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 effects of nicorandil, a nicotinamide nitrate with K(+)-channel-opening activity, was investigated in several models of ischemia-reperfusion injury in conscious and anesthetized dogs or isolated buffer-perfused rat hearts. In several models of reversible ischemic injury (stunned myocardium) in dogs, nicorandil resulted in an enhanced recovery of regional systolic shortening during reperfusion after a single episode of coronary artery occlusion (10-15 min). These beneficial actions of nicorandil were not shared by the nitrovasodilator sodium nitroprusside but were mimicked by the selective K(+)-channel opener EMD 52692. In a model of irreversible ischemia-reperfusion injury (i.e., 2 h of coronary occlusion followed by reperfusion) in anesthetized dogs, nicorandil produced a marked reduction of myocardial infarct size. An equihypotensive dose of the calcium antagonist nifedipine had no significant effect; however, EMD 52692 produced the same reduction in infarct size as had nicorandil. In isolated, perfused rat hearts subjected to 20 min of low-flow (1.0 ml/min) global ischemia followed by 30 min of reperfusion, nicorandil (7 microM) resulted in a significant improvement in the recovery of isovolumic left ventricular minute work during reperfusion compared with untreated hearts. Finally, the results of in vitro experiments indicated that nicorandil (10(-6) to 10(-3) M) produced a concentration-dependent inhibition of superoxide anion free radical production by human and canine neutrophils. The K(+)-channel opener EMD 52692 also inhibited superoxide production in canine neutrophils. These results indicate that nicorandil is a highly efficacious myocardial protective agent in several animal models of reversible or irreversible ischemia-reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardioprotective effects of nicorandil. 128 72

The effect of the ATP-sensitive potassium channel opener EMD 56431 on coronary vasodilation and cardioprotection in isolated rat hearts was investigated. EMD 56431 caused a significant increase in pre-ischemic coronary flow. Time to contracture and reperfusion function were significantly increased at 3, 10 and 30 microM concentrations. LDH release was significantly reduced at 10 and 30 microM concentrations. 1 microM glyburide completely abolished the protective effects found with 10 microM EMD 56431. When given during reperfusion only, 10 microM EMD 56431 showed no cardioprotection. Thus, EMD 56431 appeared to reduce the severity of ischemia/reperfusion injury. The vasorelaxant versus cardioprotective effects for EMD 56431 are similar to other potassium channel openers, such as cromakalim.
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PMID:Effect of the potassium channel opener EMD 56431 on globally ischemic rat hearts. 146 73

A possible cause for the decreased function in postischemic reperfused (= stunned) myocardium could be a decrease in Ca++ sensitivity. To test this hypothesis, we used an agent with reportedly Ca++ sensitizing properties (EMD 57033) and performed experiments on a total of 17 isolated rabbit hearts that were perfused with an erythrocyte-containing medium in a modified Langendorff setting (hct = 30%; Ca++ = 2.0 meq/l). The hearts were divided into two groups. In one group (n = 9), the Ca++ sensitizer (30 microM) was administered to nonischemic myocardium, and in a second group (n = 8), the Ca++ sensitizer was administered after 30 min of reperfusion that followed a period of 20 min normothermic, no-flow ischemia. In the nonischemic group, addition of the agent, improved left ventricular (LV) function significantly. In the ischemic group, LV-function was depressed at 30 min reperfusion compared to control. Again, the agent improved LV-function significantly. The increase in systolic and diastolic function was comparable in both groups as well as the oxygen consumption that was significantly increased after administration of the agent. In both groups, the agent neither exhibited significant, positive chronotropic nor arrhythmogenic effects. We summarize that the novel Ca++ sensitizer acts as a potent positive inotropic agent in the isolated blood-perfused rabbit heart. Because of the agent's properties to ameliorate postischemic contractile dysfunction, this general strategy may be useful for treating poorly functioning reperfused myocardium.
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PMID:Improved ventricular function by enhancing the Ca++ sensitivity in normal and stunned myocardium of isolated rabbit hearts. 770 44

Inotropic agents are used widely for pharmacological bridging of the failing heart either until recovery after surgical intervention or until transplantation. EMD 57033 is a novel specific Ca++ sensitizing agent with purportedly minor phosphodiesterase (PDE) III-inhibiting properties. It acts as an inotropic agent without raising intracellular Ca++ levels. In turn, the PDE III-inhibitor enoximone has been used for several years to treat low cardiac output syndrome. However, little is known about its effects on postischemic reperfused (stunned) myocardium. We investigated the effects of EMD 57033 (EMD; 30 microM) and enoximone (E20 micrograms/ml) on stunned myocardium. The experiments were performed on 16 isolated rabbit hearts perfused with an erythrocyte suspension (hematocrit = 30%; [Ca++] = 2.5 mM). Hearts were reperfused after a 20 min no-flow ischemia. Measurements were performed at control, 30 min after the onset of reperfusion, and after administration of one of the drugs. Both agents significantly improved the depressed systolic function [left ventricular pressure (LVP)max from 61 +/- 12 to 93 +/- 18 mmHg, and its derived pressure (dP/dt)max from 860 +/- 220 to 1340 +/- 300 mmHg/s and LVPmax from 78 +/- 9 to 83 +/- 15 mmHg, and its derivative dP/dtmax from 1040 +/- 230 to 1385 +/- 300 mmHg/s, respectively] and early relaxation (dP/dtmin from 810 +/- 250 to 1260 +/- 345 mmHg/s and from 1000 +/- 200 to 1135 +/- 295 mmHg/s, respectively) that occurred during postischemic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison between the effects of a novel Ca++ sensitizer and a phosphodiesterase inhibitor on stunned myocardium. 853 Nov 13

We investigated the effects of EMD-53998 and digoxin on Ca2+ transients and left ventricular (LV) function in indo 1-loaded Langendorff guinea pig hearts. EMD-53998 (10(-9) to 10(-5) M) and digoxin (10(-10) to 10(-6) M) increased +dP/dt and Ca2+ transients in normal hearts. The relative increase in Ca2+ transients by EMD-53998 was similar to digoxin. At 10(-5) M, EMD-53998 increased LV end-diastolic pressure. Low-flow ischemia decreased +dP/dt by 50%, while indo 1 ratio increased by 10-25%. EMD-53998 (10(-9) to 10(-6) M) effectively restored the depressed +dP/dt with little effect on indo 1 ratio, but at 10(-5) M, it markedly elevated LV end-diastolic pressure and the beneficial effect on contractile dysfunction disappeared. Digoxin (10(-10) to 10(-7) M) failed to improve LV function, but at 10(-6) M, it restored contractile dysfunction with a large increase in indo 1 ratio. The relation between indo 1 ratio and +dP/dt clearly showed that EMD-53998 restored contractile dysfunction by Ca2+ sensitization. These findings suggest that Ca2+ sensitization by EMD-53998 is an advantageous approach for ischemic contractile failure but impairs diastolic function.
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PMID:Differential effects of EMD-53998 on calcium-pressure relationship in normal and ischemic guinea pig heart. 876 Jan 90

We investigated the effect of a new Ca++ sensitizer, MCI-154, which is known to increase myofibrillar Ca++ sensitivity and maximal Ca(++)-activated force, on Ca++ transients and left ventricular (LV) function in indo-1-loaded Langendorff guinea plg hearts subjected to a reduction in coronary perfusion pressure from 80 to 40 mm Hg. During low-flow ischemia, LV contractility decreased by 50%, whereas systolic and diastolic indo-1 fluorescence ratios increased by 10%. The treatment with MCI-154 (10(-10) to 10(-6) M) 15 min after ischemia effectively restored the depressed LV function with little effect on indo-1 ratio. EMD 53998 (10(-9) to 10(-6) M), which also acts on maximal Ca(++)-activated force, restored LV function with a minimal impact on indo-1 ratio, but at 10(-5) M, EMD 53998 caused diastolic dysfunction, and its beneficial effect on systolic function disappeared. The relation between indo-1 ratio and LV contractility showed that MCI-154 and EMD 53998 restored ischemic contractile failure by Ca(++)-sensitizing action. It was noted that the restoration of LV dysfunction by MCI-154 or EMD 53998 was more pronounced than that by pimobendan, which acts primarily on Ca++ sensitivity. In contrast, the phosphodiesterase inhibitor milrinone restored LV function, but it doubled the increase in indo-1 ratio during ischemia. These findings suggest that a decrease in myofilament Ca++ responsiveness may be an important cause of ischemic contractile failure and that the restoration of depressed Ca++ responsiveness by intervention such as MCI-154 may be a promising approach for restoring the depressed function.
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PMID:Restoration of ischemic contractile failure of indo-1-loaded guinea pig heart by a calcium sensitizer, MCI-154. 885 74

We tested whether decreased Ca2+ sensitivity is a major cause for dysfunctional stunned myocardium. The experiments employed a novel Ca2+ sensitizing agent: the thiadiazinone derivative EMD 60 263. Experiments were done on 14 isolated, blood-perfused rabbit hearts. After control, seven hearts were subjected to 20 min no-flow ischemia, and then allowed to recover during 30 min reperfusion. Thereafter, EMD 60 263 was administered (3, 10 and 30 microm). For comparison, the effect of the same doses was investigated in seven non-ischemic hearts. At the low dose, the agent improved ventricular systolic function in the post-ischemic group significantly (LVPmax: 65+/-13 v 91+/-17 mmHg; dP/dtmax: 845+/-235 v 1300+/-350 mmHg/s), and non-significantly in the non-ischemic group (LVPmax: 115+/-35 v 132+/-39 mmHg; dP/dtmax: 1415+/-545 v 1885+/-720 mmHg/s). Early relaxation (dP/dtmin) was slightly improved in both groups (800+/-225 v 1050+/-220 mmHg/s post-ischemic; 1120+/-315 v 1205+/-285 mmHg/s non-ischemic). Heart rate was increased (151+/-35 v 175+/-45 beats/min) in the post-ischemic group and was unaffected in the non-ischemic group. At the higher dose, systolic ventricular function in the post-ischemic group was further improved (LVPmax: 109+/-17 mmHg, dP/dtmax: 1330+/-180 mmHg/s), but tended to decrease in the non-ischemic group (LVPmax: 121+/-40 mmHg, dP/dtmax: 1605+/-680 mmHg/s). This dose decreased heart rate in both groups (133+/-34 and 134+/-23 beats/min). 30 microm EMD 60 263 had deleterious effects in both groups. The different responses towards Ca2+ sensitization suggest that a decrease in Ca2+ sensitivity might play a role in dysfunctional stunned myocardium. Therefore, Ca2+ sensitizing agents of the thiadiazinone type could be useful to recruit a positive inotropic reserve in stunned myocardium.
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PMID:Different responses of non-ischemic and post-ischemic myocardium towards Ca2+ sensitization. 928 38

Administration of inhibitors of the Na+/H+ exchanger (NHE) have been shown to produce cardioprotective effects in a number of animal models of ischemia-reperfusion injury; however, controversy still exists as to the efficacy of these agents when administered just before reperfusion. To address this question, the efficacy of several doses of a new selective NHE-1 isoform inhibitor (IC50 for inhibition of 22Na uptake in NHE-1 expressing mouse fibroblast cells = 10.4 +/- 1.0 nM), EMD 85131 (2-methyl-5-methylsulfonyl-1-(1-pyrrollyl)-benzoyl-guanidine), was tested in a canine infarct model in which the left anterior descending coronary artery was occluded for 60 min followed by 3 hr of reperfusion. EMD 85131 (0.75 or 3.0 mg/kg) was infused for 15 min before left anterior descending occlusion or 15 min before reperfusion. Infarct size was determined by use of the triphenyltetrazolium chloride histochemical stain and was expressed as a percent of the area at risk. EMD 85131 (0.75 or 3.0 mg/kg) administered before left anterior descending occlusion produced a marked (*P < .05) and dose-related reduction in IS/AAR (24.3 +/- 3.6, control; 9.3 +/- 3.4%, EMD 0.75; 6.4 +/- 2.3%, EMD 3.0). These two doses of EMD also produced significant (*P < .05) reductions in infarct size/area at risk (12.2 +/- 2.1%, EMD 0.75; 13.0 +/- 2.9%, EMD 3.0) when administered 15 min before reperfusion. These results suggest that selective NHE-1 inhibitors are able to markedly reduce infarct size when given before or during ischemia and also suggest that these compounds may have clinical utility when administered after the initiation of an ischemic insult.
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PMID:A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. 965 58

The NHE-1 isoform of the Na+/H+ exchanger is excessively activated in cardiac cells during ischemia. Hence NHE-1 specific inhibitors are being developed since they could be of beneficial influence under conditions of cardiac ischemia and reperfusion. In this study, the Cytosensortrade mark microphysiometer was used to measure the potency of four new drug molecules, i.e., EMD 84021, EMD 94309, EMD 96785 and HOE 642 which are inhibitors of the isoform 1 of the Na+/H+ exchanger. The experiments were performed with Chinese hamster ovary cells (CHO K1) which are enriched in the NHE-1 isoform of the Na+/H+ antiporter. The Na+/H+ exchanger was stimulated with NaCl and the rate of extracellular acidification was quantified with the Cytosensor. The proton exchange rate was measured as a function of the NaCl concentration in the range of 10-138 mm NaCl stimulation. The proton exchange rate followed Michaelis-Menten kinetics with a KM = 30 +/- 4 mm for Na+. Addition of either one of the four inhibitors decreased the acidification rate. The IC50 values of the four compounds could be determined as 23 +/- 7 nm for EMD 84021, 5 +/- 1 nm for EMD 94309, 9 +/- 2 nm for EMD 96785 and 8 +/- 2 nm for HOE 642 at 138 mm NaCl, in good agreement with more elaborate biological assays. The IC50 values increased with the NaCl concentration indicating competitive binding of the inhibitor. The microphysiometer approach is a fast and simple method to measure the activity of the Na+/H+ antiporter and allows a quantitative kinetic analysis of the proton excretion rate.
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PMID:New drugs for the Na+/H+ exchanger. Influence of Na+ concentration and determination of inhibition constants with a microphysiometer. 1005 88

We examined whether increases in blood-brain barrier (BBB) permeability occurring after stroke can be exploited to apply protective substances selectively to ischemic tissue. To do this, the actions of the peripherally selective OP2 agonists, EMD-61569 and EMD-61747, have been compared with those of the centrally acting OP2 agonist, GR-89696, in the rat permanent focal ischemia model. EMD-61569, EMD-61747 and GR-89696 all bound with high affinity to OP2 receptors and were potent agonists in the rabbit vas deferens functional assay. These substances also potently inhibited electrically-induced overflow of dopamine from slices of rat nucleus accumbens. EMD-61747 and EMD-61569 penetrate poorly into the CNS under normal conditions and reverse haloperidol-induced L-DOPA accumulation in the nucleus accumbens of the rat only at high doses, in contrast to GR-89696. Permanent unilateral occlusion of the middle cerebral artery (MCAO) was associated with a disruption of the BBB and an increase in the concentration of EMD-61747 in the area of the infarct. GR-89696 at a dose of 0.1 mg/kg s.c. produced a reduction in infarct volume by 38% after MCAO, EMD-61569 and EMD-61747 had no influence on swelling and ischemic damage. We conclude that EMD-61747 and EMD-61569 are potent OP2 agonists, which usually have a limited ability to penetrate the BBB. The change in the properties of the BBB in ischemic tissue was not sufficient to elicit neuroprotection, since both EMD-61747 and EMD-61569 were inactive in the focal ischemia model. Conversely, GR-89696 had a robust protective action, and probably powerful OP2-typical side effects as a consequence of its unrestricted central activity.
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PMID:Effects of GR-89696 and the novel peripherally selective OP2 agonists, EMD-61569 and EMD-61747, against focal cerebral ischemia in the rat. 1032 91


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