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)

Nisoldipine is a calcium antagonist that specifically blocks the slow or voltage-dependent calcium channel up to the highest concentrations. This mode of action has been confirmed in pharmacological studies on isolated organs, electrophysiological and binding studies, and by the measurement of transmembrane calcium transport. As with other dihydropyridine calcium antagonists, an interaction with intracellular calcium reservoirs and calmodulin seems to be of minor importance. The drug exhibits higher potency, longer duration of action, and a higher binding affinity in vitro and in vivo than nifedipine. In contrast to its vasodilating and spasmolytic activity, its negative inotropic effect occurs in vitro only after higher concentrations than after nifedipine. In whole animals a secondary positive inotropic effect occurs regularly owing to sympathetic counter-regulation. The influence of nisoldipine on cardiac stimulus formation and conduction is also very slight in anesthetized animals, and is completely eliminated in awake animals and humans by counter-regulation up to very high doses. The cardiac anti-ischemic action of nisoldipine has been demonstrated in various ischemia models and is probably based predominantly on its afterload-reducing properties in addition to its spasmolytic effect on the coronary arteries. Various other suspected effects, for which there are isolated indications, e.g., inhibition of thromboxane synthesis, preload reduction, interaction with the transport of adenosine, and normalization of the sarcolemmal Na+, K(+)-ATPase activity, are probably of subordinate importance. Its antihypertensive effect is explained primarily by lowering of the peripheral resistance. There are, however, some indications that nisoldipine exerts certain effects over and above pure vasodilation. The prevention of postischemic calcium overloading in the renal tubule epithelium and the natriuretic effect are probably of importance in the therapeutic action. Clinically, nisoldipine was found more potent and prolonged in its action in comparison with nifedipine. In comparative studies, nisoldipine, 10 mg once a day, was found equieffective with nifedipine 10 mg three times or 20 mg twice a day in angina or hypertension, respectively.
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PMID:The pharmacology of nisoldipine. 315 74

Nisoldipine, a dihydropyridine with calcium channel-blocking activity, was studied in myocardial ischemia and reperfusion in cats. At an infusion rate of 3 micrograms/kg/hr, nisoldipine did not significantly alter the product of mean arterial blood pressure and heart rate, the pressure-rate index. When infusion of nisoldipine was started 30 minutes after occlusion and continued for 5 1/2 hours, nisoldipine exerted a marked antiischemic effect. This effect was manifested as a significant reduction in necrotic myocardial tissue expressed either as a percentage of area at risk (p less than 0.01) or as a percentage of total left ventricle (p less than 0.01). The washout of creatine kinase into the circulation was also reduced in nisoldipine-treated cats. When nisoldipine infusion started at 60 minutes after ischemia, the effects were still significant (p less than 0.05) but less striking, and when nisoldipine infusion was delayed until 90 minutes after ischemia, no significant cardioprotection was observed. Nisoldipine also blunted the washout of creatine kinase into the peripheral circulation on reperfusion. Thus nisoldipine exerts a cardioprotective effect in cats during myocardial ischemia independent of reducing myocardial oxygen demand. The effect is optimal when nisoldipine is given during the first 30 minutes of ischemia and declines thereafter, reaching insignificant effects at 90 minutes.
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PMID:Cardioprotective actions of nisoldipine in postreperfusion myocardial ischemia. 336 51

The effects of the calcium channel blocker nisoldipine on renal function after 60 min. normothermic ischemia and contralateral nephrectomy were studied in male Wistar rats. Nisoldipine (300 ppm) was given in a standard diet as well as one hour prior to ischemia (10 mg./kg. orally). Survival, serum urea, serum creatinine, urine volume and creatinine clearance were used to test the effectiveness of the drug. Nisoldipine treatment resulted in the survival of all animals (compared to 66.6 per cent in the untreated group) and improved immediate and long term (14 days) renal function. The drug given post ischemia only was not effective, suggesting that nisoldipine must be present in the kidney during ischemia. The beneficial effects of the drug in postischemic acute renal failure may be attributed in part to effects on postischemic renal hemodynamics. Additional direct effects on ischemic renal epithelial cells, presumably by inhibiting transmembrane calcium fluxes, cannot be excluded.
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PMID:Calcium channel blocker nisoldipine limits ischemic damage in rat kidney. 405 26

Calcium entry blockers can effectively preserve high-energy phosphates in ischemic heart. However, little is known about the optimal timing of drug therapy. The moment of nisoldipine administration in relation to its protective efficacy during ischemia and reperfusion was studied in rat hearts. Nisoldipine (50 nM), given some time before a reduction of about 90% in coronary flow diminished ATP-catabolite efflux during both ischemia and reperfusion by up to 85%. In contrast, drug administration at the onset of ischemia, or during ischemia or during reperfusion was completely without protective effect. Similarly, early nisoldipine application gave rise to ischemic ATP, adenylate charge and creatine phosphate values higher than those in untreated or late-treated hearts. Nisoldipine decreased the tension developed before ischemia by up to 66%, without affecting (post)ischemic function. Nisoldipine spares energy effectively only if administered to the heart prior to ischemia. This presumably has to do with its negative inotropy before flow reduction.
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PMID:Timely administration of nisoldipine essential for prevention of myocardial ATP catabolism. 408 50

This work was undertaken to study functional and structural changes of the cardiac sarcolemmal membrane which was isolated from the ischemic lesion in the dog. The sarcolemmal fraction was prepared, by adopting the method devised by Reeves and Sutko , from the right ventricle and the subendocardial and subepicardial layers of the left ventricle. Ischemic lesion was produced by occlusion of a branch of the left anterior descending coronary artery for a period of 1.5 hr in the thoracotomized dog, followed by release of the occlusion for 3 hr. Nisoldipine, 5 micrograms/kg, was given twice intravenously, and chlorpromazine was infused at a rate of 10 micrograms/kg X min, in addition to the administration of twice bolus doses of 400 micrograms/kg each. Nisoldipine significantly decreased the incidence of premature ventricular contractions and microvascular hemorrhage. Sarcolemmal purity was monitored by using enzyme and chemical markers; the results indicated that the membrane preparation was tenfold purified over the homogenate. Although the activities of ouabain-sensitive (Na+, K+)-ATPase and ouabain-sensitive K+-p-nitrophenylphosphatase ( pNPPase ) of the sarcolemmal preparation isolated from the subendocardial layer were similar to those from the subepicardial layer in the nonischemic left ventricle, a significant decrease in these activities was observed only when the sarcolemmal fraction isolated from the subendocardial layer of ischemic area was compared with that from the subendocardial layer of nonischemic area. In contrast, the sialic acid content of the sarcolemma from the ischemic subendocardial layer was significantly increased compared to that of the nonischemic subendocardial layer. No such changes occurred in sarcolemma prepared from the ischemic subepicardial layer. The total phospholipid content as well as phosphatidylcholine and -ethanolamine contents of the sarcolemmal membrane prepared from the subendocardial layer of ischemic area were significantly decreased compared to nonischemic area. Nisoldipine prevented the ischemia-induced alterations in sarcolemmal (Na+, K+)-ATPase, pNPPase , sialic acid and phospholipids of the subendocardial layer. Chlorpromazine showed a less consistent effect than did Nisoldipine under our experimental conditions. Our study thus demonstrates that the lipid component and function of cardiac sarcolemmal membrane are altered in the early ischemic lesion and that these alterations are nonuniform in distribution and are alleviated by some pharmacological intervention.
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PMID:Ischemia-induced changes in sarcolemmal (Na+, K+)-ATPase, K+-pNPPase, sialic acid, and phospholipid in the dog and effects of the nisoldipine and chlorpromazine treatment. 608 73

Ischemic injury was produced in the dog heart by occluding the left anterior descending coronary artery just below the second diagonal branch for a duration of 1.5 h followed by the release of occlusion. Nisoldipine, 3.5 micrograms/kg was injected intravenously 10 min before the occlusion and again 10 min before the commencement of reperfusion. The activity of serum creatine phosphokinase greatly increased after the reperfusion, and this increase was significantly suppressed by Nisoldipine. This drug, in addition, prevented ischemia-induced myocardial hemorrhage and premature ventricular contraction. Sarcolemmal membrane vesicles were prepared from an ischemic and non-ischemic portions of the myocardium 3 h after the commencement of reflow. The fraction was purified approximately 12-fold with respect to ouabain-sensitive (Na+K+)-ATPase as an indicator; contamination of mitochondria was minimum with cytochrome c oxidase as an indicator. Without treatment of Nisoldipine, the total amount of sarcolemmal phospholipid obtained from the ischemic area, as well as the amounts of phosphatidyl-choline and phosphatidyl-ethanolamine, were significantly decreased as compared with those obtained from the non-ischemic area. Nisoldipine treatment abolished the decrease in the sarcolemmal phospholipids, total as well as phosphatidyl-choline and -ethanolamine, induced by ischemia plus reperfusion. Therefore, our work indicates that the Ca++ channel antagonist, Nisoldipine, suppresses the ischemia-induced increase in phospholipid breakdown of cardiac sarcolemma probably through its inhibitory effect on the Ca++-mediated activation of membrane phospholipase, through its vasodilatory action, or both.
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PMID:The effect of a calcium channel antagonist, Nisoldipine, on the ischemia-induced change of canine sarcolemmal membrane. 631 Nov 55

We compared two newer dihydropyridine-calcium antagonists (lacidipine and nisoldipine) with the classic prototype of this group, nifedipine, in the rat working heart preparation. The hearts were paced at a frequency of 5 Hz and perfused with Tyrode's solution of 37 degrees C. The following five parameters were determined: left ventricular pressure (LVP), maximal rate of pressure increase (+dP/dtmax), aortic output (AO), coronary blood flow (CBF), and cardiac output (CO). First, dose-response curves were constructed; from these data the EC50 concentration for the three calcium antagonists was calculated. Subsequently, washout from the cardiac tissue for these three compounds was determined. The effects of lacidipine did not diminish during < or = 90-min washout, whereas the effects of nifedipine disappeared completely in 10 min. The effects of nisoldipine, however, disappeared partly in 10 min. In separate experiments, the antiischemic activity of the three calcium antagonists was analyzed, using low-flow ischemia. The calcium antagonists were used in a concentration that produced a 60% reduction in contractile force (EC60). Nifedipine and nisoldipine caused significant improvement in functional recovery. The antiischemic properties of lacidipine could not be shown because of its slow kinetic properties with accumulation in the membrane phase and slow kinetics with the channel. Nisoldipine and lacidipine appear to be more potent calcium antagonists as compared with nifedipine, whereas lacidipine displays a clearly different kinetic pattern in comparison to nifedipine and nisoldipine. In particular, the extremely slow onset and very long duration of action of lacidipine are of interest.
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PMID:Hemodynamic and antiischemic effects of nifedipine, lacidipine, and nisoldipine in rat isolated working heart. 750 27

Nisoldipine is a dihydropyridine calcium entry blocker that inhibits contraction of vascular smooth muscle with a potency that is 2-3 times greater than its impact on myocardial contractility. In isolated human coronary arteries, tonic contractions induced by serotonin are inhibited by nisoldipine with a potency 10 times greater than that in internal mammary arteries and 1,000 times greater than that in electrically driven myocardium. In contrast, nifedipine had little effect and verapamil and diltiazem had none. In this article an hypothesis is reviewed that relates vascular smooth muscle selectivity to membrane potential sensitivity. Nisoldipine's effect on calcium channel binding and blocking is enhanced by the degree of depolarization of the cell membrane. Verapamil and diltiazem are not membrane-potential sensitive. Vascular smooth muscle cells are more depolarized than myocardial cells, and human coronary arteries have a particularly small membrane potential. Thus, the potency of nisoldipine in these organs parallels the degree of membrane depolarization. This may then suggest ischemia selectivity, since membrane depolarization occurs in ischemic tissue. Nisoldipine might therefore have a potent negative inotropic effect and an enhanced vasodilator action in ischemic myocardium, yet leave normoxic regions functionally intact. Some experimental evidence is discussed.
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PMID:Why is nisoldipine a specific agent in ischemic left ventricular dysfunction? 772 22

The effects of the long-acting dihydropyridine calcium antagonist nisoldipine coat core (CC) have been investigated in > 3,500 patients with angina pectoris, hypertension, and ischemic ventricular dysfunction. In patients with angina pectoris, nisoldipine CC improved total treadmill exercise duration (p = 0.027), delayed the onset of angina pectoris (p = 0.009), and increased time to exercise-induced ST-segment depression (p = 0.061). In general, nisoldipine 20-40 mg was effective, and the dose-response curve flattened thereafter. In patients with hypertension, 10-40 mg once daily as monotherapy reduced blood pressure (p < 0.05), with a fall in diastolic pressure of > or = 10 mm Hg or a final diastolic pressure of < 90 mm Hg in 35-63% of patients. In most patients followed for a year, nisoldipine CC was continued as monotherapy. Efficacy was similar in patients < 65 and > 65 years of age. In the Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy (DEFIANT-I) study of patients recovering from myocardial infarction, nisoldipine CC had a salutary effect on diastolic ventricular function, with a higher transmitral early filling velocity and shorter isovolumic relaxation time than in patients receiving placebo. Bicycle exercise capacity was greater (by 12 W; 95% confidence interval, 0.8-23.3) and exercise-induced ischemia occurred less frequently. The nisoldipine CC data pool (3,679 patients) showed that the drug was well tolerated with a low incidence of side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Efficacy and safety of nisoldipine coat core in the management of angina pectoris, systemic hypertension, and ischemic ventricular dysfunction. 772 25

We examined the cardioprotective effect of nisoldipine against myocardial dysfunction during ischemia and reperfusion in Langendorff perfused rabbit hearts. Nisoldipine was administered to the hearts before 60 minutes of global ischemia. This agent inhibited the increase of end-diastolic pressure during ischemia and also improved the recovery of left ventricular developed pressure and coronary flow during reperfusion in a concentration-dependent manner. The maximal cardioprotective effect was observed in 10(-8) M nisoldipine. The beneficial effect was associated with an increase of coronary flow during reperfusion. Therefore, both the nisoldipine-increased coronary flow during reperfusion and the inhibition of ischemic contracture by nisoldipine seem to play a crucial role in improving myocardial dysfunction of ischemic-reperfused hearts.
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PMID:Improvement of ischemic myocardial dysfunction by nisoldipine. 794 79


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