nitroarginine and Cholestasis

Nitric oxide (NO) has an important role in controlling heart rate and contributes to the cholinergic antagonism of the positive chronotropic response to adrenergic stimulation. Based on evidence of NO overproduction in cholestasis and also on the existence of bradycardia in cholestatic subjects, this study aimed to evaluate the chronotropic effect of epinephrine in isolated atria of cholestatic rats and determine whether alterations in epinephrine-induced chronotropic responses of cholestatic rats are corrected after systemic inhibition of NO synthase (NOS) with N(G)-nitro-L-arginine (L-NNA). Male Sprague-Dawley rats were used. Cholestasis was induced by surgical ligation of the bile duct under general anesthesia and sham-operated animals were considered as control. The animals were divided into three groups, which received either L-arginine (200 mg/kg/day), L-NNA (10 mg/kg/day) or saline. One week after the operation, a lead II ECG was recorded from the animals, then spontaneously beating atria were isolated and chronotropic responses to epinephrine were evaluated in a standard oxygenated organ bath. The results showed that plasma gamma-glutamyl transpeptidase and alanine aminotransferase activity was increased by bile-duct ligation, and that L-aginine treatment partially, but significantly, prevented the elevation of these markers of liver damage. The results showed that heart rate of cholestatic animals was significantly less than that of sham-operated control rats in vivo and this bradycardia was corrected with daily administration of L-NNA. The basal spontaneous beating rate of atria in cholestatic animals was not significantly different from that of sham-operated rats in vitro. Meanwhile, cholestasis induced a significant decrease in chronotropic effect of epinephrine. These effects were corrected by daily administration of L-NNA. Surprisingly L-arginine was as effective as L-NNA and increased the chronotropic effect of epinephrine in cholestatic rats but not in sham-operated animals. Systemic NOS inhibition corrected the decreased chronotropic response to adrenergic stimulation in cholestatic rats, and suggests an important role for NO in the pathophysiology of heart rate complications in cholestatic subjects. The opposite effect of chronic L-arginine administration in cholestasis and in control rats could be explained theoretically by an amelioration of cholestasis-induced liver damage by chronic L-arginine administration in bile duct-ligated rats

Topics: Alanine Transaminase; Animals; Arginine; Bradycardia; Cholestasis; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epinephrine; gamma-Glutamyltransferase; Heart Atria; Heart Rate; In Vitro Techniques; Male; Nitric Oxide; Nitroarginine; Rats; Rats, Sprague-Dawley; Tyrosine; Vasoconstrictor Agents

Cholestasis liver disease is associated with clinical and experimental findings consistent with increased opioidergic neuromodulation, increased plasma total activity, and elevated plasma enkephalin concentrations. The effect of the nitric oxide (NO) synthase inhibitor, L-nitro-arginine (L-NA, 0.03, 0.1, 0.3, 1 mg/kg), and the nitric oxide precursor, L-Arg (30 mg/kg), on antinociception induced by bile duct resection or sham operation, as well as on opioid dependence, was examined in male albino Swiss mice. Repeated (5 days) administration of L-NA attenuated signs of dependence, as assessed by naloxone (5 mg/kg)-precipitated withdrawal, and decreased the antinociception; however, L-Arg potentiated withdrawal signs and increased the antinociception. The results of this study support the involvement of the L-arginine/nitric oxide pathway in the opioidergic-dependent manifestation of cholestasis in an animal model.

Topics: Acute Disease; Animals; Arginine; Behavior, Animal; Bile Ducts; Cholestasis; Enzyme Inhibitors; Male; Mice; Naloxone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Reaction Time; Substance Withdrawal Syndrome

Following the naloxone administration in bile duct resected animals, striking opioid withdrawal signs are observed due to increased opioidergic tone. Pretreatment of animals with L-nitro arginine, a nitric oxide synthase inhibitor, reduces the naloxone-precipitated withdrawal signs as well as increase the antinociception. The results of this study support evidence for the involvement of the L-arg-nitric oxide pathway in opioidergic-dependent manifestation of cholestasis in an animal model.

Topics: Analgesia; Animals; Behavior, Animal; Cholestasis; Male; Mice; Naloxone; Narcotic Antagonists; Nitroarginine; Opioid Peptides; Pain Measurement; Substance Withdrawal Syndrome