Cardiac and vascular effects of nitric oxide synthase inhibition in lipopolysaccharide-treated rats

Abstract

In the present study, intraperitoneal injection of lipopolysaccharide (10 mg/kg) to anaesthetized rats produced a gradual fall in mean arterial pressure in 6 h. Aortic rings from lipopolysaccharide-treated rats showed a significant reduction in the contractile response to vasoconstrictors. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, two nitric oxide synthase (NOS) inhibitors, abolished this vascular hyporeactivity. In ventricular myocytes isolated from lipopolysaccharide-treated rats, both electrically induced Ca2+ transients and the intracellular Ca2+ response to β-adrenergic stimulation were significantly depressed when compared with those recorded from myocytes from sham control rats. L-NAME and aminoguanidine alone had no effects on electrically stimulated Ca2+ transients in ventricular myocytes either from control or lipopolysaccharide-treated rats. However, these two NOS inhibitors augmented the intracellular Ca2+ response to β-adrenergic stimulation in myocytes from lipopolysaccharide-treated rats, but not in control myocytes. In addition, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of nitric oxide (NO)-sensitive guanylyl cyclase, also reversed the intracellular Ca2+ hyporesponsiveness to β-adrenergic stimulation in myocytes from lipopolysaccharide-treated rats. In cardiac myocytes from lipopolysaccharide-rats pretreated with aminoguanidine, the intracellular Ca2+ hyporesponsiveness to β-adrenergic stimulation was abolished. However, there still existed a depressed Ca2+ response to electrical field stimulation. These data indicate that NO following lipopolysaccharide stimulation contributes to vascular hyporeactivity and the depressed intracellular Ca2+ response to β-adrenergic stimulation in lipopolysaccharide-treated rats, but is not responsible for the reduced Ca2+ response to electrical stimulation in our experimental conditions. (C) 2000 Elsevier Science B.V.