Biomedical subjects

M J Rand

Publications and source records attributed to M J Rand.

At least 91 records · Page 5Linked to original sources

PubMed1989

Evidence for a role of nitric oxide in the neurotransmitter system mediating relaxation of the rat anococcygeus muscle.

1. The nitric oxide (NO) synthesis inhibitor NG-monomethyl-L-arginine (L-NMMA), but not D-NMMA, inhibited the NANC-mediated relaxations of the rat anococcygeus muscle, but did not affect the relaxation produced by sodium nitroprusside. 2. The inhibitory effect of L-NMMA was reversed by L-arginine but not by D-arginine, and prior exposure to L-arginine blocked the effect of L-NMMA. 3. The noradrenergically mediated contractions of the anococcygeus elicited by field stimulation were slightly enhanced by L-NMMA, but the response to noradrenaline was not affected. 4. The results suggest that NANC transmission in the rat anococcygeus muscle involves the generation of NO from arginine.

Animals↗

PubMed1989

Examination of the paradoxical lack of responsiveness of the guinea-pig vas deferens to tyramine.

1. The isolated superfused vas deferens from the guinea-pig was more sensitive to the contractile action of noradrenaline than that from the rat. Tyramine had about 10% of the potency of noradrenaline on the rat vas deferens, but had no contractile activity on the guinea-pig vas deferens (potency less than 0.1% of noradrenaline). 2. The response of the guinea-pig vas deferens to noradrenaline was not affected by tyramine in a concentration that produced a clear contractile response of the rat vas deferens. 3. Noradrenaline and tyramine released less radioactivity from guinea-pig than from rat vasa deferentia in which noradrenergic transmitter stores had been labelled with 3H-noradrenaline. In vasa deferentia from either species, tyramine released less radioactivity than noradrenaline. 4. Pretreatment with the monoamine oxidase inhibitor iproniazid increased the amount of radioactivity released by tyramine from vasa deferentia of both species, increased the contractile response of the rat vas deferens to tyramine, and resulted in the appearance of a contractile response to tyramine in the guinea-pig vas deferens. 5. alpha-methyltyramine, which is not a substrate for monoamine oxidase, had about the same potency as tyramine in releasing radioactivity from vasa deferentia of both species, and in contracting the rat vas deferens, but was virtually without contractile activity on the guinea-pig vas deferens. 6. Pretreatment with iproniazid resulted in the appearance of a contractile response to alpha-methyltyramine in the guinea-pig vas deferens. 7. Pretreatment with iproniazid resulted in change in the composition of the radioactivity released by tyramine, with an increase in the proportion of noradrenaline and a decrease in the proportion of deaminated products. There was also an increase in the amount of endogenous noradrenaline released by tyramine. 8. It was concluded that the main factor accounting for the lack of reactivity of the guinea-pig vas deferens to tyramine is intraneuronal metabolism of the noradrenaline displaced by it.

Amphetamines↗

PubMed1989

Alpha 2-adrenoceptor agonists enhance responses to certain other vasoconstrictor agonists in the rat tail artery.

1. The effects of the alpha2-adrenoceptor agonists clonidine, rilmenidine, TL99 and UK14304 on the vasoconstrictor response to sympathetic nerve stimulation and on the concentration-response curves to noradrenaline and phenylephrine were compared in two isolated, perfused vascular tissues: the rat tail artery (which has both postjunctional alpha 1- and alpha 2-adrenoceptors), and the rabbit ear artery (in which only alpha 1-adrenoceptors are present postjunctionally). 2. In the rabbit ear artery, the first observable effect of alpha 2-adrenoceptor agonists was inhibition of vasoconstrictor responses to sympathetic nerve stimulation. This occurred with concentrations of the alpha 2-adrenoceptor agonists which were far below those producing vasoconstriction. Responses to noradrenaline were not affected. 3. In contrast, in the rat isolated perfused tail artery, alpha 2-adrenoceptor agonists, in concentrations that produced no other observable effects, enhanced the vasoconstrictor responses to sympathetic nerve stimulation and to noradrenaline. Much higher concentrations of alpha 2-adrenoceptor agonists produced vasoconstriction in most preparations and only then reduced the response to sympathetic nerve stimulation. The enhancing effect of alpha 2-adrenoceptor agonists was blocked by idazoxan, but not by prazosin. 4. Vasoconstrictor responses in the rat tail artery to the relatively selective alpha 1-adrenoceptor agonist phenylephrine were enhanced by alpha 2-adrenoceptor agonists. The enhancement of the response to phenylephrine was greater than that to the mixed alpha 1- and alpha 2-adrenoceptor agonist noradrenaline. 5. Vasoconstrictor responses in the rat tail artery to vasopressin, ATP and KCl, like those to alpha 1-adrenoceptor agonists, were enhanced by alpha 2-adrenoceptor agonists.2+owever, vasoconstrictor responses to

Adrenergic alpha-Agonists↗

PubMed1989

Alpha 2-adrenoceptor agonists enhance vasoconstrictor responses to alpha 1-adrenoceptor agonists in the rat tail artery by increasing the influx of Ca2+.

1. The alpha 2-adrenoceptor agonists TL99 (2-(N N-dimethyl)amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene) and UK14304 (5-bromo-6-[2-imidazoline-2-yl-aminol]-quinoxaline), in concentrations that are less than 1% of those producing vasoconstriction, enhance vasoconstrictor responses to noradrenaline and phenylephrine in isolated perfused preparations of the rat tail artery. 2. The enhancing effect was abolished when Ca2+ was absent and by the calcium channel blocking drug diltiazem. 3. alpha 2-Adrenoceptor agonists had no effect on the component of the responses to noradrenaline and phenylephrine that is attributable to mobilization of intracellular Ca2+, but enhanced the component attributable to influx of extracellular Ca2+. 4. These results suggest that the enhancing effect of alpha 2-adrenoceptor agonists on responses of the rat tail artery to alpha 1-adrenoceptor agonists involves an increase in Ca2+-influx into smooth muscle cells through Ca2+ channels that are opened when alpha 2-adrenoceptors are activated.

Adrenergic alpha-Agonists↗

PubMed1989

Rilmenidine differs from clonidine in that it lacks histamine-like activity.

Studies were carried out to determine whether rilmenidine, a recently introduced antihypertensive agent with a similar mechanism of action of clonidine, possesses histamine-like activity on tissues responding to histamine H2-receptor agonists. In guinea-pig isolated atria, both histamine and clonidine caused concentration-dependent positive chronotropic effects which were blocked by the histamine H2-receptor antagonist cimetidine (5 microM); in contrast, rilmenidine produced a concentration-dependent negative chronotropic effect which was not altered by cimetidine. In stilboestrol-treated rat isolated uterus contracted by KCl, histamine and clonidine produces concentration-dependent relaxations which were blocked by cimetidine (5 microM); rilmenidine also produced relaxation, but this was not affected by cimetidine (5 microM). These findings suggest that rilmenidine, unlike clonidine, does not activate histamine H2-receptors in either guinea-pig atria or rat uterus.

Adrenergic alpha-Agonists↗

PubMed1988

The neurotoxicity of tunicamycin.

The neurotoxicity of tunicamycin, an inhibitor of glycosylation of glycoproteins and a potential anti-tumour agent, was investigated by injection of the chemical directly into the lateral ventricle of the brain of rats. A delayed neurological syndrome developed due to anoxic necrosis of brain cells and spongy degeneration of the white matter. In many brains the lesion had the characteristic features of an infarct. Since the predominant lesion was vascular, the action of tunicamycin on blood vessels was investigated in vitro using rabbit aortic rings. In this system the normal relaxation response to acetylcholine in aortic rings pre-contracted with noradrenaline was progressively inhibited as exposure of the ring to tunicamycin increased from 2 h to 5 h. This relaxation response depends on the release of endothelium-derived relaxing factor from endothelial cells. Hence it is proposed that the important primary target in tunicamycin neurotoxicity is endothelial cells of the brain microvessels.

Animals↗

PubMed1988

Functional and morphologic effects of ioxilan, iohexol, and diatrizoate on endothelial cells.

The effects of a new contrast agent, ioxilan, on vascular endothelium were compared with those of iohexol and diatrizoate. Rabbit aortic rings were incubated in contrast medium (CM) (350 mgI/mL) or Krebs solution as a control agent, for 5 minutes. Scanning and transmission electron micrographs showed that iohexol and ioxilan produced irregularities in the cell borders and in some vesicles, whereas diatrizoate produced intercellular gaps and numerous vesicles containing myelin figures. The ability of the endothelial cells to release endothelium-derived relaxing factor was tested by measuring the dilator response to acetylcholine. Incubation of aortic rings in CM for 5 minutes caused no changes in responses. However, 15-minute contact with diatrizoate irreversibly reduced the dilator response to 49%, and contact with sucrose (2100 mOsm/kg) reduced it to 9%. After incubation for 60 minutes, iohexol reduced the dilator response to 43%, while ioxilan caused no change. Since the hydrophilicity of the nonionic compounds, ioxilan and iohexol, is similar, while ioxilan's osmolality is substantially lower, the endothelial changes detected by electron microscopy and induced by the CM are attributable to their chemical properties, whereas the loss of dilator response appears to be mediated by high osmolality.

Animals↗

PubMed1988

Vasodilatation and vasoconstriction in the rabbit isolated aorta. Effects of ioxilan, iohexol, and diatrizoate.

The vasomotor effects of contrast media (CM), ioxilan, iohexol, and diatrizoate, and their isoosmotic sucrose solutions as controls, were studied in vitro in rings of thoracic aortas of rabbits. When the osmotic pressure of CM or controls reached the region of 380 mOsm/kg, vasoconstriction developed, reaching a maximum in about 1 hour; it was reversible. It could not be blocked by phentolamine, and therefore did not involve alpha-adrenoceptors. When added to aortic rings precontracted with noradrenaline, all of the CM produced vasodilatation, while reactions to sucrose varied. When endothelium was removed, CM still produced vasodilatation, suggesting a direct chemotoxic effect on smooth muscle. The dilatation effect does not involve the muscarinic receptors, beta-adrenoceptors, or stimulation of prostacyclin synthesis, since the vasodilator response was not blocked by atropine, propranolol, or indomethacin. Blockage of calcium channels did not appear to be a contributing factor. Since the dilator response to all CM was augmented in the presence of the phosphodiesterase inhibitor, iso-butylmethylxanthine (IBMX), it is likely that CM produce vasodilatation chemotoxically by activating the production of a cyclic nucleotide.

Animals↗

PubMed1988

Involvement of alpha 1-adrenoceptors in chronotropic responses to endogenously released amines in the pithed rat.

1. In pithed rats, yohimbine (1 mg/kg i.v.) enhanced the positive chronotropic responses to spinal stimulation of cardiac sympathetic nerves with eight pulses delivered at 2 or 4 Hz, indicating that auto-inhibition was operating, but did not increase responses to shorter lengths of trains of 8 pulses at 8, 16 or 32 Hz which did not allow sufficient time for auto-inhibition to come into effect. 2. The positive chronotropic response to cardiac sympathetic nerve stimulation with eight pulses at 8 Hz of about 60 beats/min was not affected by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg), but was reduced to about 20% of the control value by propranolol (1 mg/kg). 3. In the presence of propranolol, the residual positive chronotropic responses to cardiac sympathetic nerve stimulation were virtually abolished by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg). 4. The positive chronotropic response to tyramine (0.1 mg/kg i.v.) was reduced from 100 to 12 beats/min by propranolol (1 mg/kg), and the residual response was abolished by prazosin. 5. The findings indicate that noradrenaline released from cardiac sympathetic terminals by nerve stimulation or by tyramine acts on alpha 1-adrenoceptors to produce a positive chronotropic response that is revealed when beta-adrenoceptors are blocked.

Animals↗

PubMed1988

Rilmenidine acts as a partial agonist at prejunctional alpha 2-adrenoceptors in guinea-pig atria.

1. The present study was carried out to determine whether rilmenidine, a recently introduced antihypertensive agent which acts on alpha 2-adrenoceptors, has partial agonist activity on prejunctional alpha 2-adrenoceptors in guinea-pig atria. 2. Isolated preparations of guinea-pig atria were incubated with [3H]-noradrenaline and the efflux of radioactivity induced by stimulation of intramural sympathetic nerves was used as an index of release of transmitter noradrenaline. 3. Rilmenidine (1 mumol/l) inhibited noradrenaline release evoked by short trains (five, 20 and 50 pulses) of sympathetic nerve stimulation and this inhibitory effect of rilmenidine was antagonized by the alpha 2-adrenoceptor antagonists, idazoxan (0.1 and 0.3 mumol/l) and rauwolscine (0.3 mumol/l) whereas it was not affected by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). 4. On the other hand, rilmenidine (1 mumol/l) enhanced noradrenaline release evoked by long trains (150 and 300 pulses) of stimulation and this effect was also abolished by idazoxan (0.1 mumol/l). 5. These findings suggest that the effects of rilmenidine on transmitter release depend on the degree of auto-inhibition: when the concentration of noradrenaline in the biophase of the prejunctional alpha 2-adrenoceptors is low, rilmenidine acts as an agonist, but when the concentration is high it acts as an antagonist. Thus, rilmenidine, like clonidine, is a partial agonist on prejunctional alpha 2-adrenoceptors in guinea-pig atria.

Adrenergic alpha-Agonists↗

PubMed1988

Pre- and postjunctional effects of neuropeptide Y on the rabbit isolated ear artery.

1. In the isolated perfused and superfused rabbit ear artery, neuropeptide Y (NPY, 0.3-100 nmol/l) had no direct vasoconstrictor action, but produced a concentration-dependent and reversible enhancement of vasoconstrictor responses to both sympathetic nerve stimulation and exogenous noradrenaline. 2. In arteries in which the noradrenergic transmitter stores had been radiolabelled with [3H]-noradrenaline, 100 nmol/l NPY inhibited the stimulation-induced (1 Hz for 30 s) release of radioactivity, but the lower concentrations tested (10 and 30 nmol/l) had no effect. NPY (10, 30 and 100 nmol/l) had no effect on the resting release of radioactivity. 3. Thus, NPY in low concentrations enhances vasoconstrictor responses in the rabbit ear artery by a postjunctional action; prejunctionally, NPY inhibits stimulation-induced transmitter release when it is present in high concentrations.

Animals↗

PubMed1988

A technique for simultaneously comparing the release of noradrenaline evoked by field stimulation and by propagated nerve impulses in rabbit ear arteries.

1. A technique has been described which utilized radiotracer methods to measure the release of transmitter noradrenaline, simultaneously, from segments of rabbit ear artery subjected to field stimulation and propagated nerve impulses. 2. The release of radioactivity from arteries labelled with 3H-noradrenaline was much greater in the segment subjected to field stimulation than in the segment stimulated by propagated nerve impulses. 3. The release of radioactivity from segments invaded by nerve impulses decreased progressively with increases in frequency through the range of 10-50 Hz, using 150 pulses at 10, 15, 20, 30 and 50 Hz. However, the release remained constant in the field stimulated segments throughout the frequency range used.

Animals↗

PubMed1988

Comparison of the effects of phenoxybenzamine and uptake blockade on noradrenaline efflux from rabbit ear arteries evoked by field stimulation and propagated nerve impulses.

1. A comparison has been made of the effects of blockade of prejunctional alpha-adrenoreceptors and blockade of transmitter noradrenaline uptake in segments of rabbit ear arteries subjected to field stimulation or neuronally propagated impulses. 2. The relationship between evoked release and frequency of stimulation differed in artery segments subjected to field stimulation and those receiving propagated nerve impulses. However, the effectiveness of phenoxybenzamine in increasing stimulation-induced efflux of radioactivity decreased as the frequency of stimulation increased in artery segments subjected to either field stimulation or neuronally propagated impulses. 3. Blockade of neuronal and extraneuronal uptake had no effect on evoked efflux from field-stimulated artery segments but it did produce a marked and significant enhancement of release evoked by propagated nerve impulses.

Animals↗

PubMed1988

Facilitation of noradrenaline release from sympathetic nerves in rat anococcygeus muscle by activation of prejunctional beta-adrenoceptors and angiotensin receptors.

1. Isolated preparations of rat anococcygeus muscle were incubated with [3H]-noradrenaline and the efflux of radioactivity induced by stimulation of intramural sympathetic nerves was used as a measure of release of transmitter noradrenaline. Isometric contractile responses were also measured. 2. Angiotensin I (0.03 microM) and angiotensin II (0.03 microM) produced non-sustained contractile responses and enhanced the stimulation-induced (S-I) effluxes of radioactivity as well as the contractile responses to electrical stimulation. These effects were blocked by the angiotensin II receptor antagonist saralasin (0.03 microM), and the effect of angiotensin I, but not angiotensin II, was blocked by the angiotensin converting enzyme inhibitor captopril (0.1 microm). 3. The findings indicate that there are both pre- and postjunctional receptors for angiotensin II and that angiotensin I is converted to angiotensin II in the anococcygeus muscle preparation. 4. Isoprenaline (0.1 microM) slightly enhanced the S-I efflux of radioactivity, and produced a greater enhancement after neuronal uptake blockade with desipramine (0.03 microm) and alpha-adrenoceptor blockade with phentolamine (1 microM). 5. The facilitatory effect of isoprenaline on S-I efflux of radioactivity was abolished by propranolol (0.3 microM), but was not affected by low concentrations of saralasin (0.03 microM) or captopril (0.1 microM) which abolished the effect of angiotensin I. The findings suggest that isoprenaline acts directly on prejunctional beta-adrenoceptors to enhance S-I noradrenaline release, rather than indirectly by releasing angiotensin II from within the tissue. Higher concentrations of saralasin (0.1 microM) or captopril (5 microM) did block the facilitatory effect of isoprenaline. The significance of this finding is not clear.

Angiotensin I↗

PubMed1987

Calcium antagonists inhibit positive chronotropic responses to alpha 1-adrenoceptor activation in rat isolated atria.

Positive chronotropic responses of rat isolated atria to phenylephrine were reduced by propranolol (0.3 microM) and the residual response was further depressed by the selective alpha 1-adrenoceptor antagonist prazosin (1 nM) but not yohimbine (10 nM), confirming that a component of the response to phenylephrine was due to activation of alpha 1-adrenoceptors. When beta-adrenoceptors were blocked by propranolol, the positive chronotropic response to phenylephrine was enhanced by increasing the calcium concentration and by the calcium channel activator Bay K 8644 (0.1 microM), whereas the response was decreased by lowering the calcium concentration and by the calcium antagonists verapamil (10 nM), nifedipine (10 nM) and diltiazem (100 nM). In the presence of prazosin, when phenylephrine acts only on beta-adrenoceptors, calcium antagonists had no effect on the response. In rat isolated aortic strips in a calcium-free, high K+ (40 mM) solution, verapamil (10 nM), nifedipine (10 nM) and diltiazem (100 nM) shifted the calcium-induced contraction curves to the right, but prazosin (10 nM) had no effect, indicating that it is not a calcium antagonist. The calcium antagonists in the concentrations stated above had no effect on phenylephrine-induced contractions of rat aortic strips in normal Krebs-Henseleit solution, indicating that they did not block alpha 1-adrenoceptors in these concentrations. Taken together, these data suggest that the positive chronotropic effect of phenylephrine resulting from activation of alpha 1-adrenoceptors involves an increased influx of calcium through channels that are sensitive to organic calcium antagonists.

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

PubMed1987

Effects of angiotensin converting enzyme inhibitors and saralasin on noradrenergic and cholinergic transmitter release in guinea pig isolated atria.

The interactions of the converting enzyme inhibitors captopril and enalaprilat and the angiotensin II receptor antagonist saralasin with cardiac autonomic neuroeffector transmission were investigated in guinea pig isolated atria. Noradrenergic transmitter stores were radiolabeled by incubation with [3H]-noradrenaline. In other atria, cholinergic transmitter stores were radiolabeled by incubation with [3H]-choline. Neither captopril nor enalaprilat significantly altered the resting or stimulation-induced (2 Hz, 30 s) efflux of radioactivity in atria that had been incubated with either [3H]-noradrenaline or [3H]-choline. Saralasin also did not significantly alter the resting or stimulation-induced efflux in atria incubated with [3H]-choline. However, in atria incubated with [3H]-noradrenaline, saralasin slightly increased the resting efflux without altering the stimulation-induced efflux. The findings of the present study suggest that neither captopril, enalaprilat, nor saralasin interferes with either noradrenergic or cholinergic transmitter release.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1987

Effects of the opioid peptides [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8 on cholinergic neurotransmission in the rabbit isolated atria.

1. The effect of the opioid peptides [Met5]enkephalin-Arg6-Phe7 (MEAP) and [Met5]enkephalin-Arg6-Gly7-Leu8 (MEAGL) were compared with those of [Leu5]enkephalin and [D-Ala2,Met5]enkephalinamide (DAME) on cholinergic neurotransmission in the rabbit isolated atria. 2. Rabbit isolated atria had a resting rate of 190 beats/min. In the presence of the beta-adrenoceptor antagonist propranolol (0.3 mumol/l), atria responded to electrical field stimulation with a cholinergically mediated negative chronotropic response. The opioid peptides had no effect on the resting rate, but inhibited the negative chronotropic response to field stimulation. The IC50 values for inhibiting the cholinergic responses were 1.4 mumol/l for [Leu5]enkephalin (LE), 1.4 mumol/l for MEAP, 1.3 mumol/l for MEAGL and 0.2 mumol/l for DAME. Responses of a similar magnitude to exogenous acetylcholine were unaffected. 3. Thus, MEAP, MEAGL and LE had similar potencies but DAME was about seven times more potent in inhibiting cholinergic neurotransmission in the rabbit isolated atria. The site of inhibition appears to be prejunctional.

Animals↗

PubMed1987

Modulation of neuroeffector transmission.

Local mechanisms that regulate transmitter release at autonomic neuroeffector junctions may be classified into four main types: (a) Automodulation, involving a feedback effect of the transmitter on receptors associated with the prejunctional terminals resulting in a restraint on the facilitation of release that occurs when a train of nerve impulses invades the terminals. Changes in the composition of the transmitter, such as the presence of adrenaline as a cotransmitter together with noradrenaline, can result in increased facilitation of transmission. (b) Transneuronal modulation involving an effect of the transmitter released from terminals of one type on adjacent terminals of another type; thus, noradrenaline release may be inhibited by acetylcholine released from cholinergic nerve terminals adjacent to the noradrenergic terminals. (c) Transjunctional modulation involving a feedback effect on the prejunctional nerve terminals of one or more factors released from effector cells. Such substances include adenyl compounds (adenosine and/or ATP) and metabolites of arachidonic acid. (d) Hormonal modulation involving the action of blood-borne hormones or locally generated hormone-like substances on prejunctional terminals. Some of the substances involved in modulation may act in more than one way; thus, opioids may function as cotransmitters or as hormones, and adenyl compounds may be cotransmitters or be released from effector cells. The effects of exogenous drugs on the substances involved in the modulation of transmission and on the prejunctional receptors for these substances account for many anomalous actions of drugs used or proposed for use in therapeutics.

Acetylcholine↗