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)

Positive inotropy requires a rise in myocardial oxygen consumption (MVO2); as far as PDE-III-inhibitors' beneficial hemodynamic effects, increases in contractility are controversial, in part probably because accurate proving is rather tedious. The clinician, however, requires a clear concept of whether or not enoximone (EN), for example, carries the risk of myocardial ischemia when used in patients with coronary artery disease. Using the analysis of pressure-volume relations, we recently established contractility-increasing as a partial effect of EN. There are indications suggesting that the inotropy-induced added increase in MVO2 of the PDE-III-inhibitor drugs could be compensated for by the simultaneous vasodilation and changes in compliance, so that as a net effect an unchanged MVO2 might result. Since, on the other hand, PDE-III-inhibitor drugs have been said to generate antiischemic properties, further clinical investigations with EN clearly seemed indicated and they are the subject of the present report: In five patient groups with stabile angina (AP) studied the following parameters and methods, respectively, were used for the evaluation of EN-induced changes of the anginal threshold: exercise, using pacing and ergometry; PA- and PC-pressure measurements; MVO2, indirectly assessed; hemodynamic profile and regional wall motion as assessed in the immediate post pacing phase; ST- T-segment evaluation; thalium-201 perfusion scintigraphy; myocardial perfusion, indirectly assessed. Lack of EN-induced AP (ischemia) and an increased AP threshold indicated that the drug can be used safety in patients with heart failure, including that due to coronary artery disease.
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PMID:[Effects of the phosphodiesterase III inhibitor in ischemic heart disease]. 192 97

The alpha 1-adrenergic receptor exists as at least two distinct subtypes, alpha 1a and alpha 1b. Based on hydrophobic exclusion studies and limited proteolysis of the cloned receptor, it appears to possess characteristics analogous to other membrane-bound receptors including seven membrane spanning domains, three extracellular, and three intracellular loops, with extensive glycosylation near the extracellular amino terminus. Although the receptor is coupled to phospholipase C in cardiac myocytes, with activation resulting in the production of inositol trisphosphate (IP3) and diacylglycerol, recent findings suggest that the receptor may also be linked to phospholipase A2, phospholipase D, and cyclic nucleotide phosphodiesterase. The alpha 1-adrenergic receptor has been shown to increase in response to myocardial ischemia in a number of different species and to mediate not only positive inotropic effects, but also to contribute substantially to arrhythmogenesis. The increase in alpha 1-adrenergic receptors can also occur in isolated adult ventricular myocytes in response to hypoxia, a mechanism which appears to be secondary to the sarcolemmal accumulation of long-chain acylcarnitines. This increase in alpha 1-adrenergic receptors in hypoxic myocytes is also linked to an enhanced increase in IP3 in response to receptor stimulation. These and other findings obtained in vivo during ischemia suggest that alpha 1-adrenergic mechanisms can become prominent in myocardium under pathophysiologic conditions in which a depressed contractile state exists and may therefore serve as a secondary inotropic system. However, the arrhythmogenic effects of stimulation of the alpha 1-adrenergic receptor in the ischemic heart in man may contribute substantially to arrhythmogenesis and, thereby, to the incidence of sudden cardiac death.
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PMID:Modulation of alpha-adrenergic receptors and their intracellular coupling in the ischemic heart. 196 2

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.
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PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92

To evaluate the efficacy of 31P magnetic resonance spectroscopy (31P MRS) as a diagnostic method for abnormal testicular function, we examined three conditions using rat testes, ischemia, irradiation, and hormone manipulation. 1) Ischemia: Immediately after clamping of the feeding vessels, ATP signals began to fall and disappeared within 60 minutes. With the release of blood supply after 3 hours of ischemia, ATP appeared within 2 hours. However, after more than 4 hours of ischemia, ATP did not recover within 2 hours and the testis became necrotic after 1 week. 2) Irradiation: 31P MRS of the testis 2 weeks after irradiation with 10 Gy., 9 MeV showed a significant decrease (P < 0.05) in the PME/beta-ATP ratio from 1.30 +/- 0.11 (control level) to 1.11 +/- 0.12 and a decrease in PME/PDE ratio from 1.43 +/- 0.17 to 1.13 +/- 0.20. However 3 weeks later, the PME/beta-ATP ratio recovered to a control level. 3) Hormone manipulation: In the testes 5 weeks after weekly intramuscular injections of estradiol benzoate and testosterone enanthate, PDE/beta-ATP ratio significantly increased (P < 0.01) from 0.83 +/- 0.09 (control level) to 1.03 +/- 0.19. 31P MRS is a non-invasive method for evaluation of various testicular abnormalities, and ATP signals may be useful to evaluate an acute ischemic change for example testicular torstion and the changes of PME, PDE signals may be useful parameters in the assessment of the status of spermatogenesis.
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PMID:[Experimental studies on evaluation of rat testicular function by 31P magnetic resonance spectroscopy]. 778 56

This study tested the hypothesis that a reperfused ischemic myocardial region of the dog heart would be unable to increase its function in response to amrinone, a specific cyclic AMP phosphodiesterase (cAMP-PDE) inhibitor, due to loss of cAMP-PDE activity in the region. The global contractility (+dp/dtmax), regional percent shortening (ultrasonic crystals), and developed force (miniature force gauge) were measured on a continuous basis throughout a 6-hour experiment and regional blood flow (radioactive microspheres) in open-chest pentobarbital-anesthetized mongrel dogs. The left anterior descending coronary artery (LAD) was isolated and ligated for 2 hours and allowed to reperfuse for 4 hours. This myocardial region was compared to a nonischemic region supplied by the circumflex artery. At the end of the 4-hour reperfusion period, 9 dogs were treated with amrinone (5 mg/kg) and three dogs were not treated with amrinone. The hearts were rapidly excised and frozen in liquid nitrogen. Cyclic AMP and cAMP-PDE activity was determined in homogenates of myocardial tissue. Blood flow decreased during occlusion in the LAD region and returned toward control with reperfusion. Flow increased nonsignificantly with amrinone. the basal cyclic AMP content of the two regions was not different. The cAMP-PDE activity was reduced 24% in the LAD region compared to the control region. There were no ischemia-induced changes in the enzyme characteristics. These experiments demonstrated increased global function in the ischemic reperfused myocardium after amrinone was administered (dP/dtmax: 2092 +/- 538 to 3277 +/- 688 mmHg/sec).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of ischemia-reperfusion on myocardial cyclic AMP and cyclic AMP phosphodiesterase: effects of amrinone on regional myocardial force and shortening. 826 38

The effect of inotropes on myocardial ischemia is difficult to predict because they may influence the determinants of myocardial O2 demand and O2 supply differently. Several PDE-inhibitors have been reported to possess antiischemic properties related to their hemodynamic and O2-sparing effects. To assess whether PDE-inhibitors also possess direct cardioprotective properties, the effects of amrinone (2.5 x 10(-5) mol/L) in comparison to isoproterenol (5 x 10(-9) mol/L) and ouabain (1.5 x 10(-7) mol/L) were studied in isolated rabbit hearts perfused according to Langendorff at a constant pressure (70 cmH2O) and electrically driven at a constant pacing rate. Regional ischemia was induced by coronary artery ligation and quantified by epicardial NADH fluorescence. All substances significantly increased the actively developed left ventricular pressure to a similar extent (+20%) (P < 0.05). Coronary flow was significantly decreased by ouabain (-15%) and significantly increased by isoproterenol (+25%) and particularly by amrinone (+50%) (P < 0.05). Neither ouabain nor isoproterenol significantly changed the intensity or the distribution pattern of NADH fluorescence, whereas the size of the ischemic zone was significantly reduced by amrinone (-25%) (P < 0.05). The PDE-inhibitor amrinone was shown to possess a direct cardioprotective effect by improving myocardial perfusion and O2 supply in isolated rabbit hearts.
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PMID:Beneficial effect of amrinone on the size of acute regional ischemia in isolated rabbit hearts. 826 39

Several signal transduction pathways have been implicated in the mechanism of protection induced by ischemic preconditioning (PC). For example, stimulation of a variety of G-protein coupled receptors results in stimulation of protein kinase C (PKC) which has been suggested to act as common denominator in eliciting protection. PC also significantly attenuated cAMP accumulation during sustained ischemia, suggesting involvement of an anti-adrenergic mechanism. The aim of this study was to evaluate the beta-adrenergic signal transduction pathway (as evidenced by changes in tissue cAMP and cAMP- and cGMP-phosphodiesterase) during the PC protocol as well as during sustained ischemia. Isolated perfused rat hearts were preconditioned by 3 x 5 min global ischemia (PC1,2,3) interspersed by 5 min reperfusion, followed by 25 min global ischemia. Tissue cAMP- and cGMP-PDE activity as well as cAMP and cGMP levels were determined at different time intervals during the PC protocol and sustained ischemia. Tissue cAMP increased with each PC ischemic event and normalized upon reperfusion, while PDE activity showed the opposite, viz a reduction during ischemia and an increase during reperfusion. Except for PC1, tissue cGMP showed similar fluctuations. Throughout 25 min sustained ischemia, cAMP- and cGMP-PDE activities were higher in PC than in nonpreconditioned hearts, associated with a significantly lesser accumulation in cAMP and higher cGMP levels in the former. Fluctuations in cyclic nucleotides during preconditioning were associated with concomitant changes in PDE activity, while the attenuated beta-adrenergic response of preconditioned hearts during sustained ischemia may partially be due to increased PDE activity.
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PMID:Role of cyclic nucleotide phosphodiesterases in ischemic preconditioning. 977 98

Cilostazol (Pletal), a quinolinone derivative with a cyclic nucleotide phosphodiesterase type 3 (PDE3) inhibitory activity, was recently approved by the Food and Drug Administration for treatment of symptoms of intermittent claudication (IC). However, the underlying mechanisms of action are not entirely clear. In this study, we showed that cilostazol inhibited adenosine uptake into cardiac ventricular myocytes, coronary artery smooth muscle, and endothelial cells with a median effective concentration (EC50) approximately 10 microM. In vivo, cilostazol increased cardiac interstitial adenosine levels after a 2-min ischemia in rabbit hearts (329 +/- 92% increase vs. 102 +/- 29% ischemia alone). The combination of cilostazol and 2-min ischemia reduced infarction from subsequent 30-min regional ischemia and 3 h of reperfusion (infarct size was 18 +/- 4% vs. 53 +/- 3% in the hearts with 2-min ischemia alone or 48 +/- 2% in the hearts treated with cilostazol alone). In contrast, milrinone had no effect on either adenosine uptake or interstitial adenosine levels. These data show that cilostazol, unlike milrinone, inhibits adenosine uptake, and thus potentiates adenosine accumulation from a 2-min ischemia. Future studies are needed to investigate the role of adenosine in the treatment of IC by cilostazol.
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PMID:Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication. 1097 93

In the present study, we investigated the activity and expression of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) and the effects of calpains in rat heart after ischemia and reperfusion. Immunohistochemical studies indicated that CaMPDE in normal heart is localized in myocardial cells. Rat ischemic heart showed a decrease in CaMPDE activity in the presence of Ca2+ and calmodulin; however, in ischemic-reperfusion tissue a progressive increase in Ca2+ and calmodulin-independent cyclic nucleotide phosphodiesterase (CaM-independent PDE) activity was observed. Perfusion of hearts with cell-permeable calpain inhibitor suppressed the increase of Ca2+ and CaM-independent PDE activity. Protein expression of CaMPDE was uneffected by hypoxic injury to rat myocardium. The purified heart CaMPDE was proteolyzed by calpains into a 45 kDa immunoreactive fragment in vitro. Based on these results, we propose that hypoxic injury to rat myocardium results in the generation of CaM-independent PDE by calpain mediated proteolysis, allowing the maintenance of cAMP concentrations within the physiological range.
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PMID:Calmodulin-dependent cyclic nucleotide phosphodiesterase in an experimental rat model of cardiac ischemia-reperfusion. 1192 71

Phosphodiesterase type-5 (PDE-5) inhibitors including sildenafil, vardenafil and tadalafil are a new class of vasoactive drugs that have been developed for treatment of erectile dysfunction in patients. A growing number of studies in recent years suggest that sildenafil may be used clinically for treatment of pulmonary hypertension and endothelial dysfunction. In addition, recent studies primarily from our laboratory suggested that sildenafil has preconditioning-like powerful cardioprotective effect in the animal models of ischemia-reperfusion injury. Sildenafil has been found to exert cardioprotection through nitric oxide generated from endothelial and/or inducible nitric oxide synthases and opening of mitochondrial ATP-sensitive potassium channels. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE-5 inhibitors, such as sildenafil, could have an enormous impact on bringing the long-studied phenomena of ischemic and pharmacologic preconditioning to the clinical forefront.
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PMID:Cardioprotection with phosphodiesterase-5 inhibition--a novel preconditioning strategy. 1487 43


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