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This study investigates mechanisms underlying [β.sub.3]-adrenergic activation of the endothelial nitric oxide synthase (eNOS) in myocardial tissue of wild-type (WT) and [β.sub.3]-adrenoceptor knockout ([β.sub.3]-KNO) mice, in the absence and presence [...]

The antinociceptive effects of nicotine are exerted by the interaction with subtypes of nicotinic acetylcholine receptors (nAChRs), present in neuronal pathways responding to pain. Mice lacking the alpha4 subunit of the neuronal nAChR were generated using homologous recombination techniques, and studied together with mutant mice lacking the Beta2 nAChR subunit. Homozygous alpha4-1- mice did not express high-affinity ((super3)H)nicotine and ((super3)H)epibatidine binding sites in the brain. Both types of mutant mice exhibited reduced antinociceptive effects of nicotine.

This study investigates mechanisms underlying beta3-adrenergic activation of the endothelial nitric oxide synthase (eNOS) in myocardial tissue of wild-type (WT) and beta3-adrenoceptor knockout (beta3-KNO) mice, in the absence and presence of BRL 37344 (BRL), the preferential beta3-adrenoceptor selective agonist. Nitric oxide (NO)-liberation was measured after the application of BRL (10 micromol/L), using fluorescence dye diaminofluorescein (DAF), in left ventricular cardiac preparations. Phosphorylation of eNOSSer1177, eNOSThr495, eNOSSer114, and eNOS translocation, and alterations of 8-isoprostaglandin F2alpha (a parameter for reactive oxygen radical generation), after application of BRL (10 micromol/L), were studied using immunohistochemical stainings in isolated, electrically stimulated (1 Hz) right atrial (RA) and left ventricular (LV) myocardium. An increased NO release after BRL application (10 micromol/L) was observed in the RA and LV myocardial tissue of WT mice, but not in beta3-KNO mice. This NO liberation in WT mice was paralleled by an increased eNOSSer1177, but not eNOSThr495, phosphorylation. A cytosolic eNOS translocation was observed after the application of BRL (10 micromol/L) only in the RA myocardial tissue of WT mice. A BRL (10 micromol/L)-dependent increase in eNOSSer114 phosphorylation was observed only in the LV myocardial tissue of WT mice; this was paralleled by an increase in 8-isoprostaglandin F2alpha. In murine myocardium, 3 beta3-adrenoceptor-dependent activation pathways for eNOS exist (i.e., a translocation and phosphorylation of eNOSSer1177 and eNOSSer114). These pathways are used in a regional-dependent manner. beta3-adrenergic oxygen-derived free radical production might be important in situations of enhanced beta3-adrenoceptor activation, as has been described in human heart failure.