Norepinephrine-stimulated MAP kinase activity enhances cytokine-induced NOproduction by rat cardiac myocytes

The effect of norepinephrine (NE) on cytokine-stimulated nitric oxide (NO) production by cardiac myocytes has not been previously reported. NE alone c aused no significant increase in NO2- levels over vehicle. Addition of NE t o interleukin-lp (IL-1 beta) significantly increased inducible NO synthase (iNOS) mRNA expression, iNOS protein, and NO2- production vs. IL-1 beta alo ne. Addition of the alpha-adrenergic blocker prazosin or the beta-adrenergi c blocker propranolol partially reduced the NE-mediated increase in iNOS mR NA expression and NO2- production. Addition of prazosin and propranolol tog ether completely abolished the NE-induced increase in iNOS mRNA expression and NO2- production. NE significantly enhanced mitogen-activated protein (M AP) kinase activity that was reduced by prazosin, propranolol, and PD-98059 , a selective MAP kinase kinase inhibitor. Addition of PD-98059 reduced the NE-mediated increase in iNOS mRNA expression and NO2- production. We repor t for the first time that NE enhances IL-1 beta-stimulated NO production by activation of alpha- and beta-adrenergic receptors through a novel MAP kin ase mechanism.