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)

Org 7797 is effective against ventricular fibrillation (VF) induced during ischemia. In Langendorff-perfused pig hearts, application of three premature stimuli to nonischemic myocardium between 3 and 5 min after coronary occlusion always resulted in VF in the absence of drug. In no instance when Org 7797 was present (2-10 microM) could VF be induced, although sustained and nonsustained ventricular tachycardias (VTs) could still be initiated in about two thirds of treated hearts. We determined the effects of Org 7797 on wavelength in normal and ischemic myocardium during regular driving at a cycle length of 350 ms. Wavelength, the algebraic product of conduction velocity and refractory period, is considered a useful parameter in assessing efficacy of antiarrhythmic agents in preventing reentrant arrhythmias. Conduction velocity was obtained by analyzing the spread of activation under 121 unipolar electrodes (1 mm apart) placed around a central stimulus electrode. Refractory periods were determined with premature test stimuli at an intensity of twice diastolic threshold. Both in normal and ischemic myocardium Org 7797 (5-10 microM) produced a marked shortening of wavelength. This should predispose to reentry. However, Org 7797 prolonged the refractory period at the fastest possible driving rate from 154 to 247 ms and attenuated (5 microM) or prevented (10 microM) shortening of the refractory period during application of subsequent premature stimuli. The antifibrillatory effect of the drug may be explained by prolongation of wavelength at very short cycles.
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PMID:Mechanism of antifibrillatory action of Org 7797 in regionally ischemic pig heart. 169 95

The role of blood platelets in ischemia- and reperfusion-induced arrhythmias and the efficacy of three calcium blocking drugs (verapamil, diltiazem, and nicardipine) in preventing the arrhythmias were investigated. Using anesthetized rats, we measured platelet count (Pc) continuously in vivo with a Technicon autocounter. Thromboxane B2 (TxB2) and 6-keto-PGF1 alpha levels in blood from coronary sinus were determined by radioimmunoassay (RIA). Myocardial ischemia and arrhythmias were monitored from lead I ECG during and after occlusion of the left anterior descending coronary artery (LAD) for 7 min. Ischemia-induced arrhythmias were mainly ventricular ectopic contractions (VECs), whereas reperfusion produced VECs, ventricular tachycardia (VT), and reversible and irreversible ventricular fibrillation (VF). Both ischemia and reperfusion decreased platelet count and increased TxB2 level in blood from the coronary sinus. The effects of the CEBs were determined at two dose levels (0.1 and 0.3 mg/kg). Each calcium entry blocker (CEB), at both dose levels, significantly inhibited ischemia-induced arrhythmias. Verapamil and diltiazem significantly reduced reperfusion-induced VECs, prevented VT and irreversible VF, and reduced the number of animals with reversible VF. Nicardipine in preventing arrhythmias was not very effective at either dose. The CEBs also inhibited both ischemia- and reperfusion-induced decreases in PC with a moderate increase (up to 7%) as compared with levels in sham-operated controls. The CEBs also significantly reduced TxB2 levels in blood from the coronary sinus. These results indicate that ischemia and postischemic reperfusion both induce platelet aggregation in rats. Aggregating platelets release biologically active substances including thromboxane A2 (TxA2) which exacerbates existing ischemia and facilitates generation of arrhythmias. CEBs inhibit platelet aggregation and TxA2 release and enhance PGI2 synthesis, thereby preventing arrhythmias.
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PMID:Occlusion and reperfusion-induced arrhythmias in rats: involvement of platelets and effects of calcium antagonists. 169 43

Efficacy of flecainide was investigated in 50 patients with sustained ventricular tachycardia (n = 38) or ventricular fibrillation (n = 12) during a 4-week in-hospital and 1-year follow-up period. Furthermore, the predictive value of programmed electrical stimulation, Holter monitoring, and exercise testing on outcome of long-term treatment was studied. Etiology of the tachyarrhythmia was coronary artery disease in 37 patients and other etiologies in 13 patients. The success rate of flecainide after 1 year, based on intention to treat, was 54%. The success rate during the in-hospital phase was 84% (in six patients flecainide was discontinued because of tachyarrhythmia and in two because of side effects). Calculated after 4 weeks hospitalization, the success rate was 78% for patients with tachyarrhythmias based on coronary artery disease and 55% for patients with tachyarrhythmias based on other etiologies (11 patients showed recurrences and two patients severe side effects). Patients with tachyarrhythmias based on coronary artery disease showed a lower ejection fraction and earlier recurrence than patients with arrhythmias based on other etiologies. Proarrhythmic effects developed in six patients (12%). Electrophysiological evaluation was performed in 28 patients at baseline and after intravenous flecainide. Negative predictive value of the electrophysiological evaluation after intravenous flecainide for patients with inducible tachyarrhythmias at baseline (n = 21) was 40%. For Holter monitoring (n = 24) this value was 86%. Non-ischemia-related induction of tachycardia by exercise was present in two of 30 patients on flecainide; both patients showed recurrence of the tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Flecainide: long-term effects in patients with sustained ventricular tachycardia or ventricular fibrillation. 169 10

The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.
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PMID:Effects of combined thromboxane synthetase inhibition/thromboxane receptor antagonism in two models of sudden cardiac death in the canine: limited role for thromboxane. 169 68

Local inhibition of angiotensin-converting enzyme (ACE, kininase II) produces both attenuation of angiotensin (Ang) II generation and bradykinin (BK) degradation. To delineate the participation of BK in the cardioprotective actions of ACE inhibitors, experiments were performed in rats and dogs with cardiac ischemia-reperfusion injuries. (I) In rat isolated perfused working hearts with regional myocardial ischemia, BK in concentrations as low as 1 X 10(-9) M increased coronary flow (CF) and reduced the incidence and duration of reperfusion ventricular fibrillation (VF). In addition, enzyme activities of lactate dehydrogenase (LDH) and creatine kinase as well as lactate output were decreased in the venous effluent of BK-perfused hearts, which also showed improved cardiodynamic and metabolic parameters. Even concentrations of BK lower than 1 X 10(-10) M, which were without influence on coronary flow, exerted comparable beneficial metabolic effects connected with reduced incidence and duration of VF. Combined perfusions with threshold concentrations of BK (1 X 10(-12) M) and the ACE inhibitor ramiprilat (2.58 X 10(-9) M), which were ineffective given alone, resulted in a marked cardioprotective effect. Perfusion with Ang II (1 X 10(-9) M) aggravated reperfusion arrhythmias and worsened myocardial metabolism. BK perfusion prevented this deterioration in a concentration-dependent manner, whereas the Ang II receptor antagonist saralasin was only marginally effective. The BK antagonist D-Arg-[Hyp2, Thi5,8, D-Phe7]-BK (1 X 10(-5) M) completely abolished the cardioprotective effects of BK or the ACE inhibitor. However, higher concentrations of BK (1 X 10(-7) M) or ramiprilat (2.58 X 10(-5) M) competitively reversed these properties of the BK antagonist. (II) In anesthetized dogs, BK was infused into the coronary artery in a dose of 1 ng/kg/min during occlusion (90 min) and reperfusion (30 min) of the left descending coronary artery (LAD)--a dose without effects on cardiovascular parameters. In line with the findings in isolated ischemic rat hearts, BK infusion reduced LDH activities and lactate concentrations in the coronary sinus blood, whereas myocardial tissue levels of glycogen and energy-rich phosphates were increased in the infarcted area. The cardioprotective effects produced by perfusion with BK or by reduction of BK degradation through local interference with ACE favor a role for BK in ischemia-reperfusion injuries in rats and dogs.
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PMID:Local inhibition of bradykinin degradation in ischemic hearts. 169 70

The effects of superoxide dismutase (SOD) on reperfusion-induced ventricular fibrillation (R-VF) were determined in isolated, perfused rat hearts with reperfusion after durations of regional myocardial ischemia ranging from 5 to 37.5 min. SOD (100 U/ml) was perfused during both ischemia and reperfusion periods. Regional myocardial ischemia was produced by acute occlusion of the left anterior descending coronary artery (LAD). Reperfusion after a brief period of ischemia (8 min) resulted in R-VF in 33% of SOD-perfused hearts as compared with 100% of control hearts that exhibited this arrhythmia (p less than 0.05). The incidence of R-VF was not affected by SOD with intermediate duration of ischemia of 10, 15, and 22.5 min. Reperfusion after a relatively long 30-min period of ischemia did not result in R-VF in control hearts, but 87% of SOD-treated hearts still exhibited this arrhythmia (p less than 0.05). No hearts exhibited R-VF with reperfusion after 37.5 min of ischemia. Thus, SOD shifted the occurrence of R-VF to longer durations of ischemia without affecting the peak incidence of this arrhythmia. In contrast to effects of SOD on incidence of R-VF, SOD had no effect on onset times of this arrhythmia. Nor did SOD affect reperfusion-induced ventricular tachycardia (VT), heart rate (HR), or coronary flow. These results suggest that SOD may have delayed onset of electrophysiologic derangements that were specifically responsible for R-VF. SOD may be classified as a modulator of R-VF.
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PMID:Delay of occurrence of reperfusion-induced ventricular fibrillation in the isolated rat heart with superoxide dismutase. 170 Feb 19

The effects of probucol, a lipophilic antioxidant, on the myocardial dysfunction (stunning) observed during reperfusion after 15-min ischemia in rabbit heart were studied. Rabbits received food with or without 1% probucol for 3 weeks. They were then anesthetized and prepared for recording of myocardial segment shortening, arterial blood pressure (BP), left ventricular pressure (LVP), rate of development of LVP (dP/dt), and a lead II ECG. Regional myocardial ischemia was produced by acute occlusion of the first marginal branch of the left coronary artery. Myocardial segment shortening was depressed after reperfusion in control rabbits. In comparison, myocardial segment shortening was significantly greater in probucol-treated rabbits than in control rabbits during reperfusion, indicating a beneficial effect. No hemodynamic or ECG changes measured could explain this difference. The number of premature ventricular contractions was reduced in the probucol-treated group, although the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) were not. Concentrations of probucol in serum and heart of five rabbits were 15.0 +/- 1.2 micrograms/ml and 17.5 +/- 2.5 micrograms/g (mean +/- SEM), respectively. Only probucol concentrations in the serum were positively correlated with the improvement in myocardial segment shortening (r = 0.91, p = 0.03). We conclude that a clinically relevant serum concentration of probucol reduces ischemia-induced myocardial stunning in the rabbit.
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PMID:Probucol reduces myocardial dysfunction during reperfusion after short-term ischemia in rabbit heart. 170 50

Isolated hearts excised from normotensive (NT) and spontaneously hypertensive (SH) rats subjected to transient normothermic global ischemia were used to study the effect of chronic treatment with iloprost on reperfusion-induced arrhythmias and myocardial ion shifts. After 30 min of ischemia, iloprost given s.c. in doses of 10, 50, 100 and 200 micrograms/kg per day for 14 days reduced the incidence of reperfusion-induced ventricular fibrillation (VF) in isolated hearts from the control value of 91 to 83, 75, 50 (P less than 0.05) and 25% (P less than 0.01) respectively, in NT rats. In the SH groups, the incidence of VF was also reduced from 100 to 75, 58, 33 (P less than 0.01) and 17% (P less than 0.001), respectively, with 10, 50, 100 and 200 micrograms/kg per day of iloprost. A similar reduction was observed in the incidence of reperfusion-induced ventricular tachycardia (VT). Ischemia and reperfusion caused significant changes in myocardial ion contents, i.e. an increase in Na+ and Ca2+ and a decrease in K+ and Mg2+ concentrations. The myocardial water content was also increased in parallel to the Na+ gain. The effect of iloprost given s.c. in doses of 50 and 200 micrograms/kg per day for 14 days was also measured on myocardial ion contents after 15- or 30-min ischemia and 30-min ischemia plus 10-min reperfusion. The higher iloprost dose significantly reduced the myocardial Na+, Ca2+ and water gains and the loss of K+ induced by ischemia and reperfusion in the NT and SH groups, while the decrease in Mg2+ content was alleviated only in SH rats. The results suggest that long-term iloprost treatment reduces the incidence of reperfusion-induced VF and VT by preventing Na+, Ca2+ and water accumulation as well as K+ and Mg2+ loss from myocardial tissue.
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PMID:Effect of iloprost on reperfusion-induced arrhythmias and myocardial ion shifts in isolated rat hearts. 170 6

We have investigated the contribution of the renin-angiotensin system to the damage caused by 40-min global ischemia in the isolated rat heart. A converting enzyme inhibitor, enalaprilat (70 nM), an angiotensin II receptor antagonist, compound 89 (2 microM), and an inhibitor of rat renin, CGP 44099A (20 nM), given before ischemia reduced the median duration of ventricular fibrillation on reperfusion to a similar extent (5.53, 5.72, and 5.14 min, respectively, compared to 13.98 min in the control group) but had no effect on creatine phosphokinase release (22.2 +/- 2.6, 22.1 +/- 6.8, and 24.1 +/- 3.6, IU/30 min, respectively, compared to 19.9 +/- 1.9 IU/30 min) or recovery or left ventricular developed pressure (67 +/- 6, 73 +/- 7 and 71 +/- 6%, respectively, compared to 66 +/- 3% after 30 min reperfusion). The increase in coronary resistance and left ventricular diastolic pressure on reperfusion was not affected by any of the agents. All three agents also tended to reduce the duration of ventricular fibrillation when given only on reperfusion. We conclude that angiotensinogen is present in the rat heart and it is converted to angiotensin I by a renin or a renin-like aspartic proteinase. The angiotensin I is converted to angiotensin II by converting enzyme. The angiotensin II formed is an important mediator of postreperfusion ventricular fibrillation in the isolated rat heart but does not contribute to the reduction in mechanical function produced by global ischemia in this preparation.
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PMID:Involvement of the renin-angiotensin system in ischemic damage and reperfusion arrhythmias in the isolated perfused rat heart. 171 94

The contribution of intracellular calcium to ventricular fibrillation (VF) was investigated using chronically instrumented dogs with healed myocardial infarctions. A 2-minute coronary occlusion was initiated during the last minute of exercise. Fourteen animals developed ventricular fibrillation (susceptible) whereas the remaining 12 did not (resistant) during this exercise plus ischemia test. The test was then repeated for the susceptible animals after pretreatment with the intracellular calcium chelator BAPTA-AM (1.0 mg/kg). BAPTA-AM significantly reduced left ventricular dp/dt max and prevented VF in 8 of 12 susceptible animals. Conversely, myocardial cytosolic calcium levels were increased in resistant animals using the calcium channel agonist Bay K 8644 (30 micrograms/kg) or phenylephrine (10 micrograms.kg-1.min-1 3-5 min before occlusion). Bay K 8644 induced VF in all 5 resistant animals tested whereas phenylephrine induced VF in 8 of 12 resistant animals. BAPTA-AM pretreatment attenuated the hemodynamic effects of Bay K 8644 or phenylephrine and prevented VF in five of five Bay K 8644- and four of seven phenylephrine-treated animals. Finally, the endogenous level of calcium/calmodulin (Ca-CaM)-dependent phosphorylation of 170- and 55-kDa substrate proteins was measured (as an index of intracellular free calcium concentration). In the susceptible dog heart, the endogenous level of Ca-CaM-dependent phosphorylation was estimated to be two- to threefold higher than that observed in resistant dog heart. Treatment of resistant dog tissue with the calcium ionophore A23187 increased the level of Ca-CaM-dependent phosphorylation of these two proteins to the level observed in susceptible dog heart. These data suggest that elevated cytosolic calcium facilitates development of malignant arrhythmias and that elevated cytosolic calcium levels may be present in animals particularly susceptible to ventricular fibrillation.
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PMID:Elevated myocardial calcium and its role in sudden cardiac death. 171 9


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