Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to determine whether trandolaprilat, an active form of angiotensin I converting enzyme (ACE) inhibitor, may improve ischemia/reperfusion-induced contractile dysfunction and metabolic derangement of isolated rat hearts. Ischemia (25 min) and subsequent 60-min reperfusion resulted in a small recovery of post-ischemic left ventricular developed pressure (LVDP), a sustained increase in left ventricular end-diastolic pressure, an increase in the release of creatine kinase and ATP metabolites from the perfused heart, and changes in myocardial sodium, potassium, calcium and magnesium contents. Treatment with 10-100 microM of trandolaprilat for the last 10 min of pre-ischemia recovered approximately 50-90% of pre-ischemic LVDP during reperfusion, whereas that with 30-100 microM of enalaprilat restored approximately 55-65% of the pre-ischemic LVDP. Treatment with either trandolaprilat or enalaprilat at these concentrations attenuated the release of creatine kinase and ATP metabolites into the perfusate during reperfusion. Treatment with 30 microM trandolaprilat suppressed ischemia/reperfusion-induced changes in myocardial ion content. Treatment with bradykinin during the last 10 min of pre-ischemia also resulted in a post-ischemic contractile recovery with a degree similar to that of the trandolaprilat-treated hearts. E4177, an AT1-antagonist, showed no effect on ischemia/reperfusion-induced changes in cardiac parameters. The enhancement of post-ischemic contractile recovery by the ACE inhibitor was abolished by treatment with either Hoechst 140, a bradykinin (BK2) antagonist, or diclofenac, a cyclooxygenase inhibitor. These results suggest that trandolaprilat is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts and altered BK metabolism is, at least in part, involved in this effect.
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PMID:Beneficial effects of angiotensin I converting enzyme inhibitor on post-ischemic contractile function of perfused rat heart. 887 76

Here, we report a familial spinocerebellar ataxia (FSCA), which has clinical features similar to Friedreich's ataxia, an ataxia with isolated vitamin E deficiency, and ataxia telangiectasia. However, the serum levels of creatine kinase, gamma-globulin, and alpha-fetoprotein were elevated, and biochemical and genetic analyses ruled out diagnosis of these three ataxias as well as other FSCAs. Thus, this family is thought to have a new type of FSCA.
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PMID:Familial spinocerebellar ataxia with cerebellar atrophy, peripheral neuropathy, and elevated level of serum creatine kinase, gamma-globulin, and alpha-fetoprotein. 970 52

This study was designed to investigate the role of angiotensin (Ang II) in the cardioprotective effect of ischemic preconditioning. Isolated perfused rat heart was subjected to global ischemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase (CK) release to assess the degree of cardiac injury. Myocardial infarct size was estimated macroscopically by using triphenyl tetrazolium chloride (TTC) staining. Four episodes of ischemic/Ang II preconditioning markedly reduced LDH and CK release in the coronary effluent and decreased myocardial infarct size. The cardioprotective effect of Ang II preconditioning was abolished by CV 11974, AT1-receptor antagonist, whereas no such effect was noted with CV 11974 in ischemic preconditioning. PD 123319, AT2-receptor antagonist, produced no marked effect on Ang II preconditioning and ischemic preconditioning induced reduction in myocardial injury. On the basis of these results, it may be concluded that activation of AT1 receptors may be involved in angiotensin-induced pharmacologic preconditioning. But it may not be involved in the cardioprotective effect of ischemic preconditioning in isolated rat heart.
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PMID:Role of angiotensin in cardioprotective effect of ischemic preconditioning. 1022 65

Two angiotensin AT1 receptor antagonists with different receptor binding characteristics, candesartan (insurmountable antagonism) and losartan (surmountable antagonism), were compared as regards their effects on angiotensin II-induced vasoconstriction and on myocardial ischemia/reperfusion injury. In isolated rat hearts perfused under constant flow, it was found that at equipotent concentrations candesartan (10 nM) and losartan (3 microM) almost completely inhibited the angiotensin II-induced increase in coronary perfusion pressure. However, if a washout period was introduced before the angiotensin II challenge, the effect of losartan quickly vanished, while that of candesartan remained. In hearts subjected to 25 min of global ischemia and 45 min of reperfusion, pre-treatment with candesartan (10 nM) or losartan (3 microM) immediately prior to ischemia improved the recovery of left ventricular developed pressure as compared to the effect of vehicle (69 +/- 3.2 and 64 +/- 2.3 vs. 44 +/- 6.2%, respectively; mean +/- S.E.M, P < 0.05). When ischemia was initiated following 30 min of washout after drug administration, the recovery of left ventricular developed pressure was higher in the candesartan group (73 +/- 3.2%, P < 0.05), but not in the losartan group (63 +/- 2.8%), than in the vehicle group (58 +/- 4.8%). The cumulative creatine kinase release during the first 30 min of reperfusion in the washout experiments was lower in the candesartan group (28.5 +/- 2.30 U, P < 0.05), but not in the losartan (40.8 +/- 6.73 U) group, than in the vehicle group (48.1 +/- 4.35 U). No significant difference between groups in left ventricular end-diastolic pressure and coronary perfusion pressure was found. The present results demonstrate that angiotensin AT1 receptor antagonists at equipotent concentrations could differ in their cardioprotective effects in hearts subjected to ischemia/reperfusion. It is suggested that the insurmountable AT1 receptor characteristics of candesartan could provide more persistent cardioprotection than the surmountable receptor characteristics of losartan.
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PMID:Effects of the insurmountable angiotensin AT1 receptor antagonist candesartan and the surmountable antagonist losartan on ischemia/reperfusion injury in rat hearts. 1051 55

Molecules that induce ribosomal read-through of nonsense mutations in mRNA and allow production of a full-length functional protein hold great therapeutic potential for the treatment of many genetic disorders. Two such read-through compounds, RTC13 and RTC14, were recently identified by a luciferase-independent high-throughput screening assay and were shown to have potential therapeutic functions in the treatment of nonsense mutations in the ATM and the dystrophin genes. We have now tested the ability of RTC13 and RTC14 to restore dystrophin expression into skeletal muscles of the mdx mouse model for Duchenne muscular dystrophy (DMD). Direct intramuscular injection of compound RTC14 did not result in significant read-through activity in vivo and demonstrated the levels of dystrophin protein similar to those detected using gentamicin. In contrast, significant higher amounts of dystrophin were detected after intramuscular injection of RTC13. When administered systemically, RTC13 was shown to partially restore dystrophin protein in different muscle groups, including diaphragm and heart, and improved muscle function. An increase in muscle strength was detected in all treated animals and was accompanied by a significant decrease in creatine kinase levels. These studies establish the therapeutic potential of RTC13 in vivo and advance this newly identified compound into preclinical application for DMD.
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PMID:Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. 2269 82

The angiotensin II type 1 receptor (AT1R) antagonist protects the heart against acute ischaemia-reperfusion injury. The underlying mechanism is unclear. To determine the effects of angiotensin II type 1 receptor blockade, valsartan on AT1 and AT2 receptor during ischaemia reperfusion in isolated rat, the hearts of 24 SD rats were isolated, linked to Langendorff perfusion apparatus, and exposed to ischaemia for 30 min.The left ventricular systolic pressure, maximal uprising velocity of left ventricular pressure (+dp/dt(max)), maximal decreasing velocity of left ventricular pressure (-dp/dt(max)) and coronary flow were measured after stabilization of the perfusion.The isoenzyme of creatine kinase in the effluent liquid from the heart, AT1 and AT2 receptor mRNA and protein expression were measured after stabilization of the perfusion. The results showed that ischaemia-reperfusion induced a marked decrease in left ventricular systolic pressure, +dp/dt(max) and -dp/dt(max) indicating severe cardiac dysfunction and decreased coronary effluence. Concurrently, myocardial AT1 and AT2 receptor mRNA and protein expression were increased with valsartan. However, AT2 receptor mRNA and protein expression decreased during ischaemia-reperfusion. The creatine kinase levels at different time points of the valsartan group were significantly lower. The results suggested that valsartan improved left ventricular function and increased coronary effluence because the angiotensin receptor blocker valsartan induced cardioprotection associated with upregulating AT2 receptor protein and mRNA expression after ischaemia-reperfusion in isolated rats.
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PMID:Valsartan-induced cardioprotection involves angiotensin II type 2 receptor upregulation in isolated ischaemia and reperfused rat hearts. 2613 5