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Intravenous administration of 5-hydroxytryptamine (5-HT) caused a dose-dependent contraction in the lower esophageal sphincter in the opossum. The smallest dose of 5-HT which caused a detectable contraction of the sphincter was 0.5 mug/kg, and a maximal sphincter contraction was produced by a dose of 40 mug/kg. Methysergide converted the contractile effect of 5-HT to a dose-dependent fall in the sphincter pressure; maximal inhibition of 77.2 +/- 7.2% of the resting pressure occurred with a dose of 40 mug/kg. The inhibitory effect of 5-HT was antagonized by tetrodotoxin, 5 MeO-DMT, and 5-HT tachyphylaxis. 5 MeO-DMT enhanced 5-HT-induced contraction of the sphincter. In the presence of 5 MeO-DMT and methysergide, 5-HT still caused a brief contraction of the sphincter; this contraction appeared to be due to stimulation of postganglionic cholinergic neurons as it was antagonized by tetrodotoxin or atropine. Reserpinization caused enhancement of the sphincter contraction by 5-HT. In the reserpinized animals in the presence of methysergide, 5-HT caused a small initial contraction followed by prolonged inhibition; atropine antagonized the initial contraction, while inhibition was antagonized by 5 MeO-DMT. These studies are consistent with the view that 5-HT exerts several different effects on the sphincter. 5-HT causes contraction of the sphincter by its direct action on the muscle and also by stimulation of cholinergic excitatory neurons. In addition, 5-HT inhibits the sphincter by stimulation of nonadrenergic inhibitory neurons.

Intravenous administration of dopamine caused a dose-dependent reduction in the lower esophageal sphincter pressure and contractions in the lowermost part of the body of the esophagus in the opossum. A dose of 5 mug per kg produced maximal response. The onset of contractions in the body occurred around 20 sec after the onset of the sphincter response. The effect of dopamine was different from isoproterenol, which caused no contractions in the body and caused reduction in sphincter pressure, and from phenylephrine, which also caused no contractions in the body but caused contraction of the sphincter. Moreover, the effect of 5 mug per kg of dopamine was blocked by haloperidol but not by phentolamine, propranolol, bilateral cervical vagotomy, or tetrodotoxin. These studies suggested the presence of selective dopamine receptors which mediated contraction of the esophageal body and relaxation of the sphincter muscle. Since vagal stimulation also causes contraction in the body and relaxation of the sphincter, it was possible that vagal effect on the esophagus was mediated by dopamine receptors. However, haloperidol did not block the effect of electrical stimulation of vagus nerve on body of the esophagus or the lower esophageal sphincter.

Serum nickle was estimated by atomic absorption spectrometer in 20 healthy controls and in 25 cases of acute myocardial infarction at 12 hourly intervals upto 48 hours, after the onset of chest pain. The mean serum nickel was 0.27 micrograms/dl in healthy controls and 0.40,050,049 and 0.30 micrograms/dl in patients of acute myocardial infarction. The serum nickel values were significantly (P less than 0.001) raised upto 36 hours in acute myocardial infarction when compared with controls.

Experiments were performed in anesthetized opossums to study the nature of vagal control on the small bowel. Electrical activity was recorded in the duodenum, jejunum, and ileum with silver chloride electrodes. Slow waves and spike potentials were observed at all three sites. There was a decreasing frequency gradient of slow waves and the incidence of slow waves with spikes in the aboral direction. Vagotomy had no effect on the electrical activity. Vagal stimulation at threshold stimuli inhibited spike potentials in all three segments of small intestine, but slow waves were not affected. Vagal stimulation after sectioning of the gut proximal to the electrodes converted the response from inhibition to excitation. These studies suggest that a) vagus carries both excitatory and inhibitory influences to the small bowel; b) inhibitory influences are dominant in the intact opossum small intestine; and c) the nature of the response obtained with vagal stimulation may be explained on the basis of the paths taken by inhibitory and excitatory fibers.

Lower esophageal sphincter pressures were monitored with water-filled catheters in anesthetized opossums. Muscarinic agonists McN-A-343 and bethanechol were administered in the arterial supply of the sphincter. McN-A-343 caused relaxation after a brief contraction of the sphincter. Bethanechol caused a dose-dependent contraction. Tetrodotoxin antagonized the inhibitory effect of McN-A-343 but did not antagonized sphincter contraction caused by McN-A-343 or bethanechol. The mean ED50 values were 6.9 nmol/kg i.a. for McN-A-343-induced relaxation, 10.5 nmol/kg i.a. for McN-A-343-induced contraction and 0.4 nmol/kg i.a. for bethanechol-induced contraction. Atropine caused a dose-dependent rightward shift in the dose-response curves of inhibitory and excitatory effects of the two muscarinic agonists. Pirenzepine caused a dose-dependent rightward shift in the dose-response curves of McN-A-343-induced relaxation. Pirenzepine did not modify sphincter contraction caused by the muscarinic agonists. 4-Diphenylacetoxy-N-methylpiperidine methiodide, on the other hand, did not modify McN-A-343-induced sphincter relaxation but caused dose-dependent rightward shifts in the dose-response curves of sphincter contraction caused by McN-A-343 or bethanechol. These studies suggest that there are two distinct types of muscarine receptors in the opossum lower esophageal sphincter. The M1 muscarine receptors are present on the inhibitory neurons and participate in the synaptic transmission between vagal preganglionic and intramural postganglionic inhibitory neurons. They are activated by McN-A-343 and antagonized by pirenzepine. The M2 muscarine receptors are located directly on the sphincter muscle. They are also activated by McN-A-343, but are selectively activated by bethanechol and are antagonized by 4-diphenylacetoxy-N-methylpiperidine methiodide.

Studies were performed in anesthetized opossums. The electrical changes, recorded using a suction electrode applied to the outside of the esophagus, and mechanical activity, recorded by an intraluminal catheter, were monitored from 5 cm above the lower esophageal sphincter. Swallowing was associated with membrane hyperpolarization followed by depolarization and spike burst. Electrical stimulation of the decentralized vagus also caused a prompt hyperpolarization followed by an overshoot depolarization. Single pulses of stimulation caused primarily hyperpolarization. The amplitude and duration of hyperpolarization increased with increasing frequencies of vagal stimulation. Spike burst occurred as the membrane potential was recovering from the peak hyperpolarization and moving toward peak depolarization. The latency of onset of spike burst decreased with increasing frequency of vagal stimulation. The muscle contraction occurred after a latency. The latency of contractions, like the latency of spike burst, decreased with increased frequency of vagal stimulation. These studies show that (a) membrane hyperpolarization is present during the latent period of contraction associated with swallowing, suggesting that swallow-induced esophageal response may be mediated by vagal inhibitory pathway to the esophagus and (b) spike bursts can be temporally dissociated from depolarization by changing the vagal stimulation frequency, suggesting that spike burst and depolarization may be mediated by different excitatory mechanisms.

The effects of hydralazine on blood lipids, systolic pressure and cardiac performance were assessed in male Wistar rats, 6 weeks after they were made diabetic with streptozotocin (STZ). STZ-induced diabetes results in a loss of body weight, hyperglycemia and hypoinsulinemia. These effects are not altered after hydralazine treatment. STZ-diabetes also produced a significant bradycardia, elevation of blood pressure, hyperlipidemia and decreases in the levels of triiodothyronine and thyroxine. Hydralazine treatment successfully prevented all these alterations. In addition, cardiac performance was depressed in the untreated diabetic animals, but the cardiac performance of the hydralazine-treated diabetic animals showed a definite improvement. Thus, hydralazine controlled the high serum lipids and blood pressure and improved cardiac performance in STZ diabetic rats.

The investigation was undertaken to study the mechanism of the inhibitory effects of clonidine on the oestrogen-primed rat isolated uterus. Clonidine produced dose-dependent relaxations of the rat isolated uterus which were competitively blocked by yohimbine but not by prazosin. Metiamide, a specific H2-histamine receptor antagonist, inhibited clonidine-induced responses only at a high concentration (1.0 X 10(-6)M). Propranolol, a beta-adrenoreceptor antagonist produced competitive antagonism of the clonidine responses. Like clonidine, noradrenaline also produced dose dependent relaxations of the rat isolated uterus. The responses to noradrenaline were not antagonized by either prazosin or yohimbine but were competitively antagonized by propranolol. The responses to clonidine were significantly inhibited by reserpine pretreatment (5 mg/kg; i.p., 24 h before) whilst responses to noradrenaline were significantly increased by this treatment. It is concluded that clonidine inhibits the uterus via an action on alpha 2-adrenoreceptors and possibly also to a lesser extent on H2-histamine receptors, leading ultimately to release of noradrenaline from endogenous stores which causes relaxation by acting on beta-adrenoreceptors.

Experiments were performed in anesthetized opossums. Electrical and mechanical activity was recorded simultaneously from the esophageal body at 5, 3, and 1 cm above the lower esophageal sphincter (LES). Esophageal responses were evoked by electrical stimulation of vagal efferents or by induced swallowing. Electrical and mechanical activity was associated in 86% and dissociated in 14% of the 1,200 responses examined. The frequency of dissociation was dependent on the site in the esophagus and the frequency of vagal efferent stimulation (P less than 0.05). The interval between the onset of electrical and mechanical events, called electromechanical delay, had a regional gradient: 5 cm above LES greater than 3 cm greater than 1 cm (P less than 0.01). This delay was also dependent on the frequency of stimulation. The amplitude of spike burst and the number of spikes in a burst closely correlated with the amplitude of contraction. These studies show that electromechanical responses and dissociations are dependent on the regional level in the esophagus and the frequency of vagal stimulation.

Isolated lower esophageal sphincter (LES) relaxation, defined as a transient sphincteric relaxation unaccompanied by esophageal peristalsis, has been shown to precede most episodes of gastroesophageal reflux in humans. We studied the genesis of isolated LES relaxation in anesthetized opossums by observing the response of four components of the deglutition reflex (mylohyoid electrical activity, pharyngeal contraction, esophageal peristalsis, and LES relaxation) to pharyngeal tactile stimulation, electrical stimulation of superior laryngeal nerve (SLN) afferents or cervical vagal efferents, and to balloon distention of the esophageal body. A single pharyngeal stroking evoked isolated LES relaxation in 56% of 160 instances. The proportion of isolated relaxations in response to SLN electrical stimulation varied inversely with the stimulus frequency, occurring in 64% of the responses at 5 Hz and 4% of the responses at 30 Hz. A full four-component deglutition sequence was most likely to occur at the higher frequencies of SLN electrical stimulation. Esophageal balloon distention elicited isolated LES relaxations or no response at low distending volumes, whereas at higher volumes LES relaxation and esophageal contraction predominated. Isolated LES relaxation had significantly less magnitude than relaxations accompanied by esophageal contractions. Bilateral cervical vagotomy abolished all LES and esophageal body responses induced by pharyngeal stroking and SLN stimulation, and rendered the esophageal body and LES less responsive to small volumes of distention. Vagal efferent stimulation produced isolated LES relaxation at lower frequency stimulation and LES relaxation with esophageal contractions at higher frequency stimulation. These studies show that isolated LES relaxation represents incomplete expression of either the deglutitive reflex or the peripheral reflex mediating secondary peristalsis.

The absolute counts on basophil and eosinophil leucocytes, percentage of vacuolated eosinophil cells and whole blood histamine were determined in 30 controls and 34 patients with bronchial asthma. The basophil counts rose from the quiescent to pre-attack stage and then fell in the acute stage of bronchial asthma. The eosinophil counts, the percentage of vacuolated eosinophils and the blood histamine content increased significantly during an asthmatic attack. An attack of bronchial asthma was precipitated if the blood histamine rose to or above 200 ng/ml or a 50% rise occurred from its quiescent level. The inter-relationship between cytomorphological variations and blood histamine content in various stages of bronchial asthma is discussed.

Intravenous administration of nicotine sulfate caused a dose-dependent reduction in the lower exophagel sphincter pressure in anesthetized opossums. The maximal reduction in pressure of 85.0 +/- 2.6% was observed with a dose of 50 mug per kg. The effect of 50 mug per kg was not antagonized by bilateral cervical vagotomy, atropine, propranolol or by catecholamine depletion with reserpine. The sphincter relaxation produced by 50 mug per kg of nicotine was antagonized during tachyphylaxis produced by a larger dose (4 mg per kg) of nicotine. Nicotine tachyphylaxis also blocked the vagal-stimulated relaxation of the sphincter. It is suggested that the main action of nicotine on the sphincter in intact animals is caused by its effect on the noncholinergic, nonadrenergic inhibitory neurons which lie in the vagal pathway to the lower esophageal sphincter.

The present study was undertaken to investigate the autoinhibition and desensitization of 5-hydroxytryptamine (5-HT) using another agonist MK-212 on guinea pig ileum. 5-HT and MK-212 produced dose dependent contractions of guinea pig ileum. The responses to MK-212 were reduced in the presence of 5-HT and vice versa. Neither 5-HT nor MK-212 produced any change in the responses to histamine, acetylcholine or KCl. Increase in Ca++ in bathing fluid reversed the desensitization produced by MK-212 or 5-HT. Our data suggest that 5-HT and MK-212 produce desensitization which is specific for serotonergic receptors and possibly involves Ca++ ions.

Studies were performed on anesthetized opossums. Lower esophageal sphincter pressures were measured with waterfilled and continously perfused catheters anchored in the sphincter. Administration of adenosine 5'-triphosphate (ATP) and ADP in the left gastric artery usually produced an initial contraction followed by a more prolonged inhibition. Adenosine, on the other hand, produced only inhibition. The effect of ATP was not modified by phentolamine (1 mg/kg), propranolol (1 mg/kg) or atropine (30 micrograms/kg). Tetrodotoxin partially antagonized (P less than 0.05) the inhibitory effects of ATP and adenosine, but augmented the excitatory effect of ATP (P less than 0.05). 2-2'-Pyridylisatogen tosylate selectively antagonized the effects of ATP without modifying the effect of adenosine. This antagonist, however, did not modify the resting sphincter pressure or the vagal stimulated sphincter relaxation. Dipyridamole enhanced the inhibitory effect of adenosine, but did not augment vagal stimulates sphincter relaxation. There was no cross-tachyphylaxis between ATP and adenosine. Tachyphylaxis, either to ATP or adenosine, did not inhibit the vagal stimulated sphincter relaxation. These studies show that: (a) ATP and adenosine may act on different receptor sites to modify sphincter pressure; (b) only a small part of the inhibitory effect of ATP and adenosine is mediated by the inhibitory neurons; (c) neither ATP nor adenosine appears to be the inhibitory transmitter released by the noncholinergic, nonadrenergic inhibitory neurons in the vagal pathway to the lower esophageal sphincter.

Ranitidine in lower doses, (100 ng and 1 microgram) accelerated the rate of reaction of the enzyme acetylcholinesterase with the substrate acetylthiocholine. However, in higher doses (10 micrograms and 100 micrograms) it inhibited the enzyme activity. In rat anococcygeus muscle preparation, the responses to acetylcholine were significantly inhibited in lower doses whereas in higher doses there was a dose-dependent potentiation of the responses to acetylcholine by ranitidine. The responses to carbachol were however, not affected by ranitidine in the same preparation. Our data suggest cholinomimetic as well as cholinolytic activity of ranitidine.

Currently it is believed that lower esophageal sphincter closure is maintained by tonic neurohormonal activity. Studies were performed to evaluate the role of neural and myogenic activity in the genesis of resting sphincter pressure in the opossum. The neural activity in the sphincter was blocked by intravenous administration of the puffer fish poison, tetrodotoxin, in intact animals. The respiration in these animals was assisted with a respirator, their blood pressure was supported by intravenous administration of Ringer's solution, and their body temperature was maintained by heating lamp. The lower esophageal sphincter pressures were measured with water-filled and continuously perfused catheters which were anchored to the lower esophageal sphincter using a new technique. Tetrodotoxin blocked the sphincter response to neural stimulation with vagal stimulation, esophageal distention, and local electrical stimulation of the sphincter. The mean resting sphincter pressure before tetrodotoxin was 59.0 +/- 2.6 mm Hg, and it was 64.4 +/- 6.9 mm Hg after tetrodotoxin (P greater than 0.05). During neural block with tetrodotoxin, the sphincter response to administration of isoproterenol or bethanechol was similar to that during the control period (P greater than 0.05). These studies show that: (1) Tetrodotoxin can be administered in intact animals to achieve complete block of neural activity in the lower esophageal sphincter; (2) sphincter muscle is not adversely affected by tetrodotoxin; and (3) block of neural activity does not alter the resting lower esophageal sphincter pressure.