Sarkar, David A.; (2003) Effect of (nitric oxide) NO donors on cardiac function. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Previous reports have demonstrated a range of negative and latterly positive inotropic responses in cardiac preparations exposed to NO. We set out to investigate the effect of NO donors on isolated myocytes and to elucidate the underlying mechanism and experimental factors governing the observed response. In isolated guinea-pig ventricular cardiomyocytes newer classes of NO donors including nitrosothiols (GSNO and SNAP) and NONOates (DEANO) induced a positive inotropic response. SNP and GTN showed no positive inotropy. The response was enhanced by co-administration of isoprenaline and reversibly abolished by the free NO scavenger oxyhaemoglobin. ODQ (soluble guanyl cyclase inhibitor) and Rp-cAMPS (protein kinase A inhibitor) did not abolish the effect. Measurement of myocyte cyclic nucleotides demonstrated a rise in cGMP, but not cAMP. Microelectrode recordings of the action potential and steady state ICa during exposure to DEANO (10?M) found no change in the action potential, though the ICa was increased with preservation of the current-voltage relationship. A faster rate of NO donor decomposition was associated with positive inotropy. Breakdown of nitrosothiols was enhanced by the presence of myocytes. Functionally the fast NO releaser DEANO was more likely to induce an increase in cell shortening compared with the slow releaser detanonoate. Positive inotropy was demonstrated in rabbit and human myocytes (from failing and non-failing hearts) but not in rat. In multi- cellular preparations the inotropic effect was reduced or absent. Myocytes from guinea-pigs treated with lipopolysaccharide demonstrated a depressed response to -adrenoceptor stimulation, which was not reversed by the nitric oxide synthase (NOS) inhibitor L-NAME. The positive inotropic response to DEANO (10 M) was unaffected. In conclusion the experiments demonstrated a positive inotropic effect of certain NO donors with variation in the response related to NO donor kinetics, animal species and preparation complexity. The effect was independent of cyclic nucleotides and mediated via the L-type calcium channel.

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