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Pharmacology. 1993;46(1):43-9.
Iterative stimulation of pancreatic islets by glipizide.

Malaisse WJ, Lebrun P.

Laboratory of Experimental Medicine, Erasme Medical School, Brussels Free University, Belgium.

Iterative administrations of glipizide (2 mumol/l) for 10 min each to perifused rat pancreatic islets provoked at low glucose concentration (2.8 mmol/l) rapid and rapidly reversible decreases in 86Rb outflow, rapid and rapidly reversible increases in 45Ca outflow and modest stimulations of insulin release. In the presence of Ca2+, the reascension in 86Rb outflow was preceded by a transient fall in effluent radioactivity upon withdrawal of the sulfonylurea. At a higher concentration of D-glucose (8.3 mmol/l), glipizide provoked, each time, biphasic and rapidly reversible increases in both 86Rb and 45Ca outflow, as well as in insulin release. These results are compatible with the view that glipizide decreases K+ conductance, leading to depolarization of the B-cell plasma membrane and gating of voltage-sensitive Ca2+ channels. In the presence of 8.3 mmol/l D-glucose, however, the inhibitory effect of glipizide on effluent K+ permeability may be masked by activation of Ca(2+)-sensitive K+ channels. The present data also indicate that glipizide is able to evoke, at the occasion of iterative administrations, biphasic ionic and secretory responses, without evidence of tachyphylaxis.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8434031&dopt=Abstract




J Vasc Res. 1993 Jan-Feb;30(1):2-12.
Vascular pharmacology of ATP-sensitive K+ channels: interactions between glyburide and K+ channel openers.

Meisheri KD, Khan SA, Martin JL.

Upjohn Laboratories, Upjohn Company, Kalamazoo, MI 49001.

This study in isolated rabbit superior artery (RMA) investigated the interactions between glyburide, a known blocker of vascular ATP-sensitive K+ channels (KATP), and several chemically diverse potassium channel openers (PCOs): minoxidil sulfate (MNXS; 5 microM), pinacidil (1 microM), cromakalim (0.5 microM) and RP-49356 (1 microM; a PCO from Rhone Poulenc). Relaxation time courses for these PCOs were obtained in norepinephrine (NE; 5 microM)-precontracted RMA, and the concentrations of PCOs found to be equipotent to each other in terms of the degree of maximum relaxation (about 80%) and the time course of relaxation (within 15 min) were chosen for further study. This was taken as a functional indicator of a similar degree as well as similar kinetics of K+ channel opening by these PCOs. Pretreatment with glyburide (10-500 nM) produced a dose-dependent inhibition of the PCO relaxation time course. The glyburide IC50s against pinacidil, MNXS and RP-49356 were statistically similar and ranged from 72-79 nM. The glyburide IC50 against cromakalim was a modest 2-fold higher, at 148 nM. In contrast, pretreatment with charybdotoxin (200 nM) produced no significant inhibition of the maximum relaxation produced by these PCOs. Furthermore, glipizide, a sulfonylurea that is 10- to 25-fold less potent than glyburide for insulin secretion, was found to be 20- to 30-fold less potent than glyburide as a vascular KATP antagonist. These data suggest a mechanistic model in which these structurally diverse PCOs share a common critical step in the sequence of events leading to the KATP opening, and that glyburide interferes with this common critical step to produce a similar type of blockade against all four PCOs. Interaction studies with glyburide and pinacidil demonstrated 15 min to be the optimal pretreatment time for glyburide to produce maximal inhibition. Glyburide also reversed existing pinacidil relaxation regardless of the degree of pre-existing relaxation. These data suggest that glyburide is able to produce its blockade regardless of the state of K+ channel activation. Studies on the effect of pH (6.4 vs. 7.3) showed that at acidic pH, pinacidil became less effective and the effectiveness of glyburide was significantly enhanced, whereas the actions of D600 remained unchanged. These data suggest the effects of both openers and blockers of the KATP are strongly pH dependent.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8435468&dopt=Abstract




J Clin Endocrinol Metab. 1993 Mar;76(3):752-6.
Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses.

Boyle PJ, Justice K, Krentz AJ, Nagy RJ, Schade DS.

Department of Medicine, University of New Mexico School of Medicine, Albuquerque 87131-5271.

Emergency therapy of sulfonylurea overdoses with glucose is often unsatisfactory because glucose stimulates insulin release and initiates a need for escalating quantities of hypertonic glucose to maintain normoglycemia. We tested the hypothesis that octreotide, an analog of somatostatin, would reverse hyperinsulinemia induced by a sulfonylurea overdose. Eight normal subjects received glipizide (1.45 mg/kg) on three occasions. Within 3 h, all subjects became hypoglycemic (< 50 mg/dL) and were initially treated with 50% dextrose followed by 1) dextrose infusion, 2) octreotide (30 ng/kg.min, iv), or 3) diazoxide (300 mg, iv, every 4 h). Euglycemia (85 mg/dL) was maintained with supplementary dextrose in treatment limbs 2 and 3. Insulin concentrations were 4-5 times greater with dextrose alone or in combination with diazoxide than with octreotide (P < 0.01). Dextrose requirements during diazoxide or dextrose alone were not different, but were both greater than those during octreotide treatment (P < 0.0001). All therapies were stopped at 13 h. Glucose levels remained above 3.6 mmol/L (65 mg/dL) in six of eight subjects receiving octreotide for the remaining 4 h. Glucose fell to below 3.6 mmol/L within 1.5 h of stopping either dextrose or diazoxide in each subject. Overall, octreotide reduced and in four of eight subjects entirely eliminated the need for exogenous glucose after a large overdose of glipizide. We conclude that octreotide is safe and effective and should be strongly considered as a logical therapeutic alternative for this metabolic emergency.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8445035&dopt=Abstract












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