Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of hypoxia on the myocardial uptake and pharmacodynamics of quinidine were studied in isolated perfused rabbit hearts. Hearts were perfused with a modified Krebs-Henseleit buffer that was equilibrated with either 95% O2-5% CO2 (normoxia) or 95% N2-5% CO2 (hypoxia). The myocardial quinidine accumulation was determined from concentration differences in aortic perfusate and coronary sinus effluent. Under hypoxic conditions, the myocardial concentration of quinidine (12.0 +/- 3.6 micrograms/g) was significantly reduced compared to normoxic conditions (24.8 +/- 8.5 micrograms/g, p less than 0.01). Greater increases in QRS complex duration were observed during hypoxia (10.0 +/- 1.0 ms) compared to normoxia (7.5 +/- 1.3 ms; p less than 0.05). Greater increases in MAP duration were also observed during hypoxia (64 +/- 14 ms) compared to normoxia (37 +/- 14 ms; p less than 0.01). The myocardial concentration-effect relationships describing changes in QRS complex duration, QT interval, MAP duration, and ventricular effective refractory periods were linear in both groups. The curves of the concentration-effect relationships observed during hypoxia were shifted to the left compared to those observed during normoxia and the slopes of these relationships were also significantly greater (p less than 0.05). These pharmacokinetic and pharmacodynamic interactions may be explained by the development of acidosis during hypoxia since the pH of the coronary sinus effluent decreased significantly during hypoxia (7.10 +/- 0.04) compared to the normoxic group (7.25 +/- 0.04, p less than 0.001). Thus, although hypoxia reduces the myocardial accumulation of quinidine, greater electrophysiologic effects are observed compared to normoxic conditions. These observations likely relate to a change in responsiveness of acidotic tissue to quinidine.
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PMID:Influence of hypoxia on the myocardial uptake and pharmacodynamics of quinidine in isolated perfused rabbit hearts. 170 29

We have recently demonstrated that myocardial adaptation to ischemia triggers a tyrosine kinase regulated signaling pathway leading to the translocation and activation of p38 MAP kinase and MAPKAP kinase 2. Since oxidative stress is developed during ischemic adaptation and since free radicals have recently been shown to function as an intracellular signaling agent leading to the activation of nuclear transcription factor, NFkappaB, we examined whether NFkappaB was involved in the ischemic adaptation process. Isolated perfused rat hearts were adapted to ischemic stress by repeated ischemia and reperfusion. Hearts were pretreated with genistein to block tyrosine kinase while SB 203580 was used to inhibit p38 MAP kinases. Ischemic adaptation was associated with the nuclear translocation and activation of NFkappaB which was significantly blocked by both genistein and SB 203580. The ischemically adapted hearts were more resistant to ischemic reperfusion injury as evidenced by better function recovery and less tissue injury during post-ischemic reperfusion. Ischemic adaptation developed oxidative stress which was reflected by increased malonaldehyde formation. A synthetic peptide containing a cell membrane-permeable motif and nuclear sequence, SN 50, which blocked nuclear translocation of NFkappaB during ischemic adaptation, significantly inhibited the beneficial effects of adaptation on functional recovery and tissue injury. In concert, SN 50 reduced the oxidative stress developed in the adapted myocardium. These results demonstrate that p38 MAP kinase might be upstream of NFkappaB which plays a role in ischemic preconditioning of heart.
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PMID:An essential role of NFkappaB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. 966 50

Heart failure is associated with an increase in plasma nitrate and nitrite (NOx). To date there is still some controversy regarding the causes of nitrate accumulation during the development of heart failure. The goal of this study was to analyze the underlying mechanisms that cause accumulation of plasma nitrates during the development of heart failure in dogs. Dogs were chronically instrumented for measurement of hemodynamics and renal function. Hearts were paced initially at 210 bpm for 3 weeks and then at 240 until the development of heart failure. Hemodynamics, renal function, renal blood flow, arterial blood gases, hemoglobin, plasma and urine NOx levels, and creatinine levels were measured weekly. Heart failure was assessed by hemodynamic alterations, physical signs such as lethargy, ascites, cachexia, and postmortem evidence of cardiac hypertrophy. LVSP (from 127 +/- 3 to 106 +/- 3 mmHg), LV dP/dt (from 2658 +/- 173 to 1439 +/- 217 mmHg/s), MAP (from 101 +/- 1.9 to 83 +/- 1.8 mmHg) fell, whereas LVEDP tripled (from 6.4 +/- 0.9 to 20 +/- 2.6 mmHg), and heart rate rose (from 101 +/- 4.2 to 117 +/- 6.3 bpm), all changes P < 0.05. RBF (from 146 +/- 10 to 96 +/- 9.9 ml/min), urine output (V) (from 0.26 +/- 0.02 to 0.16 +/- 0.02 ml/min), GFR (from 63 +/- 1.8 to 49 +/- 2 ml/min), and Na excretion (from 45 +/- 4.5 to 14 +/- 4.6 microEq/min) all decreased (P < 0.05), whereas RVR increased (from 0.68 +/- 0.05 to 0.94 +/- 0.1 mmHg/ml/min). These changes took place during a rise in plasma NOx (from 3.7 +/- 0.5 to 16+/-3.3 microM), a decrease in urine NOx (from 33 +/- 9.9 to 8.1 +/- 4.9 microM), and a concurrent increase in NOx reabsorption (from 221 +/- 31 to 818 +/- 166 nmol/min). There was a direct correlation between the increase in plasma NOx levels and an increase in filtered load (r(2) = 0.97, P = 0.02), a negative correlation between NOx levels and NOx excretion (r(2) = 0.65 P < 0.09), and a direct correlation between plasma NOx levels and NOx reabsorption (r(2) = 0.97, P = 0.02). These results indicate that elevated plasma NOx during heart failure are most likely the result of an impairment of the renal function and not increased NOx production. Furthermore, without knowing changes in renal function the measurement of plasma NOx in and of itself is a meaningless index of NO formation.
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PMID:Plasma nitrate accumulation during the development of pacing-induced dilated cardiac myopathy in conscious dogs is due to renal impairment. 1117 32

The efficacy of Withania somnifera (Ws) to limit myocardial injury after ischemia and reperfusion was explored and compared to that of Vit E, a reference standard known to reduce mortality and infarct size due to myocardial infarction. Wistar rats (150-200 g) were divided into six groups and received orally saline (sham, control group), Ws-50/kg (Ws control and treated group) and Vit E-100 mg/kg (Vit E control and treated group) respectively for 1 month. On the 31st day, rats of the control, Vit E and Ws treated groups were anesthetized and subjected to 45 min occlusion of the LAD coronary artery followed by 60 min reperfusion. Hemodynamic parameters: systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), left ventricular peak (+)LVdP/dt and (-)LVdP/dt were monitored. Hearts were removed and processed for histopathological and biochemical studies: Myocardial enzyme viz, creatin phosphokinase (CPK), and antioxidant parameters: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx) were estimated. Postischemic reperfusion produced significant cardiac necrosis, depression of left ventricular functions (MAP, LVEDP, (+) and (-)LVdP/dt) and a significant fall in GSH (p < 0.01), SOD, CAT (p < 0.05), LDH and CPK (p < 0.01) as well as an increase in MDA level (p < 0.05) in the control group rats as compared to sham group. The changes in levels of protein and GPx was however, not significant. Ws and Vit E favorably modulated most of the hemodynamic, biochemical and histopathological parameters though no significant restoration in GSH, MAP (with Vit E) were observed. Ws on chronic administration markedly augmented antioxidants (GSH, GSHPx, SOD, CAT) while Vit E did not stimulate the synthesis of endogenous antioxidants compared to sham. Results indicate that Ws significantly reduced myocardial injury and emphasize the beneficial action of Ws as a cardioprotective agent.
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PMID:Cardioprotection from ischemia and reperfusion injury by Withania somnifera: a hemodynamic, biochemical and histopathological assessment. 1522 84

The p38 MAP kinases are stress-activated MAP kinases whose induction is often associated with the onset of heart failure. This study investigated the role of p38 MAP kinase isoforms in the regulation of myocardial contractility and ischemia/reperfusion injury using mice with cardiac-specific expression of kinase dead (dominant negative) mutants of p38alpha (p38alphadn) or p38beta (p38betadn). Hearts were subjected to 20 min ischemia and 40 min reperfusion. Immunofluorescence staining for p38alphadn and p38betadn protein was performed on neonatal cardiomyocytes infected with adenovirus expressing flag-tagged p38alphadn and p38betadn protein. Basal contractile function was increased in both p38alphadn and p38betadn hearts compared to WT. Ischemic injury was increased in p38betadn vs. WT hearts, as indicated by lower posti-schemic recoveries of contractile function and ATP. However, despite a similar increase in contractility, ischemic injury was not increased in p38alphadn vs. WT hearts. Immunohistological analysis of cardiomyocytes with comparable levels of protein overexpression show that p38alphadn and p38betadn proteins were co-localized with sarcomeric alpha-actinin, however, p38alphadn was detected in the nucleus while p38betadn was exclusively detected in the cytosol. In summary, attenuated p38 activity led to increased myocardial contractility; specific isoforms of p38 and their sub-cellular localization may have different roles in modulating ischemic injury.
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PMID:Effect of p38 MAP kinases on contractility and ischemic injury in intact heart. 1970 73