Beta-adrenergic receptor 1 selective antagonism inhibits norepinephrine-mediated TNF-alpha downregulation in experimental liver cirrhosis.

BACKGROUND: Bacterial translocation is a frequent event in cirrhosis leading to an increased inflammatory response. Splanchnic adrenergic system hyperactivation has been related with increased bacterial translocation. We aim at evaluating the interacting mechanism between hepatic norepinephrine and inflammation during liver damage in the presence of bacterial-DNA. ANIMALS AND METHODS: Forty-six mice were included in a 16-week protocol of CCl(4)-induced cirrhosis. Laparotomies were performed at weeks 6, 10, 13 and 16. A second set of forty mice injected with a single intraperitoneal dose of CCl(4) was treated with saline, 6-hydroxidopamine, Nebivolol or Butoxamine. After 5 days, mice received E. coli-DNA intraperitoneally. Laparotomies were performed 24 hours later. Liver bacterial-DNA, norepinephrine, TNF-alpha, IL-6 and beta-adrenergic receptor levels were measured. RESULTS: Bacterial-DNA translocation was more frequent in CCl(4)-treated animals compared with controls, and increased as fibrosis progressed. Liver norepinephrine and pro-inflammatory cytokines were significantly higher in mice with vs without bacterial-DNA (319.7 ± 120.6 vs 120.7 ± 68.6 pg/g for norepinephrine, 38.4 ± 6.1 vs 29.7 ± 4.2 pg/g for TNF-alpha, 41.8 ± 7.4 vs 28.7 ± 4.3 pg/g for IL-6). Only beta-adrenergic receptor-1 was significantly increased in treated vs control animals (34.6 ± 7.3 vs 12.5 ± 5.3, p=0.01) and correlated with TNF-alpha, IL-6 and norepinephrine hepatic levels in animals with bacterial-DNA. In the second set of mice, cytokine levels were increased in 6-hydroxidopamine and Nebivolol (beta-adrenergic receptor-1 antagonist) treated mice compared with saline. Butoxamine (beta-adrenergic receptor-2 antagonist) didn't inhibit liver norepinephrine modulation of pro-inflammatory cytokines. CONCLUSIONS: Beta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl(4)-treated mice with bacterial-DNA.

ß2 adrenergic-mediated reduction of blood glutamate levels and improved neurological outcome after traumatic brain injury in rats.

BACKGROUND: Isoflurane-anesthetized rats subjected to traumatic brain injury (TBI) show a transient reduction in blood L-glutamate levels. Having previously observed that isoproterenol produces a sustained decrease in blood glutamate levels in naive rats, we investigated the possible effects of nonselective and selective ß1 and ß2 adrenergic agonists and antagonists both on blood glutamate levels and on the neurological outcomes of rats subjected to TBI. METHODS: Rats received either 10 mL/kg of isotonic saline 1 hour after TBI, 50 µg/kg of isoproterenol pretreatment 30 minutes before TBI, 10 mg/kg of propranolol pretreatment 60 minutes before TBI, 10 mg/kg of metoprolol pretreatment 60 minutes before TBI, or 10 mg/kg of butaxamine pretreatment 40 minutes before TBI and 10 minutes before pretreatment with 50 µg/kg isoproterenol or 10 mg/kg of propranolol 60 minutes after TBI. A neurological severity score (NSS) was measured at 1, 24, and 48 hours after TBI. Blood glutamate, blood glucose, mean arterial blood pressure, and heart rate were measured at the time of drug injection, at the time of TBI, 60 minutes after TBI, and 90 minutes after TBI. RESULTS: Blood glutamate levels decreased spontaneously by 60 minutes after TBI in the control group (P<0.05), reverting to baseline levels by 90 minutes after TBI. A pretreatment with either 10 mg/kg of metoprolol 60 minutes before TBI or with 50 µg/kg of isoproterenol 30 minutes before TBI also reduced blood glutamate levels (P<0.05) both at 90 minutes after TBI and improved the NSS measured 24 and 48 hours after TBI in comparison with the control saline-treated group. However, a 10-mg/kg butoxamine pretreatment 40 minutes before TBI and 10 minutes before pretreatment with 50 µg/kg of isoproterenol or 10 mg/kg of propranolol 60 minutes before TBI neither affected blood glutamate levels across time after TBI nor caused any significant change in the NSS measured 24 and 48 hours after TBI in comparison with the control saline-treated group. A strong correlation (r(2)=0.73) was demonstrated between the percent decrease in blood glutamate levels at 90 minutes after TBI and the percent improvement of NSS measured 24 hours after TBI. CONCLUSIONS: The results suggest that the transient blood glutamate reduction seen after TBI is the result of a stress response and of the activation of the sympathetic nervous system through the ß2 adrenergic receptors, causing an increase of the brain-to-blood efflux of glutamate observed with excess brain glutamate levels after a brain insult. This strongly correlates with the neurological improvement observed 24 hours after TBI.

Effects of selective beta-adrenoceptor antagonists on gastric ulceration in the rat.

Metoprolol and butoxamine, beta-adrenoceptor antagonists which act selectively at the beta 1- and beta 2-adrenoceptors, respectively, have been investigated for their actions on the ethanol, indomethacin and cold-restraint stress ulcer models. Oral administration of butoxamine but not metoprolol significantly attenuated gastric mucosal damage in the three types of ulcer model. Intraperitoneal injection of butoxamine reduced indomethacin ulceration but not that of the other two models. The stimulatory effect of butoxamine on the gastric mucosal potential difference and intramucosal mucus level correlated positively with its anti-ulcer action. Only oral administration of butoxamine significantly increased the mucosal prostaglandin E2 (PGE2) level but not after intraperitoneal injection. Oral administration of butoxamine also significantly increased the mucosal PGE2 level in the three types of ulcer model but this drug was only effective in the indomethacin ulcer model after intraperitoneal injection. Gastric acid and pepsin output were not affected by either drug. Metoprolol significantly reduced systemic blood pressure; this could be attributed to a reduction in gastric mucosal blood flow. These results imply that beta 2-adrenoceptors play a significant role in the pathogenesis of gastric ulceration. We suggest that the anti-ulcer effect of butoxamine was in part a result of strengthening of the mucosal barrier but that this was not effected by modification of acid or pepsin secretions in the stomach. Stimulation of PGE2 in the gastric mucosa could contribute in part to the anti-ulcer action of the drug, especially when given by the oral route.

Effects of adrenolytic drugs on the antihypertensive action of beta-blocking agents in the acute neurogenic hypertensive dog.

1. The antihypertensive action of three beta-blocking agents (dl-propranolol, dl-atenolol and butoxamine) was studied before and after pretreatment with adrenolytic drugs (reserpine and guanethidine) in acute neurogenic hypertensive (sino-aortic denervated) anesthetized dogs. 2. High doses of reserpine (2 mg/kg s.c.) suppressed both the effects of sino-aortic denervation and the antihypertensive action of dl-propranolol (1 mg/kg i.v.) 3. Pretreatment with reserpine (1 mg/kg i.p.) or guanethidine (15 mg/kg i.v.) delayed the manifestation of the antihypertensive action of dl-propranolol (1 mg/kg) observed in untreated (control) animals. 4. In a similar way, both dl-atenolol (1 mg/kg i.v.) and butoxamine (1 mg/kg i.v.) lost their antihypertensive effects after reserpinization. 5. These results indicate that the antihypertensive action of the three studied beta-blocking agents seen in debuffered animals depends upon the integrity of peripheral sympathetic nervous system under our experimental conditions. These effects are compatible with the view that beta-adrenoceptor blocking agents may exert, at least partly, their antihypertensive action through blockade of peripheral beta prejunctional adrenoceptors.

Effects of sympatholytic agents on amanita phalloides toxicity in the rat.

Some sympatholytic agents have been tested for the ability to counteract either the hepatotoxic or the lethal effect of A. phalloides in rats. Propranolol displayed a marked preventive action on the liver damage induced by the poison, but only a moderate influence on the lethality. Reserpine was uneffective in terms of liver derangement, but exerted some protection against the general toxic effect of A. phalloides. Other alpha- or beta-adrenolytic compounds failed to afford any significant protection with respect to both liver injury and lethality. It is suggested that propranolol might interfere with transport or binding of phallotoxins to the liver.