Positive inotropic effects of NO donors in isolated guinea-pig and human cardiomyocytes independent of NO species and cyclic nucleotides.
430 - 439.
OBJECTIVE: To characterise the inotropic response of isolated myocytes to a range of structurally unrelated NO donors and to assess the role of NO release kinetics, NO species and cyclic nucleotides in mediating the observed changes. METHOD: Guinea-pig (GP) and human myocytes were prepared by enzymatic digestion. Paced contractile amplitude was recorded at 37 degrees C. NO release was measured by reduction of oxyhaemoglobin and using an NO electrode. Cyclic nucleotides were measured using a tritium labelled competitive binding assay. RESULTS: The NO donors S-nitrosoglutathione (GSNO) and diethylamine/NO (DEA/NO) produced positive inotropic effects in GP myocytes at (10(-5) M) (25 and 111% increases of contraction amplitude).The response to GSNO was significantly enhanced in the presence of a low concentration of isoprenaline (3x10(-10) M). Positive inotropy was observed with a range of both thiol and non-thiol donors, amongst which a fast rate of NO release was associated with positive inotropy. The response to GSNO was abolished by the free NO scavenger oxyhaemoglobin, but not by ODQ (soluble guanylyl cyclase [sGC] inhibitor), Rp-cAMPS (protein kinase A inhibitor) or thapsigargin (sarcoplasmic reticulum Ca(2+) uptake blocker). Direct measurement of cyclic nucleotides showed a rise in cGMP but not cAMP. Human ventricular myocytes showed a significant increase of contraction with GSNO (48+/-15.8%, n=7, P<0. 05) in the presence of isoprenaline and a marked response to DEA/NO alone. CONCLUSIONS: Isolated GP and human myocytes show a positive inotropic effect with certain NO donors. This is independent of sGC and cAMP. The rate of NO release from donors appears important in mediating the effect
|Title:||Positive inotropic effects of NO donors in isolated guinea-pig and human cardiomyocytes independent of NO species and cyclic nucleotides|
|Additional information:||UI - 20545136 LA - eng RN - 0 (Cardiotonic Agents) RN - 0 (Diethylamines) RN - 0 (Nitric Oxide Donors) RN - 0 (Nitroso Compounds) RN - 0 (S-nitro-N-acetylpenicillamine) RN - 10102-43-9 (Nitric Oxide) RN - 109-89-7 (diethylamine) RN - 31356-94-2 (8-bromocyclic GMP) RN - 52-67-5 (Penicillamine) RN - 57564-91-7 (S-nitrosoglutathione) RN - 60-92-4 (Cyclic AMP) RN - 70-18-8 (Glutathione) RN - 7665-99-8 (Cyclic GMP) RN - 7683-59-2 (Isoproterenol) PT - Journal Article DA - 20001215 IS - 0008-6363 SB - IM CY - NETHERLANDS JC - COR|
|Keywords:||AGENTS, AMP, analogs & derivatives, analysis, Animal, ASSAY, BINDING, cardiomyocyte, cardiomyocytes, Cardiotonic Agents, Cells, Cultured, Contraction, Cyclic AMP, Cyclic GMP, Diethylamines, DONORS, Dose-Response Relationship, Drug, drug effects, effects, ELECTRODE, enhanced, Glutathione, guinea pig, Guinea Pigs, Guinea-pig, heart, INCREASES, INHIBITOR, Isoproterenol, KINASE, Kinetics, Lung, Male, measurement, medicine, metabolism, Myocardial Contraction, Myocardium, myocytes, nitric oxide, Nitric Oxide Donors, NITRIC-OXIDE, Nitroso Compounds, Nucleotide, Nucleotides, OXIDE, Penicillamine, pharmacology, PROTEIN, protein kinase, RANGE, REDUCTION, release, response, SOLUBLE GUANYLYL CYCLASE, Stimulation, Chemical, Support, Non-U.S.Gov't, Tritium, UK, uptake|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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