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 pretreatment with selective beta 1-adrenoceptor blockers (dl-nebivolol or atenolol) on myocardial mechanical activity, mitochondrial function, morphology, and calcium cytochemistry was studied during normothermic ischemic arrest and reperfusion of isolated working rabbit hearts. The hearts subjected to 25 min of ischemia followed by 30 min of post-ischemic reperfusion showed typical signs of severe myocardial ischemic damage. The ultrastructural changes showed a good relation with the changes in mechanical activity and mitochondrial function. To determine whether these changes could be prevented or reduced by beta 1-adrenoceptor blockade, dl-nebivolol or atenolol (0.62 mg/liter) was added to the perfusate 30 min before the induction of ischemia. The results showed that dl-nebivolol exerted a protective effect on recovery of mechanical activity, on mitochondrial function during reperfusion as well as on the ultrastructure as examined at the end of the reperfusion period. On the other hand, atenolol failed to protect the myocardium against ischemia-reperfusion damage in the isolated working rabbit heart.
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PMID:Normothermic ischemic cardiac arrest in the isolated working rabbit heart: effects of dl-nebivolol and atenolol. 167 98

The influence of global ischemia on cardiac beta-adrenoceptors was studied in rat and guinea pig Langendorff hearts (LH), both by functional and binding experiments using the specific beta-adrenoceptor ligand (-)-[125I]-iodocyanopindolol. Neither ischemia (30 or 60 min) nor postischemic reperfusion caused any change in beta-adrenoceptor density, affinity or in the beta 1/beta 2 ratio in LH of normal rats or in LH of rats pretreated with reserpine or 6-hydroxydopamine (6-OHDA), or in guinea pig LH, whereas perfusion of rat LH with 10(-5) M isoprenaline (15 min) caused the expected decrease in beta-adrenoceptor density. After ischemia, isoprenaline was no longer able to influence beta-adrenoceptor density, suggesting that the internalization mechanism is impaired. In functional studies, perfusion of the rat LH with 10(-5) M isoprenaline (15 min) shifted the concentration-response curve for isoprenaline to the right. Thirty-minute global ischemia virtually abolished the inotropic but not the chronotropic response to isoprenaline. Ischemia did not impair the inotropic response to ouabain or to calcium, indicating that the contractile apparatus itself was still largely intact. Our results suggest that the contractile failure after ischemia is not caused by a decrease in beta-adrenoceptor density or by a defect in the contractile apparatus but by an impaired second-messenger system.
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PMID:Discrepancies between inotropic responses and beta-adrenoceptor characteristics after global ischemia in isolated hearts. 172 64

Although silent ischemia may be linked to increases in cardiovascular morbidity and mortality, the long-term effects of a strategy aimed at the detection and treatment of this asymptomatic condition have not been fully explored. We therefore have developed the Atenolol Silent Ischemia Trial (ASIST), the first multicenter, randomized, prospective study of the prognostic implications of silent ischemia in asymptomatic and minimally symptomatic patients with coronary artery disease. Inclusion criteria for study patients were documented coronary artery disease, evidenced angiographically or by previous myocardial infarction, and transient ischemia, evidenced by abnormalities of regional wall motion, stress thallium-201, or exercise electrocardiogram. The main objective of ASIST is to assess the influence of frequency and duration of symptomatic and asymptomatic ischemic episodes on the occurrence of fatal and nonfatal cardiac events. Atenolol, a beta 1-selective adrenergic blocker, was chosen as the therapeutic intervention because of its potential benefits in treating both symptomatic and asymptomatic ischemia. Ambulatory electrocardiographic monitoring will be used to measure the frequency and duration of ischemic episodes during daily life. The predictive ability of short-term (4-week) effects on long-term (52-week) response to atenolol treatment is also being assessed, along with the economic impact of this diagnostic and therapeutic strategy. Given the current emphasis on reducing morbidity and mortality associated with coronary artery disease, ASIST results should shed light onto the long-term management and prognostic implications of this otherwise asymptomatic condition.
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PMID:The prognostic and economic implications of a strategy to detect and treat asymptomatic ischemia: the Atenolol Silent Ischemia Trial (ASIST) protocol. 181 Jun 81

The effects of regression of left ventricular hypertrophy following atenolol and bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats (SHR) were studied. Atenolol (50 mg/kg/day) and bunazosin (5 mg/kg/day) were administered to SHR from 19 to 26 weeks of age, whereas tap water was given to control SHR and normotensive Wistar-Kyoto rats (WKY). Both atenolol and bunazosin significantly decreased arterial blood pressure and significantly decelerated the increase in left ventricular weight in SHR. At the end of the long-term treatment, hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The pressure-rate product and the extent of recovery of the coronary flow after reperfusion following 30 min of ischemia in the bunazosin-treated SHR were significantly higher than those in the control SHR and the atenolol-treated SHR. The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were significantly lower than those in the reperfused WKY. Both atenolol and bunazosin improved the restoration of ATP and CrP in SHR after reperfusion following 30 min of ischemia. In conclusion, antihypertensive therapy with either atenolol or bunazosin was effective in preventing cardiac hypertrophy and ischemic damage caused by different mechanisms. Factors resulting from stimulation of the cardiac alpha 1 adrenoceptor may play an important role in the development of hypertensive cardiac hypertrophy, just as factors resulting from stimulation of the beta 1-adrenoceptor do.
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PMID:Effects of regression of left ventricular hypertrophy following atenolol or bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats. 183 20

Although the benefit of beta-adrenergic blocking agents in acute coronary ischemia has been well documented, it is unclear whether the responsible mechanisms include the modification of platelet function. In recent studies, metoprolol appeared to reduce the total number and duration of episodes of silent ischemia in patients with stable coronary artery disease throughout the day. This effect was not associated with a change in baseline or circadian variability of the platelet aggregability. Since the treatment caused significant decreases in heart rate and blood pressure, the drug effect is more likely to be based on reduction of myocardial oxygen demand. Metoprolol, however, prevented a platelet aggregability increase and intracellular cAMP decrease during exercise stress testing in patients with stable angina pectoris. We speculate that this effect of beta 1-adrenergic blockade may be due to hemodynamic and neurohormonal changes, or possibly also to an increase in synthesis or release of platelet inhibiting substances.
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PMID:Beta 1-blockade and acute coronary ischemia. Possible role of platelets. 195 17

The purpose of this study was to explore alterations in the life cycle of adrenergic receptors and the Gs protein in the heart of ischemic animals. In initial experiments left anterior descending coronary artery occlusion was performed in guinea pigs. Sarcolemmal (SL) and light vesicle (LV) (presumably intracellular) fractions were prepared. Both fractions contained a substantial number of beta-adrenergic receptors and alpha 1-adrenergic receptors: the relative proportion of beta-adrenergic receptors in LV/SL was greater than for alpha 1-adrenergic receptors. Myocardial ischemia produced a rapid externalization of beta-adrenergic receptors from LV to SL. alpha 1-adrenergic receptors also increased in SL but without an apparent externalization from LV. Pretreatment of animals with either the non-selective beta-antagonist propranolol or the beta 1-selective antagonist atenolol increased the number of SL beta-receptors and blunted the ischemia-induced increase in SL beta-adrenergic receptors. Treatment with the partial agonist pindolol did not cause up-regulation of beta-receptors, and did not block ischemia-induced externalization. In the second part of this study, we have begun to examine post-receptor events in a rat model of myocardial ischemia. Ligation of the distal left main coronary artery in the rat led to an increase in SL beta-receptors. As G proteins play a pivotal role in transducing receptor occupancy to activation of effector molecules, we measured levels of Gs which stimulates adenylate cyclase activity, using an ELISA technique. In rat SL the amount of alpha s markedly decreased within 15 min of coronary occlusion. There was no transfer of Gs activity to the light vesicle fraction. These studies indicate the dynamic nature of adrenergic receptors and the alpha s protein in the sarcolemma in myocardial ischemia. Changes in adrenergic receptor number and in G protein expression may contribute to the altered pathophysiology of the ischemic heart.
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PMID:Beta-adrenergic receptors and the Gs protein in myocardial ischemia and injury. 196 4

The short-term effects of oral diltiazem on hemodynamics and distribution of cardiac output at rest and during semiupright bicycle exercise were evaluated in eight patients with stable effort angina on long-term beta 1-adrenergic blockade. Cardiac output and iliofemoral blood flow were measured using thermodilution. The patients were exercised to the same work load on a bicycle before and 2 h after oral diltiazem (60 mg in two patients and 120 mg in six). At maximal exercise, diltiazem reduced heart rate from 94 +/- 5 to 88 +/- 6 beats/min (p less than 0.01), mean arterial pressure from 139 +/- 5 to 127 +/- 4 mm Hg (p less than 0.01) and systemic vascular resistance from 9.7 +/- 0.7 to 8.4 +/- 0.4 x 10(2) dynes.s.cm-5 (p less than 0.05) compared with control. During exercise, cardiac output, iliofemoral blood flow, mean pulmonary wedge pressure and mean right atrial pressure were not altered, but stroke volume increased from 119 +/- 11 to 131 +/- 10 ml (p less than 0.05). Maximal ST segment depression during exercise was decreased and angina was less. Diltiazem does not alter the distribution of the cardiac output during exercise but improves ischemia.
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PMID:Effects of diltiazem and long-term beta 1-adrenergic blockade on hemodynamics and blood flow during exercise in patients with stable angina pectoris. 196 60

The effect of betaxolol, a beta 1-adrenoceptor antagonist, on ischemic myocardial metabolism was studied in dog hearts subjected to an occlusion of the left anterior descending coronary artery for 10 or 30 min. Betaxolol (0.1 or 0.3 mg/kg) was injected i.v. 5 min before ischemia. Betaxolol decreased heart rate, (+)dp/dt, coronary flow and blood pressure. Coronary occlusion decreased the levels of creatine phosphate, adenosine triphosphate, total adenine nucleotides and energy charge potential in the ischemic myocardium. Ten minutes after ischemia, betaxolol significantly diminished these impairments of energy metabolism. Even 30 min after ischemia, a higher dose of betaxolol significantly inhibited the depletion of total adenine nucleotides. Myocardial ischemia produced a breakdown of glycogen, an accumulation of lactate and an inhibition of glycolytic flux through the phosphofructokinase reaction. Betaxolol also reduced these alterations of carbohydrate metabolism 10 min after ischemia. These results indicate that betaxolol delays the onset of myocardial metabolic change from aerobic to anaerobic during ischemia and hence reduces the severity of myocardial ischemic injury.
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PMID:[Effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial energy and carbohydrate metabolism in dogs]. 197 37

Although the general pharmacokinetics of midazolam (M) are well documented, little is known about the possible effects of a thigh tourniquet on the distribution and elimination of this drug. METHOD. Institutional approval for the study and individual informed consent were obtained. We studied 30 patients (ASA-I) without premedication who electively underwent a surgical procedure of the lower limb. Patients were divided into three groups of 10. The procedure was done in groups I and II with and in group III without tourniquet use. Anesthesia was induced in groups I and II with 0.1 mg/kg M, fentanyl 5 micrograms/kg, alcuronium-dichloride 0.15 mg/kg and etomidate 0.1-0.2 mg/kg i.v. and maintained with enflurane 0.3-1.0 vol.-%. About 20 min after midazolam injection and after exsanguination the tourniquet was applied on the proximal thigh in group I. In group II anesthesia was induced with etomidate 0.2 mg/kg and alcuronium-dichloride 0.15 mg/kg i.v., and maintained about 20 min with enflurane 1.0-1.5 vol.-% until exsanguination and tourniquet application. After this, these patients also received 0.1 mg/kg M and 5 micrograms/kg fentanyl i.v. Through an indwelling arterial line, blood samples were obtained prior to and 2, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165 and 180 min after M injection. Plasma M levels were measured by high-performance liquid chromatography with UV detection. These concentrations were fitted to a two-compartment open model. Comparison between groups was performed using the Kruskal-Wallis test and p less than 0.05 was considered to indicate significance. RESULTS. The groups were all comparable in age and weight, and groups I and II also in duration of thigh ischemia. Midazolam elimination half-time (t beta 1/2) was significantly shorter in group II than in groups III and I (52 min vs 126 min and 139 min; p less than 0.05). Of the calculated distribution volumes (volume of the central compartment, volume in the steady state and volume in the elimination phase), only the volume in the steady state was significantly smaller in group II than in groups III and I (p less than 0.05). Groups III and I did not differ significantly in the computed parameters. The measured initial midazolam mean concentrations in group II were twice those in groups III and I (655 ng/ml vs 323 ng/ml and 332 ng/ml). Since clearance was not significantly different between any two groups, the shorter t beta 1/2 in group II was probably due to the reduced distribution volume. CONCLUSION. These data demonstrate that in the presence of a thigh tourniquet the timing of the injection - before or after application of the tourniquet is of decisive importance. Injection after the application of a tourniquet leads to an higher plasma level and shortens the elimination half-life.
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PMID:[The effect of a thigh tourniquet on the pharmacokinetics of midazolam]. 204 8

Ischaemia imposes a progression of damage on the myocardium, starting with a loss of adenosine triphosphate, creatine phosphate, potassium and active tension-generating capacity. These changes progress until the tissue is incapable of maintaining ionic homeostasis, is depleted of purine precursors and shows evidence of structural disorganization. Upon reperfusion the ischaemia-induced damage is exaggerated, primarily because of the accompanying uncontrolled gain in calcium, increasing tissue osmolarity and release of endogenous noradrenaline. When used prophylactically, calcium antagonists attenuate many of the deleterious effects of ischaemia and reperfusion. We have previously shown that long-term administration of verapamil to rats (50 mg/kg daily, orally) depletes their cardiac stores of noradrenaline (NA) (3.9 +/- 0.3 micrograms/g dry wt in controls vs 0.9 +/- 0.1 micrograms/g dry wt NA after 6 weeks of therapy). This loss of NA was not accompanied by a change in beta 1-adrenoceptor density (35.5 +/- 1.9 fmol/mg protein for controls vs 31.2 +/- 2.3 fmol/mg protein after 6 weeks of therapy). Verapamil withdrawal after 6 weeks of therapy resulted in a restoration of ventricular NA levels; within 2 days they had recovered to 75% of their original values. The density of the beta 1-adrenoceptor was unaltered. Withdrawal of verapamil results in rapid repletion of cardiac NA, with an initial but transient reduction in beta 1-adrenoceptor density. The absence of beta 1-adrenoceptor "up-regulation" under these conditions probably contributes to the absence of withdrawal problems upon cessation of verapamil therapy.
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PMID:Effect of verapamil withdrawal on cardiac beta 1-adrenoceptor density. 217 7


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