Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The calcium sensitivity of force production of cardiac muscle fibres is altered by certain drugs. The sites of action of three such compounds (pimobendan, sulmazole, isomazole) within the myofibril have been investigated. Calmodulin antagonists, perhexilene and bepridil, which have been shown to alter the calcium dependence of myofibrillar ATPase activity and oxmetidine, an H2-receptor antagonist which binds to calmodulin, were also studied. 2. The rates of dissociation of calcium from both the regulatory and high affinity sites on bovine isolated cardiac troponin C (cTnC) were measured in a stopped-flow fluorimeter. The rates of dissociation were found to be 136.5 +/- 16 s-1 and 1.3 +/- 0.20 s-1 (mean +/- s.e.mean, n = 11 determinations; conditions: 100 mM KCl, 10 mM MOPS, 3 mM MgCl2, 0.1 mM dithriothreitol, pH 7.0, 15 degrees C). Sulmazole, isomazole and perhexiline (final concentration of 50 microM) had no effect on the rate of Ca2+ dissociation from the regulatory Ca2+ site, indicating that these compounds do not act on cTnC directly. 3. The rate of dissociation of Ca2+ from the regulatory site was slightly reduced (approximately 20%) by pimobendan (50 and 100 microM) and was somewhat increased by oxmetidine (28% at 100 microM). 4. Bepridil (25 microM) reduced the rate of dissociation by 50%, indicating a direct effect of bepridil on TnC. 5. Sulmazole, isomazole, perhexiline, pimobendan (50 microM) and bepridil (25 microM) were without effect on the rate of dissociation of Ca2+ from the high affinity Ca2+/Mg2+ sites. Oxmetidine caused 24% decrease in the rate of Ca2+ dissociation from these sites. 6. The rate of dissociation of Ca2+ from the regulatory site on the complex of troponin-tropomyosin (TnTm) was measured. Sulmazole and pimobendan (50 microM) were without effect on the rate of dissociation of Ca2+ from the regulatory site in the protein complex, and isomazole (50 microM) caused only a slight reduction (23%). Perhexiline (50 microM) or bepridil (10 microM) reduced the rate of Ca2 dissociation by about 50%. The rate of dissociation of Ca2+ from the high affinity Ca2 +/Mg2 + sites was not altered by sulmazole, isomazole, or pimobendan (50 microM), but was decreased - 35% by perhexiline (50 microM) or bepridil (10 microM).
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PMID:The effects of reported Ca2+ sensitisers on the rates of Ca2+ release from cardiac troponin C and the troponin-tropomyosin complex. 220

Perhexiline is a lysosomotropic agent which has proved to be very valuable to certain patients suffering from angina pectoris. However long-term administration of the drug may induce hepato- and neuro-toxicity. Using HTC cells (a rat hepatoma-derived cell line) whose plasma membranes were labeled with NaB[3H]4 after oxidation by NaIO4, endocytosis and recycling of labeled asialo-orosomucoid (ASOR) receptors were investigated in the presence of 50 mumols/l perhexiline maleate. The results demonstrate that the drug induces a significant decrease of the rate of both the internalization and the recycling of ASOR receptors. The mechanisms responsible for these effects have not yet been elucidated. However, the current findings may be related to the previously observed inhibitory effect of perhexiline on cellular (Na+, K+)-ATPase and Mg++-ATPase activities. Our findings would then reflect insufficient cellular energy production, resulting from depressed ATP hydrolysis in the presence of perhexiline.
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PMID:Effects of perhexiline maleate on asialo-orosomucoid receptor endocytosis and recycling in HTC cells. 261

The weakly basic, lipophilic Ca++ antagonists perhexiline and cinnarizine have been compared with the calmodulin inhibitor W-7 and the cardiotonics Vardax and APP-201-533 for the ability to modulate Ca++-dependent contractile protein interactions directly, as well as Ca++-calmodulin-mediated myosin light chain phosphorylation, in arterial actomyosin or cardiac myofibrils. Both perhexiline and cinnarizine inhibited arterial myosin P-light chain phosphorylation and superprecipitation of arterial actomyosin over the concentration range of 10 to 200 microM. Concomitant inhibition of arterial superprecipitation and phosphorylation by perhexiline (IC50 = 33 microM) and cinnarizine (IC50 = 60 microM) was similar to W-7 (IC50 = 35 microM), and was characterized by a rightward shift in the pCa superprecipitation and pCa-light chain phosphorylation relationships, depressed maximum activity and attenuation by 2 microM exogenous calmodulin. However, whereas inhibition of superprecipitation and P-light chain phosphorylation by W-7 was equal at different Mg++ concentrations, relatively greater inhibition with perhexiline and less inhibition with cinnarizine was apparent as the free Mg++ concentration was lowered. In cardiac myofibrils prepared from both bovine and canine ventricles, perhexiline stimulated Mg-adenosine triphosphatase (ATPase) activity and cinnarizine was without effect, whereas W-7 significantly depressed ATPase activity. Perhexiline was 10-fold more potent and 3-fold more efficacious than either Vardax or APP-201-533 in canine cardiac myofibrils. Whereas APP-201-533 increased Ca++ sensitivity and maximum ATPase activity (Vmax), perhexiline increased Ca++ sensitivity, but not Vmax, and W-7 depressed both parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the calcium antagonists perhexiline and cinnarizine on vascular and cardiac contractile protein function. 316 16