Ontogeny of cholinergic and adrenergic cardiovascular regulation in the domestic chicken (Gallus gallus)

Adrenergic and cholinergic tone on the cardiovascular system of embryonic chickens was determined during days 12, 15, 19, 20, and 21 of development. Administration of the muscarinic antagonist atropine (1 mg/kg) resulted in no significant change in heart rate or arterial pressure at any developmental age. In addition, the general cardiovascular depressive effects of hypoxia were unaltered by pretreatment with atropine. In addition, the ganglionic blocking agent hexamethonium (25 mg/kg) did not induce changes in heart rate. The beta-adrenergic antagonist propranolol (3 mg/kg) induced a bradycardia of similar magnitude on all days studied, with a transient hypertensive action on days 19-20, indicating the existence of an important cardiac and vascular beta-adrenergic tone. Injections of the alpha-adrenergic antagonists prazosin or phentolamine (1 mg/kg) reduced arterial pressure significantly on all days of incubation studied. Collectively, the data indicate that embryonic chickens rely primarily on adrenergic control of cardiovascular function, with no contribution from the parasympathetic nervous system.     

The effect of disorders of the estrous function in female rats on the realization of multigenerational carcinogenic effect of N-nitrosomethylurea

The F1 female rats exposed to N-nitrosomethylurea (NMU) in dose 20 mg/kg on the 21st day of gestation and postnatal induction of persistent estrus syndrome revealed an increased incidence of tumours of the central nervous system (CNS) as compared to F1 exposed to NMU transplacental action only (25.0-2.5%, respectively). Carcinogenic effect was observed in F2 females as well, and was manifested in the development of malignant tumours of the nervous system and kidney but with a lower frequency than in F1 rats. The same modifying factors--persistent estrus syndrome--did not produce any significant effect on carcinogenesis in F2 animals.     

Mechanisms of the antinociceptive action of (?) Epicatechin obtained from the hydroalcoholic fraction of Combretum leprosum Mart & Eic in rodents

ABSTRACT: BACKGROUND: The mechanisms of the antinociceptive activity of () epicatechin (EPI), a compound isolated from the hydroalcoholic fraction of Combreum leprosum Mart & Eicher. METHODS: were assessed in the model of chemical nociception induced by glutamate (20 mumol/paw). To evaluate the mechanisms involved, the animals , male Swiss mice (25-30 g), received EPI (50 mg/kg p.o.) after pretreatment with naloxone (2 mg/kg s.c. opioid antagonist), glibenclamide (2 mg/kg s.c. antagonist K + channels sensitive to ATP), ketanserin (0.3 mg/kg s.c. antagonist of receptor 5-HT2A), yoimbine (0.15 mg/kg s.c. alpha2 adrenergic receptor antagonist), pindolol (1 mg/kg s.c. 5-HT1a/1b receptor antagonist), atropine (0.1 mg/kg s.c. muscarinic antagonist) and caffeine (3 mg/kg s.c. adenosine receptor antagonist), ondansetron (0.5 mg/kg s.c. for 5-HT3 receptor) and L-arginine (600 mg/kg i.p.). RESULTS: The antinociceptive effect of EPI was reversed by pretreatment with naloxone and glibenclamide, ketanserin, yoimbine, atropine and pindolol, which demonstrates the involvement of opioid receptors and potassium channels sensitive to ATP, the serotoninergic (receptor 5HT1A and 5HT2A), adrenergic (receptor alpha 2) and cholinergic (muscarinic receptor) systems in the activities that were observed. The effects of EPI, however, were not reversed by pretreatment with caffeine, L-arginine or ondansetron, which shows that there is no involvement of 5HT3 receptors or the purinergic and nitrergic systems in the antinociceptive effect of EPI. In the Open Field and Rotarod test, EPI had no significant effect, which shows that there was no central nervous system depressant or muscle relaxant effect on the results. CONCLUSIONS: This study demonstrates that the antinociceptive activity of EPI in the glutamate model involves the participation of the opioid system, serotonin, adrenergic and cholinergic.     

The effect of alpha- and beta-adrenergic antagonists of the self-stimulation phenomenon

In an attempt to evaluate the possible existence of alpha- and/or beta- adrenergic components of the self-stimulation reward system, rats were injected (i.p.) with chlorpromazine hydrochloride (2.5 mg/kg), phentolamine hydrochloride (5 mg/kg), and propranolol hydrochloride (10 mg/kg). The alpha- adrenergic antagonists (chlorpromazine and pehntolamine) inhibited self-stimulation but the beta-adrenergic blocker (propranolol) was without significant effect. Self-stimulation is apparently mediated by the alpha-adrenergic system.     

Integrative mechanisms of the formation of the small intestine motor effects

Contractile responses of the small intestine to serotonine and histamine are mediated by cholinergic neurones, while the inhibitory responses of the substances--by nonadrenergic inhibitory neurones of the enterometasympathetic nervous system. An inhibitory response of the small intestine to met-enkephalin results from its depressing action on the effector cholinergic neurones. Catecholamines activate enteric cholinergic neurones via presynaptic beta-adrenoceptors and inhibit them via pre- and postsynaptic alpha-adrenoceptors. The cholinergic neurones of the enterometasympathetic nervous system seem to be under a double adrenergic control, and a mechanisms seems to exist in the small intestine for adrenergic activation of its contractile apparatus.     

Chronopharmacological study of furosemide; (V). Influence of pretreatment with 6-hydroxydopamine

Our previous indirect evidences suggested that the adrenergic nervous system is involved in the mechanisms responsible for the time-dependent changes in the effects of furosemide in Wistar rats. In the present study, the role of this system was examined more directly by means of 6-hydroxydopamine-induced sympathectomy. Thirty mg/kg of 6-hydroxydopamine hydrobromide (6-OH-DA) (n = 9) or its vehicle alone (n = 9) was injected intra-arterially (i.a.) twice in Wistar rats. Furosemide (5 mg/kg) was administered i.a. at 1000 hrs (03HALO*) or at 2200 hrs (15HALO). Urine was collected for 60 min after the drug and urinary excretion of sodium and furosemide were determined respectively. Urine volume and urinary excretion of sodium and furosemide were significantly greater at 1000 hrs (03HALO) than at 2200 hrs (15HALO) in the vehicle-injected rats as observed in the previous study. However these administration-time-dependent changes in the effects of furosemide disappeared in the rats with 6-OH-DA. Thus, the present study provides more direct evidence and supports our original hypothesis concerning the mechanisms of this chronopharmacological phenomenon of the agent. Since 6-OH-DA does not penetrate the central nervous system from the blood stream, the present data also indicate that the peripheral adrenergic system is involved in this event.     

Effect of phenoxybenzamine on luteinizing hormone release in the female rat

To clarify the mode of action of phenoxybenzamine, an alpha adrenergic blocking agent, its effects upon plasma LH levels in ovariectomized rats and upon the ovulatory LH surge expected between 1400 and 1600, the critical period, on the day of proestrus in normal rats were studied. A single injection of phenoxybenzamine, 20 mg/kg, given at 1300 on the day of proestrus bokced ovulation (1 out of 7 ovulating), while plasma LH did not differ from controls between 1500 and 1600. An additional injection of 20 iu HCG at 1500 prevented the ovulation block (83% ovulating). A single phenoxybenzamine injection at 1700 failed to prevent ovulation (5 out of 7 ovulating). The beta adrenergic blocking agents, propanolol and MJ 1999, did not affect ovulation. Treatment with phenoxybenzamine for 2 days, 20mg/kg/day, for 8 days, 10mg/kg/day, were did not prevent the rise causing a reduction in blood flow through the ovary rather than acting as a neurogenic stimulus in the hypothalamus.     

Antagonism by N-methyl levallorphan-methane sulphonate (SR 58002 C) of morphine-elicited acute and chronic central and peripheral effects

The peripheral activity of the quaternary narcotic antagonist N-methyl levallorphan-methane sulphonate (SR 58002 C) at opioid sites located in the periphery and in the central nervous system (CNS), was studied by different approaches in rats after subcutaneous injection (s.c.). Pretreatment with SR 58002 C 2,8 or 32 mg/kg s.c. 10, 50 or 110 min before buprenorphine consistently reduced buprenorphine in vivo binding only in the small intestinal longitudinal muscle with attached myenteric plexus (MP), whereas naloxone (1 mg/kg s.c.) 10 min before buprenorphine lowered buprenorphine binding in MP and brain (without cerebellum). Plasma levels were not altered by SR 58002 C or naloxone. The same doses of SR 58002 C injected 10, 50 or 110 min before morphine selectively antagonized the inhibition of transit of a charcoal meal along the small intestine (mainly a peripheral effect) induced by the agonist, but did not antagonize morphine-elicited analgesia in the hot-plate test (central effect). Naloxone (1 mg/kg s.c.) injected 10 min before morphine antagonized both agonist effects simultaneously. In morphine-dependent rats SR 58002 C (0.25, 1, 4 and 32 mg/kg s.c.) induced diarrhea, dose-dependently, in most animals within the first 30 min, while jumping, measured in the same rats, occurred in some animals, not dose-dependently, from 60 min on. Naloxone (1 mg/kg s.c.) induced both effects in most rats. These findings suggest that, although SR 58002 C probably penetrates the blood-brain barrier in some morphine-dependent rats, it discriminates peripheral and CNS opioid effects.     

Effect of adrenergic antagonists and cyclooxygenase inhibitors on the nicotine-induced hypothalamic-pituitary-adrenocortical activity.

Nicotine is a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Systemic nicotine acts via central mechanisms to stimulate by multiple pathways the release of ACTH from the anterior pituitary corticotrops and corticosterone from the adrenal cortex. Nicotine may stimulate indirectly the hypothalamic paraventricular nucleus, the site of the corticotropin-releasing hormone (CRH) neurons which activates ACTH release. In the present studies an involvement of adrenergic system and prostaglandins synthesized by constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2) in the nicotine-induced HPA response in rats was investigated. Nicotine (2.5-5 mg/kg i.p.) significantly increased plasma ACTH and corticosterone levels measured 1 hr after administration. Adrenergic receptor antagonists or COX inhibitors were injected i.p. 15 min prior to nicotine and the rats were decapitated 1 hr after the last injection. Prazosin (0.01-0.1 mg/kg), an alpha1-adrenergic antagonist, significantly decreased the nicotine-evoked ACTH and corticosterone secretion. Yohimbine (0.1-1.0 mg/kg), an alpha2-adrenergic antagonist, moderately diminished ACTH response, and propranolol (0.1-10 mg/kg), a beta-adrenergic antagonist, did not significantly alter the nicotine-induced hormones secretion. Pretreatment with piroxicam (0.2-2.0 mg/kg), a COX-1 inhibitor, considerably impaired the nicotine-induced ACTH and corticosterone secretion. Compound NS-398 (0.2-5.0 mg/kg), a selective COX-2 blocker did not markedly alter these hormones secretion, and indomethacin (2 mg/kg), a non-selective COX inhibitor significantly diminished ACTH response. These results indicate that systemic nicotine stimulates the HPA axis indirectly, and both adrenergic system and prostaglandins are significantly involved in this stimulation. Noradrenaline, stimulating postsynaptic alpha1-adrenergic receptors, and prostaglandins, synthesized by COX-1 isoenzyme, are of crucial significance in the nicotine-induced ACTH and corticosterone secretion.     

Catecholamine concentration in adrenergic plexuses of the spleen and intestine during cold-induced and emotional stress

Computer analysis and histochemical techniques were used to investigate catecholamine concentration in the adrenergic plexuses of the spleen and small intestine in rats. The concentration was found to increase during both emotional and short-term cold-induced stress. Injection of 10 mg/kg guanethidine i.p. does not counteract cold-induced accumulation of catecholamines in the adrenergic plexuses of the spleen and small intestine. During emotional stress, by contrast, an accumulation of this sort does take place. The mechanisms potentially underlying catecholamine accumulation in the adrenergic plexus of these organisms associated with different types of stress are discussed. Cold-induced stress is thought to produce catecholamine synthesis in the adrenergic nerve endings of the prevertebral ganglia, whereas emotional stress leads to catecholamine uptake by adrenergic terminals from the blood.Institute of Physiology, Academy of Sciences of the Byelorussian SSR, Minsk. Translated from Neirofiziologiya, Vol. 22, No. 3, pp. 347–354, May–June, 1990.     

The effects of serotonergic and adrenergic receptor antagonist on prolactin release in the monkey.

The influence of serotonergic and adrenergic antagonists on serum prolactin levels was studied in ketamine anesthetized monkeys. Methysergide, a serotonergic receptor blocker, at 0.035, 0.1 and 1 mg/kg body weight induced a rapid and transient increase in serum prolactin. Cyproheptadine, another serotonergic receptor blocker, at 0.05, 0.5 and 1 mg/kg induced a rapid and sustained increase in serum prolactin. SQ 10631, a third serotonergic receptor blocker, had a minimal effect on increasing basal prolactin levels even at doses as high as 10 mg/kg. Propranolol, a β adrenergic blocker, at a dose of 5 mg/kg induced a small sustained increase in serum prolactin, while a lower dose (1 mg/kg) had a slight but significant effect. Phentolamine, an α adrenergic receptor blocker, at a dose of 5 mg/kg induced a rapid and transient increase in plasma prolactin while a lower dose (1 mg/kg) had no effect. Phenoxybenzamine, a potent α adrenergic receptor blocker, had only a minimal effect on prolactin release even at doses of 3 and 5 mg/kg. It appears that the time course and extent of prolactin release differs among neural antagonists even within the same biogenic amine system.     

Influence of adrenergic nervous and prostaglandin systems on hydralazine-induced renin release

The role of the beta-adrenergic nervous and prostaglandin systems in vasodilator-induced activation of the renin-angiotensin system was studied in conscious rats. The plasma renin activity (PRA) response to intravenous hydralazine (0.25, 0.5 and 1 mg/kg body wt.) was compared to the PRA response following administration of similar doses of hydralazine to rats pretreated with either indomethacin (3 mg/kg body wt. i.v.) or indomethacin and propranolol (1 mg/kg body wt. i.v.). PRA increased significantly above control levels after each of the hydralazine doses. In rats pretreated with indomethacin, PRA did not increase with the 0.25 mg/kg dose of hydralazine; increased significantly with the 0.5 mg/kg dose but remained significantly lower than the PRA response in the absence of indomethacin; and increased with the 1 mg/kg dose to a level not significantly different from PRA in rats receiving only hydralazine. When rats were pretreated with indomethacin and propranolol, PRA did not increase significantly in response to either the 0.25 or 0.5 mg/kg doses of hydralazine. Although a statistically significant increase in PRA was noted with the 1 mg/kg dose of hydralazine, the level of PRA achieved was very low and only 15% of that observed with the other two treatment regimens (i.e., hydralazine alone or indomethacin and hydralazine). These results demonstrate that vasodilator-induced renin release is only partially mediated via the prostaglandin system, that the degree of this control is related to the intensity of vasodilator stimulus and that renin release following administration of hydralazine can be attributed almost entirely to activation of the beta-adrenergic nervous and prostaglandin systems.     

Reversal of ketamine/xylazine anesthesia in the rabbit with yohimbine

Ketamine and xylazine used in combination have been shown to be effective, easily administered, cost efficient agents for surgical anesthesia in the rabbit. The effect of xylazine on the central nervous system has been shown to be mediated through alpha-2 adrenergic receptors. Yohimbine, an alpha-2 adrenergic antagonist has been shown to reverse xylazine induced depression and partially antagonize ketamine in other species. We evaluated the antagonistic effect of yohimbine on ketamine/xylazine anesthesia in the rabbit. Six New Zealand White rabbits were anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (10 mg/kg) to establish baseline parameters including respiratory rate, heart rate, and palpebral, pedal and postural reflex activity. Fourteen days later each rabbit was subjected to the same anesthetic regimen followed 30 minutes later by the intravenous administration of yohimbine (0.2 mg/kg). The duration of anesthesia estimated by the time elapsed between the loss and return of the palpebral reflex was reduced in the yohimbine treated trial (means = 29.7 +/- 1.9 minutes) compared to the control trial (means = 67.0 +/- 13.5 minutes). The palpebral reflex returned within 5 minutes following yohimbine treatment. Our results indicated that yohimbine is an effective antagonist of ketamine/xylazine anesthesia in the rabbit. Yohimbine decreases anesthetic duration after intravenous administration and also may aid in the control of undesirable anesthetic effects and overdosage.     

Antinociceptive effect of the agonist of 5-HT1A receptors buspirone in the model of abdominal pain in dogs

We have demonstrated that activation of 5-HT1A receptors with buspirone promotes visceral analgesia in awake dogs. The administration of 0.035 mg/kg (i.m.) of the drug caused depression of viscero-motor (contraction of the abdominal muscles) and pressor (increase in the heart rate) responses to noxious distension of the large intestine. An increase in the dose to 0.07 and 0.14 mg/kg did not enhance the antinociceptive effect of buspirone but triggered basal tachycardia. The obtained results provide evidence of the inhibitory role of 5-HT1A receptors in modulating visceral pain sensitivity and the possibility of an exciting effect of their activation on the cardiovascular system.     

Adrenergic control of lacrimal secretion in rabbits

Stimulation of the preganglionic trunk of the ipsilateral superior cervical sympathetic ganglion with square wave electrical pulses produced secretion from the main excretory duct of the rabbit lacrimal gland. The secretion was inhibited by propranolol (1 mg/kg) and metoprolol (10 mg/kg) but not by phenoxybenzamine (2 mg/kg) and atropine (25 micrograms/kg). The results indicate that the sympathetically induced secretion in the rabbit lacrimal gland occurs through an adrenergic mechanism. The adrenergic receptors in the lacrimal gland is most likely of beta 1-type.     

Effect of bisacodyl and cascara on growth of aberrant crypt foci and malignant tumors in the rat colon.

Laxatives abuse has been associated with an increased risk for colon cancer. However, little is known about laxatives long-term carcinogenic potential in experimental studies. The present study was designed to investigate the effects of bisacodyl (4.3 and 43 mg/kg) and cascara (140 and 420 mg/kg) on azoxymethane (AOM)-induced aberrant crypt foci (ACF) and tumors. Animals, divided in 10 groups were treated with AOM and laxatives (alone or in combination) for 13 weeks. At the end of treatment animals were killed and the colon removed and analysed for the determination of ACF and tumors. Bisacodyl (4.3 and 43 mg/kg), given alone, did not induce the development of colonic ACF and tumors. Bisacodyl (4.3 mg/kg) coupled with AOM increased the number of crypt per focus, but not the number of tumors. Bisacodyl (43 mg/kg) significantly increased the number of crypt per focus and tumors. Cascara (140 and 420 mg/kg) did not induce the development of colonic ACF and tumors and did not modify the number of AOM-induced ACF and tumors. The results of the present study indicate a possible promoting effect of bisacodyl on rat colon carcinogenesis (especially at higher doses) and absence of any promoting or initiating activity of a laxative and diarrhoeal dose of cascara.     

Vegetative nervous system's contribution to the development of stress induced gastric ulcers]

A vegetative nervous system contribution to the development of stress-induced gastric ulcers has been investigated. The experiments involved male Wistar rats. Vegetative nervous system activity has been assessed with acetylcholine brain and stomach tissue levels and synthesis as well as adrenaline and noradrenaline levels in adrenals and gastric wall. The results have shown, that ulcerogenic effect of stress is accompanied by the increase in both cholinergic and adrenergic activities. Moreover, it has been shown, that markedly strong stimulation of the adrenergic system in some rats, together with pharmacologic activation of alpha-adrenergic receptors, inhibits the development of stress-induced gastric ulcers.     

Adrenergic mechanisms of the regulation of stages of chemical carcinogenesis: role of presynaptic receptors

A modifying effect of a catecholamine precursor (L-DOPA, 20 mg/kg, intraperitoneally) on various stages (initiation and promotion) of hepatocarcinogenesis, induced by N-nitrosodiethylamine (NDEA, 85 mg per 1 litre of tap water) was studied in chronic experiments on 150 male rats. L-DOPA administration prior to NDEA (influence on initiation) stimulated hepatocarcinogenesis considerably, while its administration after NDEA (influence on promotion) inhibited the realization of a carcinogenic effect. A statistically significant decrease in noradrenaline hypothalamus content was identified during early stages of chemically induced neoplastic transformation of hepatic cellular elements (stages of diffuse and focal proliferation). The results are discussed in terms of the regulatory role of the tone of the adrenergic autonomous nervous system component at the level of presynaptic inhibitory receptors in realization of the chemical carcinogenic effect.     

Further evidence of the inhibitory role of perifornical hypothalamic beta-adrenergic receptors in the feeding behaviour of hungry rats

The reduction of food intake in hungry rats induced by salbutamol (10 mg/kg/i.p.) was prevented by IPS 339 (5 mg/kg, i.p.) a selective beta 2 adrenergic antagonist, but not by metoprolol (10 mg/kg i.p.), a blocker of beta 1 adrenergic receptors. Similarly, bilateral injections of IPS 339 (32 micrograms/1 microliter) but not metoprolol (80 micrograms/1 microliter) in the perifornical hypothalamic area completely antagonized the anorectic effect of intraperitoneal salbutamol, suggesting an involvement of beta 2 adrenergic receptors in this brain area. Clenbuterol, a beta 2 adrenergic agonist which readily crosses the blood-brain barrier, was 10-100 times more potent than salbutamol in inhibiting feeding consumption of deprived rats when injected intraperitoneally and this effect was also selectively antagonized by pretreatment with IPS 339. Neither IPS 339 nor metoprolol injected in the perifornical hypothalamus significantly modified the anorectic effect of diethylpropion (5 mg/kg i.p.) whereas it was partially prevented by intraperifornical injection of 1-propranolol (52 micrograms/2 microliter), a non-selective beta antagonist, suggesting that both beta 1 and beta 2 adrenergic receptors in the hypothalamus contribute to the mechanism by which diethylpropion causes anorexia.     

Lack of involvement of metallothionein expression in pancreatic carcinogenesis by N-nitrosobis (2-oxopropyl) amine in Syrian hamsters.

The possible involvement of metallothionein (MT) in pancreatic ductal carcinogenesis by N-nitrosobis(2-oxopropyl) amine (BOP) in hamsters was investigated. Hamsters received subcutaneous (s.c.) injections with dissolved BOP to 70 mg/kg body weight (BW) followed 7 days later by 20 mg/kg BW BOP and they were sacrificed at 4, 11, 16 and 27 weeks after the beginning of the experiment. MT expression was studied by immunohistochemistry and MT contents were assayed biochemically. Pancreatic ductal hyperplasias were developed from 11 weeks on and carcinomas from 16 weeks on, the incidence of the latter reaching 73% at the end of experiment. However, while normal appearing proliferating duct cells were sometimes positive, MT expression was not evident in hyperplasia (H), atypical hyperplasia (AH) or carcinoma (C), and MT contents did not significantly differ in pancreas of hamsters receiving saline or BOP at any time point. The results suggest that MT is not involved in pancreatic duct carcinogenesis. However, the presence of MT in proliferating ducts not related to carcinogenesis may suggest some unknown role for MT in cellular homeostasis.