Cytokines and nitric oxide synthase inhibitor as mediators of adrenergic refractoriness in cardiac myocytes

Abstract

We have previously proposed that pro-inflammatory cytokines and nitric oxide (NO) contributed to reversible myocardial depression in patients with sepsis and congestive heart failure. Sepsis and heart failure are also associated with refractoriness to β-adrenoceptor agonists. Therefore, the chronotropic effects of cytokines and the NO synthase inhibitor, N G-methyl- l-arginine (NMA), on β-adrenoceptor stimulation of neonatal cardiac myocytes were studied. Tumor necrosis factor α, interleukin-1β and interleukin-6 but not interleukin-4 or interleukin-5 significantly enhanced spontaneous beating rates compared to untreated myocytes in serum-free media for 48 h ( P<0.01; n=12 for each). NMA also significantly enhanced spontaneous beating rates ( P<0.01; n=12 for each). Only interleukin-1β treatment resulted in significant nitrite production, immunohistochemical staining for inducible nitric oxide synthase and detection of inducible NO synthase messenger RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). However, tumor necrosis factor α, interleukin-1β, interleukin-6, and NMA each completely blocked the positive chronotropic effects of the β-adrenoceptor agonist, isoproterenol ( P<0.01; n=12 for each). These findings are most consistent with an inducible NO synthase-independent effect of cytokines and NMA on the chronotropic responses of neonatal cardiac myocytes to β-adrenoceptor stimulation. This effect of cytokines and NMA on adrenergic signaling may involve a myocardial constitutive NO synthase or an NO-independent mechanism.