Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of Verapamil, a potent calcium antagonist, upon pancreatic glucagon release was investigated in the isolated, perfused canine pancreas. Verapamil at concentrations ranging between 10(-5)-10(-4) mol/l caused a dose-related inhibition of glucagon release at a glucose concentration of 25 mg/dl. The inhibition was an immediate and reversible phenomenon. The inhibitory effect was reduced when the Ca2+ concentration was increased from 1.3 to 5.0 mmol/l. The results are compatible with earlier findings from our laboratory demonstrating that calcium plays a key role in the stimulus-secretion coupling of glucagon release.
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PMID:Effect of Verapamil on pancreatic glucagon release from the isolated, perfused canine pancreas. 61 40

The study investigated the effects of metformin and phenformin, at "therapeutic" concentrations, on the pancreatic A-, B- and D- cell response to glucose using the isolated perfused rat pancreas model. Changes in the rate of pancreatic lactate output after these biguanides were also evaluated. Metformin--at 1.5 micrograms/ml--and phenformin--at 100 ng/ml--were separately infused both at 160 mg/dl and 300 mg/dl glucose levels. Neither metformin nor phenformin affected glucagon or somatostatin secretion during these two metabolic stimuli with glucose, nor did they significantly influence insulin response to the lower glucose stimulus. Both metformin and phenformin enhanced insulin response to 300 mg/dl glucose infusion and increased the second phase of the B-cell secretory profile but only phenformin significantly enhanced the pancreatic lactate output rate during the 300 mg/dl glucose infusion. Infusion with dichloroacetate (a stimulator of the mitochondrial pyruvate oxidation) or with verapamil (a calcium antagonist) alone did not modify the insulin response to high glucose concentrations. During metformin infusion dichloroacetate neither modified metformin's effects on B-cell response to high glucose nor did it affect the pancreatic lactate output rate. On the other hand dichloroacetate opposed phenformin's effects on the B-cell response to high glucose and reversed the rise in the pancreatic lactate output rate. Verapamil inhibited the effect of metformin on the B-cell response to high glucose but failed to affect phenformin's influence on high-glucose induced insulin release. These data suggest both metformin and phenformin potentiate--at least in rats--the late phase of insulin secretory response to high glucose. However metformin seems to influence pancreatic B-cell activity mainly by facilitating the trans-membrane calcium ion influx responsible for the second phase of insulin release. Phenformin's influence seems indirect since it increases pancreatic lactate production which mediates the enhanced B-cell response to glucose.
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PMID:Do metformin and phenformin potentiate differently B-cell response to high glucose? An in vitro study on isolated rat pancreas. 167 60

With a glucose-responsive beta-cell line (HIT cells), we tested the hypothesis that the cytosolic free-Ca2+ level ([Ca2+]i) is an intracellular signal through which a rise in cyclic AMP (cAMP) levels is transmitted to potentiate glucose-stimulated insulin secretion. In these cells, glucose stimulates the acute release of insulin without increasing [Ca2+]i or altering cAMP content. Either forskolin or 3-isobutylmethylxanthine (IBMX) potentiated glucose-stimulated insulin secretion and increased cAMP levels. At either a submaximal glucose concentration or maximally stimulatory glucose concentration, both IBMX and forskolin triggered a rapid rise in [Ca2+]i (1.9- and 1.5-fold increase over basal levels, respectively). Similarly, glucagon stimulated a 1.3-fold increase in [Ca2+]i over basal levels. The effect on [Ca2+]i required glucose and was secondary to Ca2+ influx through voltage-dependent Ca2+ channels because it was blocked by either chelation of extracellular Ca2+ with EGTA or by the Ca2+-channel blockers verapamil and nimodipine. Verapamil also inhibited IBMX potentiation of glucose-stimulated insulin secretion and the IBMX-induced rise in [Ca2+]i in a dose-dependent manner with IC50s of 2 x 10(-5) and 4 x 10(-6) M, respectively. We conclude that in the beta-cell, a rise in cAMP levels increases Ca2+ influx through voltage-dependent Ca2+ channels and that this represents a mechanism by which cAMP potentiates glucose-stimulated insulin secretion in beta-cells.
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PMID:Effect of rise in cAMP levels on Ca2+ influx through voltage-dependent Ca2+ channels in HIT cells. Second-messenger synarchy in beta-cells. 247 99

Verapamil-induced cardiovascular depression has been examined in dial-urethane-anesthetized open chest dogs. Verapamil was administered slowly intravenously until the mean arterial pressure was decreased by approximately 45 mm Hg. The dose of verapamil required to reach the hemodynamic endpoint was 1,495 +/- (SE) 165 micrograms/kg. In a second group, interactions between beta-adrenergic blockade, propranolol 1 mg/kg (i.v.), and verapamil were examined. Although propranolol alone had only minor hemodynamic effects, the cardiac depressant dose of verapamil was reduced significantly to 450 +/- 105 micrograms/kg. After cardiovascular depression with verapamil or verapamil plus propranolol, glucagon was administered to assess its inotropic activity using cumulative doses of 5, 15, and 45 micrograms/kg over 20 min. Glucagon produced a dose-dependent recovery of heart rate, mean arterial pressure, and PR interval. Depressed contractility assessed by peak positive dP/dt and right ventricular isometric contractile force also recovered after glucagon. These results suggest a significant interaction between the potency of verapamil as a myocardial depressant and the state of the myocardium as affected by beta-blockade. Cardiac depression by verapamil or verapamil in combination with propranolol was reversible by glucagon.
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PMID:Cardiovascular depression by verapamil: reversal by glucagon and interactions with propranolol. 342

We evaluated the effect of treatment with placebo or verapamil (320 mg/day) for 2 weeks on glucose-induced insulin secretion and hypoglycemia-stimulated counterregulatory hormone secretion in hypertensive patients. Verapamil treatment was associated with a significant reduction in diastolic blood pressure (P = 0.02 vs. placebo). During a hyperglycemic clamp (plasma glucose raised 125 mg/dl above basal level) maintained for 90 min, plasma insulin increased 4- to 5-fold (early) and then to values 8- to 10-fold above baseline (late). These increments were identical during placebo or verapamil treatment. The rates of glucose metabolized during each study also were similar, suggesting that no significant change in insulin action occurred during drug treatment. When plasma glucose was allowed to decline precipitously from hyperglycemic levels (220 mg/dl) to nadirs ranging from 42-77 mg/dl, plasma concentrations of glucagon, cortisol, epinephrine, and norepinephrine all increased; however, no consistent differences in the counter-regulatory hormone responses could be attributed to verapamil therapy. We conclude that physiologically effective drug concentrations of verapamil capable of influencing blood pressure do not have a significant effect on secretion of glucoregulatory hormones in man.
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PMID:Influence of oral verapamil on glucoregulatory hormones in man. 388 35

The influence of Verapamil, a calcium antagonist, on circulating levels of glucose, insulin and glucagon has been evaluated in 5 normal subjects and in 5 patients with non insulin-dependent diabetes (NIDDM). An oral glucose tolerance test was performed both in basal conditions and during intravenous infusion of the drug (5 mg/h). Administration of Verapamil didn't induce any significant change on the three parameters. The small decrease of glycemia in patients affected by NIDDM and treated with Verapamil was not related to reduction of glucagonemia.
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PMID:[Effects of calcium antagonists on pancreatic endocrine secretion]. 388 22

1 The vasodilator effects of glucagon and adenosine cyclic 3',5'-monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca(2+)) antagonists.2 The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3-isobutyl-l-methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX).3 Amongst the four phosphodiesterase inhibitors, IBMX (10 mug/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon-induced vascular relaxations (ED(50) of glucagon in the presence of IBMX = 9.2 +/- 1.0 ng/ml).4 Ca(2+) antagonists such as verapamil and SKF 525A produced a dose-dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 mug/ml) also antagonized cyclic AMP-induced vascular relaxations.5 The vasodilator effect of verapamil was inhibited dose-dependently by raising the concentration of extracellular Ca(2+) from 0.05 to 0.2 g/l (or 1.25 to 5.0 mM) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca(2+) influx.6 Disodium edetate (Na(2)EDTA, 210 to 840 mug/l) produced a dose-dependent vasodilator effect which was attributed to the facilitation of Ca(2+) extrusion from the smooth muscle cells and/or Ca(2+) binding to the cell membrane. The relaxation produced by Na(2)EDTA was significantly blocked by verapamil (10 mug/ml) or SKF 525A (10 mug/ml).7 The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca(2+) extrusion from the vascular smooth muscle cells and/or Ca(2+) binding to or sequestration into intracellular sites, presumably via a cyclic AMP-dependent mechanism.
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PMID:Studies on the mechanism of action of glucagon in strips of rabbit renal artery. 615 33

Verapamil and diltiazem, calcium channel blockers, inhibited significantly the glucagon-induced glucose output and 45Ca efflux from perfused rat liver at concentrations higher than 50 microM when the perfusate contained calcium. Although the blockers partially interfered with glucagon-induced elevation of cyclic AMP in the tissue, they also inhibited the effects of cyclic AMP. The blockers did not show the inhibitory effects in the absence of perfusate calcium. However, the inhibition of calcium influx into hepatocytes by omission of extracellular calcium or addition of EGTA did not interfere with these effects of glucagon and cyclic AMP. In the presence of extracellular calcium, the blockers did not inhibit cyanide-induced glucose output, indicating that the activity of glycogen phosphorylase and later processes leading to glucose output were not affected by the blockers. These data suggest that, in the presence of calcium, the blockers inhibit the effect of glucagon also at a step (or steps) subsequent to cyclic AMP production and before the activation of phosphorylase b, probably by inhibiting glucagon-induced mobilization of calcium from intracellular calcium pools rather than inhibiting calcium influx into hepatocytes.
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PMID:Inhibition by calcium channel blockers of the glycogenolytic effect of glucagon in perfused rat liver. 628 Apr 34

To study the effects of two Ca antagonists, nifedipine and niludipine, on insulin and glucagon secretion, experiments were performed using an in situ local circulation of the canine pancreas. The test drugs were injected into the pancreatic artery in three graded doses (5, 10 and 100 nmoles/kg) during arginine infusion, and blood samples were taken from the pancreatic vein. Verapamil, 10, 100 and 1,000 nmoles/kg, administered in the same way, was used as a control drug. Nifedipine, 5 to 100 nmoles/kg, decreased plasma insulin (IRI) and increased plasma glucagon (IRG) in the pancreatic vein, but caused no marked changes of blood glucose levels in five dogs. Niludipine, 5 to 100 nmoles/kg, injected into the pancreatic artery of 5 dogs, did not change blood glucose levels, but decreased slightly plasma IRI in the pancreatic vein and increased plasma IRG. Verapamil administered to 5 dogs caused no remarkable change of blood glucose or plasma IRG but decreased plasma IRI slightly. The maximum secretion of insulin was significantly lowered by nifedipine and niludipine, and that of pancreatic glucagon markedly increased by niludipine. The experiments revealed that Ca antagonists inhibit insulin secretion, and increase glucagon, and proved that calcium plays an important role in the A cell function of the pancreas.
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PMID:Effects of Ca antagonists, nifedipine, niludipine and verapamil, on endocrine function of the pancreas. 635 51

Verapamil has previously been found to inhibit insulin release from pancreatic beta-cells in laboratory animals. In our department, however, both oral pretreatment with verapamil for one week and a 3-hour iv infusion of the drug improved the tolerance to oral glucose in type II diabetics without affecting insulin release. It failed, however, to potentiate the hypoglycaemic effect of oral glibenclamide therapy in patients with type II diabetes. Since iv infusion of verapamil left the portal vein glucose response to glucose ingestion unaffected in normoglycaemic patients (being portal vein catheterised for diagnostic purposes), it seems unlikely that the hypoglycaemic effect of verapamil could have been due to reduced glucose absorption from the gut. More likely is that verapamil, in the diabetic patients, influenced metabolic processes inside the hepatocytes that are of importance for glucose homeostasis. In-vitro experiments have shown that calcium affects factors of importance for the glucose metabolism. Accordingly, calcium triggers the stimulus-secretion coupling process which leads to insulin release from the pancreatic beta-cells (1). Calcium also tightens cell membranes, thereby decreasing their permeability to various substances, including glucose (2). Finally, calcium mediates cellular responses to glucagon stimulation (3,4) and thus affects the hepatic glucose output. Calcium apparently influences glucose metabolism by several pathways and different overall effects on the blood glucose concentration may be forthcoming depending on which of these pathways is the dominating one.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of verapamil on glucose tolerance. 637 85


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