Rats; Rats, Sprague-Dawley; Rosiglitazone; Sensitivity and Specificity; Thiazolidinediones; Time Factors

The present study was undertaken to compare the effects of chronic hyperinsulinemia with or without insulin resistance on the autonomic control of heart rate (HR) in rats.. Male Sprague-Dawley rats were implanted subcutaneously with insulin (3 mU/kg x min) or vehicle-filled osmotic minipumps for 8 weeks. Insulin-infused rats were further divided into insulin resistant (IR) and insulin sensitive (IS) groups according to the results of the homeostasis model assessment method and euglycemic hyperinsulinemic clamp study. Autonomic function in HR control was indicated by arterial baroreflex sensitivity (BRS) after a bolus injection of phenylephrine or sodium nitroprusside.. Compared with those in control group, plasma insulin levels were elevated about threefold and 1.5-fold in the IR and IS groups at the end of week 8, respectively. Blood glucose level remained basal in the IR group, but was significantly lower in the IS group. The elevated mean arterial pressure (MAP) observed in IR was not exhibited in IS. The HR and BRS in reflex tachycardia were significantly increased in the IR and IS groups, but the BRS in reflex bradycardia was not different among all rats. Propranolol eliminated the tachycardia and enhanced BRS responses in both groups. Methylatropine further accelerated tachycardia and diminished the enhanced BRS in the IR group. However, in IS, the enhanced BRS remained after methylatropine was given. The intrinsic HR was similar among all groups. The baseline MAP, HR, and BRS in reflex tachycardia were significantly correlated to plasma insulin levels but not to the Si value, an index of insulin sensitivity.. The present results demonstrate that hyperinsulinemia but not insulin resistance is a dominant contributing factor to the development of arterial baroreflex abnormalities in this chronic hyperinsulinemic model, which may simultaneously enhance sympathetic nerve activity and possibly vagal withdrawal if insulin resistance coexisted.

Topics: Animals; Atropine Derivatives; Autonomic Nervous System; Baroreflex; Blood Glucose; Disease Models, Animal; Heart Rate; Hyperinsulinism; Insulin; Insulin Resistance; Male; Parasympatholytics; Rats; Rats, Sprague-Dawley; Tachycardia; Vagus Nerve

The Wistar fatty (WF) rat is a model of obese Type 2 diabetes mellitus (DM). These rats were bred by crossing Zucker fatty (ZF) and Wistar-Kyoto (WKY) rats. A homo-allelic leptin receptor gene mutation has been reported in ZF rats. We report here how these genetic factors contribute to plasma insulin regulation. The fasting plasma insulin levels were higher in WKY and Wistar lean (WL) rats than in Zucker lean (ZL) rats (p<0.05). The levels in WF and ZF rats were higher than in their respective lean littermates, WL and ZL rats (p<0.05). After intragastric glucose load, the plasma insulin increase was reduced upon pretreatment by intracerebroventricular (i. c.v.) methylatropine (an antagonist of the cholinergic receptor) injection in WL rats (p<0.05) but not in WF rats. Plasma glucagon-like peptide-1 (GLP-1) response to intragastric glucose load was not affected by methylatropine. After selective hepatic-vagotomy, plasma insulin levels increased in wild-type ZL rats (p<0.05). This increase was not observed in heterozygote ZL rats. Surprisingly, this response of plasma insulin was not shown in wild-type WL and WKY rats. ZF and WF rats did show a prominent decrease in insulin response (p<0.05). These results indicate that the genetic factor in ZF rats is associated with impaired vagal nerve-mediated control of insulin secretion. The genetic factor in WKY rats may diminish sensitivity to the vagal information of insulin release and contribute to insulin resistance. Therefore, we conclude that the presence of both genetic factors in a homo-allelic state is important to the development of DM in WF rats.

Topics: Animals; Atropine Derivatives; Blood Glucose; Carrier Proteins; Crosses, Genetic; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon; Glucagon-Like Peptide 1; Glucose Tolerance Test; Injections, Intraventricular; Insulin; Insulin Resistance; Insulin Secretion; Mutation; Obesity; Peptide Fragments; Protein Precursors; Rats; Rats, Inbred WKY; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Vagotomy; Vagus Nerve