The role of brain cholinergic system in renal sodium, potassium and water excretion in rats

In anesthetized rats intracerebroventricular (i. c. v.) injection of cholinergic agonist carbachol induced significant natriuresis, kaliuresis and diuresis (P < 0.05). Among them, the degree of natriuresis was changed with carbachol in a dose-dependent manner (r = 0.9997, P < 0.05). These responses were completely blocked by cholinergic M receptor antagonist atropine or N receptor antagonist hexamethonium pretreatment. Such effects of carbachol were inhibited in part by pretreatment with adrenergic alpha receptor antagonist phentolamine. These results indicate that the natriuresis, kaliuresis and diuresis induced by i. c. v. injection of carbachol were primarily mediated by both muscarinic and nicotinic receptors in the brain, while the effect was in part mediated secondarily via adrenergic alpha receptor.     

Tracheal vascular dilatation elicited by vagal nerve stimulation in rats

We investigated the effects of the electrical stimulation of a unilateral cervical vagal nerve on the blood flow in the trachea using laser Doppler flowmetry in urethane anesthetized Wistar King rats. Stimulation for 30 s at 1, 2, 5, 10, 20 or 50 Hz with 10 V intensity caused an increase in tracheal blood flow (TBF) in a frequency-dependent manner; the effects were most dominant with the 10-Hz stimulation among the six frequencies used. The increased responses of TBF with the muscarinic receptor antagonist atropine (1.0 mg/kg, i.v.) were significantly reduced when compared with those without atropine at 5 Hz stimulation (123.3 +/- 11.9% vs. 180.1 +/- 24.5%). This shows the existence of vasodilation due to a cholinergic mechanism. The increased responses of TBF after the ganglion blocking agent hexamethonium (20 mg/kg) i.v. administration were significantly reduced when compared with those without hexamethonium at 1, 2 Hz stimulation (1 Hz: 18.9 +/- 2.7% vs. 35.4 +/- 4.7%, 2 Hz: 40.5 +/- 8.9% vs. 58.8 +/- 6.7%); this shows the existence of vasodilation due to a non-cholinergic parasympathetic efferent mechanism which itself appears to be due to the release of neuropeptides such as VIP and PHI. The increased responses after hexamethonium administration were augmented probably because of the enhanced release of other neuropeptides like SP and CGRP especially at 10 Hz and 20 Hz stimulation. These findings suggest that the mechanism of vasodilation by the activity in the vagal fibers in the trachea of the rat has cholinergic and non-cholinergic efferent components and a non-cholinergic afferent component. In rats, the afferent component may play an important role in controlling tracheal vascular changes.     

The role of central muscarinic and nicotinic receptors in the regulation of sodium and potassium renal excretion

The effect of intraseptal injection of carbachol and nicotine on urinary output of Na+ and K+ in untreated rats as well as in animals pretreated with locally injected atropine, hexamethonium, dibenamine and propranolol was studied in order to evaluate the relative role played by central muscarinic and nicotinic receptors in the regulation of salt and water renal excretion. The injection of 30-250 nmol of nicotine into the medial septal area caused a dose-dependent increase in Na+ and K+ urinary output whereas urine volume was little affected. The effect of 30 nmol of nicotine was blocked by pretreatment with 100 nmol of hexamethonium. In addition, pretreatment with 5 nmol of either hexamethonium or atropine partially antagonized the natriuretic and kaliuretic effect of 1 nmol of carbachol. Also the alpha-blocking agent, dibenamine (150 nmol) antagonized, while the beta-blocker, propranolol (100 nmol) significantly enhanced the effect of carbachol. Propranolol (100 nmol) alone caused a small, but significant increase in Na+ and K+ renal excretion. These results indicate that stimulation of both muscarinic and nicotinic receptors in the septal area, as caused by carbachol, elicits increased disposition of Na+ and K+ by the kidneys. Also, part of the effects of carbachol appear to be mediated by the release of endogenous catecholamines, acting on central alpha receptors to increase Na+ and K+ urinary excretion. On the other hand, simultaneous activation of beta-receptors by the released amines would partially inhibit this effect.     

A further contribution to the question of trophic and hormonal influences on the noradrenaline content of the male reproductive tract: effect of combined androgen and estrogen treatment of prepuberally castrated rats

The pressor response to the intracisternal (i.c.) injection of carbachol (1 mug) in anesthetized rats was analyzed. This response was significantly reduced by the intravenous (i.v.) injection of guanethidine (5 mg), hexamethonium (10 mg) or phentolamine (5 mg), and conversely, potentiated by i.v. desmethylimipramine (0.3 mg), while propranolol (0.5 mg) i.v. selectively inhibited the enlargement of pulse pressure and the tachycardia following i.c. carbachol (1 mug). On the other hand, the pressor response to i.c. carbachol (1 mug) was almost completely blocked by i.c. atropine (3 mug) or hexamethonium (500 mug), and significantly reduced by i.c. chlorpromazine (50 mug) but significantly potentiated by i.c. desmethylimipramine (30 mug). The pressor response to i.c. carbachol (1 mug) remained unchanged after sectioning of the bilateral cervical vagal nerves but disappeared after sectioning of the spinal cord (C7-C8). From the above result it is suggested that the pressor response to i.c. carbachol ortral and peripheral adrenergic mechanisms, and that the sympathetic trunk is the main pathway.     

Muscarinic receptor subtype involvement in brain cholinergic stimulation by intracerebroventricular neostigmine in sinoaortic denervated rats

1. The present studies evaluated the participation of central muscarinic receptors in the cardiovascular effects of centrally injected neostigmine, a quaternary anticholinesterase, in conscious, sham-operated rats and in sinoaortic denervated animals. 2. The dose-dependent pressor effect of neostigmine (0.1 to 1 microg i.c.v.) was greater in sinoaortic denervated rats than in sham-operated animals, but only a dose-dependent bradycardic effect was seen in sham-operated rats. 3. Doses of 3.3 nmol (i.c.v.) of both the M1 muscarinic antagonist, pirenzepine, and the M3 muscarinic antagonist, 4-DAMP, prevented the pressor response to 1 microg of neostigmine in sham-operated rats and in sinoaortic denervated animals; however, the M2 muscarinic antagonist, AF-DX116, partially blocked this response in sham-operated rats while failing to do so in sinoaortic denervated rats. In sham rats, doses of 3.3 nmol (i.c.v.) of both pirenzepine and 4-DAMP prevented the bradycardic response to 1 microg (i.c.v.) of neostigmine, whereas AF-DX116 induced a partial blockade. 4. 4-DAMP, at the dose of 0.3 nmol (i.c.v.), but not pirenzepine at the same dose, prevented the pressor effect of neostigmine (0.1 to 1 microg i.c.v.) in both groups of rats. Both muscarinic antagonists at this dose prevented the bradycardia elicited by the anticholinesterase (0.1 to 1 microg i.c.v.), but 4-DAMP showed a greater antagonistic action on this cardiac effect than pirenzepine. In sham-operated rats, i.c.v. injection of 0.3 nmol of AF-DX116 failed to modify the cardiovascular responses to 0.3 microg of neostigmine. 5. Results suggest mainly an involvement of brain M3-subtype muscarinic receptors in the cardiovascular effect of intracerebroventricular administration of anticholinesterase neostigmine in both groups of rats.     

Chemical stimulation of the brain: Relationship between neural activity and water ingestion in the rat.

Implanted cannulae in the lateral septal nucleus, lateral hypothalamic area, or lateral caudate nucleus of 76 male Long-Evans rats. Ss then received injections of carbachol, atropine sulfate, or isotonic saline. Injecting carbachol into cholinergic drinking sites in the limbic system (septal nucleus or lateral hypothalamus) produced an immediate increase in neural firing at the stimulated site and at a contralateral nonstimulated site. The time course of the change in neural firing was similar to the time course of water ingestion. Increased neural firing was not produced by cholinergic stimulation of nondrinking caudate nucleus sites or by atropine or isotonic saline injection into the limbic system or caudate nucleus. Results suggest that drinking results from increased neural firing in a diffuse cholinergically coded circuit whose activity facilitates water ingestion. (27 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Renal effects of intracerebroventricularly injected tachykinins in the conscious saline-loaded rat: receptor characterization

1. The effects of intracerebroventricularly (i.c.v.) injected substance P (SP), neurokinin A (NKA) and [MePhe7]neurokinin B (NKB) were investigated on renal excretion of water, sodium and potassium in the conscious saline-loaded rat. The central effects of [MePhe7]NKB were characterized with selective tachykinin antagonists for NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 820) receptors. 2. Whereas SP or NKA (65 or 650 pmol) failed to modify the renal responses, [MePhe7]NKB (65-6500 pmol) produced dose-dependent and long-lasting (30-45 min) decreases in renal excretion of water (maximal reduction at 65 pmol: from 66.14 +/- 7.62 to 21.07 +/- 3.79 microliters min-1), sodium (maximal reduction at 65 pmol: from 10.19 +/- 2.0 to 1.75 +/- 0.48 mumol min-1) and potassium (maximal reduction at 65 pmol: from 4.31 +/- 1.38 to 0.71 +/- 0.27 mumol min-1). While 650 pmol [MePhe7]NKB elevated urinary osmolality, neither 65 pmol nor 6.5 nmol [MePhe7]NKB altered this parameter. 3. Both the antidiuresis and antinatriuresis induced by [MePhe7]NKB (65 pmol) were significantly blocked by the prior i.c.v. injection of R 820 (1.3 nmol, 5 min earlier), although the potassium excretion was only partially reduced. However, R 820 did not affect the antidiuresis and antinatriuresis elicited by endothelin-1 (1 pmol, i.c.v.). On its own, R 820 decreased renal potassium excretion with no effect on urinary osmolality and renal excretion of water and sodium. The i.c.v. co-injection of RP 67580 and SR 48968 (6.5 nmol each, 5 min earlier) failed to modify the renal responses to [MePhe7]NKB in a similar study. 4. The central effects of [MePhe7]NKB (65 pmol) on renal excretion were blocked by the prior i.v. administration of a linear peptide vasopressin V2 receptor antagonist (50 micrograms kg-1, 5 min earlier). 5. These results suggest that the central NK3 receptor, probably located in the hypothalamus, is implicated in the renal control of water and electrolyte homeostasis through the release of vasopressin in the conscious saline-loaded rat.     

A conservation principle and its effect on the formulation of Na-Ca exchanger current in cardiac cells

In the rat the exact role of vagal fibers and the interaction between the extrinsic and intrinsic neural system in distention-induced gastrin release are still a matter of debate. Accordingly, the aim of the present study was to examine the contribution of afferent and efferent vagal fibers as well as intrinsic neurons on gastrin response to gastric distention. In anesthetized rats graded gastric distention by 5, 10 and 15 ml saline for 20 min caused a significant volume-dependent increase of plasma gastrin levels by 12+/-6 pg/ml (5 ml saline, n = 8, P =0.05), 26+/-7 pg/ml (10 ml saline, n = 10, P < 0.05) and 37+/-7 pg/ml (15 ml saline, n = 8, P < 0.01 ), respectively. To examine the role of the extrinsic vagal innervation, gastrin response to distention was studied in anesthetized rats after bilateral truncal vagotomy (n = 9) or selective afferent vagotomy following pretreatment with capsaicin (n = 6). Stimulation of gastrin release by 10 ml distention in sham-operated control rats was reversed to an inhibition after truncal vagotomy (26+/-7 vs. -11+/-4 pg/ml; P<0.05) and capsaicin-treatment (37+/-18 vs. -34+/-11 pg/ml; P<0.05). A contribution of cholinergic mechanisms to this vagovagal-mediated stimulation of distention-induced gastrin release was excluded, since atropine (100 microg/kg/h; n = 8) further augmented distention-stimulated gastrin release. Since bombesin/gastrin-releasing peptide (GRP)-neurons contribute to vagally stimulated gastrin secretion, we have examined gastrin response to distention in the presence of the specific bombesin-receptor antagonist D-Phe6-BN(6-13)OMe (400 microg/kg/h: n = 10). This bombesin-antagonist completely reduced distention-stimulated gastrin release in vivo. In contrast, distention of the isolated, extrinsically denervated stomach significantly decreased gastrin release by 13+/-5 pg/min (5 ml saline, n = 8, P < 0.05), 28+/-8 pg/min (10 ml saline, n = 11, P < 0.05) and 35+/-10 pg/min (15 ml saline, n = 8, P < 0.01), respectively, without changing the activity of bombesin/GRP-neurons. Distention-induced decrease of gastrin release was attenuated to 50 percent by atropine (10(-7) M: n = 10) or tetrodotoxin (TTX) (10(-6) M; n = 10), respectively. These data demonstrate, that in anesthetized rats distention-stimulated gastrin secretion depends on the activation of a vagovagal reflex and intrinsic bombesin/GRP-neurons. In contrast distention of the isolated rat stomach inhibits gastrin release in part via intrinsic cholinergic pathways and other as yet unknown mechanisms.     

Intraventricular anti-cholinergics do not block cholinergic hippocampal RSA or neocortical desynchronization in the rabbit or rat

Electroencephalographic (EEG) electrodes and ventricular cannulae were implanted in 8 rabbits and 12 rats. Two anti-cholinergic agents, atropine sulfate and scopolamine hydrobromide, were given systemically (1-50 mg/kg) and intraventricularly (5-800 mug). Systemic but not intraventricular injections blocked sensory stimulation-induced or eserine-induced neocortical desynchronization and hippocampal RSA in rats and rabbits which were immobile and either undrugged or ethanol intoxicated. Systemic injections also blocked hippocampal RSA but not neocortical desynchronization in rats given sensory stimulation under urethane anaesthesia, while intraventricular injections only reduced RSA amplitude. Neither systemic nor intraventricular injections blocked neocortical desynchronization or hippocampal RSA recorded from animals when they walked in a motor driven wheel. These experiments support the hypothesis that there are two types of neocortical desynchronization and hippocampal RSA, one cholinergic and one non-cholinergic. They also suggest that atropine and scopolamine pass more readily to the neural system responsible for cholinergic EEG activity from the capillary bed than from the ventricular fluid.     

Calcium channel blockers inhibit the antidipsogenic effect of central injections of zinc in rats

Previous data from our laboratory have indicated that acute third ventricle injections of Zn2+ elicit a significant antidipsogenic response in rats in three different situations; dehydration, and central angiotensinergic or cholineric stimulation. In the present study we analyzed whether this response depends on voltage-dependent calcium channels. Dehydrated (14 h of water deprivation, overnight) animals received 2-microliters i.c.v. injections of zinc acetate (Zn(Ac)2; 300 pmol/rat) after pretreatment with the voltage-dependent calcium channel blockers gadolinium (Gd3+; 0.03, 3.0 and 30 pmol/rat) or verapamil (VER; 0.027, 0.05 and 0.11 pmol/rat). Both blockers reserved the antidipsogenic effect of third ventricle injections of Zn2+ in a dose-dependent manner. After 120 min, animals pretreated with saline receiving Zn(Ac)2 drank 3.10 +/- 0.57 ml/100 g body weight while those pretreated with Gd3+ at the highest dose displayed a water intake of 5.45 +/- 0.41 ml/100 body weight (P < 0.01). Animals pretreated with the vehicle of VER receiving Zn(Ac)2 drank 3.15 +/- 0.45 ml/100 g while animals pretreated with VER at the highest dose receiving Zn(Ac)2 drank 6.16 +/- 0.62 ml/100 g (P < 0.01). The antidipsogenic effect of Zn(Ac)2 seems to be specific since the metal (same dose and injection procedures) did not modify food intake in rats after 24 h of food deprivation. It is suggested that Zn2+ exerts its antidipsogenic effect by activation of mechanism(s) depending on the functional integrity of voltage-dependent calcium channels.     

Thyrotropin-releasing hormone affects the oxytocin, vasopressin and prolactin release in female rats during midlactation: relation to suckling

The effect of thyrotropin-releasing hormone (TRH; 200 ng i.c.v.) on oxytocin (OT), vasopressin (AVP) and prolactin (PRL) release was estimated in female Wistar rats during midlactation. The hypothalamo-neurohypophysial radioimmunoassayed OT and AVP storage as well as blood plasma level of both neurohypophysial hormones and PRL in females suckled or not suckled have been studied. I.c.v. administration of TRH increased AVP content both in the hypothalamus and neurohypophysis of suckled females; however, plasma AVP level did not change. TRH increased the hypothalamic as well as neurohypophysial OT content during suckling. Simultaneously, TRH inhibited OT release into the blood plasma. On the contrary, in not suckled females TRH increased OT plasma concentration. I.c.v. TRH raised the PRL concentration in plasma of lactating but, at the moment, not suckled females. On the contrary, i.c.v. TRH injection into females just suckled was followed by a decrease in PRL plasma level. TRH probably acts in the central nervous system as an inhibitory neuromodulating factor for the vasopressin release. Also, it cannot be excluded that TRH--otherwise known to enhance the PRL release--suppresses the oxytocin-prolactin positive feedback mechanism when activated temporarily by suckling.     

5-Hydroxytryptamine induces forestomach hypomotility in sheep through 5-HT4 receptors

The effects evoked by 5-hydroxytryptamine (5-HT; serotonin) on forestomach myoelectric activity were investigated in conscious sheep. Myoelectric signals were recorded with electrodes chronically implanted in the reticulum, rumen (dorsal sac) and omasal body, and were analysed by a computer-based method. The 5-HT receptors and the neuronal pathways involved in these actions were studied. The intravenous (i.v.) infusion of 5-HT (8 micrograms kg-1 min-1 for 5 min) evoked an inhibition of activity of the whole forestomach. Methiothepin, injected i.v. at 0.1 mg kg-1, inhibited rumen secondary contractions and omasum activity. However, forestomach activity remained unchanged after the administration of 0.2 mg kg-1 of ketanserin, ondansetron, tropisetron, GR-113808, phentolamine, propranolol, domperidone and naloxone. Atropine (0.2 mg kg-1), hexamethonium (2 mg kg-1) or haloperidol (0.1 mg kg-1) abolished rumen secondary cycles and inhibited omasum activity. In addition, atropine also suppressed primary cycles. GR-113808 blocked all 5-HT-induced effects. Furthermore, atropine or hexamethonium prevented the 5-HT-evoked inhibition of reticulorumen primary cycles. In contrast, the remaining antagonists did not alter the 5-HT-evoked forestomach hypomotility. In conclusion, 5-HT induces inhibition of forestomach myoelectric activity through 5-HT4 receptors, these actions being mediated by cholinergic neural pathways involving muscarinic and nicotinic receptors. However, adrenergic, dopaminergic or opiate pathways are not implicated.     

Effects of ACh on the electric activity of rostral ventrolateral medullary neurons of rat in vitro

Extracellular single-unit discharges were obtained from 165 spontaneously active neurons within the region of the rostral ventrolateral medulla (RVLM) by glass microelectrode from 89 brain slices of the Sprague-Dawley rats. The units could be divided into three types: regular (61.8%), irregular (24.2%) and silent (14%). Acetylcholine (ACh, 0.1, 0.3 mumol/L) showed four kinds of effects on spontaneous discharges of RVLM neurons: excitatory, inhibitory, biphasic and non-responsive, counting respectively 41.8%, 20%, 3% and 35.2% of the neurons tested. The excitatory effect of ACh was dose-dependent. The effects, either excitatory or inhibitory, of ACh (n = 49) were mostly blocked by atropine (0.3 mumol/L, n = 42). The excitatory effect of ACh (n = 14) could be blocked mainly by selective antagonist of M1 receptor, pirenzepine (PZ, 30 nmol/L, n = 9), but not by selective antagonist of M2 receptor, methoctramine (MT) and AFDX-116. The inhibitory effect of ACh (n = 10) could be blocked mostly by M2 receptor antagonist MT (30 nmol/L, n = 7); and this inhibitory effect (n = 9) could be blocked mostly by another M2 receptor antagonist AFDX-116 (30 nmol/L, n = 6), but not by M1 receptor antagonist PZ.     

Effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairment in rats

The role of kappa opioid receptor agonists in learning and memory is controversial. In the present study, the effects of U-50,488H on scopolamine-, mecamylamine- and dizocilpine-induced learning and memory impairments in rats were investigated. Scopolamine (3.3 mumol/kg s.c.), a muscarinic cholinergic antagonist, and mecamylamine (40 mumol/kg s.c.), a nicotinic cholinergic antagonist, significantly impaired learning and memory in rats in a step-through type passive avoidance test. Administration of U-50,488H (0.17 or 0.51 mumol/kg s.c.) 25 min before the acquisition trial reversed the impairment of learning and memory induced by scopolamine and mecamylamine. Although low doses of scopolamine (0.17 mumol/kg) and mecamylamine (12 mumol/kg) had no effect, concurrent administration of both antagonists induced impairment of learning and memory. Scopolamine significantly increased acetylcholine release in the hippocampus as determined by in vivo brain microdialysis. On the other hand, mecamylamine significantly decreased acetylcholine release. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, whereas it only partially blocked the increase of acetylcholine induced by scopolamine. On the other hand, an endogenous kappa opioid receptor agonist, dynorphin A (1-13), did not block the increase in acetylcholine release induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine (4.9 nmol/rat i.c.v.), a selective kappa opioid receptor antagonist. U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA receptors by dizocilpine ((+)-MK-801). These results suggest that U-50,488H reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release induced by mecamylamine via the kappa receptor-mediated opioid neuronal system.     

Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9% NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 +/- 0.04 ml/min vs 1.45 +/- 0.18 ml/min in vehicle-treated rats, P < 0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 +/- 0.34 ml/60 min and 3.39 +/- 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.     

Cardiovascular and behavioural effects of intracerebroventricularly administered tachykinin NK3 receptor antagonists in the conscious rat

1. In the conscious rat, three tachykinin NK3 receptor antagonists, namely SR142801 ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)pro pyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), R820 (3-indolylcarbonyl-Hyp-Phg-N(Me)-Bzl) and R486 (H-Asp-Ser-Phe-Trp-beta-Ala-Leu-Met-NH2) were assessed against the intracerebroventricular (i.c.v.) effects induced by senktide, a selective NK3 receptor agonist, on mean arterial blood pressure (MAP), heart rate (HR) and motor behaviour. 2. Senktide (10-650 pmol per animal; i.c.v; n = 4-16) at the lowest dose caused a significant fall in MAP (-10 +/- 6 mmHg), while at the highest doses (100 and 650 pmol), senktide caused a rise in MAP (9 +/- 3 and 12 +/- 1 mmHg, respectively) when compared to vehicle. The intermediate doses (25 and 65 pmol) had no effect on MAP. The highest two doses caused a tachycardia of 62 +/- 15 and 88 +/- 8 beats min(-1), respectively. The dose of 65 pmol had a biphasic effect on HR, an initial bradycardia of 47 +/- 12 beats min(-1) followed by a tachycardia of 46 +/- 14 beats min(-1). The lowest doses caused either a rise of 52 +/- 10 beats min(-1) (25 pmol) or no effect (10 pmol) on HR. All doses of senktide caused similar increases in face washing, sniffing and wet dog shakes except at the dose of 100 pmol, when wet dog shakes were more than double those observed with the other doses. 3. The antagonist SR142801 (100 pmol -65 nmol per animal; i.c.v.; n = 6-8) caused increases in MAP at the highest two doses (6.5 and 65 nmol) while HR, dose-dependently, increased (23 +/- 6 to 118 +/- 26 beats min[-1]) and the onset dose-dependently decreased. The (R)-enantiomer, SR142806 (100 pmol - 65 nmol per animal; i.c.v.; n = 6-8) only caused rises in MAP (13 +/- 2 mmHg) and HR (69 +/- 11 beats min[-1]) at the highest dose. These drugs had no apparent effect on behaviour, except for the highest dose of SR142801 which increased sniffing. The antagonist R820 (650 pmol - 6.5 nmol per animal; i.c.v.; n = 6) had no effect on MAP or HR and only increased sniffing behaviour at 6.5 nmol. At 650 pmol (n = 6), R486 had no effect on any variable, but at 3.25 nmol, i.c.v. (n = 4) a delayed tachycardia and a significant increase in all behavioural variables were observed. 4. The cardiovascular responses induced by 6.5 nmol SR142801 and 25 pmol senktide were inhibited by R820 (6.5 nmol, 5 min earlier i.c.v.). In contrast, R820 failed to affect the central cardiovascular and behavioural responses induced by 10 pmol [Sar9, Met(O2)11]substance P, a NK1 receptor selective agonist. The senktide-induced behavioural changes were not inhibited by R820 (6.5 nmol, i.c.v.) while R486 (650 pmol, i.c.v.) blocked both the cardiovascular and behavioural responses to 25 pmol senktide. A mixture of antagonists for NK1 (RP67580; 6.5 nmol) and NK2 (SR48968; 6.5 nmol) receptors injected i.c.v. did not affect the cardiovascular response to SR142801. Cross-desensitization was shown between the central responses to SR142801 and senktide, but not between SR142801 and [Sar9, Met(O2)11]substance P. 5. The antagonists SR142801 and SR142806 (6.5-650 nmol kg(-1); n = 5-7), given i.v., did not evoke any cardiovascular or behavioural changes, except a delayed bradycardia for SR142806 (650 nmol kg[-1]), and also failed to inhibit the increase in MAP evoked by senktide (4 nmol kg(-1), i.v.). However, at the highest dose, both drugs slightly reduced the senktide-induced tachycardia. 6. Although the present data are consistent with the in vitro pharmacological bioassays and binding data, showing that SR142801 is a poor antagonist at rat peripheral NK3 receptors, they suggest that SR142801 has a partial agonist action at these receptors centrally. A separation of the cardiovascular and behavioural effects mediated by central NK3 receptor activation was achieved with SR142801 and R820 but not with R486. These results could be explained by the existence of NK3 receptor subtypes in the rat or by the differential activation and inhibition of the same receptor protein linked to the production of different second messengers. Differences in the pharmacokinetic or pharmacodynamic properties of the antagonists cannot be excluded at this time.     

Immediate X-radiation induced contractions of the isolated guinea pig terminal ileum: the localization of the effect by drugs

Tone and motility of the isolated guinea pig ileum were increased by irradiation with a dose of 10 krd. The maximal effect corresponds to that induced by 0.001 microng/ml acetylcholine or 0.3 microng/ml nicotine. The pharmacological analysis of this effect performed with acetylcholine and nicotine and several blocking agents including hexamethonium, atropine, tetrodotoxin, diphenhydramine, and verapamil suggests that radiation acts on the postganglionic parasympathetic neuron and the neuromuscular synapse. The mechanism of radiation is likely to consist of both an increased release of acetylcholine from the postganglionic neuron and a sensibilization of the cholinergic receptor site at the smooth muscle cell. The latter effect is thought to result from an increased contractile action induced by acetylcholine or nicotine in the irradiated ileal smooth muscle.     

Lack of task specificity and absence of posttraining effects of atropine on learning.

Three experiments, with 91 male Lister rats, examined the effect of the cholinergic antagonist atropine on the acquisition of learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions, on the retention of performance acquired in the absence of the drug, and on memory consolidation immediately after daily training trials. In Exp I, intraperitoneal atropine sulfate (10 or 50 mg/kg) injected 30 min prior to training severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Exp II, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in Ss previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects of gross sensorimotor impairments. In Exp III, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in Ss trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypotheses that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Results demonstrate dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes. (50 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of antihypertensive treatment on vasopressin secretion and on its osmoregulation in moderate hypertension

BACKGROUND: Changes in plasma osmolality and arterial pressure can affect the secretion of vasopressin (AVP). OBJECTIVE: To investigate the effect of a drug-induced lowering of the arterial pressure on the plasma concentration of AVP and on its osmoregulation in moderately severe uncomplicated hypertensives. DESIGN AND METHODS: A group of 33 moderate uncomplicated and untreated essential hypertensives of both sexes (mean age 48 +/- 1 years, average arterial pressure 171 +/- 3/108 +/- 2 mmHg) was studied. We measured AVP and other plasma and urine variables in 21 of them before and after administration of a hypertonic NaCl solution (100 mmol NaCl in 50 ml). Antihypertensive treatment with a single drug or, if necessary, with a combination of drugs was initiated for eight of these subjects and hypertonic saline administration was repeated after 1 month of treatment. The hypertonic stimulus was administered to the other 12 subjects after acute lowering of the arterial pressure by continuous intravenous infusion either of 0.3 mg clonidine in 100 ml (n = 6) or of 50 mg sodium nitroprusside in 250 ml (n = 6). RESULTS: Administration of hypertonic saline to untreated hypertensives increased their AVP level from 1.6 +/- 0.28 to 5.4 +/- 0.7 pg/ml (n = 21, P < 0.01). Their mean arterial pressure was lowered after pharmacological treatment for 1 month (n = 8) from 125 +/- 2 to 101 +/- 2 mmHg; their baseline AVP level remained unchanged (1.2 +/- 0.21 versus 0.9 +/- 0.25 pg/ml); after hypertonic saline had been administered to hypertensives with lowered arterial pressures, their AVP level increased to 6.0 +/- 1.03 pg/ml (P < 0.01). The AVP level in subjects whose MAP had been lowered acutely by administration of clonidine (n = 6) or of sodium nitroprusside (n = 6; on the average, from 132 +/- 3 to 110 +/- 4 mmHg) increased concurrently from 1.6 +/- 0.63 to 3.4 +/- 0.7 pg/ml (P < 0.05); after administration of the hypertonic saline the AVP level increased to 10.8 +/- 2.22 pg/ml (P < 0.01). This stimulated value was significantly (P < 0.01) higher than that observed after hypertonic saline had been administered to untreated hypertensives (5.4 +/- 0.7 pg/ml). CONCLUSIONS: Acute lowering of the arterial pressure in moderate essential hypertension appears to facilitate the secretion and osmoregulation of AVP. On the other hand, during prolonged antihypertensive treatment, baroreflex regulation of the secretion of AVP appears to be set at a lower operating point, thus exerting the same influence on the release of AVP as it did before antihypertensive treatment.