SUBSENSITIVITY TO BETA-ADRENOCEPTOR AGONISTS IN PACEMAKERS ISOLATED FROM SENESCENT RATS

1. The effects of aging on the responsiveness of the isolated pacemaker of the rat to the chronotropic effect of norepinephrine, isoproterenol and soterenol were studied. 2. Pacemakers isolated from senescent rats (22-24 months old) showed subsensitivity to norepinephrine, isoproterenol and soterenol, when compared with pacemakers isolated from young rats (3-4 months old). The maximum response to the partial agonist soterenol was reduced. 3. Determination of the pA2 value of metoprolol in pacemakers isolated from senescent and young rats showed that the chronotropic response is mediated by a homogeneous beta-1-adrenoceptor population. 4. Inhibition of extraneuronal uptake did not potentiate the chronotropic effect of isoproterenol in pacemakers isolated from senescent rats. Addition of cocaine shifted the concentration-effect curve for norepinephrine only 2.2-fold to the left in senescent rats. 5. It is concluded that, during aging, impairment of the extraneuronal and neuronal uptake mechanisms has an important role in the control of chronotropic responsiveness to catecholamines.22591792

SUPERSENSITIVITY TO ISOPRENALINE AND EPINEPHRINE IN RIGHT ATRIA ISOLATED FROM RATS SUBMITTED TO A SINGLE SWIMMING SESSION

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FOOTSHOCK STRESS-INDUCED SUPERSENSITIVITY TO ISOPRENALINE IN THE ISOLATED PACEMAKER OF THE RAT - EFFECTS OF THE COMPOUNDS RU-38486 AND RU-28362

1. Three daily sessions of inescapable footshock stress of 30 min duration each increased the sensitivity of the isolated pacemaker of the rat to the chronotropic effect of isoprenaline. 2. The effect of inescapable footshock stress on the sensitivity of the isolated rat pacemaker to the chronotropic effect of isoprenaline was prevented by the daily administration of the compound RU-38486, a potent antiglucocorticoid which blocks the cytosolic receptor for corticosterone. 3. The administration of the compound RU-28362. a potent agonist of the cytosolic receptor for corticosterone, during 3 days to rats which were not submitted to footshock stress induces supersensitivity to the chronotropic effect of isoprenaline. 4. It is concluded that corticosterone plays an important role in the qualitative control of the rat pacemaker beta-adrenoceptor population during adaptation to repeated footshock stress.23478779

Antiulcerogenic mechanisms of dehydrocrotonin, a diterpene lactone obtained from Croton cajucara

The bark of Croton cajucara Benth. is used in Brazilian folk medicine as an infusion to treat gastrointestinal disorders. The aim of the present study was to assess the mechanisms involved in the antiulcerogenic activity of dehydrocrotonin (DHC), a diterpene isolated from C. cajucara bark. We studied the effects of DHC on pylorus ligature (Shay) in mice treated with the drug (100 mg/kg) by the intraduodenal route. DHC did not induce any alteration in gastric volume in Shay mice but modified the pH and total acid concentration of gastric juice. Incubation of gastric juice with DHC did not reduce gastric acidity compared to control. We also investigated the effects of DHC on the response to histamine of Fight atria isolated from guinea pigs and on the response to carbachol of stomach fundus strips from rats. The concentration-response curves for the chronotropic effect of histamine in guinea pig right atria were shifted to the right, with a significant decrease in the maximum response, in the presence of DHC. Similar results were obtained with DHC (30 mu M) for the concentration-response curves to carbachol in the isolated rat stomach. The ability of DHC to increase PGE(2) release from rat stomach mucous cells was also studied. We observed that DHC induced a significant increase in PGE(2) production (60% compared to control). In addition, the effects of DHC on the healing of acetic acid-induced gastric ulcer in rats were evaluated 14 days after acid injection. Oral administration of DHC (100 mg/kg per day) for 14 consecutive days had no effect on gastric ulcer healing in rats. Thus, the protective effect of DHC on induced gastric lesions could be, due to synergistic effects, e.g., an increase in PGE(2) release and non-competitive antagonism of H-2-receptors and of muscarinic receptors. Whereas the former result represents an increase in the protective factors, the latter one shows a decrease in the aggressive factors against the gastric mucosa.65432533

Anti-ulcerogenic mechanisms of a lyophilized aqueous extract of Dalbergia monetaria L-in rats, mice and guinea-pigs

The decoction of Dalbergia monetaria L. is popularly used in Brazil for the treatment of gastric ulcer and the lyophilized aqueous extract (LAE) of D. monetaria has significant anti-ulcerogenic activity and inhibits gastric ulcer lesions induced by pylorus-ligature, ethanol and hypothermic-restraint stress. This work was conducted to identify the antiulcerogenic mechanisms of action of the LAE of D. monetaria. We analysed the effect of the LAE on prostaglandin E-2 (PGE(2)) synthesis and on the characteristics (pH, volume and total acid content) of gastric juice. The antagonism between the LAE and histamine or carbachol was also analysed. The LAE increased gastric mucosal PGE(2) synthesis compared with control (89.7 +/- 21.5 and 52.6 +/- 11.8 pg mg(-1) respectively) as assayed by enzyme immunoassay in the rat stomach. The LAE reduced the total acid content of gastric juice, but did not modify pH or gastric volume significantly, in Shay rats. Dose-response curves to histamine were shifted to the right in guinea-pig isolated right atria (pD(2) values were 5.77 +/- 0.2 and 5.42 +/- 0.3, respectively, in the absence and presence of the LAE), with a significant reduction in maximum response (140 +/- 15.1 and 98 +/- 13.0, respectively). The same effect was observed when the agonist was isoprenaline. The LAE had no effect on the dose-response curve to carbachol in rat fundus strips. Thus, the protective effect of the LAE on induced gastric lesions might be because of synergistic effects, e.g. increased PGE(2) synthesis and antagonism of H-2 histamine and beta-adrenergic receptors, reducing gastric acid secretion. Increased PGE(2) synthesis results in increased protection, and antagonism of H-2 histamine and beta-adrenergic receptors reduces aggressive factors against the gastric mucosa.51673574

Salivary cortisol concentrations, stress and quality of life in women with endometriosis and chronic pelvic pain

The objective of this study was to evaluate the perceived stress index, quality of life, and hypothalamus-pituitary-adrenal axis activity in women with endometriosis and chronic pelvic pain. For the study, 93 women with endometriosis and 82 healthy women volunteered. The visual analogue scale (VAS) (0 = no pain; 10 = severe pain) was used to determine pain intensity; the perceived stress questionnaire (PSQ) defined stress index, and the health-related quality-of-life (HRQOL)-SF-36 questionnaire was used to evaluate quality of life. Salivary cortisol was measured at 0800, 1600, and 2000h and the awakening cortisol response was assessed to evaluate the hypothalamus-pituitary-adrenal axis activity. The results show that women with endometriosis and chronic pelvic pain of moderate intensity (4.1 +/- 0.58, mean +/- SEM) have higher levels of perceived stress (0.55 +/- 0.01 versus 0.42 +/- 0.01, p < 0.05), a poorer quality of life expressed as lower scores for all items of the inventory and hypocortisolism. Lower levels of salivary cortisol were observed in all three samples collected, as well as in the awakening cortisol response, for women with endometriosis (0.19 +/- 0.09 mu g/dl) when compared with controls (0.78 +/- 0.08 mu g/dl, p < 0.051), and it was independent of pain intensity and Mental health (MH) scores in SF-36. We concluded that women with endometriosis and chronic pelvic pain show low concentrations of salivary cortisol and a high level of perceived stress, associated with a poor quality of life. Whether the hypocortisolism was an adaptive response to the aversive symptoms of the disorder or a feature related to the etiology of endometriosis remains to be elucidated.115390397Foundation for the Support of Research in the State of Sao Paulo [03/09173-3]Improvement of University Level PersonnelFoundation for the Support of Research in the State of Sao Paulo [03/09173-3

Effect of swimming session duration and repetition on metabolic markers in rats

The aim of this study was to investigate the profile of metabolites in male rats subjected to 50-60 min of swimming on three protocols: group A, a single 50 min swimming session; group B, one session a day for three days (5 min on day 1, 15 min on day 2 and 30 min on day 3); and group C, one session a day for 5 days, with increasing duration from 5 min on day 1, 15, 30, 45 and 60 min on consecutive days. The interval between sessions was 24 h. Measurements were made after the last swimming session. Controls did not swim. The glycogen content of liver and gastrocnemius and soleus muscle was depleted in the three groups that swam, but blood glucose concentration was significantly increased only in group B. Serum lactate concentrations were greater than the controls in groups A and B. There were significant increases in serum free fatty acid concentrations in all groups that swam. The increases in plasma free fatty acids may have resulted from lipolysis stimulated by endogenous catecholamines in groups A and C, since basal lipolysis measured in vitro was unchanged by swimming. The large increase in basal lipolysis in group B may have contributed to the rise in plasma free fatty acids. Adipocytes from rats in groups A and B were supersensitive to epinephrine, whereas those from group C were not. We conclude that the metabolic alterations were less pronounced after the last of five swimming sessions over 5 days than after a single session, even though session duration and the contribution of the physical component were similar. Glucose mobilization, but probably not utilization, was similar in the three groups that swam. The mechanisms of lipid mobilization from adipose tissue differed, depending on the stress paradigm. The metabolic changes in groups A and B indicated that three daily swimming sessions were insufficient to cause adaptation. The results contrast with previous findings for foot-shock stress, which leads to sensitization rather than adaptation in response to repeated stimuli.6212713

Evidence for two atypical conformations of beta-adrenoceptors and their interaction with Gi proteins

In this study, we investigated whether the responses of right atria from sinoaortic denervated rats to CGP12177 (4(3-t-butylamino-2-hydroxypropoxy benzidimidazole-2 one, hydrochloride)), isoprenaline and norepinephrine desensitized in parallel and whether CGP12177 interacted with distinct conformations of beta-adrenoceptors. Right atria from rats 48 h after sinoaortic denervation were subsensitive to isoprenaline, norepinephrine and CGP12177. One week after sinoaortic denervation, the sensitivity to CGP12177 had recovered whereas the responses to isoprenaline and norepinephrine were still subsensitive, suggesting that the binding sites for these molecules showed independent behavior. In atria from 48 h sinoaortic-denervated rats, propranolol or 3 mu M CGP20712A (2-hydroxy-5(2-((2-hydroxy-3-(4((methyl-4-trifluormethyl)1H imidazole-2-yl)-phenoxypropyl) amino) ethoxy)-benzamide monomethane sulphonate)) blocked the responses to 10 nM-1 mu M CGP12177 and steepened the curves. The concentration-response curves to CGP12177 in the presence of 10118,551 (erythro-DL-1(-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol) were biphasic, suggesting that CGP12177 interacted with at least two conforinations of beta-adrenoceptors that showed negative cooperativism, one acting through beta(2)-adrenoceptor-Gi and the other via adrenoceptor-Gs. This hypothesis was confirmed in right atria from sinoaortic-denervated rats treated with pertussis toxin. (c) 2005 Elsevier B.V. All rights reserved.5134167110911