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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in action potential duration (APD) were studied during ischemic/reperfusion injury preceded or not by preconditioning in isolated rat hearts. Hearts were perfused on a Langendorff apparatus with Krebs-Henseleit carbonate buffer and submitted to 25-min global low-flow ischemia (coronary flow, 0.3 mol x min-1) followed by 30-min reperfusion. In hearts that had been preconditioned, two intermittent periods of total ischemia for 5 min each, separated by 5-min reflow, were performed before low-flow ischemia. At the end of the ischemic period, APs were significantly prolonged in nonpreconditioned hearts; this prolongation was abolished by preconditioning. Moreover, preconditioning increased the recovery of the contractile function. Therefore, ischemia can widen APD. The results also showed that in rats, preconditioning can be produced in a manner qualitatively similar to preconditioning in other species. Verapamil (3 x 10(-9) mol x min(-1)) or 4-aminopyridine (4-AP, 3 x 10(-6) mol x min(-1)) applied exclusively during low-flow ischemia significantly improved postischemic contractile function in nonpreconditioned hearts (25.9 +/- 4.4. and 37.9 +/- 2.4 vs. 12.9 +/- 5.3%, respectively) as well as in preconditioned hearts (61.8 +/- 4.2 and 55.5 +/- 4.7 vs. 36.0 +/- 1.4%, respectively). With verapamil, this protection was associated with a decrease in APD at 90% of repolarization in the nonpreconditioned hearts (APD90 32.2 +/- 0.1 vs. 71.1 +/- 6.7 ms at the end of ischemia). With 4-AP, this same protection was associated with an increase in APD in the preconditioned hearts (APD90 67.7 +/- 0.7 vs. 48.5 +/- 2.6 ms at the end of ischemia). Both agents given during a 25-min ischemic challenge improved myocardial recovery in nonpreconditioned and preconditioned hearts, despite discordant effects on the AP. Furthermore, the action of these agents was cumulative with the effect of preconditioning.
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PMID:Mechanical and electrophysiological effects of preconditioning in isolated ischemic/reperfused rat hearts. 863 99

In this study, we tested if the mechanism of protection of a calcium channel blocker, Verapamil (VER), was due to modulation of neutrophil infiltration after ischemia/reperfusion injury, in a rat renal ischemic model. Forty-four Sprague-Dawley rats were subjected to 75 min of warm ischemia and immediate contralateral nephrectomy. The animals were divided into two groups: the ischemic control (IC) group, which received normal saline, and the experimental group that received VER 1.25 mg/kg. The drug was administrated intravenously after ligation of the renal pedicle, before reperfusion. Survival was followed for 7 days. Laboratory tests included renal function tests, with serum creatinine (SCr) and blood urea nitrogen (BUN), light histology and neutrophil infiltration, measured by the myeloperoxidase test in renal tissue. Better survival rate was observed in the VER group (85% at 7 days vs control 50%) (P = 0.08). SCr and BUN at 48 and 72 hr showed a statistical significant difference between the two groups (VER lower than IC P < 0.05). Histological damage was significantly less in the VER group (P < 0.05). Neutrophil infiltration was significantly decreased in the VER group when compared to the IC group (P < 0.05). We concluded then, that VER had a downregulating effect on neutrophil infiltration and this might be an important mechanism of protection during the development of renal ischemic damage.
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PMID:Mechanism of protection of verapamil by preventing neutrophil infiltration in the ischemic rat kidney. 865 27

Calcium channel antagonists can reduce calcium overload induced by myocardial ischemia and thereby protect against malignant arrhythmias. However, these drugs may also adversely affect cardiac contractile function. Mibefradil is a new calcium antagonist that can inhibit cardiac calcium current without reducing myocardial force development. The effects of mibefradil on the inducibility of arrhythmias both before and during ischemia were therefore evaluated in animals with healed infarctions. First, a 2-min coronary occlusion was made during the last minute of exercise (n = 48): 25 animals had ventricular fibrillation (susceptible), whereas 23 did not (resistant). On a subsequent day, programmed electrical stimulation (PES, 8 paced beats followed by two extrastimuli) induced ventricular tachycardia in 19 of 25 susceptible animals but in none of the resistant animals (chi square = 24.6, P < .001). Verapamil (n = 14), diltiazem (n = 13) and mibefradil (n = 14) elicited significant dose-dependent decreases in refractory period and in the Q-Tc interval (except mibefradil) yet failed to prevent PES-induced arrhythmias. Diltiazem and verapamil also increased P-R interval and reduced the maximum rate of change of left ventricular pressure, whereas mibefradil did not. However, all three drugs abolished arrhythmias induced by PES during ischemia. In contrast, lidocaine suppressed PES-induced arrhythmias but failed to prevent ischemically induced arrhythmias. Thus mibefradil can prevent ischemically induced ventricular fibrillation without adverse actions on either A-V nodal conduction or contractile function. These data further suggest that calcium entry may play a critical role in the initiation of ventricular fibrillation during ischemia, whereas other factors must be responsible for the extrasystoles induced by PES.
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PMID:The effects of mibefradil, a novel calcium channel antagonist on ventricular arrhythmias induced by myocardial ischemia and programmed electrical stimulation. 866 18

Angina pectoris is a significant risk predictor in patients with atherosclerotic heart disease. The major complications are myocardial infarction, heart failure, and arrhythmias. Plaque rupture turns stable angina pectoris into acute coronary syndrome by provoking platelet aggregation and thereby thrombus formation. Verapamil significantly inhibits platelet aggregation and thrombus formation, which may be one of several reasons for the protective effect of verapamil on reinfarction in patients recovering from myocardial infarction. Ischemia may lead to left ventricular dilation and diastolic dysfunction, and thereby heart failure. In postinfarction patients intervention with verapamil significantly reduced the use of diuretics compared with placebo, indicating that anti-ischemic intervention may prevent heart failure. Ventricular arrhythmias are significantly associated with arrhythmic as well as non-arrhythmic death. The lack of preferential association of ventricular arrhythmias with arrhythmic death rather than nonarrhythmic death may imply that arrhythmias are provoked by ischemia. Antiarrhythmic intervention in postinfarction patients significantly increases death and arrhythmic events compared with placebo, especially in patients with residual ischemia. This may be due to a significant slowing of conduction during ischemia in patients treated with antiarrhythmic agents. In animal studies anti-ischemic agents prevent or suppress ventricular arrhythmias during ischemia, whereas traditional antiarrhythmic drugs have no effect or even worsen the arrhythmias, especially during episodes with elevated sympathetic activity. Verapamil significantly reduces plasma norepinephrine levels and the norepinephrine release during ischemia, whereby ventricular arrhythmias may be prevented. Also, supraventricular arrhythmias are significantly associated with myocardial ischemia and are prevented by verapamil. In patients with atherosclerotic heart diseases, angina pectoris is a significant risk predictor, but anti-ischemic intervention should be considered even in patients in whom the major problem is heart failure or arrhythmias.
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PMID:Anti-ischemic intervention as prognosis improvement in patients with coronary artery disease, with special focus on verapamil. 867 96

Antianginal drug treatment reduces symptoms and ischemia but may also influence the prognosis of patients with stable angina pectoris. The Atenolol Silent Ischemia Study (ASIST) compared atenolol and placebo treatment (about 140 patient-years on each) in patients with mainly silent ischemia and found less aggravation of angina and a tendency toward fewer cardiac complications with atenolol treatment. The Total Ischaemic Burden European Trial (TIBET) compared slow release nifedipine, atenolol, or the combination (about 450 patient-years on each) and found no significant differences with regard to cardiac complications, a nonsignificant trend toward better prognosis on combined treatment, and more side effects on nifedipine alone compared with the other treatments. The Angina Prognosis Study in Stockholm (APSIS) compared metoprolol and verapamil (about 1,400 patient-years on each) and found similar effects on cardiovascular endpoints, tolerability, and psychosocial variables with the 2 treatments. Hypothesis-generating subgroup analyses in APSIS suggest that treatment effects may differ in hypertensive and diabetic subgroups. Beneficial effects in primary and secondary prevention, together with data from ASIST, suggest that beta 1 blockade influences prognosis favorably. The safety of short-acting nifedipine in ischemic heart disease is questioned, but TIBET data suggest that slow release nifedipine may be safe. Verapamil has beneficial effects after myocardial infarction (Danish Verapamil Infarction Trial II) and shows similar efficacy as metoprolol in the APSIS study. The paucity of placebo data (antianginal treatment cannot be withheld during long periods of time in symptomatic patients) precludes firm conclusions regarding effects of drug treatment on prognosis. It is argued that patients with stable angina pectoris do well on medical treatment, and that beta 1 blockers, verapamil, and, possibly, slow-release nifedipine may influence their prognosis favorably.
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PMID:Prognosis of patients with stable angina pectoris on antianginal drug therapy. 867 97

The purpose of this study was to investigate the protective effects of the calcium channel blocker verapamil on warm ischemia-reperfusion injury to the liver using a rat model. Ischemia of the left and median lobes was created by total inflow occlusion for 60 min followed by 24 hr of reperfusion. Hepatocell injury was assessed by the release of liver enzymes [alanine aminotransferase (ALT) and lactic dehydrogenase (LDH)], reduced (GSH) and oxygenated (GSSG) plasma glutathione and total biliary glutathione. Hepatocyte function was quantitated by measuring bile flow. Rats were randomized to one of two groups: pretreatment with iv verapamil (0.3 mg/kg) or iv normal saline (controls). Verapamil significantly increased bile flow and GSH efflux while decreasing plasma ALT and LDH compared to those in controls 24 hr after liver ischemia-reperfusion (LIR). A significant correlation existed between bile flow and biliary GSH efflux at 1 but not 24 hr after LIR, suggesting that early LIR injury is mediated predominantly by generation of oxygen free radicals. Liver enzyme elevation and bile flow were inversely correlated at 24 but not 1 hr after injury. We conclude that verapamil significantly protects the liver against warm LIR injury. The minimal protective effect of verapamil on early liver ischemia-reperfusion demonstrates that verapamil does not prevent the early generation of oxygen radicals upon reperfusion. However, the significant restoration of biliary GSH efflux and hepatocyte protection at 24 hr suggests involvement of calcium ions in late hepatocyte injury. Verapamil's protective effects may be related to attenuating pathophysiologic events occurring beyond 1 hr of reperfusion. Future studies investigating the protective effects of verapamil on warm LIR injury should be carried out for at least 24 hr postreperfusion.
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PMID:Protective effects of the calcium channel blocker verapamil on hepatic function following warm ischemia. 881 26

Verapamil (VRP) improves ischemic tolerance of different organs including brain, kidney, liver and heart. We report here on the effects of preischemic VRP treatment on skeletal muscle function following 3 h of tourniquet ischemia and 2 h of reperfusion using a rodent model. Postischemic and contralateral limbs were evaluated. Fast (musculi peronei)- and slow-twitch muscles (musculus soleus) of both limbs were excised and electrically stimulated in vitro. VRP pretreatment was found to significantly decrease tetanic peak tension of both contralateral nonischemic m. soleus and mm. peronei. Furthermore, VRP improved fatigability of slow-twitch muscles of both ischemic and contralateral limbs [increase of fatigue index from 0.04 +/- 0.009 (0 mg/kg) to 0.10 +/- 0.019 (4 mg/kg)], but not of fast-twitch muscles. These data indicate that the effects of VRP on postischemic skeletal muscle function depend on fiber composition.
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PMID:Effects of verapamil on skeletal muscle function following ischemia and reperfusion. 883 64

Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.
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PMID:Disappearance with ischaemic depolarization of the antifibrillatory activity in a sodium channel blocker and appearance in calcium channel blocker. 912 97

We tested the hypothesis that elevation of [Ca2+]i during ischemic preconditioning (IPC) stimulates protein kinase C (PKC), which confers the protection against the ischemic injury. Langendorff-perfused rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion (I/R). In preconditioned groups, hearts were subjected to either IPC, consisting of 5-minute global ischemia and 10-minute reperfusion, or high-Ca2+ preconditioning (HCPC), ie, the 5-minute perfusion of higher Ca2+ perfusate (2.3 mmol/L Ca2+) followed by 10-minute perfusion of normal perfusate (1.8 mmol/L Ca2+), and then were subjected to I/R. A significant functional recovery and decreased lactate dehydrogenase release were observed in HCPC and IPC hearts compared with ischemic control hearts. ATP contents of preconditioned hearts were significantly higher than those of the ischemic control hearts. The cell structure in preconditioned hearts was preserved better than that in the ischemic control hearts. Furthermore, the activation and translocation of PKC from cytoplasm to sarcolemma were observed in the preconditioned hearts. Verapamil administered during IPC significantly attenuated the salutary effects of IPC. Administration of chelerythrine, a specific PKC inhibitor, completely abolished the HCPC- and IPC-induced cardioprotection. The translocation of PKC by IPC was blocked by verapamil or chelerythrine. Immunohistochemical study using rabbit polyclonal antibody against PKC isoforms indicated that stress induced by IPC or HCPC evoked the translocation of PKC alpha and PKC delta to the cell membrane. Translocation of PKC isoforms was attenuated by the treatment with verapamil or chelerythrine. These results demonstrate that (1) a transient increase in [Ca2+]i during IPC is an important trigger for the activation of PKC, which is responsible for cardioprotection; (2) the elevation of [Ca2+]i during IPC, at least partly, resulted from Ca2+ entry via voltage-dependent Ca2+ channel; and (3) activation and translocation of PKC alpha and PKC delta occur during IPC and HCPC and may be important in preconditioning.
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PMID:Ca2+ as a mediator of ischemic preconditioning. 916 81

Experimental studies have shown the limitation by calcium antagonists of the propensity to fibrillation secondary to the occlusion of a large coronary artery. However, this capacity, studied in the acute phase of infarction, is less obvious and still under debate. Ischemia was therefore produced in anesthetized, open-chest pigs by complete occlusion of the left anterior descending coronary artery according to two modes, either near its origin during brief but increasing periods (30, 60, 120, 180 s, etc) or half-way from this origin for a much longer time (60 min). The time course of vulnerability to fibrillation was monitored by ventricular fibrillation threshold (VFT), measured by trains of diastolic stimuli of 100 ms. Verapamil was administered in a 50 micrograms/kg dose followed by 2 micrograms/kg/min infusion. 1) In the case of brief proximal occlusions under pacing at a constant high rate (180 beats/min), verapamil slowed the decline of VFT from 6-8 mA to nearly 0 mA. VFT was 4.4 +/- 0.4 mA after 60 s ischemia, whereas it had already fallen to 1.8 +/- 0.3 mA (p < 0.001) in the absence of the drug. Accordingly, the onset of spontaneous fibrillation which depends on the decrease in VFT to about 0 mA was prolonged from 2-3 to 6-9 min. Bradycardia, concurrently produced by verapamil, is a factor which enhances these alterations. 2) In the case of a persistent midportion occlusion of the artery under sinus rate, fibrillations were similarly delayed by verapamil from 14-25 to 23-49 min after occlusion, but they were more numerous. VFT was lowered to critical values later, but also for a longer time. The period propitious to fibrillation was prolonged because the return of VFT to higher values reflecting hypoexcitability subsequent to the first cell injury was substantially delayed. Consequently, calcium antagonists should often prevent ventricular fibrillation when transient ischemia disappears before VFT falls to the vicinity of 0 mA. In contrast, a real benefit could not be expected from these drugs when ischemia is persistent since they then only delay fibrillations, the number of which is increased.
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PMID:Calcium antagonists and prevention of ventricular fibrillation induced by transient or persistent ischemia. 920 Nov 11


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