Intracerebroventricular injection of hemicholinium-3 lowers blood pressure in conscious spontaneously hypertensive rats but not in normotensive rats

Intracerebroventricular (icv) injection of hemicholinium-3 (HC-3) in doses of 10–20 μg causes a dose-related decrease in the blood pressure of conscious spontaneous hypertensive (SH) rats but not of normotensive rats. HC-3 also reduces heart rate (HR) in both SH and normotensive rats. The bradycardia was blocked by intravenous injection of methylatropine, implicating increased vagal activity as a cause of the response. The decrease in HR also was blocked by icv injection of atropine but not by icv injection of mecamylamine, suggesting that the bradycardia is mediated via central muscarinic receptors. In contrast, the fall in blood pressure in SH rats was not influenced by intravenous administration of methylatropine or by the icv injection of either atropine or mecamylamine.     

Effect of subdiaphragmatic vagotomy and cholinergic agents in the hypothalamic-pituitary-adrenal axis activity.

In the present study, we examined whether the vagus nerve is involved in mediating the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic muscarinic and nicotinic agonists, carbachol and nicotine. The site of HPA axis muscarinic stimulation was determined using peripheral (i.p.) and intracerebroventricular (i.c.v.) administration of carbachol, atropine sulphate (AtrS) and atropine hydrobromide (AtrBr). The i.p. carbachol-(0.5 mg/kg)-induced corticosterone response was significantly reduced by i.p. pretreatment with AtrBr (0.1 mg/kg), but was not diminished by i.c.v. AtrS (0.1 mug). The increase in corticosterone secretion induced by i.c.v. carbachol (2 microg) was totally abolished by i.c.v. pretreatment with AtrS (0.1 microg) but was not altered by i.p. AtrBr. Subdiaphragmatic vagotomy performed 2 weeks earlier substantially decreased the i.p. carbachol (0.2 mg/kg)-induced ACTH response and markedly augmented ACTH and corticosterone response to a higher dose of carbachol (0.5 mg/kg) in comparison with the responses in sham operated rats. Vagotomy abolished the stimulatory effect of i.p. nicotine in a low dose (1 mg/kg) on ACTH and corticosterone secretion; the ACTH response to higher dose (2.5 mg/kg) was considerably reduced, while corticosterone response remained unaffected. These results suggest that carbachol given i.c.v. evokes considerable corticosterone response by stimulation of central cholinergic muscarinic receptors. A major part of the i.p. carbachol-induced corticosterone secretion results from peripheral cholinergic muscarinic receptor stimulation. Subdiaphragmatic vagotomy moderately intensified the carbachol-induced ACTH and corticosterone secretion. Vagotomy significantly reduced the nicotine-induced ACTH secretion, possibly by the involvement of vagal afferents. The nicotine-induced corticosterone secretion is not exclusively regulated by circulating ACTH but by various intra-adrenal regulatory components.     

Regulation of Histamine Turnover via Muscarinic and Nicotinic Receptors in the Brain

To clarify the regulation of central histaminergic (HAergic) activity by cholinergic receptors, the effects of drugs that stimulate the cholinergic system on brain histamine (HA) turnover were examined, in vivo, in mice and rats. The HA turnover was estimated from the accumulation of tele-methylhistamine (t-MH) during the 90-min period after administration of pargyline (65 mg/kg, i.p.). In the whole brain of mice, oxotremorine, at doses higher than 0.05 mg/kg, s.c., significantly inhibited the HA turnover, this effect being completely antagonized by atropine but not by methylatropine. A large dose of nicotine (10 mg/kg, s.c.) also significantly inhibited the HA turnover. This inhibitory effect was antagonized by mecamylamine but not by atropine or hexamethonium. A cholinesterase inhibitor, physostigmine, at doses higher than 0.1 mg/kg, s.c., significantly inhibited the HA turnover. This effect was antagonized by atropine but not at all by mecamylamine. None of these cholinergic antagonists used affected the steady-state t-MH level or HA turnover by themselves. In the rat brain, physostigmine (0.1 and 0.3 mg/kg, s.c.) also decreased the HA turnover. This inhibitory effect of physostigmine was especially marked in the striatum and cerebral cortex where muscarinic receptors are present in high density. Oxotremorine (0.2 mg/kg, s.c.) and nicotine (1 mg/kg, s.c.) also decreased the HA turnover in the rat brain. However, these effects showed no marked regional differences. These results suggest that the stimulation of central muscarinic receptors potently inhibits the HAergic activity in the brain and that strong stimulation of central nicotinic receptors can also induce a similar effect.     

Central muscarinic control of the pattern of small intestinal motility in rats

The effects of central and peripheral administration of muscarinic agonists and antagonists on small intestinal motility were examined in conscious rats chronically fitted with electrodes implanted in the duodeno-jejunal wall and a cannula in a cerebral lateral ventricle. Intracerebroventricular (i.c.v.) administration of either atropine or pirenzepine at doses from 1 to 10 micrograms, 15 min before a 3 and 6 g lab chow meal significantly reduced the duration of the postprandial disruption of the migrating myoelectric complexes (MMC). The reduction was significantly greater for atropine, a mixed M1 and M2 muscarinic receptor antagonist, than for pirenzepine, an antagonist with a high affinity for M1 receptors. At a higher dose (10 micrograms) intra peritoneal (i.p.) administration of atropine or pirenzepine did not modify the postprandial disruption of MMC. Oxotremorine (10 ng) a M2 agonist, but not McNeil A343 (5 micrograms), a selective M1 agonist, given i.c.v. in fasted rats disrupted for 1.5 h the MMC pattern. At the same doses given i.p. oxotremorine and McNeil A343 disrupted the MMC for 15 and 45 min respectively. We conclude that the postprandial changes in the small intestinal motility involve muscarinic receptors, mainly of M2 subtype, at the level of the central nervous system.     

Investigation of the mechanisms involved in the central effects of glucagon-like peptide-1 on ethanol-induced gastric mucosal lesions

The aim of this study was to investigate the effects of intracerebroventricularly injected glucagon-like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and to elucidate the mechanisms involved. Absolute ethanol was administered through an orogastric cannula 5 min before GLP-1 (1 microg/10 microl) injection. One hour later, the rats were decapitated, their stomachs were removed and scored for mucosal damage. GLP-1 inhibited the ethanol-induced gastric mucosal damage by 92%. Centrally injected atropine sulphate, a muscarinic receptor antagonist (5 microg/10 microl), prevented the gastroprotective effect of GLP-1, while mecamylamine, a nicotinic receptor antagonist (25 microg/10 microl), was ineffective. Peripherally injected atropine methyl nitrate (1 mg/kg) did not change the effect of GLP-1, but mecamylamine (5 mg/kg) blocked it. Cysteamine, a somatostatin depletor (280 mg/kg, s.c.), did not affect the protective activity of GLP-1, while inhibition of nitric oxide (NO) synthesis by L-NAME (3 mg/kg, i.v.) significantly abolished the protective effect of GLP-1 on ethanol-induced gastric mucosal lesions. We conclude that central muscarinic and peripheral nicotinic cholinergic receptors and NO, but not somatostatin, contribute to the protective effect of intracerebroventricularly injected GLP-1 on ethanol-induced gastric mucosal damage.     

Central cholinergic influence on self-administration of morphine and amphetamine

Atropine and methylatropine were tested in rats for an ability to alter the reinforcing action of intravenous morphine sulfate and d-amphetamine sulfate (60 μg/kg/injection). Atropine blocked the self-administration of morphine, but methylatropine did not. Similarly, atropine but not methylatropine prevented the establishment of a conditioned reinforcer based on passive intravenous infusions of morphine. Self-administration of d-amphetamine was enhanced by atropine but not by methylatropine. The results indicate that a central cholinergic system exerts an influence on the brain mechanisms which are affected by morphine or d-amphetamine to produce positive reinforcement.     

Histamine and prolactin liberation in the rhesus monkey

The effect of intra venous (i.v.) or intra cerebroventriculaire (i.c.v.) administration of histamine (HA) on plasma prolactin (PRL) levels was investigated in ovariectomized Rhesus Monkeys. Intra venous injection of 50 micrograms/kg HA increased the plasma PRL concentration but icv administration of 10 and 50 micrograms decreased PRL plasma levels. Intra venous injection of 2-thiazolyl-éthylamine, a H1 receptor agonist, rapidly stimulated PRL release (peak PRL concentration at 5 min) suggesting a direct effect on the pituitary. In contrast intra venous administration of the H2 receptor agonist, impromidine, inhibited PRL release at low doses. High doses of impromidine increased PRL concentrations but this effect was delayed (PRL peak values were reached at 20 minutes). Our results show that HA may influence PRL release in the primate via H1 and H2 receptors located at both pituitary and central levels.     

Cardiovascular responses to intrathecal administration of endomorphins in anesthetized rats

Endomorphins (EMs), the endogenous, potent and selective mu-opioid receptor agonists, have been shown to decrease systemic arterial pressure (SAP) in rats after intravenous (i.v.) administration. In the present study, cardiovascular responses to intrathecal (i.t.) injection of EMs were investigated in urethane-anesthetized rats. It is noteworthy that EMs elicited decreases in SAP and heart rate (HR) in a dose-dependent manner; 10-300nmol/kg were injected intrathecally. Furthermore, these vasodepressor and bradycardic effects were significantly antagonized by naloxone (0.5mg/kg, i.t.). Interestingly, i.t. (5mg/kg) or i.v. (50mg/kg) administrations of N(omega)-nitro-l-arginine methylester (l-NAME) attenuated the vasodepressor and bradycardic effects. Moreover, pretreatment of the rats with muscarinic receptor antagonist atropine (2mg/kg, i.v.) and alpha-adrenoceptor antagonist phentolamine (1mg/kg, i.v.) significantly reduced the vasodepressor effects of EMs. Nevertheless, pretreatment with beta-adrenoceptor antagonist propranolol (2mg/kg, i.v.) could only block the bradycardia effects induced by EMs, but had no significant effects on the hypotension. In summary, all the results suggested that i.t. administration of EMs decreased SAP and HR which were possibly mediated by the activation of opioid receptors in the rat spinal cord. In addition, nitric oxide (NO) release in both the spinal cord and in peripheral tissues might regulate the cardiovascular activities of EMs, and the muscarinic receptor and adrenoceptor played an important role in the regulation of the cardiovascular responses to i.t. administration of EMs.     

Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization

The heterogeneity of muscarinic receptors was examined in sympathetic ganglia and atria by “in vitro” binding techniques and functional studies. As tools we have used the classical antagonist atropine, the selective antagonist pirenzepine and the unique muscarinic agonist McN-A-343. In binding studies atropine showed similar affinities to muscarinic sites in ganglionic and atrial membranes with dissociation constants of 1.1 and 3.2 nM, respectively. In contrast, pirenzepine displayed a distinctly different binding profile. In atria it bound to an homogenous population of low affinity sites (diss. const. 620 nM) while in ganglia it revealed the presence of two sites: a major population of high affinity sites (diss. const. 11 nM) and a minor one of lower affinity (diss. const. 280 nM). The functional correlate of the receptor properties in the two tissues was studied in the pithed rat by measuring A) the increase of arterial pressure evoked by McN-A-343 through selective activation of muscarinic receptors in ganglia and B) the bradycardia elicited by acetylcholine release in the heart through vagal stimulation. Mirroring the “in vitro” binding data atropine inhibited both muscarinic responses in the same narrow range of doses (2–30 μg/kg i.v.) whereas pirenzepine showed similar potency to atropine in inhibiting ganglionic stimulation (ED50 4.1 μg/kg i.v.) but was almost two orders of magnitude weaker in blocking vagal bradycardia (ED50 172 μg/kg i.v.). These data suggest that McN-A-343 and pirenzepine act selectively on a common muscarinic receptor subtype, a finding which agrees with the view that muscarinic receptors are heterogenous and that excitatory ganglionic receptors (Ml) are distinguishable from those (M2) present in effector organs like smooth muscle and heart.     

Octreotide-induced drinking, vasopressin, and pressure responses: role of central angiotensin and ACh

The involvement of central angiotensinergic and cholinergic mechanisms in the effects of the intracerebroventricularly injected somatostatin analog octreotide (Oct) on drinking, blood pressure, and vasopressin secretion in the rat was investigated. Intracerebroventricular Oct elicited prompt drinking lasting for 10 min. Water consumption depended on the dose of Oct (0.01, 0.1, and 0. 4 microgram). The drinking response to Oct was inhibited by pretreatments with the intracerebroventricularly injected angiotensin-converting enzyme inhibitor captopril, the AT(1)/AT(2) angiotensin receptor antagonist saralasin, the selective AT(1) receptor antagonist losartan, or the muscarinic cholinergic receptor antagonist atropine. The dipsogenic effect of Oct was not altered by prior subcutaneous injection of naloxone. Oct stimulated vasopressin secretion and enhanced blood pressure. These responses were also blocked by pretreatments with captopril or atropine. Previous reports indicate that the central angiotensinergic and cholinergic mechanisms stimulate drinking and vasopressin secretion independently. We suggest that somatostatin acting on sst2 or sst5 receptors modulates central angiotensinergic and cholinergic mechanisms involved in the regulation of fluid balance.     

Hypoinsulinemic and hyperglycemic effects of beta-endorphin in rabbits

The present study was designed to investigate the in vivo effects of beta-endorphin on plasma levels of glucagon, insulin and glucose in rabbits, and to elucidate some of the mechanisms involved. beta-Endorphin (50 micrograms) injected intravenously into fasted rabbits, decreased plasma levels of insulin (-4.5 +/- 1.3 microU/ml, P less than 0.05) and increased plasma levels of glucose (+2.7 +/- 0.4 mmol/l, P less than 0.05). Similar hypoinsulinemic and hyperglycemic effects were observed for 25 and 2.5 micrograms beta-endorphin in fasted and 50 and 0.5 micrograms beta-endorphin in fed rabbits. beta-Endorphin produced slight and transient increases in plasma levels of glucagon at the highest dose in fed rabbits, only (+80 +/- 9 pg/ml, P less than 0.05). The beta-endorphin-induced hypoinsulinemia was not inhibited by phentolamine, yohimbine, propranolol or atropine, which is in consistency with a direct inhibitory effect of beta-endorphin on the beta-cell in rabbits. The beta-endorphin-induced hyperglycemia was reduced by naloxone (+0.8 +/- 0.1 mmol/l) but not by N-methyl-naloxone (ORG 10908) a peripheral opiate receptor blocking drug (+2.2 +/- 0.2 mmol/l), suggesting a central nervous action on opiate receptors. This central action of beta-endorphin was probably not mediated by catecholamine release or other stimulation of adrenergic or muscarinic receptors, since the beta-endorphin-induced hyperglycemia was not inhibited by phentolamine, yohimbine, propranolol or atropine. These results suggest that the beta-endorphin-induced hyperglycemia was caused, at least in part, by a peripheral inhibition of insulin release and a central stimulation on glucoregulation.     

Antinociceptive effect of spinal cholinergic stimulation: interaction with substance P

Activation of central muscarinic receptors results in an antinociceptive response in experimental animals. Employing intrathecal (i.t.) injection and radiant heat applied to a rat's tail as the experimental paradigm, a spinally-mediated antinociceptive response was obtained following injection of cholinergic agonists. Since "cholinergic' analgesia is mediated independently of the opiate system, the possibility was considered that this response was mediated through inhibition of the local release of substance P. Rats were prepared with indwelling i.t. catheters which terminated in the L2-L3 region of the spinal cord. I.t. injection of carbachol (0.05-5 micrograms) or neostigmine (1-10 micrograms), but not nicotine (0.5-10 micrograms) produced dose-related increases in tail flick latencies. Pretreatment with i.t. injection of atropine or hemicholinium-3 significantly inhibited the antinociceptive response to neostigmine. Spinal substance P levels were measured 30 min following 0.5 micrograms carbachol. Levels in the dorsal horn were reduced by 30% compared with saline controls. Levels in the ventral horn were unchanged by carbachol. These results support the role of endogenous spinal acetylcholine in pain modification and suggest an interaction with substance P neurons of the dorsal spinal cord.     

Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist

AF-DX 116 (see chemical name below) is a competitive antagonist of muscarine receptors in peripheral organs. In contrast to pirenzepine, its behaviour in functional experiments indicates selectivity for the M2 muscarinic subtype. In pithed rats AF-DX 116 inhibits vagally-induced bradycardia, an M2 response, (ED50 32 micrograms/kg i.v.) in preference to the M1-mediated pressor response to McN-A-343 (ED50 211 micrograms/kg i.v.). AF-DX 116 further discriminates among M2 receptors, showing a high affinity for the cardiac muscarine receptors. In isolated preparations, AF-DX 116 has a tenfold higher affinity for the muscarine receptors of the heart (pA2 7.33) than for those in smooth muscles (pA2 6.39-6.44). The same profile appears from animal studies, where the compound is a more potent antagonist of either endogenously or exogenously activated cardiac muscarine responses as compared to vascular, smooth muscle or secretory responses. In general, the ratios of potencies (ED50) observed in cardiac vs. other muscarine mediated functions ranged between 30 and 50. Atropine showed no discrimination, inhibiting all muscarine responses in the same range of doses. In the conscious dog intravenous AF-DX 116 increased basal heart rate, and completely reversed the reflex bradycardia induced by clonidine. Tachycardia was dose-related (ED50 79 micrograms/kg i.v.), and occurred independently of background sympathetic tone. AF-DX 116 clearly distinguishes between M1- and M2-mediated responses; it also emphasizes the long-recognized heterogeneity among the peripheral M2 subtypes. AF-DX 116, for its pronounced cardioselectivity, may have a therapeutic potential in the treatment of sinus bradycardia.     

Central oxotremorine antagonist properties of pirenzepine

Pirenzepine, the prototype M1 muscarinic receptor antagonist, is an important compound for investigating the functional significance of M1 receptors at the integrated level of behavior but may have limitations imposed by its physical chemistry. Like the nonselective antagonist methylatropine, pirenzepine is highly hydrophilic and crosses the blood-brain-barrier with difficulty. We compared methylatropine with pirenzepine, given intraperitonealy, as antagonists of the behavioral effects of peripheral or central muscarinic activation. Lever-press responses of male Sprague-Dawley rats were maintained under a schedule requiring 10 responses for each food delivery. Administration of oxotremorine or the quaternary analog oxotremorine-M decreased rates of responding by at least 90%. Both methylatropine and pirenzepine antagonized the behavioral effects of oxotremorine-M; maximum reversal was 70%. Although methylatropine was about 30 times more potent than pirenzepine as an antagonist of the peripheral muscarinic activity of oxotremorine-M, it was inactive as an antagonist of oxotremorine when given in doses up to 153 mumol/kg. Pirenzepine, however, reversed oxotremorine-induced behavioral effects, with a maximum antagonism of 50%. These results suggest that pirenzepine interacts with central muscarinic receptors when administered systemically without producing marked behavioral effects of its own. Systemically administered pirenzepine may thus be a useful tool in further investigations of the relevance of M1 receptors to behavioral function.     

Propranolol and methylatropine antagonize the cardiovascular effects produced by microinjection of the TRH analog MK-771 into the preoptic suprachiasmatic nucleus

Thyrotropin-releasing hormone (TRH) has been shown to increase heart rate as well as blood pressure when administered into rat brain. The present study investigated the mechanism by which the TRH analog MK-771 produces these effects when injected into the preoptic suprachiasmatic nucleus (POSC). MK-771, at a dose of 125 pmol (50 ng), produced significant increases in both heart rate and blood pressure. These effects occurred within 5 minutes of microinjection and lasted approximately 20-30 minutes. Pretreatment with either the beta-adrenergic antagonist propranolol or the muscarinic antagonist methylatropine, administered into the POSC, significantly altered the response produced by MK-771. Propranolol, at a dose of 7 nmol, and methylatropine at a dose of 0.5 nmol, significantly inhibited the tachycardia produced by MK-771. In addition, methylatropine, at a dose of 0.5 nmol, significantly reduced the increase in diastolic pressure produced by the TRH agonist. These results are consistent with the idea that TRH agonists, when administered centrally, produce cardiovascular alterations through the autonomic nervous system.     

C-terminal amide to alcohol conversion changes the cardiovascular effects of endomorphins in anesthetized rats

Endomorphin1-ol (Tyr-Pro-Trp-Phe-ol, EM1-ol) and endomorphin2-ol (Tyr-Pro-Phe-Phe-ol, EM2-ol), with C-terminal alcohol (-ol) containing, have been shown to exhibit higher affinity and lower intrinsic efficacy in vitro than endomorphins. In the present study, in order to investigate the alterations of systemic hemodynamic effects induced by C-terminal amide to alcohol conversion, responses to intravenous (i.v.) or intracerebroventricular (i.c.v.) injection of EM1-ol, EM2-ol and their parents were compared in the system arterial pressure (SAP) and heart rate (HR) of anesthetized rats. Both EM1-ol and EM2-ol induced dose-related decrease in SAP and HR when injected in doses of 3-100 nmol/kg, i.v. In terms of relative vasodepressor activity, it is interesting to note that EM2-ol was more potent than endomorphin2 [the dose of 25% decrease in SAP (DD25) = 6.01+/-3.19 and 13.99+/-1.56 nmol/kg, i.v., respectively] at a time when responses to EM1-ol were less potent than endomorphin1. Moreover, decreases in SAP in response to EM1-ol and EM2-ol were reduced by naloxone, atropine sulfate, L-NAME and bilateral vagotomy. It indicated that the vasodepressor responses were possibly mediated by a naloxone-sensitive, nitric oxide release, vagus-activated mechanism. It is noteworthy that i.c.v. injections of -ol derivatives produced dose-related decreases in SAP and HR, which were significantly less potent than endomorphins and were attenuated by naloxone and atropine sulfate. In summary, the results of the present study indicated that the C-terminal amide to alcohol conversion produced different effects on the vasodepressor activity of endomorphin1 and endomorphin2 and endowed EM2-ol distinctive hypotension characters in peripheral (i.v.) and central (i.c.v.) tissues. Moreover, these results provided indirect evidence that amidated C-terminus might play an important role in the regulation of the cardiovascular system.     

Effects of morphine on hexamethonium-sensitive and -resistant excitatory responses of stomach to stimulation of vagal trunk in cats

Electrical stimulation of the vagal trunk with 10 Hz in frequency, 3 ms in duration and 15 volt in intensity for 10 s in cats produced an excitatory response of the stomach and the response was composed of two phases, an initial rapid excitation during stimulation period and the late multi-peak response after stimulation period. The initial response was inhibited by the administrations of hexamethonium (10 mg/kg, i.v.) and atropine (100 micrograms/kg, i.v.). The late response was not inhibited by hexamethonium but was inhibited by atropine (100 micrograms/kg, i.v.). The hexamethonium-sensitive initial excitation was not affected by the administration of morphine and gamma-aminobutyric acid (GABA). On the other hand, the hexamethonium-resistant late response was attenuated by the treatment with morphine (1 to 10 mg/kg, i.v.) and GABA (100 to 500 micrograms/kg, i.v.). Such inhibitory actions of morphine and GABA on the late response were antagonized by picrotoxin. From these results, it was concluded that morphine might inhibit specifically the hexamethonium-resistant late excitatory response of the stomach without affecting the hexamethonium-sensitive initial excitatory response and the inhibitory effect of morphine on the late response of stomach might be due to action of GABA released from the intramural neurons of gastric walls in cats.     

Central muscarinic modulation of fetal blood pressure and heart rate

It has previously been demonstrated that the fetal lamb cardiovascular system can respond to peripheral muscarinic stimulation. However the role of central muscarinic mechanisms in modulating fetal cardiovascular function has not been described. Pilocarpine is a muscarinic agonist that readily crosses the blood-brain barrier and was therefore employed to examine both central and peripheral muscarinic mechanisms in modulating fetal cardiovascular function. Fetal lambs were prepared for chronic intrauterine recording of fetal blood pressure (FBP) and heart rate (FHR). Direct administration of pilocarpine to the fetus resulted in an immediate dose-dependent decrease in both systolic and diastolic blood pressure and a rapid fall in FHR. The initial phase of hypotension was very short-lived (1-2 min) and was subsequently followed by a significant increase in systolic, diastolic and pulse pressures (30-60 min). Fetal heart rate gradually returned to control levels by 30 min after pilocarpine administration. Atropine pretreatment was effective in completely blocking the cardiovascular actions of pilocarpine, while methylatropine was only able to block the initial hypotensive and bradycardiac response. A prolonged tachycardia was also unmasked by methylatropine pretreatment. These data suggest that the initial hypotension and bradycardia in response to pilocarpine administration are mediated via peripheral muscarinic receptors, while stimulation of central muscarinic receptors result in hypertension and tachycardia. These data confirm that, as in the adult, central cholinergic mechanisms are involved in the modulation of cardiovascular function in the developing fetus.     

Inhibitory effects of beta-alanine on the vagal efferent and afferent excitatory responses of the stomach to stimulation of vagal trunk in cats.

The effects of beta-alanine on the electrically evoked vagal efferent (hexamethonium-sensitive initial excitatory response) and afferent (hexamethonium-resistant delayed excitatory response) responses of the cat stomach were studied. beta-alanine (30 to 300 micrograms/kg, i.v.) dose-dependently inhibited both the efferent and afferent response. The IC50 values of beta-alanine on the efferent and afferent response were 296 +/- 65 micrograms/kg and 128 +/- 35 microgram/kg, respectively. Maximal inhibitory effects of beta-alanine (300 micrograms/kg, i.v.) appeared about 1 hr after the injection. Glycine and taurine (100 to 10,000 micrograms/kg) did not affect these responses. Treatment with hexamethonium (10 mg/kg, i.v.) prevented the efferent response, but augmented the afferent response. The treatment with hexamethonium abolished the inhibitory effect of beta-alanine on the afferent response. Both picrotoxin (100 and 500 micrograms/kg, i.v.) and bicuculline (2000 micrograms/kg, i.v.) antagonized the inhibitory effects of beta-alanine on the vagal efferent and afferent responses of the stomach. The present experiments clearly demonstrated that beta-alanine inhibited both the vagal efferent and afferent excitatory responses of stomach to electrical stimulation of vagal trunk in cats.     

Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious rats

Corticotropin releasing factor (CRF) is one of the most important factors in the mechanism of stress-induced stimulation of colonic motility. However, it is controversial whether stress-induced stimulation of colonic motility is mediated via central or peripheral CRF receptors. We investigated the hypothesis that peripherally injected CRF accelerates colonic motility through the central CRF receptor, but not the peripheral CRF receptor. A strain gauge transducer was sutured on the serosal surface of the proximal colon. Colonic motility was monitored before and after the peripheral injection of CRF. An in vitro muscle strip study was also performed to investigate the peripheral effects of CRF. Subcutaneous injection of CRF (30-100 microg/kg) stimulated colonic motility in a dose-dependent manner. The stimulatory effect of peripherally administered CRF on colonic motility was abolished by truncal vagotomy, hexamethonium, atropine, and intracisternal injection of astressin (a CRF receptor antagonist). No responses to CRF (10(-9) -10(-7) M) of the muscle strips of the proximal colon were observed. These results suggest that the stimulatory effect of colonic motility in response to peripheral administration of CRF is mediated by the vagus nerve, nicotinic receptors, muscarinic receptors, and CRF receptors of the brain stem. It is concluded that peripherally administered CRF reaches the area postrema and activates the dorsal nucleus of vagi via central CRF receptors, resulting in stimulation of the vagal efferent and cholinergic transmission of the proximal colon.