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)

We investigated temporal differences in the protective action of three types of Ca2+ channel blockers in myocardial ischemia, focusing particularly on the blocking ability under depolarizing conditions. The effects of diltiazem, verapamil, and nifedipine on extracellular potassium concentration ([K+]e), acidosis, and level of metabolic markers were examined during 30-min global ischemia and postischemic left ventricular (LV) function in isolated guinea pig hearts. Diltiazem and verapamil, but not nifedipine, inhibited the late phase (15-30 min) of [K+]e elevation, whereas all three blockers delayed the onset of the early phase (0-8 min) of [K+]e elevation. Diltiazem and verapamil inhibited ischemic contracture and improved postischemic LV function to a greater extent. These differences appeared to be linked to preservation of ATP and creatine phosphate and delay of cessation of anaerobic glycolytic activity. Maneuvers to preserve energy sources during ischemia (decrease in external Ca2+ concentration or pacing at a lower frequency) attenuated the late phase of [K+]e elevation. Inhibition of LV pressure was potentiated 12- and 8.2-fold by diltiazem and verapamil, respectively, at 8.9 mM K+ as compared with 2.9 mM K+, whereas that by nifedipine was unchanged. These results indicate that the differential cardioprotection of Ca2+ channel blockers in the late period of ischemia correlates with preservation of high-energy phosphates as a result of different Ca2+ channel blocking abilities under high [K+]e conditions.
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PMID:Temporal differences in actions of calcium channel blockers on K+ accumulation, cardiac function, and high-energy phosphate levels in ischemic guinea pig hearts. 1021 60

A role for K+ and Ca2+ channel blockers in cardiac contractile dysfunction and myocardial ionic imbalance was examined in isolated rat hearts with 35-min ischemia and 60-min reperfusion. The K+ channel blockers glibenclamide (1-30 microM) and sematilide (1-30 microM), Ca2+ channel blockers diltiazem (0.1-3 microM) and nicardipine (0.03-1 microM) and fast Na+ channel blocker tetrodotoxin (0.01-0.3 microM) were delivered for the last 3-min pre-ischemia. Ischemia-induced increase in Na+ content was attenuated by diltiazem and tetrodotoxin at all concentrations employed and by nicardipine at 0.3 microM, whereas the ischemia-induced loss of K+ was suppressed partially by glibenclamide and sematilide and almost completely by the two drugs in combination. Left ventricular developed pressure of untreated hearts did not recover upon reperfusion, which was associated with increases in myocardial Na+ and Ca2+ contents and decreases in K+ and Mg2+ contents. Glibenclamide and sematilide neither enhanced the post-ischemic recovery of left ventricular developed pressure nor affected cation changes during reperfusion. Diltiazem enhanced the recovery of left ventricular developed pressure and attenuated imbalance of the myocardial Na+ during ischemia and of all myocardial cations examined during reperfusion. The effects of nicardipine on these parameters were small. Tetrodotoxin enhanced the recovery of left ventricular developed pressure and reversed the imbalance of all myocardial cations examined during reperfusion in a concentration-dependent manner. The results suggest that blockade of transmembrane flux of K+ during ischemia plays a minor role in the improvement of post-ischemic contractile recovery, rather blockade of transmembrane flux of Na+ attenuates the ischemia and reperfusion injury.
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PMID:Relationship between myocardial cation content and injury in reperfused rat hearts treated with cation channel blockers. 1037 13

l-cis Diltiazem, an optical isomer of diltiazem, protects against myocardial dysfunction in vitro, whereas its Ca2+ channel blocking activity is about 100 times less potent than that of diltiazem. However, there is no evidence that l-cis diltiazem actually protects against ischemia/reperfusion injury in vivo. To assess this, we employed an anesthetized rabbit model, where the left circumflex artery was occluded for 15 min and reperfused for 360 min. Treatment with diltiazem before and during ischemia (bolus 200 microg/kg and 15 microg/kg per minute for 25 min, i.v.; 575 microg/kg total) showed slightly depressed hemodynamic parameters, while l-cis diltiazem (1150 microg/kg) had no effect. Treatment with l-cis diltiazem produced a high recovery of the thickening fraction and limited the infarct size in a dose-dependent manner. Furthermore, the treatment with l-cis diltiazem (1150 microg/kg) or diltiazem (575 microg/kg) 5 min before reperfusion also limited the infarct size, but not after reperfusion. These results suggest that l-cis diltiazem affects some events in the onset of reperfusion, independently of Ca2+-channel-blocking action. Our observations are the first to show that l-cis diltiazem demonstrated its cardioprotective action in the ischemic rabbit heart in vivo.
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PMID:Treatment with l-cis diltiazem before reperfusion reduces infarct size in the ischemic rabbit heart in vivo. 1049 32

We have previously demonstrated that treatment with L-cis diltiazem reduced cardiac infarct size in vivo. To examine the effect of L-cis diltiazem on Ca(2+) overload induced by ischemia/reperfusion, we used a model for Ca(2+) overload produced by metabolic inhibition in isolated guinea pig myocytes. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was quantified by fura-2 fluorescence microscopy and Ca(2+) overload was induced by inclusion of 1 microM of carbonyl cyanide m-chrolophenylhydrazone (CCCP) for 40 min treatment followed by washout for 30 min. This treatment caused a large [Ca(2+)](i) elevation as well as a sustained contracture of the cardiomyocytes. The increase was suppressed by 10 microM of 2-[2-[4-(4-nitrobenzyloxy) phenyl] ethyl] isothiourea methanesulphonate (KB-R7943), a specific inhibitor of the Na(+)/Ca(2+) exchanger, but not by nitrendipine (10 microM). L-cis Diltiazem (10 microM) attenuated the [Ca(2+)](i) increase, suggesting that L-cis diltiazem elicits a cardioprotective effect via attenuation of the [Ca(2+)](i) increase induced by metabolic inhibition and energy repletion.
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PMID:L-cis diltiazem attenuates intracellular Ca(2+) overload by metabolic inhibition in guinea pig myocytes. 1060 80

l-cis-Diltiazem, the stereoisomer of the L-type Ca(2+) channel blocker d-cis-diltiazem, protects cardiac myocytes from ischemia and reperfusion injury in the perfused heart and from veratridine-induced Ca(2+) overload. We determined the effect of l-cis-diltiazem on the voltage-dependent Na(+) current (I(Na)) and lysophosphatidylcholine-induced currents in isolated guinea-pig left ventricular myocytes by a whole-cell patch-clamp technique. l-cis-Diltiazem inhibited I(Na) in a dose-dependent manner without altering the current-voltage relationship for I(Na) (K(d) values : 729 and 9 microM at holding potentials of -140 and -80 mV, respectively). A use-dependent block of I(Na), the leftward shift of the steady-state inactivation curve and the delay of recovery from inactivation suggest that l-cis-diltiazem has a higher affinity for the inactivated state of Na(+) channels. In addition to I(Na), the lysophosphatidylcholine-induced currents were inhibited by l-cis-diltiazem in a similar concentration range. It is suggested that inhibition of both Na(+) channels and lysophosphatidylcholine-activated non-selective cation channels contributes to the cardioprotective effect of l-cis-diltiazem.
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PMID:Electrophysiological effect of l-cis-diltiazem, the stereoisomer of d-cis-diltiazem, on isolated guinea-pig left ventricular myocytes. 1072 61

Diltiazem has cardioprotective properties following myocardial ischemic injury. However, there are controversial results regarding the beneficial effects of diltiazem on regional myocardial flow after ischemia. Therefore, we investigated the effect of diltiazem on changes in regional myocardial flow due to ischemia for different periods. Non-radioactive colored microspheres were used for this measurement in isolated rat heart. After 20 or 40 min of global ischemia and 40 min of reperfusion, regional myocardial flow was decreased, especially in the endocardial layer. The endocardial/epicardial ratio was also decreased. The decreases in endocardial flow and the endocardial/epicardial ratio were more remarkable after 40 min of ischemia than after 20 min of ischemia. Diltiazem (10(-6) M), which was administered 15 min before ischemia, prevented only the decrease in endocardial flow and endocardial/epicardial ratio after 20 min of ischemia, whereas it did not prevent that after 40 min of ischemia. Nifedipine (2x10(-6) M) did not exert a cardioprotective effect. These findings suggested that the effect of ischemia is marked in the endocardium and, also, that the protective effect of diltiazem is seen only during a decrease in endocardial flow following short-term and reversible ischemia.
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PMID:Protective effect of diltiazem against ischemia-induced decreases in regional myocardial flow in rat heart. 1085 51

The effects of L-cis and D-cis diltiazem on the extracellular potassium concentration ([K(+)]e), pH and cardiac function were compared in ischemic guinea pig hearts. Before inducing ischemia, L-cis diltiazem (10 and 30 microM) reduced the left ventricular developed pressure (LVDP) with a marginal inhibition of heart rate (HR), whereas lower doses of the D-cis isomer decreased both LVDP and HR. L-cis Diltiazem only slightly inhibited the increase in [K(+)]e and the decrease in pH but significantly inhibited ischemic contractures in contrast to the marked inhibition of these parameters produced by even low doses of the D-cis isomer. Notably, at equipotent doses for the ischemic parameters, L-cis diltiazem restored the left ventricular end-diastolic pressure (LVEDP) and HR after reperfusion to a greater extent than the D-cis isomer. These results suggest that the L-cis isomer may specifically improve postischemic function, in addition to the modest action on [K(+)]e and pH, in guinea pig hearts.
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PMID:Differences in protective profiles of diltiazem isomers in ischemic and reperfused guinea pig hearts. 1177 75

Interruption of hepatic blood flow is necessary in surgery, but the liver is sensitive to ischemia and reperfusion. Hypoxia induces an increase in intracellular calcium concentration. In previous studies, we have shown that hypoxia-reoxygenation (H/R) increased calcium influx and induced JNK(1)/SAPK(1) activation which was involved in the triggering of apoptosis. The aim of this study was to demonstrate that diltiazem, a calcium inhibitor, reduced JNK(1)/SAPK(1) activation and consequently could decrease H/R-induced apoptosis. Experiments were performed, in the presence of diltiazem, on primary cultured rat hepatocytes, subjected to warm H/R phases and in a liver ischemia-reperfusion model. The activation status of JNK(1)/SAPK(1) was evaluated by immunoprecipitation and immunohistolocalisation experiments, while apoptosis was assessed by measuring caspase activity and by TUNEL labeling. Diltiazem inhibited H/R-induced JNK(1)/SAPK(1) activation and decreased apoptosis. It could be used to improve postoperative liver function.
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PMID:Diltiazem reduces apoptosis in rat hepatocytes subjected to warm hypoxia-reoxygenation. 1193 79

The cardioprotective effect of caldaret, a novel intracellular Ca(2+) handling modulator that acts through reverse-mode Na(+)/Ca(2+) exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca(2+) uptake enhancement, against reperfusion injury was investigated. We employed a canine model of myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused caldaret (3 or 30 microg/kg per hour) for 30 min at LCX-reperfusion markedly reduced infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial/epicardial blood flow ratio (Endo/Epi ratio) or a reduction in double-product throughout the protocol. Diltiazem (2000 microg/kg per hour) also reduced infarct size (by 36.1%), but unlike caldaret, was accompanied by the significant increase in Endo/Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between infarct size and ischemic regional TMBF in all groups. Caldaret, but not diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca(2+) handling dysfunction achieved by caldaret leads to cardioprotective effects against reperfusion injury following prolonged ischemia.
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PMID:Caldaret, an intracellular Ca2+ handling modulator, limits infarct size of reperfused canine heart. 1729 42

The multidrug efflux pump P-glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug-protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a "cage" of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp.
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PMID:Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates. 2572 81


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