Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of pH was tested upon the inhibition of ATP-sensitive K+ (KATP) channels caused by the sulphonylurea drugs tolbutamide and glibenclamide. KATP channels and currents (I-KATP) were activated with SR 44866 in ventricular myocytes isolated from guinea pig hearts. Modification of either external or internal pH had little effect upon the background K+ current (IK1). External pH had no consistent effects upon I-KATP. The application of NH4Cl inhibited I-KATP and its withdrawal caused a slight rebound activation. Compared with the results obtained at pHo 7.4, inhibition of I-KATP by the sulphonylurea drugs was enhanced at pHo 6.5 and reduced at pHo 8.4. The kinetics of the recovery of I-KATP was independent of pHo. Neither internal pH 6.5 nor NH4Cl had any effect upon sulphonylurea-induced inhibition of I-KATP. The dose-response curves for inhibition of I-KATP at different pHo's were found to coincide when plotted for the unionized concentrations of the drugs. It is concluded that it is the unionized forms of the sulphonylurea drugs which are responsible for closure of KATP channels in cardiac muscle. In consequence, extracellular acidification during ischemia will increase the effective concentration of glibenclamide and may be responsible for the cardiovascular disorders associated with this treatment in noninsulin-dependent diabetics.
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PMID:Effects of pH upon the inhibition by sulphonylurea drugs of ATP-sensitive K+ channels in cardiac muscle. 162 14

Glibenclamide (Gli) 0.3, 1, 3 mg.kg-1 and tolbutamide (Tol) 3, 10, 30 mg.kg-1 iv 10 min before ischemia or ouabain infusion prevented ventricular fibrillation induced by ischemia in rat and arrhythmias induced by ouabain in guinea pig. Gli 10 mumol.L-1 and Tol 1 mmol.L-1 increased APD and ERP in rat ventricular muscle. Gli 0.1, 1, 10 mumol.L-1 and Tol 0.01, 0.1, 1 mmol.L-1 prevented and reversed the shortening of APD and ERP induced by hypoxia in guinea pig ventricular muscle. These effects of Gli and Tol were dose-dependent. The results confirmed that Gli and Tol were effective on arrhythmias induced by ischemia and ouabain by blocking ATP-sensitive potassium channel.
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PMID:Effects of glibenclamide and tolbutamide on ischemia- and ouabain-induced arrhythmias and membrane potentials of ventricular myocardium from rat and guinea pig. 181 92

Sulfonylurea derivatives glibenclamide and tolbutamide are selective blockers of ATP-sensitive K+ (KATP) channels. However, their ability to prevent cellular K+ loss and shortening of action potential duration during ischemia or hypoxia in the intact heart is modest compared with their efficacy at blocking KATP channels in excised membrane patches. In the isolated arterially perfused rabbit interventricular septum, the increase in unidirectional K+ efflux and shortening of action potential duration during substrate-free hypoxia were effectively blocked by glibenclamide, but only by very high concentrations (100 microM); during hypoxia with glucose present, glibenclamide was only partially effective at reducing K+ loss. During total global ischemia (10 minutes), up to 100 microM glibenclamide or 1 mM tolbutamide attenuated shortening of action potential duration but only reduced [K+]0 accumulation by a maximum of 32 +/- 6%. In isolated patch-clamped guinea pig ventricular myocytes in which the whole-cell ATP-sensitive K+ current was activated by exposure to the metabolic inhibitors, glibenclamide (up to 100 microM) and tolbutamide (10 mM) were only partially effective at blocking the whole-cell ATP-sensitive K+ current (maximum block, 51 +/- 10% and 50 +/- 9%, respectively), especially when ADP was included in the patch electrode solution. In inside-out membrane patches excised from these myocytes, glibenclamide blocked unitary currents through KATP channels with a Kd of 0.5 microM and a Hill coefficient of 0.5 in the absence of ADP at the cytosolic membrane surface, but block was incomplete when 100 microM ADP (+2 mM free Mg2+) was present. ADP had a similar effect on block of KATP channels by tolbutamide. These findings suggest that free cytosolic [ADP], which rises rapidly to the 100 microM range during early myocardial ischemia and hypoxia, may account for the limited efficacy of sulfonylureas at blocking ischemic and hypoxic cellular K+ loss under these conditions.
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PMID:Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle. 190 55

The chronic effects of tolbutamide on myocardial contractility of the diabetic heart during ischemia and reperfusion were evaluated in perfused, isolated rat hearts. Five experimental groups were used: (1) control rats (C), (2) insulin dependent diabetic rats (IDDM, single intravenous injection of 60 mg/kg streptozotocin (STZ) in male Sprague-Dawley rats), (3) non insulin dependent diabetic rats (NIDDM; single subcutaneous injection of 90 mg/kg STZ in 5 day neonates), (4) tolbutamide-treated IDDM and (5) NIDDM (T-IDDM, T-NIDDM; giving tolbutamide 100 mg/kg/day for 6 weeks via an orogastric tube every day, respectively). At 14 weeks of age, experiments were performed using a Langendorff perfused heart preparation. After equilibration, T (myocardial developed tension), +dT/dt (contraction velocity), -dT/dt (relaxation velocity) and RT (resting tension) were measured during a 15 min period of global ischemia, followed by reperfusion for 20 min. Basal values of T increased in both T-IDDM and T-NIDDM, compared to IDDM and NIDDM, respectively. The percent recovery rate of +dT/dt in T-IDDM increased significantly during both ischemia and reperfusion, but the change in T-NIDDM was not significant. The recovery rates of -dT/dt in T-IDDM and T-NIDDM were significantly higher throughout reperfusion than in IDDM and NIDDM, respectively. On the other hand, that of T in T-IDDM and T-NIDDM were significantly higher than IDDM and NIDDM throughout ischemia and reperfusion, respectively. The RT was significantly higher in IDDM than in C and NIDDM throughout ischemia and reperfusion. The RT was significantly lower during ischemia in IDDM, but it did not differ significantly from IDDM during reperfusion. These results indicate that chronic oral administration of tolbutamide directly improved myocardial contractility throughout ischemia and reperfusion regardless of the improvement of glycemia. The improvement was also greater in IDDM than in NIDDM.
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PMID:Chronic effects of tolbutamide on myocardial tension during ischemia and reperfusion in perfused hearts isolated from insulin dependent and non insulin dependent diabetic rats. 192 Aug 21

The ATP-sensitive potassium channel (KATP channel) is a unique ionophore in that it appears to reflect cell metabolism. In the brain, the highest density of binding sites for the KATP channel is the substantia nigra. To evaluate the role of the KATP channel in this key brain area for motor control, we used exposure to cyanide to lower intracellular ATP and thereby mimic anoxia and ischemia. Treatment with cyanide caused the activation of a potassium current in a sub-population of nigral neurones with distinct pharmacological and electrophysiological properties. The response to cyanide was abolished by the sulphonylurea tolbutamide, a potent blocker of the KATP channel. These results suggest that in the substantia nigra, the KATP channel plays a pivotal role in normal mechanisms of neuronal homeostasis in response to anoxia and ischaemia. The significance of these findings for our understanding of the cellular mechanisms in Parkinsonian degeneration is discussed.
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PMID:ATP-sensitive potassium channels counteract anoxia in neurones of the substantia nigra. 206 41

1. Ischaemia was simulated in the isolated sheep cardiac Purkinje fibre and guinea-pig papillary muscle by immersing the preparations in paraffin oil. Ion-selective microelectrodes recorded potassium (Ks+) and pH (pHs) in the thin film of Tyrode solution trapped at the fibre surface while other microelectrodes recorded intracellular pH (pHi), membrane potential and action potentials (AP) (evoked by field stimulation), or membrane current (two-microelectrode voltage clamp in shortened Purkinje fibres). Twitch tension was also monitored. The paraffin oil model reproduced the salient characteristics of myocardial ischaemia, i.e. a decrease of twitch tension; a decrease of pHi and pHs; a rise in Ks+ (by 2-3 mM); a depolarization of diastolic membrane potential; considerable shortening of the AP (up to 30% within 4 min). 2. The sulphonylurea compounds, glibenclamide (200 microM) and tolbutamide (1 mM), known inhibitors of the KATP channel, completely blocked the ischaemic rise of Ks+ and prevented AP shortening. Ischaemic tension decline was notably less pronounced in the presence of sulphonylureas. 3. The ischaemic increase of slope conductance (Purkinje fibre) was prevented by 1 mM-tolbutamide and 200 microM-glibenclamide. 4. Sulphonylureas did not affect resting membrane potential, the AP or the current-voltage relationship under non-ischaemic conditions (this also indicates that ischaemic Ks+ accumulation is not fuelled by the background K+ current [iK1] which was shown, as expected, to be Ba2+ sensitive). 5. In a normally perfused preparation, reducing intracellular ATP by inhibiting glycolysis with 2-deoxyglucose (DOG) produced a similar AP shortening plus a membrane hyperpolarization, both of which were inhibited by tolbutamide or glibenclamide. The AP shortening was not related uniquely to the fall of pHi observed under these conditions since experimentally reducing pHi (by reducing pHo in the absence of DOG) lengthened rather than shortened the AP. 6. The possibility that the ischaemic rise in Ks+ might be the cause of AP shortening was excluded by the observation that, in a normally perfused Purkinje fibre, experimentally reducing pHi (by an amount similar to that seen during ischaemia) completely neutralized the AP-shortening effect of an elevated Ko+ (from 4.5 to 6.5 mM). Furthermore, the sulphonylurea-sensitive AP shortening seen during DOG treatment could not have been associated with a Ks+ rise since, in these particular experiments, the fibres were well perfused and diastolic membrane potential hyperpolarized.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of potassium efflux and action potential shortening during ischaemia in isolated mammalian cardiac muscle. 212 31

Many clinical studies have shown an increased insulin response to oral glucose in patients with ischemia of the heart, lower limbs, or brain. Hyperinsulinemia also occurs in patients with angiographically proved atherosclerosis without ischemia and thus appears to be related to arterial disease and not to be a nonspecific response to tissue injury. Fasting insulin levels and insulin responses to intravenous stimuli, including glucose, tolbutamide, and arginine, are normal, suggesting a gastrointestinal factor may be involved in the increased insulin response to oral glucose. In patients with atherosclerosis, insulin sensitivity appears to be normal or enhanced with respect to both glucose and lipid metabolism. Five population studies have shown that insulin responses to glucose are higher in populations at greater risk of cardiovascular disease. Many of the hyperinsulinemic populations also had upper-body obesity, hypertriglyceridemia, lower high-density lipoprotein (HDL) levels, and hypertension. These prospective studies support an independent association between hyperinsulinemia and ischemic heart disease, although their results differ in detail. Hyperinsulinemia is associated with raised triglyceride and decreased HDL cholesterol levels. Total and low-density lipoprotein (LDL) cholesterol is less closely related to hyperinsulinemia. Upper-body adiposity is associated (in separate studies) with coronary heart disease, diabetes, hyperinsulinemia, and hypertriglyceridemia. Insulin and blood pressure are closely related in both normotensive and hypertensive people. Although obesity and diabetes are often found in hypertensive people, hyperinsulinemia also occurs in nonobese nondiabetic hypertensive people. Thus, hyperinsulinemia is closely associated with a cluster of cardiovascular risk factors, i.e., hypertriglyceridemia, low HDL levels, hypertension, hyperglycemia, and upper-body obesity. There is a possibility that insulin has a role in the sex differences in ischemic heart disease incidence and their absence in diabetes, but additional work is required for its clarification. Long-term treatment with insulin results in lipid-containing lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions. Insulin stimulates lipid synthesis in arterial tissue; the effect of insulin is influenced by hemodynamic factors and may be localized to certain parts of the artery. In physiological concentrations, insulin stimulates proliferation and migration of cultured arterial smooth muscle cells but has no effort on endothelial cells cultured from large vessels. Insulin also stimulates cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin and atheroma. 20-yr perspective. 199 42

We have confirmed the findings of Kantor and colleagues that ischemia-induced fibrillation in isolated Langendorff-perfused rat hearts can be prevented by glyburide, a blocker of ATP-dependent K channels. These data suggest that block of ATP-dependent K current [IK(ATP)] is a novel antiarrhythmic mechanism. This hypothesis was further tested by evaluating the effects of another sulfonylurea IK(ATP) blocker, tolbutamide (1 mM) and two agents known to activate these channels in cardiac tissue, BRL 34915 (10 microM) and pinacidil (30 microM). Similar to glyburide, tolbutamide was also effective in preventing fibrillation in this isolated rat heart model. The IK(ATP) activators enhanced the rate of tachycardia and shortened the time required for the hearts to develop fibrillation. Coadministration of glyburide with either IK(ATP) activator prevented their effects. It is concluded that activation of IK(ATP) during global ischemia contributes to the development of fibrillation in the perfused rat heart model.
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PMID:Influence of ATP-sensitive potassium channel modulators on ischemia-induced fibrillation in isolated rat hearts. 250 53

The effects of the sulphonlyurea drugs glibenclamide and tolbutamide were tested upon ATP-sensitive K+ channels activated by dinitrophenol or carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP) in ventricular myocytes isolated from rat hearts. In whole-cell current recording, 1 microM glibenclamide or 1 mM tolbutamide totally but only transiently inhibited the K+ current activated by dinitrophenol or FCCP. In cell-attached membrane patches, 1 to 100 microM glibenclamide initially inhibited the activation of ATP-sensitive K+ channels induced by dinitrophenol or FCCP, but failed to prevent the activation of these channels during contracture. Myocyte contracture induced by caffeine or Ca++ entry during K+ depolarization did not activate ATP-sensitive K+ channels. In excised membrane patches, 1 to 10 microM glibenclamide did not block completely opening of ATP-sensitive K+ channels. Neither intracellular ADP nor phosphorylable substrate were able to reliably influence the effect of glibenclamide. It is concluded that sulphonylurea drugs, otherwise highly effective blockers of this type of ion channel, were no longer able to inhibit the opening of ATP-sensitive K+ channels during the final stages of metabolic stress. These channels could therefore be responsible for both the glibenclamide-sensitive and glibenclamide-insensitive phases of K+ loss during cardiac ischemia.
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PMID:Sulphonylurea drugs no longer inhibit ATP-sensitive K+ channels during metabolic stress in cardiac muscle. 833 72

Local vasodilation in response to hypoxia or ischemia improves perfusion and O2 supply of the affected tissue. This local vasodilation thus constitutes the most important mechanism in the prevention of ischemic cell injury. The regulation of vascular tone has mainly been attributed to changes of cytoplasmatic Ca2+ ((Ca2+)i) concentrations in vascular smooth muscle cells. The mechanism underlying these changes has not, however, been elucidated so far. Using aortic strips of guinea pigs (transversally cut in spirals; normal Tyrode, in mM: NaCl 150, KCl 4.5, MgCl2 2, CaCl2 2.5, glucose 10; buffered with 10 mM HEPES at pH 7.4; equilibrated with 100% O2 at 31 degrees C) the authors could show that metabolic blockade (glucose replaced by 10 mM 2-deoxyglucose (DOG) led to a relaxation of the preparation. Thus, in four experiments, resting tension decreased from 0.75 g by 27% +/- 12% within two hours (% of maximal contractile force developed by each preparation when depolarized with 43 mM KCl and 101.5 mM NaCl). When the same experiment was carried out in the presence of 1 mM tolbutamide (a known blocker of ATP-dependent K+ channels) in vascular smooth muscle no such relaxation could be seen (n = 4). Furthermore, in the same type of preparation, similar results have been obtained upon hypoxic relaxation (100% O2 replaced by 100% N2), where 1 mM tolbutamide also prevented vasodilation. Thus, hypoxic/ischemic vasodilation in response to glycolytic inhibition (DOG) and hypoxia (N2) is based upon the opening of K+ ATP channels and hence can be prevented by sulfonylureas (the opening of K+ ATP channels would lead to hyperpolarization (increased K+ conductance, Goldmann equation), thus diminishing the open probability of voltage-gated Ca2+ channels with subsequent vasodilation). This inhibition by sulfonylureas of vasodilative response to ischemia may also constitute the so far unknown cause of the increased cardiovascular mortality seen under sulfonylurea treatment.
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PMID:Vasodilative response to hypoxia and simulated ischemia is mediated by ATP-sensitive K+ channels in guinea pig thoracic aorta. 844 33


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