Effect of selective beta-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

There is evidence for participation of peripheral β-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether β-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, β1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, β2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, β3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that β2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Effect of selective ß-adrenoceptor blockade and surgical resection of the celiac-superior mesenteric ganglion complex on delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats.

There is evidence for participation of peripheral ß-adrenoceptors in delayed liquid gastric emptying (GE) induced in rats by dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At). The present study aimed to determine whether ß-adrenoceptors are involved in delayed GE induced by phenylpyrazole derivatives and the role of the prevertebral sympathetic nervous system in this condition. Male Wistar rats weighing 220-280 g were used in the study. In the first experiment rats were intravenously pretreated with vehicle (V), atenolol 30 mg/kg (ATE, ß1-adrenergic antagonist), or butoxamine 25 mg/kg (BUT, ß2-adrenergic antagonist). In the second experiment, rats were pretreated with V or SR59230A 2 mg/kg (SRA, ß3-adrenergic antagonist). In the third experiment, rats were subjected to surgical resection of the celiac-superior mesenteric ganglion complex or to sham surgery. The groups were intravenously treated with saline (S), 240 µmol/kg Dp, AA, or At, 15 min after pretreatment with the antagonists or V and nine days after surgery. GE was determined 10 min later by measuring the percentage of gastric retention (%GR) of saline labeled with phenol red 10 min after gavage. The %GR (means±SE, n=6) values indicated that BUT abolished the effect of Dp (BUT+Dp vs V+Dp: 35.0%±5.1% vs 56.4%±2.7%) and At (BUT+At vs V+At: 33.5%±4.7% vs 52.9%±2.6%) on GE, and significantly reduced (P<0.05) the effect of AA (BUT+AA vs V+AA: 48.0%±5.0% vs 65.2%±3.8%). ATE, SRA, and sympathectomy did not modify the effects of treatments. These results suggest that ß2-adrenoceptor activation occurred in delayed liquid gastric emptying induced by the phenylpyrazole derivatives dipyrone, 4-aminoantipyrine, and antipyrine. Additionally, the released neurotransmitter did not originate in the celiac-superior mesenteric ganglion complex.

Acquisition of Pavlovian fear conditioning using ß-adrenoceptor activation of the dorsal premammillary nucleus as an unconditioned stimulus to mimic live predator-threat exposure.

In the present work, we sought to mimic the internal state changes in response to a predator threat by pharmacologically stimulating the brain circuit involved in mediating predator fear responses, and explored whether this stimulation would be a valuable unconditioned stimulus (US) in an olfactory fear conditioning paradigm (OFC). The dorsal premammillary nucleus (PMd) is a key brain structure in the neural processing of anti-predatory defensive behavior and has also been shown to mediate the acquisition and expression of anti-predatory contextual conditioning fear responses. Rats were conditioned by pairing the US, which was an intra-PMd microinjection of isoproterenol (ISO; ß-adrenoceptor agonist), with amyl acetate odor-the conditioned stimulus (CS). ISO (10 and 40 nmol) induced the acquisition of the OFC and the second-order association by activation of ß-1 receptors in the PMd. Furthermore, similar to what had been found for contextual conditioning to a predator threat, atenolol (ß-1 receptor antagonist) in the PMd also impaired the acquisition and expression of OFC promoted by ISO. Considering the strong glutamatergic projections from the PMd to the dorsal periaqueductal gray (dPAG), we tested how the glutamatergic blockade of the dPAG would interfere with the OFC induced by ISO. Accordingly, microinjections of NMDA receptor antagonist (AP5, 6 nmol) into the dPAG were able to block both the acquisition, and partially, the expression of the OFC. In conclusion, we have found that PMd ß-1 adrenergic stimulation is a good model to mimic predatory threat-induced internal state changes, and works as a US able to mobilize the same systems involved in the acquisition and expression of predator-related contextual conditioning.

Effect of Larrea divaricata Cav. extract and nordihydroguaiaretic acid upon peroxidase secretion in rat submandibulary glands.

Free radicals are involved in several diseases, including cancer, central nervous system alterations and inflammatory pathologies. Peroxidase is an oral enzyme implicated in the defence of oral cavity. It has been determined that flavonoids and lignans possess antioxidant and free radical scavenging either directly or indirectly, usually by means of increasing the secretion of free radicals scavenger enzymes. Larrea divaricata Cav. is a plant used in folk Argentine medicine for the treatment of cancer and inflammatory ailments. In this study, we have determined the effect and mechanism of action of an aqueous extract of the leaves of L. divaricata and NDGA on peroxidase secretion in female rat submandibular glands. The extract significantly increased the secretion and total peroxidase. % of secreted peroxidase (X +/- S.E.M.): extract maximum response: 150 +/- 10; % of total peroxidase (X +/- S.E.M.): extract maximum response: 1000 +/- 90. The effect of the extract on peroxidase secretion was mediated by beta1 adrenoceptors (% of secreted peroxidase: extract + atenol maximum response: 50 +/- 4 ). Meanwhile, NDGA produced a decrease in peroxidase secretion (peroxidase secreted: basal: 0.44 +/- 0.03; NDGA 2.5 x 10(-6) M: 0.20 +/- 0.02; prostaglandins E2 (PGE2) 10(-7)M: 1.32 +/- 0.5; NDGA + PGE2: 0.46 +/- 0.035), an effect that was exerted by the inhibition on prostaglandins synthesis.

Activation by Phoneutria nigriventer spider venom of autonomic nerve fibers in the isolated rat heart.

In the isolated rat heart, Phoneutria nigriventer spider venom (10-100 microg) produced a dose-dependent and reversible rise in left ventricular developed pressure. A low dose (10 microg) of venom induced a short-lasting, positive inotropic effect (P < 0.05) with no change in heart rate or coronary flow. At a dose of 50 microg, the venom caused significant positive inotropic and chronotropic responses associated with occasional ventricular arrhythmia, whereas coronary flow was not significantly affected within 10 min after venom administration. The highest dose of venom (100 microg) caused bradycardia, transient cardiac arrest, rhythm disturbances and an increase in end diastolic pressure followed by a reduction in coronary flow. Hearts treated with the non-selective beta-adrenoceptor antagonist propranolol (3 microM) and the selective beta1-adrenoceptor antagonist CGP-20712A (10 microM) were protected against all the cardiac actions of the venom. The selective beta2-adrenoceptor antagonist butoxamine (10 microM) slightly reduced the cardiac response to 50 microg, but not to 100 microg of venom. Butoxamine also prevented the reduction in coronary flow induced by 100 microg of venom. Hearts from reserpine-treated rats (5 mg kg(-1) day(-1), i.p., for 2 days) showed a marked decrease in all venom (< or = 100 microg)-induced cardiac responses. The muscarinic receptor antagonist atropine (1 microM) slightly potentiated the response to 50 microg of venom but had little or no effect on the responses to 100 microg of venom. The cardiac responses to venom (50-100 microg) were unaltered in hearts from rats treated with 8-methyl N-vanillyl-6-nonenamide (capsaicin; 50 mg/kg, s.c.). These findings indicate that P. nigriventer venom releases norepinephrine from cardiac sympathetic nerve endings and this may explain the observed increase in contractile force and heart rate.

Influence of the estrous cycle on the sensitivity to catecholamines in right atria from rats submitted to foot-shock stress.

We investigated the mechanisms of the alterations in sensitivity to catecholamines in right atria from female rats exhibiting regular 4-day estrous cycles after three foot-shock sessions at estrus, metestrus, and diestrus or at diestrus, proestrus, and estrus. Right atria from stressed rats sacrificed at diestrus showed subsensitivity to noradrenaline and adrenaline. After in vitro sympathetic denervation (38 microM 6-hydroxydopamine) plus inhibition of neuronal reuptake (0.1 microM desipramine) subsensitivity to noradrenaline was abolished, but it was again evident when extraneuronal uptake was also inhibited (10 microM phenoxybenzamine and 30 microM corticosterone). The same pretreatment abolished the subsensitivity to adrenaline. After addition of 1 microM butoxamine, a beta 2-adrenoceptor antagonist, the tissues from stressed rats were subsensitive to adrenaline. Right atria from stressed rats sacrificed at estrus did not show any alteration in sensitivity to catecholamines. We conclude that after foot-shock stress, right atria from female rats sacrificed at diestrus showed subsensitivity of the chronotropic response to catecholamines as a result of a conformational alteration of beta 1-adrenoceptors, simultaneously with an increase in beta 2-adrenoceptor-mediated response. The mechanisms seem to be similar to those which underlie stress-induced alterations in catecholamine sensitivity in right atria from male rats. However, during estrus there are some protective factors that prevent the effects of stress on right atria.

Effects of escapable and inescapable foot-shock on rat atrial beta-adrenoceptors.

The chronotropic responsiveness to norepinephrine (NE) and isoproterenol (ISO) was determined in right atria isolated from rats submitted to repeated escapable or inescapable foot-shock. Significant postjunctional supersensitivity to ISO, but not to NE, was observed in both groups. No significant change in the pA2 value of metoprolol (a selective beta 1-adrenoceptor antagonist) was detected. However, a decrease of the maximum response to soterenol, a partial agonist at beta 1-adrenoceptors, occurred only after inescapable foot-shock. The enhanced sensitivity to ISO was abolished by butoxamine (a selective beta 2-adrenoceptor antagonist) and accompanied by a marked increase in the pA2 value of this antagonist. We conclude that the ability to control the shock prevented the down-regulation of the pacemaker beta 1-adrenoceptors but not the increased participation of beta 2-adrenoceptors in the response of the rat sinoatrial node to catecholamines after repeated foot-shock.

Effects of repeated footshock stress on the chronotropic responsiveness of the isolated pacemaker of the rat: role of beta-2 adrenoceptors.

The effects of repeated footshock stress on the chronotropic responsiveness of the isolated right atria were studied. Repeated footshock stress was found to produce supersensitivity to isoproterenol and epinephrine (increase of 4.6- and 1.99-fold at pD2 level, respectively), but not to norepinephrine. Experiments using salbutamol, in the presence of an effective blocking concentration of metoprolol, showed that footshock stress increases the sensitivity (2.69-fold at pD2 level) to the selective beta-2 adrenoceptor agonist. Footshock stress had no effect on the atrial sensitivity to theophylline (1.09-fold at pD2 level). Addition of butoxamine (1 microM) suppressed footshock-induced pacemaker supersensitivity to isoproterenol and epinephrine. Footshock stress causes a small (3.23-fold) but pharmacologically unimportant increase in pacemaker pA2 value of metoprolol. However, footshock stress induces a large increase in the pacemaker beta-2 adrenoceptor affinity for butoxamine (11.48-fold, pA2 value). It is concluded that repeated footshock stress acts primarily to increase the chronotropic function of pacemaker beta-2 adrenoceptors, thus causing supersensitivity to isoproterenol, epinephrine and salbutamol.

Functional ß2-adrenoceptors in right atria isolated from footshock-stressed rats

The participation of ß2-adrenoceptors in the chronotropic response was evaluated in righ atria isolated from rats submitted to daily footshock stress for three days. Footshock increased both the sensitivity to salbutamol and the pA2 of butoxamine. These results provide additional support for the proposal that repeated footshock stress increases the functional of rat atrial postjunctional ß2-adrenoceptors

Functional beta 2-adrenoceptors in right atria isolated from footshock-stressed rats.

The participation of beta 2-adrenoceptors in the chronotropic response was evaluated in right atria isolated from rats submitted to daily footshock stress for three days. Footshock increased both the sensitivity to salbutamol and the pA2 of butoxamine. These results provide additional support for the proposal that repeated footshock stress increases the function of rat atrial postjunctional beta 2-adrenoceptors.