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• W4377029403 abstract "<b>Abstract ID 53843</b> <b>Poster Board 302</b> Ischemia impairs the function of the heart (metabolism, mechanical and electrical). Restoration of blood flow by reperfusion will end the ischemic event but can paradoxically increase heart damage through processes where intracellular calcium (Ca²⁺) signaling appears to play a central role (ischemia-reperfusion injury). During ischemia, abnormal sarcoplasmic reticulum (SR) intracellular Ca²⁺ store homeostasis induces SR Ca²⁺ overload. At the onset of reperfusion, SR overload boosts massive SR Ca²⁺ release via ryanodine receptors (RyR) causing hypercontraction, excessive production of free-radicals and calpain-mediated proteolysis, as well as mitochondrial permeability transition (MPT) pore opening. All these events associate with myocyte cell death. We aim to identify drugs that could prevent or reduce overload during ischemia, by inhibiting SR Ca²⁺ATPase (SERCA) pumping of Ca²⁺ into the SR. The focus is on a drug that could be less toxic than Thapsigargin and cyclopiazonic acid (classic SERCA blockers). Previous work showed that compounds in the 1,4-benzothiazepine family that associate with cell protection, inhibit SERCA (CGP-37157, K201). We think that SERCA block could be: 1) A class property of CGP analogs, including novel 1,4-BZTs (PH000-995, -902) and FDA-approved benzodiazepines (BZDs) and 2) A hidden characteristic of drugs that induce cell protective action in ischemia-like conditions. Drug effects on SERCA and RyRs were tested on SR microsomes isolated from rabbit or porcine striated muscle (cardiac and skeletal) using Ca²⁺ uptake and leak photometric assays. SERCA ATPase activity was also measured at constant Ca²⁺ (0.3, 1, 100 μM). Conditions tested were normal pH (7.0) or acidosis (pH 6.2-6.4) as in ischemia. Bilayers were utilized to test drug effects on RyR channel activity. Novel BZTs reduced Ca²⁺uptake in the absence and presence of ruthenium red (RyR blocker), indicating SERCA block. ATPase assays determined BZTs block of SERCA is Ca²⁺-dependent (higher potency at low Ca²⁺). Ca²⁺ leak assay and RyR channel studies found PH000902 to have full agonism on RyRs. Other BZTs displayed partial or no RyR agonism (compared to N-methyl bromoeudistomin). BZT’s properties were maintained in acidosis (pH=6.2-6.4). BZDs did not inhibit SERCA, despite being homologous to CGP, suggesting a S atom in BZT ring to be crucial for activity. Some BZD displayed partial RyR agonism. Our results also show that cell protective drugs (pimozide, carvedilol, epigallocatechin gallate) also inhibit SERCA but did not affect RyR function. In summary, SERCA inhibition is a class property of 1,4-BZTs and analogs of CGP, yet is not observed in BZDs used in therapeutics. As CGP has been found to have low toxicity in experimental animals, 1,4-BZTs could have potential for developing specific SERCA blockers to improve therapy of myocardial ischemia to attenuate reperfusion injury. Our studies also suggest that prevention of SR Ca²⁺ overload via SERCA inhibition, may be a mechanism of action of various drugs associated with cell protection. Supported by the Eskridge Bequest and W.E. McElroy Charitable Foundation" @default.
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• W4377029403 date "2023-05-18" @default.
• W4377029403 modified "2023-09-29" @default.
• W4377029403 title "SERCA Inhibition by Drugs - A Potential Therapeutic Strategy in Ischemia" @default.
• W4377029403 doi "https://doi.org/10.1124/jpet.122.538430" @default.
• W4377029403 hasPublicationYear "2023" @default.
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