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Biomedical subjects

M J Rand

Publications and source records attributed to M J Rand.

At least 109 records · Page 6Linked to original sources
PubMed1986

Cardiac alpha-adrenoceptors: postjunctional and prejunctional.

Postjunctional alpha-adrenoceptors subserve positive inotropic and chronotropic responses. When beta-adrenoceptors are blocked, agonists that act on alpha 1-adrenoceptors evoke positive chronotropic responses in the pithed rat and rat isolated atria. The rank order of potency for this effect is adrenaline greater than noradrenaline greater than phenylephrine greater than methoxamine. The order of potency for antagonists to block the responses is prazosin greater than phentolamine greater than yohimbine. Thus, the postjunctional alpha-adrenoceptors are of the alpha 1-subtype. The positive chronotropic responses elicited by activating alpha 1-adrenoceptors have a slower time course than those elicited by activation of beta-adrenoceptors. When beta-adrenoceptors are blocked by propranolol, the positive chronotropic response to phenylephrine is enhanced by increasing the calcium concentration or by the calcium channel activator Bay K 8644 (0.1 microM), whereas the response is decreased by lowering the calcium concentration or by calcium antagonists (verapamil, nifedipine, nicardipine and diltiazem). Therefore, the positive chronotropic response to alpha 1-adrenoceptor activation involves an increased influx of calcium through calcium channels. Prejunctional alpha 1-adrenoceptors are involved in autoinhibitory feedback regulation of transmitter release from noradrenergic neurones. In rat atria, the release of noradrenaline induced by sympathetic nerve stimulation is inhibited by both clonidine and methoxamine, and is enhanced (by disruption of noradrenaline-mediated autoinhibition) by both idazoxan and prazosin. Thus, the prejunctional alpha-adrenoceptors are of both alpha 1- and alpha 2-subtypes. Drugs which produce blockade of postjunctional alpha 1-adrenoceptors could also produce an increase in neurogenic release of noradrenaline due to blockade of prejunctional alpha 1-adrenoceptors, and this might result in more complex effects than would be anticipated.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Effects of tetradecapeptide renin substrate on isolated preparations of rat caudal artery, guinea-pig atria and on pithed rat blood pressure.

In rat isolated caudal artery preparations, tetradecapeptide renin substrate enhanced the responses to sympathetic nerve stimulation (0.5 Hz, 10 s). In guinea-pig isolated atria, previously incubated in 3H-noradrenaline, tetradecapeptide renin substrate enhanced the stimulation-induced efflux of radioactivity. The facilitation of noradrenergic transmission in rat caudal arteries and guinea-pig atria was blocked by the angiotensin II receptor antagonist saralasin, but was not altered by converting enzyme inhibitors. In the pithed rat tetradecapeptide renin substrate increased blood pressure and this effect was reduced by the converting enzyme inhibitor, captopril.

Angiotensin II↗
PubMed1986

Adrenaline and stress-induced increases in blood pressure in rats.

Stress was induced by immobilizing the hind limbs of rats for 12 days and housing the rats in individual cages. Control rats were housed in groups without immobilization. Blood pressure and heart rate were measured through an indwelling carotid cannula. After 10 and 12 days of immobilization and isolation, the stressed rats had significantly higher blood pressures (ca. 10 mmHg) and higher cardiac adrenaline levels (ca. 90%). After adrenal medullectomy cardiac adrenaline levels were markedly reduced in both stressed and control rats. Furthermore, the stressing procedure did not cause a rise in blood pressure in adrenal-medullectomized rats. Desipramine HCl (2 mg/kg per day), administered orally to block the neuronal uptake of adrenaline, prevented the elevation in blood pressures and cardiac adrenaline levels. Propranolol HCl (2.8 mg/kg per day), orally, also prevented the rise in blood pressure. The results are consistent with the hypothesis that activation of facilitatory prejunctional beta-adrenoceptors on sympathetic nerves by neuronally-released adrenaline may be responsible for the raised blood pressure.

Adrenal Medulla↗
PubMed1986

Positive chronotropic responses to cardiac alpha 1-adrenoreceptor activation in the pithed rat.

Adrenaline (0.1-10 micrograms/kg), noradrenaline (0.1-10 micrograms/kg) and phenylephrine (1-100 micrograms/kg) acted on both cardiac alpha 1- and beta-adrenoreceptors to induce positive chronotropic responses in the pithed rat. When beta-adrenoreceptors were blocked by propranolol (1 mg/kg), the residual chronotropic responses were due to activation of alpha 1-adrenoreceptors since they were significantly reduced by prazosin (10-100 micrograms/kg). Methoxamine (10-300 micrograms/kg) acted solely on cardiac alpha 1-adrenoreceptors to induce positive chronotropic responses which were abolished by prazosin (10-100 micrograms/kg) alone, as has been demonstrated previously for amidephrine. The rank order of potency for eliciting the positive chronotropic response to alpha 1-adrenoreceptor activation was adrenaline greater than noradrenaline greater than phenylephrine greater than methoxamine. The positive chronotropic responses to adrenaline (3-10 micrograms/kg), noradrenaline (3-10 micrograms/kg) and phenylephrine (30-100 micrograms/kg) produced by activating alpha 1-adrenoreceptors had a slower time course than did the chronotropic responses produced by activation of beta-adrenoreceptors.

Adrenergic alpha-Agonists↗
PubMed1986

The effect of beta-adrenoreceptor antagonists on the inhibition of pendular movements of rabbit ileum produced by periarterial sympathetic nerve stimulation and some sympathomimetic amines.

The effects of propranolol and of the selective beta 1- and beta 2-adrenoreceptor blocking drugs atenolol and ICI 118,551 were determined on the inhibitory responses of isolated segments of rabbit ileum to noradrenaline, isoprenaline and salbutamol and to periarterial sympathetic nerve stimulation. Responses to isoprenaline (0.04-10.24 microM) and salbutamol (1.4-89.6 microM) were blocked by propranolol in concentrations up to 5.0 and 12.8 microM, respectively. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline (0.03-1.92 microM) were unaffected by propranolol in concentrations up to 10.0 and 5.0 microM, respectively. Atenolol in concentrations up to 30.0 microM blocked responses to isoprenaline (0.04-2.56 microM) but did not affect responses to noradrenaline, salbutamol or sympathetic nerve stimulation in concentrations up to 3.0, 3.0 and 1.0 microM, respectively. However, when responses to noradrenaline and sympathetic nerve stimulation were reduced by phentolamine (1.0 microM), atenolol then produced further reductions. Responses to isoprenaline (0.04-2.56 microM) and salbutamol (1.4-89.6 microM) were blocked by ICI 118,551 in concentrations up to 0.5 microM. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline were unaffected by ICI 118,551 in concentrations up to 0.01 and 0.3 microM, respectively. Salbutamol (0.1 microM) increased the inhibitory response to sympathetic nerve stimulation and this effect was blocked by ICI 118,551 (0.01 microM). It was concluded that blockade of beta 2-adrenoreceptors, presumably located on sympathetic nerve terminals, decreases the release of transmitter noradrenaline and that blockade of beta 1-adrenoreceptors, presumably located in longitudinal smooth muscle cells, reduces the response to transmitter noradrenaline when alpha-adrenoreceptors are also blocked.

Adrenergic beta-Antagonists↗
PubMed1986

Effect of captopril on blood pressure responses to enkephalins in chloralose-anaesthetized rats.

Captopril lowered blood pressure in chloralose-anaesthetized rats and enhanced the depressor responses to metenkephalin and D-Ala-metenkephalinamide to the same extent. Since metenkephalin is a much better substrate than D-Ala-metenkephalinamide for dipeptidylcarboxypeptidase, some mechanism other than inhibition of this enzyme appears to be responsible for the enhancement by captopril of the responses to opioids. When the blood pressure had been lowered by haemorrhage, naloxone was no more effective than saline control in restoring blood pressure. However, when captopril was given after haemorrhage, the blood pressure was further lowered, and then naloxone produced a significant restoration. Hydralazine given after haemorrhage also caused a further lowering of blood pressure, then naloxone produced a lesser restoration of blood pressure than in haemorrhage plus captopril experiments. The results suggest that release of endogenous opioids may contribute to the fall in blood pressure upon bleeding.

Anesthesia↗
PubMed1985

Effect of [D-Ala2,Met5]enkephalinamide and [D-Ala2,D-Leu5]enkephalin on cholinergic and noradrenergic neurotransmission in isolated atria.

In rabbit isolated atria, [D-Ala2,Met5]enkephalinamide and [D-Ala2,D-Leu5]enkephalin (0.1-3 microM) inhibited responses to cholinergic nerve stimulation in a concentration-dependent manner without affecting responses to exogenous acetylcholine. The inhibitory effect was blocked by the opiate receptor antagonist naloxone (1 microM). In rabbit atria in which the transmitter acetylcholine stores had been radioactively labelled by preincubating the tissue in [3H]choline, tetrodotoxin (100 ng/ml) significantly (P less than 0.001) blocked the stimulation-induced (2 Hz for 3 min) release of radioactivity. Both [D-Ala2,Met5]enkephalinamide and [D-Ala2,D-Leu5]enkephalin (0.3 and 1 microM) significantly decreased stimulation-induced radioactivity release and their effects were blocked by naloxone (1 microM). In rat isolated atria, [D-Ala2,Met5]enkephalinamide and [D-Ala2,D-Leu5]enkephalin (0.3-3 microM) inhibited responses to cholinergic nerve stimulation without affecting responses to exogenous acetylcholine. The inhibitory effect was blocked by naloxone (1 microM). In guinea-pig isolated atria, responses to cholinergic nerve stimulation were unaffected by the enkephalin analogues. In rabbit, rat and guinea-pig isolated atria, responses to noradrenergic nerve stimulation and exogenous noradrenaline were unaffected by the enkephalin analogues.

Acetylcholine↗
PubMed1985

Effect of urapidil on beta-adrenoceptors of rat atria.

The effects of the antihypertensive drug urapidil were studied on chronotropic responses to isoprenaline in rat isolated atria. Urapidil (1-30 microM) antagonized the responses to isoprenaline competitively, and the pA2 value was 6.05. Thus, in addition to its alpha 1-adrenoceptor blocking action for which the pA2 value is about 7, urapidil has beta-adrenoceptor blocking activity.

Animals↗
PubMed1985

Evidence for the involvement of alpha 1-adrenoceptors in negative feedback regulation of noradrenergic transmitter release in rat atria.

Experiments were undertaken to determine if prejunctional alpha 1-adrenoceptors are involved in autoinhibitory regulation of transmitter noradrenaline release in rat atria. The noradrenergic transmitter stores in rat isolated atria were radiolabelled with [3H]noradrenaline and transmitter release was deduced from the efflux of the radiolabel evoked by field stimulation of the atrial intramural sympathetic nerves. Phentolamine (3 mumol/l) and prazosin (0.1 and 3 mumol/l) enhanced the release of radiolabel evoked by stimulation with trains of 4, 8 and 16 pulses, whereas idazoxan (10 mumol/l) enhanced release evoked by stimulation with 8 and 16 pulses. Idazoxan and prazosin were about equi-effective in enhancing the evoked release but phentolamine produced much greater enhancement than either idazoxan or prazosin. Combination of idazoxan (10 mumol/l) and prazosin enhanced the stimulation-evoked release with 4, 8 and 16 pulses to the same extent as phentolamine (3 mumol/l). The selective alpha 1-adrenoceptor agonist methoxamine (10 mumol/l) inhibited stimulation-evoked release and this effect was blocked by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). The findings indicate that alpha 1-adrenoceptors may contribute to autoinhibitory feedback regulation of transmitter release in rat atria.

Adrenergic alpha-Antagonists↗
PubMed1985

Cardiac alpha-adrenoceptors involving positive chronotropic responses.

Phenylephrine, adrenaline, and noradrenaline have been shown to act on both alpha- and beta-adrenoceptors to produce an increase in heart rate in the pithed rat and rat isolated atria. Abolition of these responses requires blockade of both types of adrenoceptors. The rank order of alpha-adrenoceptor agonists to produce positive chronotropic responses was adrenaline greater than noradrenaline greater than phenylephrine greater than methoxamine. In the case of methoxamine, positive chronotropic responses were largely due to the activation of alpha 1-adrenoceptors. The positive chronotropic responses to activation of alpha 1-adrenoceptors developed more slowly than did the response to beta-adrenoceptor activation in the pithed rat. The fact that blockade of one receptor type enhanced the positive chronotropic responses to activation of the other receptor type suggests that there may be an interaction between the cardiac alpha 1- and beta-adrenoceptors mediating positive chronotropic responses. In the rat isolated atria, the calcium antagonists verapamil (10 nmol/L) and nifedipine (10 nmol/L) also inhibited the alpha 1-adrenoceptor-mediated positive chronotropic effect of phenylephrine to the same extent as prazosin (10 nmol/L). Prazosin was not a calcium antagonist, as shown by its failure to block the contracture of the depolarized rat isolated aortic strips. Neither verapamil nor nifedipine were alpha 1-adrenoceptor antagonists at these concentrations.

Animals↗
PubMed1985

Evidence for autoinhibition of stimulation-induced noradrenaline release from vasa deferentia of the guinea-pig and rat.

Both phenoxybenzamine and idazoxan increased the efflux of radioactivity elicited by a train of stimulation (4 pulses at 5 Hz) in vasa deferentia preincubated with [3H]-noradrenaline. Phenoxybenzamine increased the release of radioactivity from vasa stimulated with a single pulse, whereas idazoxan did not. The contractile response in both guinea-pig and rat vasa was biphasic: phenoxybenzamine enhanced the initial twitch component and reduced the second component in guinea-pig vasa stimulated with a single pulse or a train of pulses. Idazoxan enhanced both phases of the response of guinea-pig vasa stimulated with a train of pulses but did not affect the response to stimulation with a single pulse. The effect of phenoxybenzamine in increasing the efflux of radioactivity produced by a single pulse of stimulation was abolished by cocaine, indicating that the increase in efflux was due to blockade of noradrenaline uptake. Contractile responses of guinea-pig vasa stimulated with a single pulse in the presence of cocaine were unaltered by phenoxybenzamine, whereas with a train of stimulation the twitch component was enhanced and the second phase was reduced. The effects of phenoxybenzamine or idazoxan on the efflux of radioactivity from rat vasa portions were qualitatively the same as were observed in whole vasa. The contractile response of the prostatic portion consisted of a rapid twitch with a single pulse of stimulation, but was biphasic with a train of stimulation; the response of the epididymal portion was biphasic with either a single pulse or a train of pulses. These results suggest that there is no inhibitory feedback modulation of noradrenaline release with a single pulse of stimulation in guinea-pig and rat vasa deferentia whereas, with a train of stimulation, there is autoinhibition of noradrenaline release.

Adrenergic alpha-Antagonists↗
PubMed1985

Interaction between the inhibitory action of acetylcholine and the alpha-adrenoceptor autoinhibitory feedback system on release of [3H]-noradrenaline from rat atria and rabbit ear artery.

Stimulation-induced increases in the efflux of radioactivity (S-I efflux) were measured in the bathing medium following labelling of the noradrenergic transmitter pools of rat atria and rabbit artery preparations with [3H]-noradrenaline. In atria stimulated with trains of 16 or 60 pulses at 2 Hz, phentolamine enhanced, whereas acetylcholine inhibited S-I efflux. With trains of 16 pulses phentolamine had a smaller enhancing effect than with trains of 60 pulses, whereas the inhibitory effect of acetylcholine was more pronounced with 16 pulses of stimulation. The inhibitory effect of acetylcholine was markedly enhanced by phentolamine when stimulation was with 60 pulses. With 16 pulses of stimulation the effect of acetylcholine was unaltered by phentolamine and abolished by the alpha 2-adrenoceptor agonist 3,4-dihydroxyphenylimino-2-imidazolidine (DPI). Phentolamine had no effect on the negative inotropic effect of acetylcholine on driven left atrial preparations. In arterial preparations stimulated with trains of 30 pulses at 1 Hz, both acetylcholine and clonidine inhibited S-I efflux, whereas yohimbine and idazoxan enhanced S-I efflux. Combining acetylcholine with clonidine did not alter the inhibitory effect of clonidine but the combination of acetylcholine with yohimbine or idazoxan abolished the marked enhancing effects of yohimbine or idazoxan on S-I efflux. These findings indicate that there may be a reciprocal interaction between prejunctional alpha-adrenoceptors and prejunctional muscarinic cholinoceptors.

Acetylcholine↗
PubMed1985

Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.

Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile.

Adrenergic beta-Agonists↗
PubMed1984

Effects of locally generated angiotensin II on noradrenergic transmission in guinea-pig isolated atria.

The extent to which cardiac neuroeffector function may be modulated by angiotensin II (AII) generated locally from angiotensin I (AI) was investigated in guinea-pig spontaneously beating isolated atria radiolabelled with [3H]noradrenaline. AI and AII were equipotent in increasing the rate and force of atrial contractions with a threshold concentration between 0.1 and 1.0 nM. In contrast, AI was approximately twenty times less potent than AII in enhancing the stimulation-induced (S-I) efflux of radioactivity. The actions of AI and AII on rate and force of atrial contractions, as well as those on S-I efflux of radioactivity, were substantially blocked by the AII receptor antagonist saralasin. On the other hand, the converting enzyme inhibitors captopril and MK-422 selectively blocked the actions of AI without affecting those of AII. These results suggest that significant local conversion of AI to AII occurs in guinea-pig isolated atria. This locally generated AII can act on myocardial AII receptors to increase rate and force of atrial contractions, and on AII receptors located on sympathetic nerve terminals to facilitate sympathetic neurotransmission. The lower potency of AI compared to AII in modulating transmitter release, in contrast to the equal potency of the peptides in mediating chronotropic and inotropic responses, may be due to conversion of AI to AII at sites remote from the neuroeffector junction.

Angiotensin I↗
PubMed1984

Effects of mianserin on noradrenergic mechanisms.

Mianserin increased stimulation-induced release of noradrenaline from guinea-pig atria and brain cortex slices. The increase still occurred when neuronal reuptake of noradrenaline was blocked by cocaine. Mianserin blocked the neuronal uptake of 3H-noradrenaline only in high concentrations (1 microM in atria produced 40% block; 10 microM in cortex produced 57% block). Lower concentrations (0.01 microM in atria; 1 microM in cortex) significantly increased stimulation-induced release of noradrenaline. It is concluded that increases in transmitter release from noradrenergic nerves produced by mianserin can be attributed to blockade of the alpha 2-adrenoceptors involved in autoinhibitory feedback mechanism at nerve terminals, rather than to blockade of neuronal reuptake of noradrenaline. This effect on noradrenergic transmission in the central nervous system could explain the antidepressant actions of mianserin in accordance with the hypothesis of Schildkraut.

Animals↗
PubMed1984

The positive inotropic action of isoprenaline is associated with the release of noradrenaline from rabbit, guinea-pig and rat atria.

The actions of isoprenaline (1 microM) were investigated in spontaneously beating isolated paired atria from rabbits, guinea-pigs and rats and in paced left atria from rabbits and rats. Isoprenaline, when applied for a 10 min period to paired atrial from rabbits, guinea-pigs and rats, produced a short-lived release of noradrenaline which appeared to be associated with the positive inotropic actions, rather than with the positive chronotropic actions. Exposures of 3 min to isoprenaline in paired atria in the three species produced increases in force and release of noradrenaline (% of tissue content) in the order: rabbit greater than guinea-pig greater than rat. The increases in rate did not differ between species. Rat atria had the highest resting rates followed by guinea-pig and rabbit atria. In rabbit left atrial preparations which were electrically paced at resting rates of approximately 61, 158 and 334 beats per min there were progressive decreases in release of noradrenaline and positive inotropic actions produced by isoprenaline with increasing rates of pacing. In rat left atrial preparations which were electrically paced at a slower rate, which was similar to that of rabbit paired atria, a greater release of noradrenaline associated with a greater positive inotropic effect was induced by isoprenaline than in rat paired atria. In rabbit paced left atria, an increase in pacing frequency alone produced small increases in force and release of noradrenaline. Verapamil (1 microM) significantly reduced the positive inotropic effect and release of noradrenaline induced by isoprenaline without affecting the positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Adrenaline mediates a positive feedback loop in noradrenergic transmission: its possible role in development of hypertension.

Adrenaline activates prejunctional beta-adrenoceptors of the beta 2-subtype on sympathetic nerve terminals and enhances noradrenergic transmission. Adrenaline can be incorporated in transmitter stores of noradrenergic nerves and, when released as a cotransmitter, activates the prejunctional beta 2-adrenoceptors, thereby mediating autofacilitation of noradrenergic transmission. Adrenaline released from the adrenal medulla in stress may be incorporated in noradrenergic transmitter stores and reach a sufficient concentration as a cotransmitter to activate the autofacilitatory feedback loop involving prejunctional beta 2-adrenoceptors, resulting in prolongation of the increases in vasomotor tone and cardiac activity that occur acutely: with frequent repetition of stress, there may be progression into a hypertensive state. In accord with this hypothesis, adrenaline administration produces persistent increases in blood pressure in rats, and plasma levels of adrenaline are elevated in a proportion of hypertensive patients; furthermore, repeated stress produces prolonged increases in blood pressure in animals and man.

Animals↗