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Biomedical subjects

M J Rand

Publications and source records attributed to M J Rand.

At least 127 records · Page 7Linked to original sources
PubMed1984

Catecholamine secretion from the rabbit adrenal gland is not modulated by a mechanism involving beta-adrenoceptors.

The possibility that catecholamine secretion from the rabbit adrenal gland is subject to modulation by a mechanism involving beta-adrenoceptors was investigated in an isolated perfused preparation of the gland. The adrenal catecholamine stores were radiolabelled with 3H-adrenaline and subsequently efflux of radioactivity was elicited by stimulation of an attached branch of the splanchnic nerve. The efflux of radioactivity evoked by nerve stimulation (1 min at 5 Hz) was not altered by isoprenaline (0.1 microM), metroprolol (0.1 microM) or (+/-)-propranolol (1 microM). Stimulation-induced efflux was reduced in the presence of a higher concentration of (+/-)-propranolol (10 microM); however, it was also reduced by (+)-propranolol (10 microM). These findings do not support the existence in the rabbit adrenal gland of a mechanism involving beta-adrenoceptors through which catecholamine secretion may be modulated.

Adrenal Glands↗
PubMed1983

Effects of clonidine on alpha-adrenoceptors in the autoperfused hindquarters of the pithed rat.

The effects of clonidine were assessed in pithed rats on responses to spinal cord stimulation of heart rate (HR), systemic blood pressure (BP) and perfusion pressure (PP) in the autoperfused hindquarters. Graded increases in HR, BP and PP were elicited by 10 s periods of spinal stimulation at frequencies of 1, 3 and 10 Hz; the vasoconstrictor responses (BP and PP) were biphasic. Clonidine (3-100 micrograms/kg) caused dose-dependent reductions of HR responses and of the first phase of BP and PP responses to spinal stimulation; the reductions were to a lesser extent with increasing frequency of stimulation. Responses to exogenous noradrenaline were unaffected by clonidine. In contrast, the second phase of the vasoconstrictor responses to 10 Hz stimulation was enhanced by clonidine (3-30 micrograms/kg): this phase of the responses is probably mediated by adrenal catecholamines. Clonidine itself (10-100 micrograms/kg) increased resting levels of BP and PP but not HR. The direct effects of clonidine as well as the effects on responses to spinal stimulation were blocked by phentolamine (1 mg/kg). The results indicate that clonidine selectively activates prejunctional alpha-adrenoceptors in the rat heart and hindquarters in vivo. The results also indicate that clonidine may potentiate the release of adrenal catecholamines, and it is suggested that it may do so by acting as an antagonist at inhibitory alpha-adrenoceptors in the adrenal medulla.

Animals↗
PubMed1983

Release of noradrenaline from rabbit atria by isoprenaline and histamine.

The release of noradrenaline accompanying positive inotropic and chronotropic actions of isoprenaline and histamine was investigated in rabbit atria in which the transmitter stores were labelled with (2H)-noradrenaline. Propranolol (3 microM) significantly reduced the isoprenaline (1 microM)-induced release of radioactivity and positive inotropic and chronotropic actions. Cimetidine (30 microM) significantly reduced the histamine (25 microM)-induced release of radioactivity and positive inotropic and chronotropic actions. Tetrotoxin (0.9 microM) significantly reduced the release of radioactivity by both isoprenaline and histamine but did not affect the positive inotropic and chronotropic actions of these drugs. The results suggest that conducted action potentials are associated with isoprenaline- and histamine-induced release of noradrenaline and it is possible that the sympathetic nerves are ephaptically stimulated by increased myocardial activity.

Animals↗
PubMed1982

Clinical pharmacology of adrenergic-adrenoreceptor-blocking drugs.

The development of beta-adrenoreceptor-blocking drugs provided an important group of agents to treat the cardiovascular disorders hypertension, angina pectoris, and cardiac arrhythmias and to manage patients with thyrotoxicosis. For clinical purposes, these drugs can be divided into two groups, that is, those with intrinsic sympathomimetic activity (ISA) and those without (non-ISA). The non-ISA drugs include propranolol, which is noncardiac selective: labetalol, which is noncardiac selective with alpha blockade: and and metoprolol and atenolol, which are cardiac selective. The drugs with ISA include pindolol, oxprenolol, and alprenolol which are noncardiac selective, and practolol which is cardiac selective. These drugs resemble isoprenaline in chemical structure, but their interaction with the beta-adrenoreceptors causes no response or only a slight response if the drug has ISA. By occupying the receptors, they block excitation by noradrenaline released from the sympathetic nerves and by adrenaline from the adrenal medulla. Drugs with ISA appear to depress cardiac activity and to interfere with bronchodilator drive less than do non-ISA drugs. Beta-blocking drugs differ considerably in their bioavailability because of differences in the rate and extent of metabolism in the first past through the liver after absorption from the gut. The therapeutic dose range varies widely for those with low bioavailability but is more predictable for those with high bioavailability. The drugs also differ in plasma protein binding and in their receptor affinities. In addition to their usual adverse effects, which include exacerbation of cardiac failure, bronchospasm, sleep disturbances, and Raynaud's phenomenon, concern has arisen about possible ocular and mucocutaneous side effects with beta-blocking drugs. This is a recognized problem with practolol, and it is not certain whether it occurs with other beta-blocking drugs. A double-blind study reported here of 110 matched patients, 36 of whom were on pindolol for more than 2 years, did not reveal any evidence of oculomucocutaneous problems related to drug treatment.

Adrenergic beta-Antagonists↗
PubMed1982

The operation of autoregulatory feedback loops in noradrenergic transmission to cardiovascular effector tissues.

The effects of alpha-adrenoceptor blocking drugs on circulating catecholamines or neurogenically released noradrenaline will depend on their relative selectivity for prejunctional or postjunctional alpha-adrenoceptors. Relatively selective prejunctional alpha-adrenoceptor antagonists will block the inhibitory feedback mechanism at sympathetic nerve terminals, thus increasing transmitter release, which will tend to overcome any postjunctional alpha-adrenoceptor blockade, and responses to sympathetic nerve stimulation will be resistant to blockade. They will have noradrenolytic activity in doses which are not sympatholytic; they may even enhance sympathetic nerve activity. In contrast, selective postjunctional alpha-adrenoceptor blocking drugs will be noradrenolytic and sympatholytic. Prazosin has weak prejunctional alpha-adrenoceptors blocking activity, but is relatively selective for postjunctional alpha-adrenoceptors. Yohimbine is relatively selective for prejunctional alpha-adrenoceptors, and phentolamine is not highly selective. Selectivity for postjunctional alpha-adrenoceptors appears to be a desirable action for an antihypertensive drug of this type.

Adrenergic alpha-Antagonists↗
PubMed1982

Positive chronotropic responses produced by alpha-adrenoreceptors in the pithed rat.

1 Phenylephrine (1-100 microgram/kg, intravenously) produced dose-dependent increases in heart rate and blood pressure in the pithed rat. 2 The positive chronotropic response to phenylephrine (10 microgram/kg) was reduced in a dose-dependent manner by propranolol (0.01-0.3 mg/kg), but higher doses of propranolol (up to 3 mg/kg) did not reduce the response by more than about 50%. The residual response was virtually abolished by phentolamine (0.3 mg/kg) or prazosin (3 microgram/kg). Labetalol (3 mg/kg) which has both alpha- and beta-blocking activity, also abolished the positive chronotropic response. 3 The pressor response to phenylephrine (1-30 microgram/kg) was enhanced by propranolol (1 mg/kg) and abolished by phentolamine (1 mg/kg) and prazosin (30 microgram/kg). Labetalol (3 mg/kg) reduced the response to phenylephrine by 73%. 4 Propranolol (0.3 mg/kg) completely blocked the chronotropic and vasodepressor effects of isoprenaline (0.1 microgram/kg). 5 It is concluded that phenylephrine acts on both alpha 1- and beta 1-adrenoreceptors to produce an increase in heart rate, on alpha 1-adrenoreceptors to produce vasoconstriction and on beta 2-adrenoreceptors to produce vasodilation. This latter effect is usually masked by the predominant vasoconstrictor action.

Adrenergic alpha-Antagonists↗
PubMed1982

Effects of histamine on the resting and stimulation-induced release of [3H]-noradrenaline in guinea-pig isolated atria.

1 The sympathetic transmitter stores of guinea-pig isolated atria were labelled with [3H]-noradrenaline. The effects of histamine (0.3 to 100 mumol/l) on resting and stimulation-induced (S-I, 2 Hz for 10 s) release of radioactivity were investigated. 2 Histamine, in low concentrations (0.3 and 1 mumol/l) had no effect on resting release but inhibited S-I release of radioactivity. The inhibition was abolished by the H2-receptor antagonist, cimetidine (10 mumol/l) and also by the H1-receptor antagonist, mepyramine (1 mumol/l). 3 The inhibitory actions of histamine on S-I release were not due to indirect effects involving alpha-adrenoceptors, beta-adrenoceptors, muscarinic cholinoceptors or prostaglandin synthesis. 4 Histamine in a high concentration (100 mumol/l) increased the resting and S-I release of radioactivity. The increase in resting release was abolished by the neuronal uptake blocking drug cocaine (30 mumol/l) but the increase in S-I release was only partially blocked by cocaine.

Animals↗
PubMed1982

Effects of impromidine, a specific H2-receptor agonist and 2(2-pyridyl)-ethylamine, an H1-receptor agonist, on stimulation-induced release of [3H]-noradrenaline in guinea-pig isolated atria.

1 The specific histamine H2-receptor agonist, impromidine (3-100 nmol/l), increased the rate and force of beating of guinea-pig isolated atria. These effects were blocked by the H2-receptor antagonist, cimetidine (30 mumol/l), but not by the H1-receptor antagonist, mepyramine (0.1 mumol/l). 2 In atria that had previously been incubated in [3H]-noradrenaline, impromidine (3-100 nmol/l) had no effect on the resting efflux of radioactivity, but concentrations of 50 and 100 nmol/l significantly increased the efflux induced by electrical stimulation (2 Hz for 10 s) of the intramural sympathetic nerves by approximately 38%; lower concentrations (3, 10 and 25 nmol/l) had no effect. 3 The effect of impromidine in enhancing stimulation-induced efflux of radioactivity was abolished by cimetidine (30 mumol/l) and by mepyramine (0.1 mumol/l). It was unaffected by the alpha-adrenoceptor antagonist, phentolamine (30 mumol/l). 4 Impromidine produced some inhibition of the uptake of [3H]-noradrenaline, but this did not account for the enhancement of the stimulation-induced efflux of radioactivity, since impromidine (50 mumol/l) still increased release in the presence of cocaine (30 mumol/l). 5 The specific H1-receptor agonist, 2-(2-pyridyl)-ethylamine (10-100 mumol/l), increased both the resting and stimulation-induced efflux of radioactivity. These effects were not blocked by mepyramine (0.1 mumol/l) or the beta-adrenoceptor antagonist, metoprolol (0.1 mumol/l). 6 The prejunctional inhibitory histamine receptors in guniea-pig atria are not classifiable into H1- or H2-type by the use of relatively specific postjunctional histamine H1- or H2-receptor agonists and antagonists.

Animals↗
PubMed1982

Are the prejunctional histamine receptors on sympathetic nerve terminals in guinea-pig isolated atria activated during anaphylaxis in vitro?

In isolated atria from sensitized guinea-pigs, antigenic challenge with ovalbumin induces an anaphylactic reaction in which there is an increased rate and force of contraction. At the same time, stimulation-induced release of [3H] noradrenaline is inhibited by 40%. Cimetidine decreased the tachycardia occurring during anaphylaxis but no effect on the inhibition of stimulation-induced transmitter release. It is known that antigenic challenge of sensitized guinea-pig atria release histamine from mast cells; this histamine acts postjunctionally to increase heart rate. However, the inhibition of noradrenergic transmitter release is not due to the stimulation of prejunctional inhibitory histamine receptors.

Anaphylaxis↗
PubMed1982

The mechanisms of the inotropic and chronotropic actions of hydralazine on rat isolated atria.

The effects of hydralazine on rat isolated atria depend on its concentration. A negative chronotropic effect due to inhibition of spontaneous release of noradrenaline was produced by concentrations of 1 x 10(-5) - 1 x 10(-4) M, but with concentrations of 2 x 10(-4) M or more the negative chronotropic effect was due to a more direct depression of pacemaker activity. A positive chronotropic effect due to release of noradrenaline was produced by a concentration of 2 x 10(-3) M; when this was abolished by reserpine pretreatment or beta-adrenoceptor blockade, the negative chronotropic effect was unmasked or accentuated. A positive inotropic effect was produced by concentrations of 6 x 10(-4) - 2 x 10(-3) M; this effect was not reduced by reserpine or beta-adrenoceptor blockade, but it was absent in a calcium-free medium and was blocked by verapamil.

Animals↗
PubMed1981

Agonistic actions of DPI (2-(3,4-dihydroxyphenylimino)-imidazolidine) on alpha-adrenoceptors and dopamine receptors.

Some of the pharmacological actions of 2-(3,4-dihydroxyphenylimino)-imidazolidine (DPI) were studied in vivo and vitro. DPI (1 nM-100 micro M) had a similar affinity but a lower intrinsic activity on alpha-adrenoceptors in rabbit aortic strips to noradrenaline (1 nM-10 micro M). DPI did not affect the uptake of [3H]noradrenaline in guinea-pig isolated atria. The effects of DPI on dopamine receptors were examined in the dog coronary and renal vasculature and in the rat isolated, perfused kidney. In the dog coronary vasculature DPI (0.005-10 micrograms, i.a.), like dopamine (5-50 micrograms, i.a.), caused an increase in coronary blood flow which was antagonized by the dopamine receptor antagonist, ergometrine. In the renal vasculature of both the rat and the dog, dopamine (5-50 micrograms, i.a.) caused vasodilatation but there was no evidence of an effect of DPI on dopamine receptors. It appears that DPI is a selective agonist for dopamine receptors in the coronary vasculature.

Adrenergic alpha-Agonists↗
PubMed1981

An interaction between prejunctional alpha-adrenoceptors and prejunctional beta-adrenoceptors.

The ability os isoprenaline to enhance transmitter release from sympathetic nerves in rat atria incubated with [3H]noradrenaline was assessed under three conditions of prejunctional alpha-adrenoceptor activation: in the presence of phentolamine, in the presence of noradrenaline, and in the absence of either drug. Isoprenaline-induced enhancement of transmitter release was inversely related to the degree of activation of prejunctional alpha-adrenoceptors. Thus there appears to be an interaction between the prejunctional alpha-adrenoceptor inhibitory mechanism and the prejunctional beta-adrenoceptor facilitatory mechanism. In rabbit ear arteries incubated with [3H]noradrenaline, isoprenaline facilitated transmitter release in the presence but not in the absence of phentolamine. Therefore in some tissues it may be necessary to block prejunctional alpha-adrenoceptors before prejunctional beta-adrenoceptors can be demonstrated.

Animals↗
PubMed1981

Adrenaline-induced hypertension in rats.

1. Rats implanted with osmotic minipumps delivering adrenaline intraperitoneally at the rate of 2.9 nmol/h had significantly higher systolic and diastolic pressures from days 2 to 6 after implantation than sham-operated controls rats. 2. Concomitant treatment with metoprolol tartrate (2.5 mg/kg, intraperitoneally, twice daily) prevented the elevation in blood pressure induced by adrenaline from osmotic minipumps. Such metoprolol treatment did not affect the blood pressure of controls rats. 3. Noradrenaline administered intraperitoneally from osmotic minipumps at the rate of 2.9 nmol/h had no significant effect on blood pressure over a 6-day period of observation. 4. Tachyphylaxis developed to the acute pressor responses to intermittent intravenous infusions of adrenaline in doses of 0.78 microgram (4.24 nmol) every 10 min, but after 14 days of such treatment systolic and diastolic blood pressures were significantly greater than in controls rats. 5. It is suggested that the increase in blood pressure produced by chronic treatment with adrenaline is due to the uptake and accumulation of adrenaline in noradrenergic nerve terminals, from which it is subsequently released as a cotransmitter that mediates a positive feedback loop on transmission by acting on prejunctional beta-adrenoceptors.

Animals↗
PubMed1981

Prejunctional alpha-adrenoreceptors subserve a physiological role in cardiac noradrenergic transmission.

1 The question whether prejunctional alpha-adrenoreceptors subserve a physiological role in a noradrenaline-mediated autoinhibitory feedback loop has been studied in guinea-pig isolated atria by stimulating the accelerans nerve and measuring chronotropic responses and the release of radioactivity after labelling transmitter stores with 3H-noradrenaline. 2 Phentolamine (0.3 micrometer) significantly enhanced chronotropic responses when stimulation was with 0.5 Hz for 30 s, but the increase in the release of radioactivity was too small to be measured reliably. When the frequency of stimulation was increased to 4 Hz for 30 s, phentolamine significantly increased the release of radioactivity but the chronotropic response to stimulation was near maximal and phentolamine had no significant effect on it. 3 With prolonged stimulation (12 min) at the lower frequency (0.5 Hz), both the release of radioactivity and the chronotropic response to stimulation were significantly enhanced by phentolamine (3 micrometers). 4 The results support a physiological role for prejunctional alpha-adrenoreceptors in guinea-pig isolated atria.

Animals↗
PubMed1981

Activation of prejunctional beta-adrenoceptors in rat atria by adrenaline applied exogenously or released as a co-transmitter.

1 Adrenaline (10 nM) significantly enhanced the stimulation-induced efflux of radioactivity from rat atria previously incubated with [3H]-noradrenaline ([3H]-NA). This effect was abolished by metoprolol (.01 muM). 2 Adrenaline in a higher concentration (1 muM) and NA (1 muM) significantly reduced the stimulation-induced efflux of radioactivity. However, in the presence of phenoxybenzamine (10 muM), adrenaline (1 muM) enhanced the efflux, whereas NA (1 muM) had no effect. 3 In rat isolated atria pre-incubated with adrenaline and then incubated with NA, both catecholamines were taken up and were released by field stimulation. When pre-incubation was with adrenaline and incubation was with [3H]-NA, metoprolol decreased the stimulation-induced efflux of radioactivity. This effect did not occur if the atria were pre-incubated with NA instead of adrenaline, suggesting tht neuronally released adrenaline activates prejunctional beta-adrenoceptors. 4 In conscious rats, intravenously administered adrenaline (6.0 and 0.6 nmol/kg) was taken up and retained in the atria and could be released by field stimulation. The release was calcium-dependent from these rats up to 24 h after administration.

Animals↗