Resting and stimulation-induced efflux of tritium from guinea-pig atria incubated with 3-H-noradrenaline.
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Animals↗
Biomedical subjects
M J Rand
Publications and source records attributed to M J Rand.
Comparison of the bromureide sedative-hypnotic drugs, bromvaletone (bromisoval) and carbromal, and their chloro analogues in mice.
1. The central depressant effects of bromvaletone, carbromal and six non-bromo analogues were compared in mice. 2. The chloro analogues of bromvaletone and carbromal were slightly less potent as central depressant agents than the bromo compounds. 3. The chloro analogue of bromvaletone had the greatest margin between central depressant and lethal doses. 4. Lipophilicity (octanol-water partition coefficient) did not provide a unifying relationship for potency within this group of eight acylureas. However, within each of the two subsets of compounds, a linear relationship was found between relative potency and lipophilicity.
Animals↗
A study in mice of bromo and chloro acylurea analogues of the sedative-hypnotic bromureides.
1. A series of 1-(2-chloroacyl)ureas, related to the sedative-hypnotic drugs bromvaletone and carbromal, was synthesized and tested in mice to determine central depressant and acute toxic effects. Four 1-(2-bromoacyl)ureas and two 3-halo compounds were included for comparison. 2. Large variations in potency were seen between the compounds. Much of this can be ascribed to differences in lipophilicity. Among homologous 1-(2-chloroacyl)ureas, those with 6 acyl carbons had maximal potency. Among groups of structural isomers, the most potent were 2-halo, 3-alkyl substituted compounds. 3. The most potent compounds were also those with the largest ratios of hypnotic to lethal activity. 4. The variation in the onset and duration of action of these compounds enables a choice to be made for a compound with a particular set of characteristics.
Animals↗
Inhibition by hydralazine of the conversion of dopamine to noradrenaline in rat atria in vitro and in vivo.
1. Hydralazine (10 to 2000 microgramol/l) produced a concentration-dependent inhibition of the conversion of (3H)-dopamine to (3H)-noradrenaline in rat isolated atria. 2. In rats treated with hydralazine (2 mg/kg, i.p.), there was an inhibition of the conversion of (3H)-dopamine to (3)-noradrenaline in the intact artia in vivo. 3. Hydralazine treatment may result in the appearance of dopamine as a significant co-transmitter in noradrenergic nerves, and this may contribute to the antihypertensive effect of hydralazine.
Animals↗
Facilitation of sympathetic transmission by prejunctional beta-adrenoceptors in cardiac and vascular tissues.
1. In rat isolated tail arteries and atria in which transmitter stores are labelled with (3H)-noradrenaline, isoprenaline in low concentrations facilitates the stimulation-induced efflux of tritium. 2. This effect is dependent on the frequency and duration of electrical stimulation, being observed only at low frequency (2 Hz) and short duration (10 s in atria and 30 s in arteries) or at high frequency (5 Hz) and long duration (1 min in atria and 4 min in arteries). 3. In atria, phenotlamine enchances tritium efflux with stimulation at 5 Hz for 1 min but not at 2 Hz for 10 s. Conversely, propranolol reduces tritium efflux with stimulation at 2 Hz for 10 s but not at 4 Hz for 1 min. 4. The results can be interpreted in terms of the selective operation, depending on the frequency and duration of electrical stimulation, of inhibitory and facilitatory feedback loops for transmitter release involving prejunctional alpha -and beta-adrenoceptors, respectively.
Adrenergic beta-Antagonists↗
Hypertension through adrenaline activation of prejunctional beta-adrenoceptors.
1. Adrenaline can enhance the stimulation-induced release of transmitter noradrenaline in sympathetically innervated tissues by activating prejunctional beta-adrenoceptors. 2. Adrenaline incorporated into sympathetic transmitter stores by neuronal uptake can be subsequently released as a co-transmitter and can then activate prejunctional beta-adrenoceptors, thus completing a facilitatory feedback loop. 3. Rats chronically treated with adrenaline develop elevated blood pressures compared to control rats. beta-Adrenoceptor blockade prevents the rise in blood pressure. 4. Activation by adrenaline of facilitatory prejunctional beta-adrenoceptors of sympathetic nerves innervating cardiovascular effector tissues may explain adrenaline-induced rises in blood pressure.
Adrenal Medulla↗
Dual effects of clonidine on rat prejunctional alpha-adrenoceptors.
1. The effects of clonidine (1.0 mumol/l) and phentolamine (3.0 mumol/l) on the stimulation-induced efflux of radioactivity were assessed in rat isolated atria and tail arteries in which transmitter stores had been labelled with (3H)-noradrenaline. 2. In atria, clonidine did not affect transmitter release when stimulation was for 10 s periods at frequencies of 1, 2 or 5 Hz, whereas at 10 Hz there was a significant 1.2-fold enhancement of release. Phentolamine enhanced release with stimulation at 5 Hz and 10 Hz by 1.5- and 2.5-fold respectively. 3. In tail arteries, clonidine reduced release when stimulation was for 30 s periods at a frequency of 1 Hz, but did not affect release at 2 Hz or 5 Hz. Phentolamine in each case produced an approximately 1.5-fold enhancement of release. 4. In the pithed rat, spinal stimulation of cardioaccelerator fibres produced a tachycardia, the magnitude of which depended on the frequency and duration of stimulation. Clonidine (10 micrograms/kg, i.v.) caused either a reduction or an enhancement of the response depending on the frequency and duration of stimulation; in the presence of phentolamine (2 mg/kg, i.v.), clonidine had no effect. 5. The results are consistent with partial agonistic actions of clonidine at prejunctional alpha-adrenoceptors in the rat cardiovascular system; such effects may be of relevance to the mechanism of the clonidine withdrawal syndrome.
Animals↗
Serotonin enhances sympathetic vasoconstrictor responses in rat isolated perfused tail artery by activation of postjunctional serotonin-2 receptors.
The effects of serotonin and the selective serotonin-2 receptor antagonist ketanserin have been investigated on sympathetic vasoconstrictor responses in rat isolated perfused/superfused proximal tail artery segments. Serotonin (6 nmol/l) markedly enhanced responses to low frequency, short duration electrical stimulation (0.1 ms pulses at 1 Hz for 10 s). Serotonin (6 nmol/l) had a very slight (less than 10 mmHg) direct vasoconstrictor effect. Both the enhancing effect of serotonin on responses to electrical stimulation and the slight direct vasoconstrictor effect were blocked by ketanserin (3 nmol/l). Ketanserin (3 nmol/l) had no significant effect on resting tone or on responses to electrical stimulation. It is concluded that serotonin enhances sympathetic vasoconstrictor responses in rat tail artery by activation of postjunctional serotonin-2 receptors. Blockade of this effect by ketanserin is entirely consistent with its antihypertensive effect in vivo.
Animals↗
Pharmacological activities of the antihypertensive drug urapidil in the rat.
Urapidil had blocking activity on alpha 1-adrenoceptors in the rat isolated caudal artery (pA2 congruent to 7) and in the anaesthetized rat. Urapidil had no clonidine like agonistic activity on alpha 2-adrenoceptors in preparations of the guinea-pig ileum (prejunctional) or dog saphenous vein (post-junctional). Urapidil (0.01-0.1 mg/kg i.v.) had a hypotensive effect in the anaesthetized rat. In a dose of 0.1 mg/kg, the depressor response was accompanied by bradycardia. Vagotomy abolished the bradycardia and attenuated the depressor response. The results indicate that the antihypertensive effect of urapidil may be due partly to blockade of postjunctional alpha 1-adrenoceptors, but in addition there is a central component of action.
Anesthesia↗
Facilitation of noradrenergic transmission by locally generated angiotensin II in guinea-pig isolated atria and in the perfused caudal artery of the rat.
In guinea-pig isolated atria, angiotensin I and angiotensin II produced concentration dependent increases in the rate of spontaneous beating and in the release of noradrenaline produced by field stimulation of sympathetic nerves. In rat isolated caudal artery preparations, both angiotensin I and angiotensin II had direct vasoconstrictor actions and also produced concentration dependent increases in constrictor responses to periarterial sympathetic stimulation. All the above effects of angiotensin I and angiotensin II were blocked by the receptor antagonist saralasin, but only those of angiotensin I were blocked by the converting enzyme inhibitor enalaprilat (MK-422). The findings confirm that angiotensin II generated locally from precursor angiotensin I within cardiac and vascular tissues may modulate noradrenergic transmitter release.
Angiotensin I↗
The alpha 2-adrenoceptor agonists clonidine, TL99 and DPI enhance vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline in the rat tail artery preparation.
1. Clonidine (1-30 nmol/l) enhanced the vasoconstrictor responses to sympathetic nerve stimulation in isolated perfused artery preparations from the rat tail. Higher concentrations of clonidine produced vasoconstriction in most artery preparations and reduced the response to sympathetic nerve stimulation. 2. The enhancing effect of clonidine was not affected by prazosin but was blocked by idazoxan, indicating that it was due to activation of alpha 2-adrenoceptors. 3. The alpha 2-adrenoceptor agonists DPI and TL99, like clonidine, enhanced vasoconstrictor responses to sympathetic nerve stimulation. 4. Vasoconstrictor responses to noradrenaline were enhanced by clonidine and TL99. 5. The findings suggest that activation of postjunctional alpha 2-adrenoceptors results in facilitation of the contractile response elicited by activation of alpha 1-adrenoceptors.
Adrenergic alpha-Agonists↗
Effects of some catecholamines on noradrenergic transmission in the rabbit ear artery.
1. The effects of noradrenaline, adrenaline, isoprenaline, dopamine and the N-methyl and alpha-methyl homologoues of dopamine were studied on tritium release and on vasoconstrictor responses to sympathetic nerve stimulation in isolated arteries of the rabbit ear after labelling noradrenergic transmitter stores with 3H-noradrenaline. These observations were made in the presence of cocaine (100 muM). 2. Noradrenaline (0-5 and 5 muM) inhibited transmitter release and abolished vasoconstrictor responses. A concentration of 0-05 muM had no effect on transmitter release, although the vasoconstrictor response was reduced and there was sometimes a vasodilator response. 3. Adrenaline in concentrations of 0-05, 0-5 and 5 muM decreased transmitter release and vasoconstrictor responses; sometimes there was a vasodilator response. 4. Isoprenaline in concentrations of 0-05, 0-5 and 5 muM did not affect transmitter release. Vasoconstrictor responses were either unaffected or enhanced by all concentrations of isoprenaline when infusions had been in progress for 15 min; but immediately after beginning the infusion of 5 muM isoprenaline, the response was reduced. 5. Dopamine (0-05, 0-5 and 5 muM) produced a concentration-dependent decrease in transmitter release, but vasoconstrictor responses were not reduced with infusions of 0-05 or 0-5 muM; during infusions of 5 muM, stimulation produced a vasodilator response.
Animals↗
Vasoconstrictor responses to the alpha 2-adrenoceptor agonist UK14304 during responses to noradrenaline, phenylephrine, serotonin and vasopressin of the rat tail artery.
In the isolated perfused rat tail artery, the alpha 2-adrenoceptor agonist UK14304 alone did not exert a direct vasoconstrictor action until a concentration of at least 30 microM was reached. However, when administered during the sustained vasoconstrictor response to 1.6 microM vasopressin, UK14304 (1-100 nM) produced additional concentration-dependent increases in perfusion pressure. The vasoconstrictor response to UK14304 in the presence of vasopressin was antagonized by idazoxan (1 microM) but was not affected by prazosin (10 nM), indicating that it was due to activation of alpha 2-adrenoceptors, and it was reduced by diltiazem (10 microM) and abolished when perfusion was done with a Ca2(+)-free solution, suggesting that the effect depends on the influx of Ca2+. UK14304 (50 nM) also produced a further increase in perfusion pressure when given during sustained vasoconstrictor responses to phenylephrine (1 microM) or low concentrations (100 nM) of noradrenaline or serotonin. However, UK14304 did not produce a further increase in perfusion pressure when given during sustained vasoconstrictor responses to higher concentrations (300 nM) of noradrenaline or serotonin: the lack of an additional effect of UK14304 was not due to the primary response to noradrenaline or serotonin being maximal. The findings show that vasoconstrictor responses following activation of alpha 2-adrenoceptors may be uncovered by an increase in vascular tone produced by some agonists.
Adrenergic alpha-Agonists↗
Facilitation of noradrenaline release by isoprenaline is not mediated by angiotensin II in mouse atria and rat tail artery.
The hypothesis that facilitation of noradrenaline release by prejunctional beta-adrenoceptors is linked to the local generation of angiotensin II was investigated in rat tail artery and mouse atria which were incubated with [3H]-noradrenaline. The outflow of radioactivity induced by electrical field stimulation of the tissues was taken as an index of noradrenaline release. In mouse atria, angiotensin II (0.01 microM) enhanced the stimulation-induced (S-I) noradrenaline release and this was blocked by saralasin (0.1 microM). Isoprenaline (0.01 microM) also enhanced the S-I release of noradrenaline, but this was not blocked by either saralasin (0.1 microM and 0.3 microM) or captopril (5 microM). Furthermore, the facilitatory effects of angiotensin II (0.1 microM) and isoprenaline (0.1 microM) were additive. In rat tail artery, the facilitatory effect of angiotensin II (0.01 microM) on noradrenaline release was blocked by saralasin (0.1 microM). The facilitatory effect of isoprenaline (0.1 microM) was blocked by propranolol (1 microM) but not by saralasin (0.1 microM) nor captopril (5 microM). These results indicate that beta-adrenoceptor-mediated facilitation of noradrenaline release occurs independently of angiotensin II in mouse atria and rat tail artery.
Angiotensin II↗