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Biomedical subjects

M A Zar

Publications and source records attributed to M A Zar.

52 records · Page 3Linked to original sources
PubMed1972

Inhibition of post-ganglionic motor transmission in vas deferens by indirectly acting sympathomimetic drugs.

1. Using field stimulation with short trains of pulses (< 10 per train), the post-ganglionic motor transmission in the mammalian vas deferens has been further analysed pharmacologically.2. In preparations taken from guinea-pigs, rats and rabbits the effects of the indirectly sympathomimetic drugs, tyramine and cocaine, could be explained entirely on the basis of the actions of released, endogenous noradrenaline.3. Tyramine produced a contraction in vasa taken from normal rats but not from normal guinea-pigs. The tyramine contraction was due to release of endogenous noradrenaline because it was not seen in preparations taken from reserpinized rats and because it was abolished in normal vasa by phenoxybenzamine or phentolamine, thus denying the supposed inaccessibility, to alpha-blockers, of the motor alpha-adrenoceptors activated by endogenous noradrenaline.4. Phenoxybenzamine or phentolamine failed to block post-ganglionic motor transmission in rat and in guinea-pig vasa.5. Tyramine strongly inhibited motor transmission in vasa taken from normal but not from reserpinized guinea-pigs.6. Tyramine produced inhibition of motor transmission in phenoxybenzamine-treated preparations taken from normal but not from reserpinized rats.7. Cocaine inhibited motor transmission in guinea-pig and in rat vasa. This effect was not due to a local anaesthetic or to a smooth-muscle depressant action because it did not occur in preparations taken from reserpinized animals.8. The inhibitory effect of tyramine or cocaine was not abolished by beta-adrenoceptor blockade with propranolol.9. Whereas reserpinization abolished the tyramine- and cocaine-inhibitions, it did not affect the inhibitory actions of noradrenaline or of PGE(2).10. Indomethacin and sodium meclofenamate, which suppress prostaglandin synthesis, did not affect the twitch-inhibiting actions of noradrenaline, tyramine or cocaine.11. These results provide further support for the conclusion that post-ganglionic motor transmission to the vas deferens is non-adrenergic in these species and assign to endogenously released noradrenaline an inhibitory role upon motor transmission.

Animals↗
PubMed1971

The mechanism of acetylcholine release from parasympathetic nerves.

1. The output of acetylcholine from the plexus of the guinea-pig ileum longitudinal strip has been used to study the mechanism of acetylcholine release. From the effects of hexamethonium and tetrodotoxin, it was inferred that 60% of the normal resting output is due to propagated activity in the plexus, and 40% to spontaneous release. Tetrodotoxin virtually abolishes the increase in output in response to electrical stimulation.2. Resting acetylcholine output is increased when the bathing medium is changed in the following ways:(a) sodium replacement by sucrose, trometamol or lithium;(b) addition of ouabain or p-hydroxymercuribenzoate (PHMB), or withdrawal of potassium;(c) the combination of PHMB and partial sodium replacement;(d) addition of potassium; this increase in output becomes greater in the absence of sodium.3. The resting output is virtually abolished by calcium withdrawal, and is restored by barium substitution for calcium. It is also reduced by raising the magnesium concentration.4. The enhanced resting output in response to sodium withdrawal also occurs in the absence of calcium.5. Cooling to 5 degrees C greatly reduces both the resting output and the output in response to raised potassium concentration or to electrical stimulation.6. The increase in resting output due to potassium excess is slight up to 25 mM [K(+)](o), but increases thereafter with about the fourth power of the potassium concentration; it is resistant to tetrodotoxin.7. Synthesis of acetylcholine by the longitudinal strip is increased when output is enhanced by electrical stimulation, by potassium excess or by addition of barium, so that the acetylcholine content of the strip is maintained approximately normal. Synthesis is reduced, in relation to output, by potassium lack or by treatment with ouabain, and is virtually abolished by sodium withdrawal.8. The theory is discussed that acetylcholine release depends on inhibition of the activity of a (Na(+) + K(+) + Mg(2+))-activated ATPase at the axonal membrane.

Acetylcholine↗
PubMed1971

Evidence against adrenergic motor transmission in the guinea-pig vas deferens.

1. Field stimulation of desheathed preparations of guinea-pig vas deferens, treated with a ganglion-blocking agent, has revealed the presence of two tetrodotoxin-susceptible components in the motor response, suggesting the existence of two sets of post-ganglionic motor nerve fibres of different excitability: one set responding maximally to pulses of 0.1-0.4 msec; the other, to pulses of 2 msec. No distinction could be made pharmacologically between the two components.2. Cooling potentiated that component in the twitch-responses which was due to stimulation of the more excitable fibres.3. The sensitivity of the longitudinal muscle to the motor action of noradrenaline was low and was subject to considerable animal variation. But normal responses to post-ganglionic field stimulation were elicited in noradrenaline-insensitive preparations, in which the twitches elicited by 5 pulses could not be matched with noradrenaline, even 100-125 mug/ml.4. In some forty experiments, small doses of noradrenaline inhibited the twitch-responses evoked by either set of motor fibres. This inhibition differed from that produced by isoprenaline in two respects. Firstly, propranolol did not antagonize the noradrenaline inhibition, thus excluding an action on beta-adrenoceptors; and secondly, noradrenaline did not depress contractions elicited by muscarine or by 5-methylfurmethide.5. Phenoxybenzamine, 10(-6) g/ml., produced a thousandfold reduction in the sensitivity of the muscle to the motor action of noradrenaline, without any decrease in the height of the twitches elicited by 0.1 or 1 msec pulses.6. The twitch-responses were not affected by combined alpha + beta adrenoceptor blockade with phentolamine and propranolol.7. Tyramine, amphetamine, tranylcypromine and prostaglandin E(2) inhibited the twitches but potentiated the contractile effect of noradrenaline.8. The twitch-responses and their inhibition by noradrenaline were present in preparations taken from reserpinized animals.9. Although the twitch-responses could be paralysed by bretylium or guanethidine, the foregoing results excluded adrenergic transmission at the motor endings. Cholinergic transmission was also excluded by negative findings with anticholinesterases, atropine, nicotine and (+)-tubocurarine.10. Motor transmission by histamine, 5-hydroxytryptamine, gamma-aminobutyric acid or ATP was also excluded.

Amphetamine↗
PubMed1970

An inhibitory action of histamine on the guinea-pig ileum.

1. In atropinized, plexus-containing preparations of the longitudinal muscle from the guinea-pig ileum, in which histamine contractions were abolished by mepyramine or diphenhydramine, an inhibitory action of histamine was revealed on the "tetanic spasms" produced by field stimulation.2. The inhibitory action of histamine on the atropine-resistant tetanic spasms, which are due to the excitation of non-cholinergic neurones in Auerbach's plexus (Ambache & Freeman, 1968a, b), was reversible. It is specific for the tetanic spasms, because histamine did not reduce contractions elicited by bradykinin, 5-hydroxytryptamine, prostaglandin E(2), nicotine or dimethylphenylpiperazinium.3. L-Histidinol and 2-mercaptohistamine exerted a considerably weaker inhibitory effect upon the tetanic spasms than histamine. Four other imidazoles tested, L-histidine, murexine, dihydromurexine and imidazolecarboxylcholine, were ineffective; so was the pyrazole ring isomer of histamine, betazole.4. The inhibitory action of histamine persisted after adrenoceptor blockade by phentolamine and pronethalol and after prior reserpinization of the guineapigs.5. The inhibitory action of histamine was also obtained after ganglionic paralysis by hexamethonium or dimethylphenylpiperazinium but was antagonized specifically by nicotine.6. On atropinized preparations of the longitudinal muscle from the guinea-pig descending colon histamine exerted, at most, an insignificant inhibitory effect on the tetanic spasms.

Animals↗
PubMed1970

Evidence for the release of two atropine-resistant spasmogens from Auerbach's plexus.

1. Two atropine-resistant response-components of nervous origin have been detected in plexus-containing preparations of the longitudinal muscle from the guinea-pig ileum, by alternate field stimulation with equal numbers of pulses at 50 Hz (response A) and at 5 Hz (response B). With trains of ten or more pulses, response A is always larger than B; the ratio of A/B (1.2-21.3) is subject to animal variation.2. Both responses are abolished by tetrodotoxin and are absent from plexus-free preparations.3. Neither response is reduced by ganglion-block with (+)-tubocurarine, dimethyltubocurarine or hexamethonium, or by ganglion-paralysing doses of nicotine; the contribution of excited preganglionic endings to these responses is therefore negligible.4. Neither response is due to a release of histamine, 5-hydroxytryptamine (5-HT) or prostaglandins, since both A and B persist in the presence of mepyramine, methysergide and the prostaglandin-antagonist SC-19220 (1-acetyl-2(8-chloro-10,11-dihydrodibenz [b,f] [1,4]oxazepine-10-carbonyl) hydrazine).5. The two response-components are affected differentially by a number of drugs.6. Histamine, 0.1 mug/ml., reduces response A to the level of B; this selective inhibition of the histamine-sensitive component in A is specifically antagonized by nicotine, 1-2.5 x 10(-5) g/ml.7. 5-HT, 0.1 mug/ml., and strychnine, 20-40 mug/ml., also reduce response A to the level of B, but these selective inhibitions are not antagonized by nicotine.8. Diphenhydramine, 10 mug/ml., produces equality of the two responses by depressing A and potentiating B.9. The inhibitory effects of the foregoing drugs are not due to catecholamine release, since they persist after alpha + beta adrenoceptor blockade with phentolamine and pronethalol, and after previous reserpinization of the guinea-pigs.10. In atropinized plexus-containing preparations of the longitudinal muscle from the guinea-pig descending colon, the responses elicited at 50 Hz and at 5 Hz are virtually equal and both appear to be of Type B since they are not inhibited by histamine, 5-HT or strychnine; diphenhydramine produces strong contractions.

Alkaloids↗
PubMed1970

Non-cholinergic transmission by post-ganglionic motor neurones in the mammalian bladder.

1. In mucosa-free preparations of the detrusor muscle electrical stimulation with 0.1 msec pulses has been utilized to reveal the non-cholinergic nature of most, if not all, of the post-ganglionic motor neurones in the guinea-pig bladder.2. The twitches elicited by 0.1 msec pulses were abolished by tetrodotoxin, but were not reduced by dimethyltubocurarine or by hexamethonium. Hexamethonium was nevertheless present in all the experiments in order to restrict acetylcholine action to ;muscarinic' receptors in the muscle fibres.3. There was little or no diminution in the twitches after prolonged exposure to atropine, 10(-8)-10(-5) g/ml., although the twitch-matching dose of acetylcholine was raised 1000-2500 times. Hence, there was no anomalous refractoriness to atropine in these ;muscarinic' receptors.4. Despite massive atropinization, the recruitment of unoccupied transmitter-receptors by means of extra pulses remained unaffected.5. Eserine failed to potentiate the atropine-resistant twitches.6. The twitches were not depressed by morphine.7. Noradrenaline produced relaxation and twitch reduction. The twitches persisted after alpha + beta adrenoceptor blockade with phentolamine + pronethalol and were unaffected by the monoamine oxidase and catecholamine-O-methyl transferase inhibitors, tranylcypromine and pyrogallol.8. Rapid contractions were elicited by 5-HT and by histamine but the twitches remained unaltered after antagonism of 5-HT by methysergide and of histamine by mepyramine.9. The twitches could be mimicked by injections of ATP, but after desensitization of the preparation to ATP the response to electrical stimulation remained unaltered.10. Prostaglandins E(2) and F(2alpha), only in large doses, produced delayed, sluggish contractions which persisted after the wash; these contractions were quite different from the responses to electrical stimulation, which were immediate, sharp and brief.11. The non-cholinergic nature of the post-ganglionic motor neurones was confirmed in the bladder of two other species, the cat and the rabbit.

Acetylcholine↗
PubMed1968

The origin of acetylcholine released from guinea-pig intestine and longitudinal muscle strips.

1. Strips of longitudinal muscle can be obtained from guinea-pig ileum either retaining or free from Auerbach's plexus.2. The denervated strip is unresponsive to electrical stimulation by brief shocks, whether given singly or in trains; it also fails to respond to nicotine or dimethylphenylpiperazinium iodide (DMPP), and eserine causes no spasm.3. Denervated strips neither contain detectable acetylcholine (< 0.4 ng/mg), nor release it spontaneously (< 5 pg/mg/min) or in response to stimulation (< 31 pg/mg/min). The acetylcholine metabolism of the innervated strip is therefore that of the adherent Auerbach's plexus. Innervated strips had a mean acetylcholine content of 28 ng/mg, a mean resting output of 94 pg/mg/min and an output in response to stimulation at 10 c/s of 700-1200 pg/mg/min.4. By comparing the responses of innervated and denervated strips it was concluded that arecoline, methylfurmethide, alpha,beta-ethylal-gamma-tri-methylammonium propanediol iodide (2268 F), muscarine, histamine, tremorine, oxytocin, and substance P, like acetylcholine, act primarily on the smooth muscle directly; and that angiotensin, barium, potassium, m-bromophenyl choline ether and 5-hydroxytryptamine have a progressively increasing proportionate effect on the nerve plexus. Nicotine and DMPP were inactive in the absence of the plexus.5. The longitudinal muscle with its accompanying plexus contains about one quarter of the acetylcholine of the whole ileum, and is responsible for about one fifth of the output to electrical stimulation.6. The volley output of acetylcholine by the innervated strip declines sharply as rate of stimulation increases. Output of acetylcholine was reduced by morphine and by cocaine, particularly when resting or when stimulated at low rates.7. Acetylcholine output by whole ileum from guinea-pig declines in the absence of glucose, but is insulin-independent. Output by strips of ileum from rats made diabetic with alloxan was similar to that from normal rats.8. The similarity in properties of acetylcholine output from innervated strips, where it must come from nervous tissue, to that from whole ileum, and the insulin-independence of output from whole ileum suggest that the whole of the acetylcholine output of intestine is nervous in origin.9. Comparison of the acetylcholine metabolism of the innervated strip with that of the superior cervical ganglion suggests that the typical features of the former (high resting output, high volley output at low rates, low minute output at high rates of stimulation, and sensitivity to morphine) may be linked with the absence of specialized neuro-effector junctions and represent a relatively primitive transmission process.

Acetylcholine↗