Anti-ischemic Activity Research Articles

ACE inhibitors for the treatment of myocardial ischemia?

Apart from their established use in the treatment of hypertension and heart failure, ACE inhibitors have been suggested to exert anti-ischemic effects. This article reviews the mechanisms of systemic and intracardiac angiotensin formation, as well as its interaction with the bradykinin, the prostaglandin, and the sympathetic nervous system. While high doses of angiotensin can precipitate myocardial ischemia. experimental data on a potential beneficial effect of ACE inhibitors on ischemic myocardial blood flow and function are inconsistent and controversial. Pooling the few available clinical data, several ACE inhibitors may attenuate myocardial ischemia at rest and during exercise. However, a significant fraction of patients does not benefit or even deteriorates. Recent experimental studies suggest a beneficial role of ACE inhibitors in attenuating reperfusion arrhythmias and postinfarction left ventricular remodeling. Unless the mechanisms and determinants of potential anti-ischemic actions of ACE inhibitors can be better defined, their use for treatment of myocardial ischemia cannot be recommended at present.

Anti-ischemic activity of dl-cis-diltiazem in relation to energy metabolism in the isolated perfused rat heart: a 31P-NMR study

Anti-ischemic activity of dl-cis-diltiazem in relation to energy metabolism in the isolated perfused rat heart: a 31P-NMR study

The effects of Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960) on ischemia-induced changes of brain acetylcholine and monoamine levels in gerbils

The changes in acetylcholine (ACh), monoamine and monoamine metabolite levels following cerebral ischemia in Mongolian gerbils were examined. In addition, the effects of Sho-saiko-to-go-keishi-ka-shakuyaku-to (TJ-960), which is a spray-dried mixture of 9 herbal drugs, on these changes were also examined. The dramatic decrement of ACh levels in ischemic gerbils was significantly inhibited by p.o. administration of TJ-960 at a daily dose of 3.5 g/kg or 700 mg/kg for one month. Norepinephrine (NE) was also reduced in all ischemic brain regions, and TJ-960 also recovered the level of NE. In ischemic gerbil brains, the dopamine (DA) levels decreased and its metabolites increased in the striatum, but DA and its metabolites in the thalamus + midbrain region increased. The serotonin (5HT) level was reduced in the cerebral cortex and hippocampus. TJ-960 inhibited these monoaminergic changes in ischemic gerbils. This suggests that TJ-960 may provide anti-ischemic action and beneficial effects on various symptoms induced by ischemia.

The thromboxane receptor antagonist SQ 30,741 reduces myocardial infarct size in monkeys when given during reperfusion at a threshold dose for improving reflow during thrombolysis

The threshold dose of the selective thromboxane receptor antagonist SQ 30,741 for increasing reflow during thrombolysis was identified and then evaluated in a model of myocardial ischemia with reperfusion. In anesthetized cynomolgus monkeys, stenotic carotid arteries were occluded with a platelet-rich thrombus by electrical stimulation and recanalized with streptokinase (680 U/min intraarterially for 1 h) and heparin (200 U/kg + 120 U/h intravenously for 3 h). Concurrent administration of SQ 30,741 (2.1 mg/kg + 0.5 mg/kg per h intravenously for 3 h; n = 4) enhanced the extent of reflow 174% compared with saline solution (n = 4; p < 0.05) during the third hour, when lower doses were ineffective.This threshold dose was tested in anesthetized African green monkeys subjected to 90 min of left circumflex coronary artery occlusion and 5 h of reperfusion. SQ 30,741 (n = 8) or saline solution (n = 11) was administered 2 min before reperfusion and continued throughout reperfusion. The heart was removed on termination of reperfusion and perfused in vitro with Evans blue and triphenyltetrazolium chloride dyes to stain tissue at risk and infarcted tissue, respectively. The percent of left ventricle at risk did not differ between saline- (37 ± 4%) and SQ 30,741-treated (35 ± 3%) monkeys. In contrast, infarcted tissue expressed as percent of the left ventricle at risk was less (p < 0.01) in monkeys receiving SQ 30,741 (31 ± 2%) than in those receiving saline solution (49 ± 5%).This 36% reduction in infarct size occurred without significant differences between treatments in hemodynamic variables and myocardial blood flows (as assessed by radioactive microspheres) measured during control, occlusion and reperfusion intervals. Thus, a dose of SQ 30,741 that stabilizes reflow after thrombolysis also possesses antiischemic activity when administered only during coronary reperfusion in monkeys.

Propionyl carnitine in stable effort angina

The aim of this study was to investigate the anti-ischemic activity of propionyl carnitine (PC) in 18 informed, volunteer male patients, aged 37-70, suffering from a typical stable effort angina. The study design was randomized, balanced, crossover, and double blinded. The study lasted 75 days. In the first 15 days of washout the patients performed two maximal symptom-limited bicycle tests to verify the repeatability of the parameters examined. Then one group received PC for 30 days 500 mg three times a day, and the other group received placebo (PL) three times a day. At the end of 30 days the groups exchanged treatments. At the end of each period, 2 hours after the last oral administration, the patients performed a maximal symptom-limited bicycle exercise test with increased loads of 10 watts/min. No significant differences were observed between the two tests performed during the wash-out period, for a 1 mm ST-segment depression time, for the time to the end of exercise, and for the rate x pressure product at the same experimental time. The oral administration of PC in coronary patients increased both the 1 mm ST-segment depression time and the time to the end of exercise. Furthermore, the drug reduced the ischemic depression of ST at maximal common work and at maximal work. After PC, the rate x pressure product was not significantly different in relation to placebo at submaximal and maximal exercise. Thus PC seems to have an antiischemiclike effect, probably related to its metabolic activity.

Acute antianginal hemodynamic effects of nicardipine in coronary artery disease

To define the short-term effects of intravenous nicardipine on exercise- and pacing-induced myocardial ischemia, 15 men with coronary artery disease were studied. Nicardipine was administered as a 2 mg bolus followed by an infusion, titrated to maintain a 10 to 20 mm Hg decrease in systolic arterial pressure. At rest, nicardipine significantly decreased systemic and coronary vascular resistances and left ventricular end-diastolic pressure but increased coronary blood flow, heart rate, and myocardial oxygen consumption. With bicycle exercise performed to evoke myocardial ischemia, nicardipine prolonged exercise duration, time to of 1 mm ST segment depression, and increased cardiac work to onset of angina in most patients. These changes in cardiac performance were not associated with alteration in the product of systolic pressure and heart rate or with increased left ventricular end-diastolic pressure. During increased heart rate induced by atrial pacing to cause ischemia, the heart rate threshold for myocardial ischemia was not changed by nicardipine. This occurred despite decreased myocardial oxygen consumption, unchanged coronary blood flow, and otherwise similar hemodynamic changes as those observed during exercise. However, left ventricular end-diastolic pressure remained lower and stroke volume increased more after nicardipine with pacing stress when compared with observations before nicardipine with the same heart rate stress. These findings support beneficial antiischemic actions of nicardipine with possible prevention of ischemia-related left ventricular dysfunction.

Long‐Term Cardiovascular Effects of Metoprolol Therapy: A Review Article

Long-term studies in primary and secondary prevention using metoprolol have showed improvement in prognosis. This review summarizes the clinical results of such studies, and puts these results into the perspective of findings in mechanistic and explanatory studies. Many possible factors may have contributed to explain the beneficial effects on prognosis. The antihypertensive action, cardiac anti-ischemic action, antifibrillatory action, antiatherogenic and antithrombotic actions of metoprolol are discussed. The additive effects of these actions may explain the clinically observed beneficial effects. In the evaluation of a specific intervention, it is important to realize the multiple actions that may contribute, and not only discuss single factors.

The antiarrhythmic efficacy of intravenous anipamil against occlusion and reperfusion arrhythmias

1. Anipamil, a long acting analogue of verapamil, was tested for its actions against arrhythmias induced by ischaemia and reperfusion in conscious and anaesthetized rats, as well as for effects on epicardial intracellular action potentials. 2. When given 15 min or 4 h before coronary occlusion, 1 and 5 mg kg-1 anipamil reduced ischaemia-induced arrhythmias in conscious rats. The same doses also reduced arrhythmias when given 15 min before occlusion in acutely-prepared anaesthetized rats. ED50 values were between 1 and 5 mg kg-1. 3. The incidence of reperfusion arrhythmias depended upon the period of regional ischaemia prior to reperfusion such that the peak incidence occurred after 5-7 min of ischaemia. Anipamil (2.5 mg kg-1, i.v.) selectively abolished the reperfusion arrhythmias induced by short periods of ischaemia, although some antiarrhythmic effects were seen for all periods of ischaemia. 4. Anipamil slowed the rate of development of R-wave increases and S-T segment elevations induced by ischaemia, but did not reduce the maximum values they attained. 5. Anipamil (2.5 mg kg-1 i.v.) lacked Class I or III electrophysiological actions on intracellular action potentials recorded in vivo from the epicardium of rat hearts. 6. In conclusion, the antiarrhythmic actions of anipamil appeared to depend upon calcium antagonism which may have reduced arrhythmias by a combination of anti-ischaemic and direct anti-arrhythmic actions. Presumed anti-ischaemic actions changed the relationship between the duration of preceding ischaemia and resulting reperfusion arrhythmias.

Anti-Ischemic Actions of Molsidomine by Venous and Large Coronary Dilatation in Combination with Antiplatelet Effects

Anti-Ischemic Actions of Molsidomine by Venous and Large Coronary Dilatation in Combination with Antiplatelet Effects

Anti-Ischemic Actions of Molsidomine by Venous and Large Coronary Dilatation in Combination with Antiplatelet Effects

Molsidomine and its vasoactive metabolite SIN-1 elicit anti-ischemic properties by a therapeutically useful pattern of different vasoactive actions combined with a cyclic GMP-mediated inhibition of platelet adhesion and aggregation. Following molsidomine or SIN-1, local venodilatation and an increase in total effective vascular compliance (as an integrated parameter of venodilatation) were observed. This reduction in preload caused a decrease in myocardial oxygen consumption. Molsidomine caused a slowly progressing dilatation (still present and significant after 4 h), while SIN-1 caused an immediate increase in diameter of the large coronary arteries. The cyclic GMP-mediated dilator effects were accompanied by similar increases in platelet cyclic GMP levels (in the effluent of perfused hearts), indicating an increased potential against platelet activation, adhesion, and aggregation. The combined effect on cardiac preload, conductance of the epicardial arteries, and inhibition of platelet activation improves the ratio between myocardial oxygen supply and demand and suppression of ischemic events.

7-OXO-PGI 2-induced late appearing and long lasting antiischemic action in dogs

7-OXO-PGI 2-induced late appearing and long lasting antiischemic action in dogs

The anti-ischaemic activity of the novel compound, CERM 11956, compared with that of bepridil and nifedipine in isolated guinea-pig hearts

A comparison between the protective activity of bedridil, its novel derivative, CERM 11956, and nifedipine in isolated electrically paced guinea-pig hearts after 60 min of global ischaemia followed by 30 min of reperfusion has been made. All three compounds exerted a significant anti-ischaemic effect, as indicated by an improved recovery of functional parameters (left ventricular pressure and coronary perfusion), a delayed onset of the ischaemic contracture, and an enhanced recovery of biochemical (CrP, ATP and adenylate energy charge) parameters. The most pronounced anti-ischaemic activity was shown by the compound CERM 11956 at concentrations that displayed only minor negative inotropic activity. From the results it may be concluded that the new bepridil derivative, CERM 11956, is a promising and potent anti-ischaemic compound, which has little influence on haemodynamic parameters.

Effect of subchronic administration of phenazepam and synthetic antioxidants on cerebral cortical synaptic membrane function of rats exposed to long-term stress

In the experiments on different animal species (mice, cats, dogs) lithium hydroxybutyrate has been shown to have antihypoxic and anti-ischemic effects. Lithium hydroxybutyrate improved the functional state of the ischemic myocardium, stimulated the accumulation of macroergic phosphates (ATP) in the heart, protected the ischemic myocardium and delayed the progression of the reversible ischemic damage into the irreversible one. The improvement of the collateral coronary circulation plays an important role in the anti-ischemic action of the drug.

Calcium antagonist activity of vinpocetine and vincamine in several models of cerebral ischaemia

AbstractThe potency and selectivity (i.e., the central vs. peripheral vascular smooth muscle activity) of the calcium antagonist (CA) effects of vinpocetine and vincamine have been compared with those of the standard CAs: flunarizine, verpamil, diltiazem, and nimodipine in rabbit basilar and splenic artery preparations. The cerebral antiischemic activity of these substances also was evaluated in five well‐documented in vivo models, i.e., hypobaric and normobaric hypoxia, global cerebral ischemia to MgCl2, cytotoxic anoxia with KCN, and cerebral edema induced by triethyl tin. Both vinpocetine and vincamine possess only weak CA activity, the potency order being: nimodipine &gt; diltiazem &gt; flunarizine = verapamil &gt; vinpocetine &gt; vincamine, with vinpocetine and flunarizine, in contrast to other compounds, showing a clear, 6‐ to 13‐fold selectivity for cerebral vascular smooth muscle. In the in vivo models, vinpocetine and flunarizine, together with vincamine, proved most active and had a larger spectrum of activity than the other CAs. These results suggest that the cerebrally selective CA effects of vinpocetine are at most only partly responsible for the effects of this compound in the in vivo models of cerebral ischemia.

Circadian Patterns of Myocardial Ischemia

Recent evidence suggests that acute myocardial infarctions tend to occur most frequently in the early morning hours after awakening. In addition, the peak time of occurrence of out-of-hospital sudden death is during the same morning period, which suggests that the pathophysiologic factors influencing these acute ischemic and arrhythmic events may be similar. Although it is clear that arising from sleep is associated with an increased heart rate and blood pressure, two important determinants of myocardial oxygen demands, other factors may be responsible for a paradoxical decrease of coronary blood flow at the same time. It is possible that vascular receptor sensitivity may vary or that the early morning hours may be associated with a hyperaggregability of platelets; this would provide an additional pathophysiologic explanation for ischemic events related to platelet aggregation and coronary thrombosis, which are known to play a central role in the initiation of unstable angina, acute infarction, and sudden death. An understanding of the circadian pattern of ischemic events may be a guide for future therapeutic interventions during this period. Studies suggest that use of medications that provide continuous antiischemic activity throughout the 24-h day should be considered.

Anti-ischaemic activity of various calmodulin antagonists.

The anti-ischaemic activity of the calmodulin antagonists trifluperazine, felodipine, W-7 and calmidazolium has been investigated in electrically paced guinea-pig hearts, perfused according to Langendorff, which were subjected to 60 min of global ischaemia followed by 30 min of reperfusion. At concentrations that induced a comparable reduction in cardiac contractile force, trifluperazine, felodipine and to a lesser extent W-7, were associated with improvement of post-ischaemic functional (LVP and coronary flow) and biochemical parameters (CrP and ATP). Furthermore, felodipine and trifluperazine delayed the onset and suppressed the maximum tension of the ischaemic contracture was observed. In contrast, calmidazolium had no anti-ischaemic effects. This lack of anti-ischaemic activity of the most potent calmodulin antagonist calmidazolium, as well as the significant calcium entry blocking activity of both trifluperazine and felodipine suggest that additional factors besides calmodulin antagonism may contribute to the anti-ischaemic activity of these compounds.

Effects of pentobarbital and ketamine on brain injury-induced anti-ischemic activity

Survival rates following incomplete brain ischemia induced during pentobarbital anesthesia were significantly higher in mice with a minor brain injury, inflicted one week before, than in those given a sham operation. Improvement of the survival rates in mice with brain injury, however, became insignificant when brain ischemia was imposed during ketamine anesthesia, suggesting that the actions of certain factors or protective mechanisms against brain ischemia, developed by brain injury, are antagonized by ketamine and/or potentiated by barbiturate anesthesia.

Defibrotide, an antithrombotic substance which prevents myocardial contracture in ischemic rabbit heart

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, reduced in a dose-dependent fashion the ischemic contracture due to low perfusion (0.2 ml/min) of isovolumic left heart of rabbit and abolished the irregular rhytym of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). Defibrotide stimulated the release of PG-like material from the heart in a dose-dependent manner without modifying the basal contractility. Both PGE 2 and PGI 2 (10 ng/ml) have an antiischemic activity on this preparation as shown by the partial reduction of the ischemic contracture and by the improvement of heart contractility upon reperfusion. Indomethacin infusion (1 μg/ml) completely removed both the antiischemic activity of Defibrotide (400 μg/ml) and its ability to increase the generation of prostaglandins in the rabbit heart. These results suggest that Defibrotide has a beneficial influence on ischemic rabbit heart through an increase in prostaglandin synthesis. However other mechanisms not necessarily related to prostaglandin generation, such as direct effect on membrane function deactivation and mitochondrial Ca 2+ overload, should be considered in explaining the antiischemic activity of Defibrotide in the rabbit heart.

Cardioprotection by anti-ischaemic and cytoprotective drugs.

Cardioprotective drugs are agents that prevent or moderate harmful consequences of impaired cardiac energetics, such as sudden coronary death (SCD) due to early post-occlusion ventricular fibrillation (EPVF), development of incapacitating myocardial necrosis. Cardioprotection may be due to anti-ischaemic action, correcting the imbalance between vascular supply and myocardial demand for blood, but also to cytoprotective effect, preserving cellular integrity in the presence of factors damaging structure and function of the cardiac cell membrane such as ischaemia, ionic imbalance and that of pH, etc. Neither anti-ischaemic nor cytoprotective effect alone, or in combination, are sufficient to warrant full cardioprotection, i.e. both prevention of SCD and limitation of infarct size. Thus the beta-blocker pindolol which is anti-ischaemic in its effect reducing myocardial O2 demand and protects from SCD and EVFP, failed to limit infarct size. Even interventions of a mainly cytoprotective type of action protecting from SCD and EPVF, such as the linoleic acid-rich diet, or lidocaine, were unable to limit infarct size, 7-oxoPGI2 (anti-ischaemic and cytoprotective) failed to protect from SCD, VF and did not limit infarct size. On the other hand the nonsteroidal anti-inflammatory drugs which, like salicylates or sulfinpyrazon, reduce myocardial O2 demand and protect from post-occlusion SCD and EPVF, effectively limiting infarct size.

Antiischaemic actions of alinidine in paced rat hearts

Antiischaemic actions of alinidine in paced rat hearts