Drugs online research references
Clin Exp Pharmacol Physiol. 1993 Jul-Aug;20(7-8):467-75.
Evidence that imidazol(id)ine- and sulphonylurea-based antagonists of cromakalim act at different sites in the rat thoracic aorta.
Challinor JL, McPherson GA.
Baker Medical Research Institute, Prahran, Victoria, Australia.
1. Ring segments of rat thoracic aorta were suspended in organ baths to record isometric tension. Tissues were precontracted with K+ (20 mmol/L), and full concentration-relaxation curves constructed to cromakalim (0.01-30 mumol/L) in the absence and presence of increasing concentrations of glibenclamide, glipizide, tolbutamide (the sulphonylureas), alinidine (an imidazolidine), phentolamine (an imidazoline), and chlorpromazine (the phenothiazine derivative). Whereas the active sulphonylureas, glibenclamide and glipizide, displayed classical competitive antagonism, the remaining compounds (alinidine, phentolamine and chlorpromazine) caused shifts in the cromakalim concentration-effect curves associated with a reduction in the slope and maximum response. 2. A single concentration of each antagonist was selected and the shift in the concentration-effect curve determined. The possibility that sulphonylurea and imidazol(id)ine antagonists act at different sites was tested using the concentration-ratio method for combined antagonists described by Paton and Rang (1965). The combination of alinidine and phentolamine (collectively called imidazol(id)ines) at a number of different concentrations (10-30 mumol/L) resulted in a concentration-ratio to cromakalim which was additive, suggesting a common site of action. Similar results were obtained when examining the interaction between two sulphonylurea compounds (glibenclamide and glipizide). However, the interaction between sulphonylurea (glibenclamide) and imidazol(id)ine (alinidine) produced concentration-ratios which were multiplicative, suggesting a different or additional site of action for compounds from these two groups. Results indicated that chlorpromazine was able to block cromakalim via an action at the same site where alinidine and phentolamine act.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8403526&dopt=Abstract
Diabet Med. 1993 Aug-Sep;10(7):633-7.
The acute effect of preprandial exogenous and endogenous sulphonylurea-stimulated insulin secretion on postprandial glucose excursions in patients with type 2 diabetes.
Groop PH, Melander A, Groop LC.
Fourth Department of Medicine, Helsinki University Central Hospital, Finland.
Sulphonylureas improve glucose tolerance by stimulating insulin secretion. Whether improved glucose tolerance results from enhanced early insulin release or greater total insulin secretion is not clear. Insulin response to a test meal in Type 2 diabetic subjects with and without a single dose (2.5 mg) of oral and intravenous glipizide were, therefore, measured. Intravenous glipizide enhanced early insulin release more than oral glipizide (134% and 80% vs control; p < 0.01), whereas total insulin release was equally improved (78% and 54% vs control; p < 0.01). Despite slight differences in insulin release, there was no difference in glucose tolerance (median area under concentration curve (AUC); 66.6 vs 61.9 mmol x min l-1; NS). The test meal was repeated after a bolus of intravenous insulin at the beginning of the meal. This allowed comparison of the effect of exogenous and endogenous insulin supply on postprandial glucose excursions. In spite of an early and fivefold larger rise in serum insulin after intravenous administration of the hormone than after intravenous glipizide (725% vs 134%; p < 0.01), postprandial glucose was no better than after glipizide (median AUC; 87.8 vs 66.6 mmol x min l-1; NS). In contrast, glucose tolerance was better after oral glipizide compared to intravenous insulin (median AUC; 61.9 vs 87.8 mmol x min l-1; p < 0.05). In conclusion, the total amount of insulin secreted seems more important than the timing of the insulin release for the postprandial glucose tolerance in Type 2 diabetic subjects. Neither endogenous nor peripheral premeal supply of insulin could normalize postprandial glucose excursions in patients with Type 2 diabetes.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8403824&dopt=Abstract
Horm Metab Res. 1993 Jul;25(7):348-52.
Effects of chronic glipizide treatment on the NIDD heart.
Schaffer SW, Warner BA, Wilson GL.
Department of Pharmacology, College of Medicine, University of South Alabama, Mobile.
Extrapancreatic activity of the sulfonylurea, glipizide, was evaluated in the neonatal streptozotocin-induced rat model of noninsulin-dependent diabetes. Two day old Wistar rats were given a bolus of streptozotocin (90 mg/kg i.p.) to cause noninsulin-dependent diabetes; these animals became severely glucose intolerant and eventually developed a cardiomyopathy characterized by reduced heart rate, contractility and cardiac output. Male littermates injected with citrate buffer served as nondiabetic controls. At four weeks of age, the nondiabetic and NIDD rats were administered by gavage either glipizide (2.5 mg/kg) or the methyl cellulose vehicle. Throughout the treatment protocol, no difference in the degree of glucose intolerance was observed between the glipizide-treated and vehicle-treated animals. Glipizide therapy also was ineffective in improving plasma insulin levels, which were significantly depressed in the diabetic group. Yet, animals treated with glipizide for one year exhibited improved myocardial contractile function relative to the vehicle-fed or ad lib fed diabetic animals. Heart rate was significantly elevated and there was a tendency for both the rate of relaxation and contractility to be elevated in sulfonylurea-treated group. Glipizide also reduced the degree of insulin resistance in the heart. Since these changes occur in the absence of changes in glucose tolerance or insulin levels, the heart appears to be very sensitive to the direct effects of the sulfonylureas.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8406318&dopt=Abstract
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