Atropine Pretreatment Research Articles

Acetylcholine induces vasodilation and prostacyclin synthesis in rat lungs

Acetylcholine causes pulmonary vasodilation, but its mechanism of action is unclear. We hypothesized that acetylcholine-induced pulmonary vasodilation might be associated with prostacyclin formation. Therefore, we used isolated rat lungs perfused with a recirculating cell- and plasma-free physiological salt solution to study the effect of acetylcholine infusion on pulmonary perfusion pressure, vascular responsiveness and lung prostacyclin production. Acetylcholine (20 ug infused over 1 minute) caused immediate vasodilation during ongoing hypoxic vasoconstriction and prolonged depression of subsequent hypoxic and angiotensin II-induced vasoconstrictions. Both effects of acetylcholine were abolished by atropine pretreatment. The prolonged acetylcholine effect, but not the immediate response, was blocked by meclofenamate, an inhibitor of cyclooxygenase. The prolonged effect, but not the immediate response, of acetylcholine was associated with an increase in perfusate 6-keto-PGF 1α concentration. The acetylcholine stimulated increase in 6-keto-PGF 1α production was inhibited by meclofenamate and by atropine. Thus, blockade of prostacyclin production corresponded with blockade of the prolonged acetylcholine effect. In conclusion, acetylcholine caused in isolated rat lungs an immediate vasodilation and a prolonged, time-dependent depression of vascular responsiveness. Whereas both acetylcholine effects were under muscarinic receptor control, only the prolonged effect depended on the cyclooxygenase pathway and, presumably, protacyclin synthesis.

Behavioural tolerance to arecoline in rats: cross-tolerance to oxotremorine and prevention by pretreatment with atropine.

In two experiments tolerance development to the effects of arecoline on operant responding for a water reward was shown to be dose-dependent, complete tolerance developing to a daily dose of 4 mg/kg, but only partial tolerance developing to a daily dose of 8 mg/kg. However, rats chronically treated with the higher dose of arecoline were least affected by a challenge dose of oxotremorine (0.2 mg/kg); i.e. the high dose group exhibited the greatest cross-tolerance to oxotremorine. Moreover, atropine (4 mg/kg) pretreatment prior to arecoline (4 mg/kg) prevented cross-tolerance to oxotremorine, indicating that dispositional mechanisms are unlikely to be involved in tolerance to arecoline.

Cardiovascular responses in the sea raven, Hemitripterus americanus, elicited by vascular compression.

Increases in the water pressure (PW) around the trunk of the sea raven (Hemitripterus americanus Gmelin) were used to evaluate the effects of vascular compression on cardiovascular variables. Cardiac output (Vb), heart rate (fH) and blood pressures in the ventral aorta, dorsal aorta and ductus Cuvier (Pva, Pda and Pdc, respectively) were measured. A 20 cm H2O increase in PW decreased vascular conductance by up to 25%. During vascular compression, a reflex bradycardia reduced Vb and attenuated the accompanying rise in arterial blood pressure. Pretreatment of the fish with the sympathetic antagonist, propranolol, further attenuated the hypertension by accentuating the reflex bradycardia. Subsequent pretreatment with papaverine, a vascular smooth muscle poison, potentiated these effects and did not reveal any autoregulatory vasodilation in the periphery. Atropine pretreatment completely abolished the reflex bradycardia, indicating that the bradycardia resulted from increased vagal cholinergic tone. The fish also exhibited cardiovascular compensation during the 2 min vascular compression. An accommodation of the barostatic reflex (reduced vagal tone) and a sympathetic tachycardia raised Vb and passively increased vascular conductance. The set point for the barostatic bradycardia was apparently temperature-sensitive.

The mechanism of vagal nerve stimulation of glucagon and insulin secretion in the dog.

The mechanism of vagal nerve stimulation of glucagon (IRG) and insulin (IRI) secretion was investigated in halothane-anesthetized dogs. Both ventral and dorsal branches of the thoracic vagi were stimulated electrically (10 Hz, 5 msec, 13.5 mA, 10 min) below the heart. Arterial and superior pancreaticoduodenal venous plasma were sampled, superior pancreaticoduodenal venous plasma flow was measured, and net pancreatic output of IRG and IRI were calculated. During vagal nerve stimulation (n = 15) net pancreatic output of IRG doubled (delta = +0.83 +/- 0.28 ng/min, P less than 0.01; baseline = 0.81 +/- 0.15 ng/ min) and IRI quadrupled (delta = +3.5 +/- 1.5 mU/min, P less than 0.025; baseline = 1.1 +/- 0.3 mU/min). Arterial glucose levels increased by 7 +/- 2 mg/dl from 108 +/- 3 mg/dl (P less than 0.005). After atropine pretreatment (n = 7), the pancreatic IRI response to vagal nerve stimulation was +0.71 +/- 0.28 mU/min (P less than 0.025), a reduction of 80%. In contrast, atropine pretreatment changed neither the IRG response (delta = +0.87 +/- 0.36 ng/min; P less than 0.05) nor the arterial glucose response (delta = +9 +/- 3 mg/dl; P less than 0.025) to vagal nerve stimulation. Hexamethonium pretreatment (n = 9) abolished the pancreatic IRG response (delta = +0.13 +/- 0.11 ng/min; NS), the arterial glucose response (delta = +0.5 +/- 1.9 mg/dl; NS) and the pancreatic IRI response (delta = +0.16 +/- 0.31 mU/min; NS) to vagal nerve stimulation. It is concluded that vagal nerve stimulation in the dog produces a moderate increase of IRG secretion, mediated by a nonmuscarinic (peptidergic?) mechanism, and a marked increase of IRI secretion, mediated by a muscarinic mechanism. Both responses are dependent on nicotinic transmission.

Effectiveness of physostigmine as a pretreatment drug for protection of rats from organophosphate poisoning

The effectiveness of physostigmine and atropine pretreatment against the lethal effects of sarin was studied in rats given lethal subcutaneous injections (130 μg/kg) of the organophospate. Pretreatment of these animals with physostigmine 30 min prior to injection of sarin reduced mortality to 28% and when the drug coadministered with atropine only 4% of the animals died. The latter treatment also reduced significantly the extent and duration of symptoms due to sarin; however, atropine, pyridostigmine, and neostigmine injected alone did not protect animals against the lethal effects of sarin. Physostigmine caused only slight inhibition of cholinesterase in blood and skeletal muscle. Cholinesterase activity in blood and muscle of rats pretreated with physostigmine before sarin administration was significantly higher than in tissues from rats injected with sarin alone. In rats receiving sarin following pretreatment with physostigmine, twitch potentiation of extensor muscles and maintenance of tension during tetanic stimulation of the nerve recovered to near control levels. Muscle function recovered despite significant inhibition of cholinesterase. Effective protection against lethality by physostigmine could be related to protection of cerebral cholinesterase since inhibition of this enzyme by sarin was lowered significantly after pretreatment with physostigmine. Alternatively, physostigmine may also interact with the nicotinic acetylcholine receptor ionchannel complex directly.

CHARACTERIZATION OF SUBSTANCE P‐INDUCED BRONCHOCONSTRICTION IN THE GUINEA‐PIG: A COMPARISON WITH ACETYLCHOLINE

Substance P (0.5-8.0 micrograms/kg, i.v.) induced bronchoconstriction in anaesthetized, mechanically-ventilated guinea-pigs, comprising increases in airways resistance and decreases in dynamic compliance. These bronchoconstrictor responses were unaffected by bilateral vagotomy, pretreatment with pheniramine (2 mg/kg, i.v.) or by pretreatment with atropine (100 micrograms/kg, i.v.). Acetylcholine-induced (4-32 micrograms/kg, i.v.) bronchoconstriction was prevented by atropine pretreatment, whereas bilateral vagotomy inhibited responses to acetylcholine. Ganglionic blockade using hexamethonium (20 mg/kg, i.v.) potentiated both substance P and acetylcholine on airways resistance and dynamic compliance. Indomethacin (1 or 5 mg/kg, i.v.) did not affect substance P-induced bronchoconstriction, whereas the higher dose enhanced acetylcholine-induced increases in airways resistance. In addition, aspirin pretreatment (20 mg/kg, i.v.) did not alter the bronchoconstrictor potency for either substance P or acetylcholine. On the other hand, the combined cyclo-oxygenase/lipoxygenase inhibitors eicosatetraynoic acid (ETYA, 20 mg/kg, i.v.) and BW755C (20 mg/kg, i.v.) potentiated both acetylcholine and substance P on airways resistance and dynamic compliance. The results suggest that substance P-induced bronchoconstriction may be modulated by the sympathetic nervous system and does not appear to be influenced by vagal or histaminergic mechanisms. The failure of indomethacin or aspirin to affect substance P-induced bronchoconstriction, together with the enhancing effects of ETYA and BW755C pretreatments, provide evidence consistent with the existence of a bronchodilator mechanism which may be inhibited by compounds inhibiting lipoxygenase enzymes.

Pharmacologic Analysis of Ketamine-Induced Cardiac Actions in Isolated, Blood-Perfused Canine Atria

Effects of ketamine were investigated on atrial rate and contractile force in the isolated, blood-perfused canine atrium. When a relatively small dose (3 micrograms) of ketamine was injected into the sinus node artery, positive chronotropic and inotropic responses were consistently observed. With doses of 10-300 micrograms i.a., biphasic (i.e., negative followed by positive) chronotropic and inotropic responses were induced. An extremely large dose of ketamine frequently produced biphasic chronotropic and only negative inotropic responses. The negative effects of ketamine were not affected by atropine pretreatment. After treatment with propranolol or imipramine, the positive effects were significantly suppressed. The effects were not influenced by tetrodotoxin. These results suggest that ketamine has (a) indirect cardioexcitatory properties mediated by a release of catecholamines which is due to a tyramine-like action, and (b) direct cardioinhibitory properties by which high doses depress the contractility rather than the pacemaker activity.

Effect and mechanism of vagal nerve stimulation on somatostatin secretion in dogs.

To investigate the effect of vagal nerve stimulation on the release of pancreatic somatostatin, we electrically stimulated (10 Hz, 5 ms, 13.5 mA, and 10 min) the thoracic vagi just below the heart in halothane anesthetized dogs (n = 15). The stimulation increased the pancreatic output of somatostatinlike immunoreactivity (SLI) (delta = +248 +/- 81 fmol/min, P less than 0.005; base-line levels = 455 +/- 150 fmol/min). min). Arterial plasma SLI levels increased as well (delta = +16 +/- 3 fmol/ml, P less than 0.001; base-line levels = 65 +/- 3 fmol/ml), reflecting stimulation of extrapancreatic SLI secretion. Significant vagal activation was verified by a fivefold increase of pancreatic output of pancreatic polypeptide (PP) (delta = +31.4 +/- 5.9 ng/min, P less than 0.001; base-line levels = 7.8 +/- 0.9 ng/min). Atropine pretreatment (n = 6) inhibited partially both the PP response (delta = +7.9 +/- 3.8 ng/min after atropine) and the pancreatic SLI response (delta = +92 +/- 29 fmol/min) to vagal nerve stimulation. However, atropine pretreatment did not modify the arterial SLI response (delta = +20 +/- 7 fmol/ml). Hexamethonium pretreatment (n = 9) completely abolished all three responses. We conclude that 1) electrical stimulation of the vagus stimulates pancreatic SLI, extrapancreatic SLI, and PP release in vivo in the dog; 2) both muscarinic and nonmuscarinic mechanisms mediate the PP and pancreatic SLI responses; 3) a nonmuscarinic mechanism mediates the extrapancreatic SLI response; and 4) all three responses are mediated via ganglionic nicotinic receptors.

Barrel rotation evoked by intracerebroventricular vasopressin injections in conscious rats. II. Visual/vestibular interactions and efficacy of antiseizure drugs

Intracerebroventricular (i.c.v.) arginine-vasopressin (AVP) injections evoke ‘barrel rotation’ (BR) in rats. This motor system abnormality was studied in a protocol where conscious rats were injected on day 1 with 1 μg i.c.v. AVP and reexposed to 0.5 μg on day 3. Three paradigms modifying visual/vestibular systems were employed: labyrinthectomy, 3-acetylpyridine (3-AP) destruction of the inferior olive and atropine pretreatment. Ambient illumination (light vs dark) was also modified. Initial (day 1) incidence of BR, increased incidence (i.e. sensitization) on day 3, and day 3 BR latency were differentially affected by the various paradigms and suggest a complex role of visual/vestibular input in modifying i.c.v. AVP-induced BR. For example, 3-AP rats tested in light and atropinized rats had a reduced responsiveness to the peptide on day 1. 3-AP-treated rats tested in dark conditions showed a normal incidence of BR on day 1, but the expected sensitization to AVP on day 3 did not occur. Combined labyrinthectomy and darkness did not modify BR incidence on either day, but altered the distribution of latency data. Four diverse antiepileptic drugs were tested for efficacy against i.c.v. AVP-induced BR in sensitized rats: phenytoin, diazepam, valproic acid and phenobarbital; all drugs reduced the proportion of rats with BR and prolonged the latency. We conclude that brain AVP may be involved in abnormal motor conditions that are modified by visual/vestibular neuronal circuits. The unusual motor output (barrel rotation) can be inhibited by diverse antiepileptic drugs.

Atropine blockade of growth hormone (GH)-releasing hormone-induced GH secretion in man is not exerted at pituitary level.

The role of acetylcholine (Ach) in the regulation of human GH secretion was assessed using atropine, which selectively blocks cholinergic muscarinic receptors. Paired tests were performed in seven normal subjects using GH-releasing hormone (GHRH) 1-44 (1 microgram/kg iv), with and without atropine pretreatment (1 mg im). The GHRH 1-44-induced GH secretory peak [20.7 +/- 4.5 (SEM) ng/ml] was completely blocked by atropine administration (2.3 +/- 0.6 ng/ml) (P less than 0.01). To determine whether this atropine blockade was at the pituitary level, a series of in vitro studies were conducted using monolayer cultures of cells from bovine anterior pituitary glands. GHRH 1-44 (10(-8) M) stimulated bovine GH release (11.1 +/- 1.5 micrograms/ml) as compared to control values (5.1 +/- 0.4 microgram/ml) (P less than 0.01). This response was not altered by 10(-6) M atropine (14.9 +/- 0.9 microgram/ml). Similar results were obtained with GHRH, 10(-9) M, with or without atropine, 10(-7) M. Addition of 10(-6) M Ach to the incubation medium significantly increased bovine GH release (12.7 +/- 1.2 microgram/ml) and the effect of 10(-6) M Ach and 10(-8) M GHRH was additive (20.9 +/- 2.1 micrograms/ml) (P less than 0.01). Similar results were obtained with Ach, 10(-5) M, and GHRH, 10(-9) M. Atropine or eserine alone did not alter basal GH secretion, and atropine blocked Ach-stimulating activity. In conclusion, atropine blockade of GHRH-induced GH secretion appears to be exerted at a site other than pituitary.

Effects of antidotes on soman-induced brain changes.

Rats were pretreated with either diazepam, atropine or benactyzine 10 min prior to soman injection. Local cerebral glucose use (LCGU) was determined during the seizure phase (15 min post soman) or pathology phase (72 h post soman). Diazepam and benactyzine pretreatment prevented convulsive activity, whereas atropine pretreatment only reduced the duration of convulsive activity after soman exposure. Each pretreatment agent had a unique impact on LCGU pattern during the seizure phase. During the pathology phase, the marked reduction in LCGU and the conspicuous brain damage associated with soman-induced seizures was minimized by all three pretreatments.

Biphasic effects of systemically administered GABA antagonists on Cardiac vagal activity

Systemic administration of the GABA antagonist picrotoxin 6.0 mg/kg i.v. elicited hypertension and a fall in sinus rate wita return to baseline levels in intact rats. Antagonists of GABA act in the supraspinal CNS to augment sympathetic outflow to the heart and vasculature. Therefore, in this study the spinal cord was transected prior to drug administration in order to eliminate sympathetically mediated effects. In spinal rats, picrotoxin 6.0 mg/kg evoked a biphasic sinus rate response characterized by an initial decrease followed by an increase above baseline sinus rate. Bilateral vagotomy or atropine pretreatment blocked sinus rate changes elicited by picrotoxin, demonstrating that these effects were vagally mediated. Midcollicular decerebration altered the biphasic sinus rate response by preventing the late rise but not the initial decrease in sinus rate. Infusion of another GABA antagonist, bicuculline, elicited a similar biphasic sinus rate response, althougthe time-course was shorter. Unexpectedly, picrotoxin or bicuculline administration in spinal rats caused an increase in mean blood pressure whicwas prevented by decerebration and different from that observed in intact rats witrespect to time course. In spinal rats pretreatment wita vasopressin antagonist, d(CH 2) 5Tyr(Me)AVP, blocked the pressor response induced by picrotoxin infusion without altering the biphasic changes in sinus rate. These results suggest that, in the rat: (1) two GABAergic inhibitory mechanisms at different levels of the neuraxis exert opposite effects on cardiac vagal activity; and (2) GABA antagonists may elevate arterial pressure by a mechanism distinct from their previously described sympathoexcitatiry effects.

A study on the aetiology of reserpine ulceration and the antiulcer action of solcoseryl in rat stomach

The aetiology of reserpine-induced gastric ulcer formation and the antiulcer effects of solcoseryl were studied in rats. Intraperitoneal injection of reserpine produced severe ulceration, as well as mast cell and histamine depletion, in the gastric glandular mucosa. Mepyramine and cimetidine markedly antagonized the gastric lesions, but did not influence the reduced mast cell count; atropine pretreatment significantly inhibited both parameters. Intramuscular injection of solcoseryl lessened ulcer severity and prevented the decreased mast cell counts and histamine levels in reserpine-treated rats. However, the same dose of solcoseryl injected intraperitoneally was ineffective. Solcoseryl, irrespective of the route of administration, did not influence the gastric secretory activities of reserpine. It is concluded that reserpine ulceration is both cholinergic- and histamine-mediated, and that the antiulcer effects of solcoseryl appear to be due to prevention of histamine depletion in the gastric mucosa.

Stimulation and inhibition of gastrointestinal propulsion induced by substance P and substance K in the rat

Substance P and substance K (neurokinin A) (dose range: 0.08-80 nmol kg-1) were tested for their effects on gastrointestinal propulsion in the rat. The peptides were given by intraperitoneal injection concurrently with the intragastric administration of a test meal containing charcoal and 51Cr. Examination 3 min after the test meal showed that high doses of substance P (greater than 0.74 nmol kg-1) and substance K (greater than 8.8 nmol kg-1) inhibited gastric emptying and gastrointestinal transit. This inhibitory effect was changed to a stimulant effect by pretreatment of the rats with atropine (3.5 mumol kg-1). Guanethidine pretreatment (67 mumol kg-1) revealed a facilitatory effect of low doses of the two tachykinins (about 1 nmol kg-1) on gastrointestinal propulsion. Examination 15 min after the test meal demonstrated that substance P (greater than 0.74 nmol kg-1) dose-dependently enhanced gastrointestinal propulsion, an effect that was also seen after atropine pretreatment. Low doses of substance K (about 1 nmol kg-1) also stimulated gastrointestinal propulsion but this effect was abolished by atropine. In addition, atropine pretreatment revealed a stimulant effect of high doses of substance K (88 nmol kg-1) on gastric emptying. These results show that the effects of substance P and substance K on gastrointestinal propulsion vary with dose and time and involve, at least partly, activation of the autonomic nervous system.

Gastric acid and vagus nerve response to GABA agonist baclofen

Baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid], a lipophilic derivative of GABA, was studied for its effect upon the efferent activity of the left cervical vagus in urethane-anesthetized rats. Baclofen (4 mg/kg, s.c.) produces neural discharges in the multifiber vagus preparation. The time course of vagal activation is well correlated with the profile of stimulation of gastric acid secretion recorded every 2 min. Atropine pretreatment (1 mg/kg) did not modify baclofen stimulation of vagal activity. These results demonstrated that a GABAB receptor agonist stimulates the parasympathetic outflow through mechanisms independent of interaction with muscarinic receptors leading to stimulation of gastric acid secretion.

Adrenergic responses of the cardiovascular system of the eel, Anguilla australis, in vivo

Heart output, arterial pressures, and heart rate were measured directly in conscious unrestrained eels (Anguilla australis) and responses to intra-arterial injection of adrenaline monitored. Adrenaline increased systemic vascular resistance, heart output, and cardiac stroke volume in all animals. In some cases small transient decreases in stroke volume and hence heart output were seen at the peak of the pressor response: These probably reflect a passive decrease in systolic emptying due to increased afterload on the heart. In most cases, adrenaline produced tachycardia; but two animals showed consistent and profound reflex bradycardia, which was accompanied by a concomitant increase in stroke volume such that heart output was maintained or increased slightly. The interaction of changes in heart output and systemic vascular resistance produced complex and variable changes in arterial pressure. There was no consistent pattern of changes in branchial vascular resistance. Atropine treatment in vivo revealed vagal cardio-inhibitory tone in some animals and always blocked the reflex bradycardia seen during adrenaline induced hypertension. In some animals, adrenaline injection after atropine pretreatment led to the establishment of cyclic changes in arterial pressure with a period of about 1 min (Mayer waves).

Histamine dose-response curves in guinea pigs.

Histamine dose-response curves were performed on anesthetized tracheostomized guinea pigs that were paralyzed and mechanically ventilated at a constant tidal volume and breathing frequency. The dose was calculated by generating an aerosol of known concentration and measuring the volume delivered to the lung. Increasing the dose was accomplished by increasing the number of breaths of aerosol delivered. The response to each dose was determined by measuring the change in airway resistance (RL) and dynamic compliance (Cdyn) using the method of Von Neergaard and Wirz (Z. Klin. Med. 105: 51-82, 1927). With increasing doses of histamine, RL increased and reached a plateau at approximately five times the base-line value and Cdyn fell to approximately 20% of its initial value. The variability in the base-line and maximum response as well as the calculated sensitivity and reactivity was less than that previously reported. Propranolol pretreatment increased resting RL and shifted the dose-response curve for RL to the left of the controls, increasing reactivity but not sensitivity. Atropine shifted the dose-response curve to the right of the control, decreasing sensitivity but without changing reactivity. The data for Cdyn showed that atropine pretreatment caused a higher resting value and propranolol pretreatment a lower value at the highest histamine dose but no differences in either sensitivity or reactivity.

Involvement of the cholinergic system in insulin and glucagon oversecretion of genetic preobesity.

The etiology of the abnormal secretion of hormones from the endocrine pancreas of genetically obese (fa/fa) rats is unknown. In this study, we tested the postulate that there is an early occurrence of increased efferent parasympathetic activity to the endocrine pancreas of these rodents. Unweaned female 17-day-old pups were anesthetized and tested by an iv bolus of arginine to stimulate insulin and glucagon output. At the time of the tests, pups were indistinguishable from each other. They were, therefore, kept to adulthood to allow for their separation into an obese (25% of total animals) and a lean (75%) group. Those animals that became obese were retrospectively referred to as preobese. Basal insulinemia and glucagonemia were identical in the two groups, as were the dynamics of arginine-induced hormone release. However, arginine-induced insulin as well as glucagon output were higher in preobese than in lean pups. These two abnormalities were abolished by acute atropine pretreatment. It is concluded that the substrate-induced insulin and glucagon oversecretion of preobese pups is an early defect that is mediated via the vagus nerve.

The modulating influences on naloxone-reversible respiratory suppression induced by thin-fiber muscular afferents

Systemic administration of the GABA antagonist picrotoxin 6.0 mg/kg i.v. elicited hypertension and a fall in sinus rate wita return to baseline levels in intact rats. Antagonists of GABA act in the supraspinal CNS to augment sympathetic outflow to the heart and vasculature. Therefore, in this study the spinal cord was transected prior to drug administration in order to eliminate sympathetically mediated effects. In spinal rats, picrotoxin 6.0 mg/kg evoked a biphasic sinus rate response characterized by an initial decrease followed by an increase above baseline sinus rate. Bilateral vagotomy or atropine pretreatment blocked sinus rate changes elicited by picrotoxin, demonstrating that these effects were vagally mediated. Midcollicular decerebration altered the biphasic sinus rate response by preventing the late rise but not the initial decrease in sinus rate. Infusion of another GABA antagonist, bicuculline, elicited a similar biphasic sinus rate response, althougthe time-course was shorter. Unexpectedly, picrotoxin or bicuculline administration in spinal rats caused an increase in mean blood pressure whicwas prevented by decerebration and different from that observed in intact rats witrespect to time course. In spinal rats pretreatment wita vasopressin antagonist,d(CH2)5Tyr(Me)AVP, blocked the pressor response induced by picrotoxin infusion without altering the biphasic changes in sinus rate. These results suggest that, in the rat: (1) two GABAergic inhibitory mechanisms at different levels of the neuraxis exert opposite effects on cardiac vagal activity; and (2) GABA antagonists may elevate arterial pressure by a mechanism distinct from their previously described sympathoexcitatiry effects.

Corelease of vasoactive intestinal polypeptide and peptide histidine isoleucine in relation to atropine-resistant vasodilation in cat submandibular salivary gland.

Parasympathetic nerve stimulation of the submandibular salivary gland in the cat caused salivary secretion, vasodilation and a corelease of vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) immunoreactivities (IR) into the venous effluent, as indicated by an increase in output. The ratio between the released VIP-IR and PHI-IR was close to 1:1. Gel-permeation chromatography of plasma from the submandibular venous effluent indicated that the released VIP-IR and PHI-IR were very similar to porcine VIP and PHI, respectively. Atropine pretreatment enhanced output of both VIP-IR and PHI-IR during the parasympathetic nerve stimulation to a similar extent (about 5-fold) compared to control stimulations. This increase could be due to an inhibitory presynaptic muscarinic receptor regulation of VIP and PHI release. Since VIP and PHI are present in the same postganglionic parasympathetic nerves in the gland and both peptides have vasodilator activity, the present data suggest that both VIP and PHI may contribute to the atropine-resistant vasodilation seen upon stimulation of the chorda-lingual nerve. The parasympathetic control of salivary gland function may thus involve, a multimessenger system with the classical transmitter acetylcholine and the peptides VIP and PHI.