Plasma Nitrosospecies And Cardiovascular Disease

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In order to examine the role of nitrosospecies in relation to cardiovascular risk factors, we determined RXNO levels (the sum of all nitrosospecies) of plasma in patients with one or more cardiovascular risk factors [74]. Levels of RXNOs were lower in such individuals compared to controls. It can therefore be concluded that endothelial dysfunction is associated with a depletion of circulating nitroso/nitrosyl species in plasma, which is likely to contribute to the increased risk for major cardiovascular events in individuals with endothelial dysfunction. Measuring circulating nitroso/nitrosyl species may help identifying individuals at risk and serve as a therapeutic surrogate marker in the future. Further studies are needed to establish whether the plasmatic RXNO pool represents a valuable parameter that allows optimal dose titration of therapeutic agents aimed at targeting endothelial dysfunction.

EFFECTS OF NITRIC OXIDE AND RSNOs ON LEFT VENTRICULAR FUNCTION

In contrast to its well-defined vasodilator effect, the role of NO on myocardial function is still a subject of significant controversy, and experimental studies suggest both positive and negative effects on left ventricular function. Thus, the fundamental question as to whether NO contributes to the maintenance of myocardial function in humans still remains unanswered.

Initial in-vitro experiments in isolated ventricular myocytes as well as in the isolated guinea pig heart suggested a negative contractile effect of NO [75-77]. A bimodal effect of NO [78], with a positive contractile effect at low concentrations but a negative one at higher concentrations was postulated. In humans, the results are limited and partly divergent [79-81]. The direct impact of NO levels on left ventricular function has never been determined in humans. We therefore applied the S-nitrosothiol S-nitrosoglutathione (GSNO) on top of inhibited NO-synthase (NOS)-activity [by infusion of NG-monomethyl-L-arginine (l-NMMA)], and the mean arterial blood pressure at the beginning of the experiments served as the target value. This led to an increase in stroke volume index (SVI), which was measured by MRI-technology, and was accompanied by a decrease in arterial blood pressure compared to l-NMMA. To investigate whether the decrease in afterload and/or a sympathetic activation is responsible for the increase in SVI, we applied the vasodilator dihydralazine (a vasodilator not influencing the NO-pathway) to decrease arterial pressure to a level comparable to that resulting from GSNO. We observed no significant change in SVI after dihydralazine, suggesting that the effect of GSNO on cardiac function cannot be explained solely by the decrease in arterial blood pressure. The lack of a significant difference in plasma noradrenaline after application of GSNO or hydralazine ruled out a major sympathetic influence of either substance on SVI. Therefore, NO (at low concentration) improves left ventricular function even after matching for afterload and sympathetic tone pointing towards a direct NO-related effect on the myocardium [82]. Because of the bimodal effects of NO [78], with a positive effect on LV function at low amounts and a negative one at high amounts, the threshold level for the switch from a positive to a negative effect of NO seems to be of importance.

PLASMA NITRITE AND eNOS-ACTIVITY

The majority of intravascular NO is inactivated by its reaction with hemoglobin to form nitrate [17] (Fig. 2). Nitrate concentrations are influenced by a variety of NO-synthase (NOS)

Endothelium

Erythrocyte

Endothelium

Erythrocyte

NO-plasma-pool mwj inactive

NO-plasma-pool

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