Cardiac and vascular effects of nitric oxide synthase inhibition in lipopolysaccharide-treated rats.
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 Ca(2+) transients and the intracellular Ca(2+) response to beta-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 Ca(2+) transients in ventricular myocytes either from control or lipopolysaccharide-treated rats. However, these two NOS inhibitors augmented the intracellular Ca(2+) response to beta-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 Ca(2+) hyporesponsiveness to beta-adrenergic stimulation in myocytes from lipopolysaccharide-treated rats. In cardiac myocytes from lipopolysaccharide-rats pretreated with aminoguanidine, the intracellular Ca(2+) hyporesponsiveness to beta-adrenergic stimulation was abolished. However, there still existed a depressed Ca(2+) response to electrical field stimulation. These data indicate that NO following lipopolysaccharide stimulation contributes to vascular hyporeactivity and the depressed intracellular Ca(2+) response to beta-adrenergic stimulation in lipopolysaccharide-treated rats, but is not responsible for the reduced Ca(2+) response to electrical stimulation in our experimental conditions.
Shan
Q
Q
Department of Physiology, Institute of Cardiovascular Sciences and Medicine, The University of Hong Kong, 5 Sassoon Road, SAR, Hong Kong, People's Republic of China. shanqixian@yahoo.com
Bourreau
J
J
D000818:Animals; D001011:Aorta / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012772:Shock, Septic / Q000209:etiology; D014661:Vasoconstriction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D011943:Receptors, Adrenergic, beta; D010656:Phenylephrine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C004479:pimagedine; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester