Role of nitric oxide and platelet-activating factor in cardiac alterations induced by tumor necrosis factor-α in the guinea-pig papillary muscle

Abstract

The present results suggest that in cardiac muscle: (1) the release of PAF triggered by TNF-alpha may account for the stimulation of NO production; (2) both PAF and NO contribute to the development of the electrical and mechanical alterations induced by TNF-alpha; (3) NO production was down-stream to the synthesis of PAF.

A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation

“…The PAF receptor antagonist BN-52021 was used at 1 M, inasmuch as a similar concentration of BN-52021 blocks the PAF-induced release of atrial natriuretic factor from rat hearts (22). Rp-8-bromoguanosine-3Ј,5Ј-cyclic monophosphorothioate (Rp-8-BrcGMPs), a cell-permeable cGMP antagonist, and 1H- [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylyl cyclase, were used at 50 M and 0.4 M, respectively. Control experiments (see RESULTS) were done to ensure that these concentrations of Rp-8-BrcGMPs and ODQ inhibit known cGMP effects in ventricular myocytes.…”

“…Most of the effects of PAF are mediated through a dedicated G protein-coupled receptor. PAF receptor activation has been linked to increases in phosphatidylinositol (3,4,5)-triphosphate and production of nitric oxide (NO) (1,2,24). Increased NO production has been shown to alter intracellular Ca 2ϩ handling in cardiac myocytes, and NO-dependent decreases in L-type Ca 2ϩ channel activity have been shown to correlate to a decrease in I/R injury in hearts (6,10,29).…”

Cytokine-Induced Modulation of Cardiac Function

“…The rapid time course and reversibility of these effects implicated the activation of myocardial cNOS. Since this initial report, several additional studies have supported a role for cNOS-derived NO in the early negative inotropic effects of the following: (1) IL-2 in isolated, blood-perfused rabbit hearts 61 ; (2) IL-6 in avian 35 and mammalian 75 myocytes; and (3) TNF-␣ and/or IL-1␤ (alone or in combination) in adult 72 and neonatal 70 mammalian myocytes, guinea pig, 69 and rat 66 muscle strips, isolated crystalloid-perfused rat hearts, 34 and human atrial trabeculae. 64 In addition to acute contractile dysfunction, cNOS-derived NO has been linked to a variety of functional abnormalities including IL-6 -mediated depression of the Ca 2ϩ transient, 35,75 TNF-␣-mediated reductions in myofilament Ca 2ϩ sensitivity, 72 and the deterioration of mechanical efficiency induced by a combination of IL-1␤, TNF-␣, and IFN-␥ (Figure 2).…”

“…57 Coronary vasoconstriction also contributes indirectly to TNF-␣-induced early 65,81 and late 31 contractile dysfunction in isolated, crystalloid-perfused rat hearts. In contrast, fewer studies support either an early stimulatory (or dual) effect 30,31,69,[82][83][84] or no detectable immediate contractile effect 7,32,38,39,44,49,85,86 of specific proinflammatory cytokines.…”

“…Fourth, careful attention needs to be focused on the experimental methodology and cytokine concentrations used. In vitro, an immediate positive inotropic effect (when reported) generally occurs very early (within 5 to 15 minutes) after exposure and at lower cytokine concentrations, 30,31,69,84 whereas negative inotropic effects become pronounced with longer periods of exposure and/or higher concentrations. Finally, Stamm et al 78 have reported significant speciesspecificity with regard to the inotropic effects of recombinant cytokines; this factor may also account for some of the variability among studies that have used cross-species sources of cytokines.…”