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Pretreatment of rats for 6 days with the ganglion blocking agent, chlorisondamine, produces a 2-3 fold increase in the sensitivity of the heart to the negative chronotropic action of carbachol and methacholine.
The effects of N,N-dimethyl-N'-phenyl-piperazinium (DMPP), 4-(m-chlorophenyl-carbamoyloxy) - 2 - butynyltrimethylammonium chloride (McN-A-343), pilocarpine, acetylcholine, methacholi-ne and nicotine in inhibiting the uptake of (3)H-(+/-)-noradrenaline by guinea-pig atria were compared. In concentrations of 1 x 10(-4)M, the percentage inhibitions were as follows: DMPP, 89.1%; McN-A-343, 78.7%; pilocarpine 43.5%; acetylcholine, 35.7%; methacholine, 32.9%; nicotine, 21.6%.
1. The pressure in the ducts of the two submaxillary glands was recorded in anaesthetized dogs in which either the superior cervical ganglion had been removed or the chorda-lingual nerve had been cut on one side, 17-30 days earlier. Noradrenaline, adrenaline, phenylephrine, acetylcholine and methacholine were injected to produce pressure rises attributed to contraction of myoepithelial cells.2. After sympathectomy increased pressure responses were obtained with all the drugs, but particularly with noradrenaline. Cocaine increased the effect of noradrenaline on the normal gland but slightly less than sympathectomy.3. Parasympathetic decentralization increased the pressure effects of acetylcholine and methacholine, and in most cases also increased those of the sympathomimetic drugs.4. It is concluded that the myoepithelial cells of this gland normally receive motor impulses from both divisions of the autonomic nervous system, and that many, if not all, of the cells are innervated by both. Disconnecting the gland from the central nervous system by either pathway causes supersensitivity of the classical post-junctional type, and sympathetic ganglionectomy causes in addition a pre-junctional sensitization.
1. The cardiovascular and behavioural effects of cholinomimetic drugs injected through a cannula chronically implanted into a lateral cerebral ventricle were examined in unanaesthetized dogs.2. Acetylcholine (ACh) (10-20 mug) produced an increase in arterial pressure and heart rate, the dogs became more alert, moved their heads, licked and swallowed and then became drowsy.3. The responses to ACh were potentiated by intraventricular physostigmine (5 mug), were abolished by intraventricular atropine (100 mug) but were unaffected by intraventricular mecamylamine (250 mug). The responses to ACh were reproducible on any one day if injections were given again after a 30 min interval but tolerance developed when ACh was injected repeatedly over periods of several days.4. Methacholine (40 mug) produced similar behavioural and cardiovascular effects to ACh but of a longer duration. The responses to methacholine were abolished by intraventricular atropine (100 mug).5. Nicotine (20-60 mug) produced a biphasic cardiovascular response of an initial brief pressor response and tachycardia followed by a secondary increase in arterial pressure and heart rate which was greater in magnitude and duration. The secondary cardiovascular effects were associated with restlessness and vomiting.6. The responses to nicotine were abolished by prior injection of mecamylamine (250 mug) but were unaffected by atropine (100 mug). The responses to nicotine were not reproducible if injections were repeated on the same day but could be again produced if a few days were allowed to elapse between injections.7. An increased heart rate occurred during the pressor response to the cholinomimetic drugs but when a comparable pressor response was produced by intravenous infusion of noradrenaline in the same unanaesthetized dogs pronounced reflex bradycardia resulted.8. The results indicate that the activation of both muscarinic and nicotinic cholinergic mechanisms leads to cardiovascular and behavioural effects in the conscious dog although the site of action and peripheral mechanisms have not been determined.
1 The guinea-pig hypogastric ganglion, perfused through its vasculature with physiological saline solutions, will respond repeatedly to nicotinic stimulant drugs injected at 4 min intervals into the perfusion stream. Stimulation is indicated by contraction of the vas deferens. After a varying number of doses of nicotinic stimulants, complete tachyphylaxis usually develops, and normally this persists for at least 1 hour. During this time, however, electrical stimulation of the hypogastric nerve is still fully effective.2 Tachyphylaxis may be reversed for varying periods of time by all of the following procedures: (a) tetanic stimulation of the hypogastric nerve; (b) injection of large doses of histamine, methacholine, or potassium chloride; (c) perfusion with saline containing ouabain 0.1 mug/ml or 80-100 mM lithium chloride, or, to a lesser extent, with potassium-free saline.3 Tachyphylaxis is always re-established with further doses of nicotinic stimulants, except during perfusion with lithium solutions.4 Atropine hastens the onset of tachyphylaxis, but does not prevent its reversal by hypogastric nerve stimulation or by histamine or potassium. However, it does prevent the reversal by methacholine and by lithium.5 Tachyphylaxis occurs in decentralized ganglia, and can be reversed by histamine, methacholine, and by tetanic stimulation of the hypogastric ganglion. Hence tachyphylaxis and its reversal cannot be due to an effect on presynaptic fibres.6 Potassium chloride stimulates the ganglion both before and after tachyphylaxis has developed to nicotinic drugs, and hence this is unlikely to be due to a depolarization block.7 It is concluded that tachyphylaxis could be due to a prolonged ganglionic hyperpolarization.
1 High concentrations of pilocarpine and methacholine consistently lowered the potencies of a series of adrenoceptor agonists as shown by displacement of complete cumulative dose-effect curves for their positive chronotropic action on rat isolated atria. The order of potency of the agonists was characteristic of beta-adrenoceptor activation and this was converted to the type which characterizes alpha-adrenoceptor activation when pilocarpine was present.2 Propranolol effectively blocked the adrenoceptor agonists in the presence of pilocarpine and phentolamine abolished the antagonistic actions of pilocarpine. Atropine, which by itself did not affect the action of the adrenoceptor agonists, abolished both the bradycardia and antagonism produced by pilocarpine.3 It is concluded that pilocarpine antagonizes adrenoceptor agonists by muscarinic cholinoceptor activation without involving classical adrenoceptors.
1 The effects of the prostaglandin synthetase inhibitor, indomethacin and the prostaglandin antagonist SC-19220 (1-acetyl-2-[8-chloro-10,11-dihydrodibenz (b,f) (1,4)oxazepine-10-carbonyl] hydrazine), were examined on the tone of the guinea-pig isolated tracheal preparation and on the responses of the preparation to prostaglandin F(2alpha), arachidonic acid and methacholine.2 Indomethacin (0.05-1.6 mug/ml) produced a long-lasting inhibition of the intrinsic tone of the tracheal preparation and of the contractile responses to arachidonic acid. Much higher concentrations of indomethacin also reduced the responses of the preparation to methacholine. This effect was readily reversible and appeared to be unrelated to the action on tone.3 The contractile responses of the preparation to prostaglandin F(2alpha) were enhanced by low concentrations of indomethacin (1-5 mug/ml) and inhibited by higher concentrations (2.5-80 mug/ml).4 SC-19220 was shown to inhibit responses of the preparation to prostaglandin F(2alpha) in concentrations (0.1-1 mug/ml) which had no effect on responses to methacholine. Similar concentrations also inhibited the intrinsic tone of the preparation and the responses to arachidonic acid.5 The evidence suggests that prostaglandins may be involved in the maintenance of tone of the guinea-pig isolated tracheal preparation.
1 Effects of cholinomimetic agents, given into the IIIrd ventricle of adult fowls (Gallus domesticus) or infused into the hypothalamus of young chicks, were tested on behaviour, respiratory rate and body temperature.2 Carbachol evoked behavioural and electrocortical arousal but lacked postural and respiratory effects. Contrariwise, pilocarpine increased respiratory rate and induced postural changes, i.e. abduction of the wings, but lacked other behavioural effects and did not alter electrocortical activity. Benzoylcholine induced tachypnoea, postural changes and brief electrocortical arousal. Acetylcholine was ineffective unless given with physostigmine, when electrocortical arousal, postural changes and tachypnoea developed. Methacholine induced tachypnoea and postural changes.3 Effects of carbachol and pilocarpine were prevented by hyoscine and those of benzoylcholine by pempidine; hyoscine and pempidine were required together to prevent the effects of methacholine and to attenuate those of acetylcholine with physostigmine.
1. The effect of a specific histamine H2-receptor antagonist, metiamide, on the acid dose-response curves for pentagastrin or methacholine was studied in rats provided with Heidenhain pouches. 2. Metiamide induced a shift to the right of the dose-response curve to pentagastrin and lowered the maximal secretion. 3. In contrast, metiamide only increased the ED50 for methacholine but did not alter the calculated maximal response. 4. The effect of metiamide on pentagastrin and methacholine-induced secretion is in agreement with the previously suggested difference in the part played by mucosal histamine in the mode of action of the two stimulatory agents.
1 The effect of isoprenaline on gastric secretion evoked by various means has been studied in conscious rats provided with Pavlov and Heidenhain pouches. 2 Interdigestive acid secretion in the Pavlov pouch was reduced by isoprenaline, whereas pepsin secretion was unaltered. 3 Central vagal stimulation effected by 2-deoxy-D-glucose injection evoked a gastric secretory response that was substantially reduced by isoprenaline. 4 2-Deoxy-D-glucose increased the mobilization of gastric mucosal histamine, an effect that was prevented by isoprenaline. 5 Isoprenaline infusion alone induced a slight increase in histamine mobilization and also a considerable elevation of immunoreactive serum gastrin concentration. 6 The secretory response to food in the Pavlov pouch was almost abolished by isoprenaline. 7 Although the acid response to histamine in the Heidenhain pouch was susceptible to isoprenaline inhibition, that to methacholine was not. 8 Pepsin secretion in the Heidenhain pouch preparation stimulated by histamine or methacholine seemed to be enhanced by isoprenaline.
1. A preparation of rat trachea and a new preparation of rat bronchi are described. Both preparations are fluid-filled and the intraluminal pressure is monitored. 2. A preparation of rat peripheral airways, the lung strip, is described. The preparation consists of a thin strip of lung parenchyma which is superfused, and contractions monitored isotonically. 3. The rat trachea and bronchi have no intrinsic tone but increases in pressure are elicited in response to methacholine. The preparations relax in response to isoprenaline and aminophylline in the presence of a methacholine-induced contraction. Both preparations respond weakly and show tachyphylaxis to 5-hydroxytryptamine (5HT). 4. The lung strip contracts with equal magnitude to methacholine and 5-HT. It exhibits intrinsic tone which is inhibited by indomethacin and relaxed by isoprenaline.
1 The effects of methacholine, atropine and adrenoceptor blockade on hypothalamic blood flow (HBF) were measured in conscious rabbits. 2 A dose of 1 microgram methacholine increased HBF while smaller and larger doses had no significant effect. 3 The vasodilatation induced by methacholine was blocked by atropine and by chemical sympathectomy of the hypothalamus with 6-hydroxydopamine. 4 The vasodilatation was reversed by propranolol but was not affected by phenoxybenzamine. 5 These results suggest that the vasodilator action of muscarinic receptor agonists on hypothalamic resistance vessels depends upon the integrity of a noradrenergic system, and is mediated via beta-adrenoceptors.
1 The characteristics of the antisecretory actions of prostaglandin E2 (PGE2) and two stable prostacyclin analogues during different rates of acid stimulation have been evaluated in the lumen-perfused isolated whole stomach of the rat and mouse. 2 In the rat isolated stomach, histamine induced a dose-dependent increase in acid output. Preincubation with PGE2 caused a dose-related and surmountable inhibition. 3 The stable prostacyclin analogues, 6 beta-PGI1 and a 16-phenoxy derivative likewise caused a surmountable inhibition of histamine-stimulated acid output from rat stomach. 4 PGE2 had inconsistent actions on the acid secretion stimulated by pentagastrin, methacholine or dibutyryl cyclic adenosine 3',5'-monophosphate. 5 In the mouse isolated stomach, acid secretion was stimulated by low concentrations of histamine, pentagastrin or methacholine. 6 PGE2 failed to inhibit histamine-stimulated acid output from mouse stomach, but high concentrations of the potent 15-phenoxy analogue did show anti-secretory activity. 7 The results indicate the usefulness of the rat isolated stomach for studying the interaction of prostaglandins with the acid secretory process in mammalian gastric mucosa.
1 The effects of long-term treatment with sodium cromoglycate (SCG) and aminophylline on antigen-induced bronchoconstriction have been studied in guinea-pigs actively sensitized according to two different regimens (one producing IgE- and IgG-like antibodies and the other producing exclusively IgG-like antibodies). 2 Treatment for three weeks with SCG (10 mg/kg) and aminophylline (10, 30 or 60 mg/kg) led to a decreased bronchial response capacity which persisted even three days after treatment ceased. In this respect SCG was effective only in guinea-pigs sensitized to produce at least partly IgE-like antibodies; aminophylline was effective in guinea-pigs sensitized to produce both IgE and/or IgG antibodies. 3 The results in vivo with SCG were reflected in vitro by a reduced capacity of chopped lung tissue to release histamine at antigen challenge; lungs from animals treated with aminophylline did not show reduced histamine releasing capacity. 4 Acute treatment with atropine was shown to reduce significantly the antigen-induced bronchial contraction in guinea-pigs sensitized to produce both IgE- and IgG-antibodies. No effect of atropine was seen on an IgG-mediated anaphylaxis. 5 Increased reactivity to methacholine but not to histamine was seen in guinea-pigs sensitized to produce both IgG- and IgE-antibodies. Long-term treatment with SCG did not affect this hyperreactivity to methacholine. 6 Decreased reactivity to isoprenaline was found in isolated tracheae taken from guinea-pigs sensitized to produce both IgE- and IgG-like antibodies compared to unsensitized guinea-pigs. Long-term treatment with SCG, but not with aminophylline, reversed this decreased reactivity.
1 A rat isolated gastric mucosal preparation was used to monitor histamine output and acid secretion during stimulation by different secretagogues. 2 In non-stimulated preparations, spontaneous histamine output decreased over 450 min. 3 Stimulation of secretion with 4 (5)-methylhistamine or dibutyryl cyclic adenosine 3'5'-monophosphate (db cyclic AMP) and theophylline did not influence histamine output. 4 Pentagastrin, gastrin and methacholine increased both acid secretion and histamine output. Pentagastrin and gastrin mobilized six times more histamine and relation to acid secretion than did methacholine. 5 Spontaneous histamine output and secretagogue-induced increases were unaffected by changes in external Ca2+ (0.0 to 7.2 mM) or Mg2+ (1.2 to 4.8 mM). 6 These results support the hypothesis that mucosal histamine plays a more important role in the action of gastrin than of cholinomimetics on the parietal cell.
1 Responses of preparations of human and porcine isolated bronchus and pulmonary artery to carbachol (CCh), methacholine, histamine, 5-hydroxytryptamine (5-HT), (-)-noradrenaline (NA), (-)adrenaline (Adr) and (+/-)-isoprenaline (Iso) were compared with responses to the same agonists in isolated lung parenchyma strips. 2 All preparations from both human and porcine lung contracted in response to histamine and all, except preparations of porcine pulmonary artery, contracted in response to CCh. Human and porcine pulmonary artery and parenchyma strip contracted in response to NA while bronchial preparations invariably relaxed. Iso caused relaxation of human and porcine bronchus and parenchyma strip. Although 5-HT was completely inactive in tissues isolated from pig lung, this amine was a powerful spasmogen in human pulmonary artery, relaxed human bronchus and caused variable responses in human parenchyma. 3 Results indicate that the pharmacological characteristics of human and porcine parenchyma strips may be explained in terms of responses of vascular or airways smooth muscle.
Untreated rats, and rats treated with methimazole (0.05% w/v in drinking water) or thyroxine (1 mg/kg, s.c., three times weekly) for 4-6 weeks to induce hypo- and hyperthyroidism respectively, were used to study the influence of thyroid hormone upon negative chronotropic and inotropic responses mediated by cardiac muscarinic receptors, and upon the affinity of these receptors for atropine. Negative chronotropic effects of methacholine were investigated by establishing partial concentration-response curves for isolated preparations of right atria. Methacholine was least potent in tissues from thyroxine-treated rats. Isolated left atria paced at 3 Hz, and spontaneously beating right atria, were used in studies of the negative inotropic effects of methacholine. This agonist was least potent in atria from the thyroxine-treated rats in which it also produced the smallest maximal responses. The negative inotropic effects of carbachol were examined on left atria paced at 3, 5 and 5.8 Hz to approximate the basal contraction rates of isolated right atria from methimazole-treated, untreated control and thyroxine-treated rats, respectively. At each of these frequencies, carbachol was most potent in atria from methimazole-treated rats, and least potent in atria from thyroxine-treated rats. Maximal responses were smallest in the latter group. pA2 values for atropine with methacholine as the agonist were obtained by the method of Arunlakshana & Schild (1959) for spontaneously beating right atria (negative chronotropic and inotropic effects) and left atria paced at 3 Hz (negative inotropic effects). Slopes of Schild plots did not differ from minus one in tissues from each of the experimental groups; pA2 values were similar, indicating that thyroid status is without effect upon the affinity of this antagonist for muscarinic receptors mediating both negative inotropic and chronotropic effects. 6 The results are discussed in the light of reports that hypothyroidism increases, and hyperthyroidism decreases the numbers of high affinity muscarinic receptor binding sites in the rat myocardium.
Effects of SCH 32651, a novel antisecretory and cytoprotective agent, on resting and stimulated acid secretion by the guinea-pig isolated fundic mucosa were studied. SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1-10 microM), the IC50 being 4.4 microM. Cimetidine and atropine at concentrations up to 100 microM were inactive. Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 microM), methacholine (1 microM) or dibutyryl cyclic AMP (0.5 mM) plus theophylline (1 mM) in a concentration-dependent manner. The IC50S against histamine, methacholine and db cyclic AMP plus theophylline were 4.2 microM, 0.71 microM and 2.9 microM, respectively. In contrast, atropine and cimetidine each at 100 microM, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline. The inhibitory effects of SCH 32651 on resting and histamine-stimulated acid secretion were readily reversible upon washing. SCH 32651 0.1 mM in the mucosal solution also greatly suppressed the resting and stimulated acid secretion. In the presence of histamine treatment, SCH 32651 concomitantly caused a marked rise in K+ entry into the mucosal solution in parallel to a decline in the appearance of H+ in the same solution. The various events demonstrated by SCH 32651 in the present study are shared by omeprazole, a potent antisecretory agent working through inhibition of gastric H+/K+-ATPase. We conclude that SCH 32651 as a potent antisecretory agent seems to act directly on the parietal cell, near or at the site of H+/K+-ATPase which is a final step in the acid secretory process triggered by various stimuli.