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M J Rand

Publications and source records attributed to M J Rand.

At least 73 records · Page 4Linked to original sources
PubMed1991

Endothelin-1 enhances vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline in the rabbit ear artery.

1. In rabbit isolated perfused ear arteries denuded of endothelium, a low concentration of endothelin-1 (0.1 nmol/L) that had no direct vasoconstrictor action produced slowly developing enhancements of vasoconstrictor responses to noradrenaline and sympathetic nerve stimulation. The enhancements reached maximal levels after 60 min of exposure to endothelin-1. 2. A higher concentration of endothelin-1 (1 nmol/L), which produced a slow-developing increase in perfusion pressure of 70 mmHg over the course of 1 h, significantly enhanced vasoconstrictor responses to sympathetic nerve stimulation for the first 30 min, after which there was no significant enhancement. Responses to noradrenaline were not enhanced by 1 nmol/L endothelin-1. 3. The enhancing effect of low concentrations of endothelin-1 on vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline may play a physiological role in modulating vasomotor function.

Animals↗
PubMed1991

Evidence that part of the NANC relaxant response of guinea-pig trachea to electrical field stimulation is mediated by nitric oxide.

1. The nitric oxide (NO) synthesis inhibitors NG-monomethyl L-arginine (L-NMMA) and L-nitroarginine methyl ester (L-NAME) reduced relaxations of guinea-pig tracheal smooth muscle elicited by stimulation of intramural non-adrenergic, non-cholinergic (NANC) nerves, but D-NMMA had no effect. L-NAME was 10-30 times more potent than L-NMMA. Relaxations produced by sodium nitroprusside and vasoactive intestinal polypeptide (VIP) were not affected by L-NMMA or L-NAME. 2. The inhibitory effect of L-NMMA on NANC-mediated relaxations was partially reversed by L-arginine but was not affected by D-arginine. 3. VIP antibody and alpha-chymotrypsin abolished or greatly reduced the relaxant action of VIP and reduced relaxations elicited by stimulation of NANC nerves; the residual NANC relaxation was further reduced by L-NAME. 4. The results suggest that NO and VIP are mediators of NANC-induced relaxations of guinea-pig tracheal smooth muscle. We propose the term 'nitrergic' to describe transmission processes which are mediated by NO.

Animals↗
PubMed1991

Effect of endothelin-1 on responses of isolated blood vessels to vasoconstrictor agonists.

The effect of endothelin-1 (ET-1) on vasoconstrictor responses of the endothelium-denuded perfused rabbit ear artery to 5-hydroxytryptamine (5-HT), histamine, and vasopressin (VP) was studied. In low concentrations with no vasoconstrictor action (0.1 and 0.3 nM), and in a concentration that increased the perfusion pressure by 70 mm Hg (1 nM), ET-1 significantly enhanced responses to the agonists studied; this enhancement was apparently mediated by an increased influx of extracellular calcium through voltage-operated channels, as it was abolished by the calcium channel antagonist nicardipine (10 nM). In contrast, higher concentrations of ET-1 (3 and 10 nM) inhibited responses to VP and 5-HT and this inhibitory effect was accentuated in the presence of nicardipine. The possible mechanism by which ET-1 exerts this inhibitory effect on vasoconstrictor responses is discussed. Because ET-1 is released from endothelial cells that are immediately adjacent to vascular smooth muscle cells, these modulatory effects of ET-1 on responses to endogenously present vasoconstrictors may play a role in vascular function.

Animals↗
PubMed1990

Nitric oxide and vasoactive intestinal polypeptide mediate non-adrenergic, non-cholinergic inhibitory transmission to smooth muscle of the rat gastric fundus.

The nitric oxide (NO) synthesis inhibitor NG-monomethyl L-arginine (L-NMMA) reduced NANC-mediated relaxations of isolated strips of the rat gastric fundus elicited by low frequencies or short periods of field stimulation, but D-NMMA had no effect. The inhibitory effect of L-NMMA on NANC-mediated relaxations was partially reversed by L-arginine but was not affected by D-arginine. A VIP antibody abolished the relaxant response to VIP and reduced the responses to stimulation. Residual responses to stimulation in the presence of VIP antibody were further reduced by L-NMMA. The tone of the fundus strip was slightly increased by L-NMMA and slightly reduced by L-arginine. The relaxation produced by VIP was slightly reduced by L-NMMA and enhanced by L-arginine. Relaxations produced by peptide histidine isoleucine, sodium nitroprusside or isoprenaline were not affected by L-NMMA or L-arginine. The results suggest that NO as well as VIP is involved in NANC-mediated relaxations of the rat gastric fundus.

Animals↗
PubMed1990

Vasoconstrictor responses of rat tail artery to sympathetic nerve stimulation contain a component due to activation of postjunctional beta- or alpha 2-adrenoceptors.

The role of alpha 1-, alpha 2- and beta-adrenoceptors in vasoconstrictor responses to sympathetic nerve stimulation was investigated in perfused proximal segments of rat tail artery by using selective blocking drugs. Prazosin (1 nM) markedly reduced the responses but idazoxan (100 nM) did not, and propranolol (1 microM) significantly enhanced them, indicating that the vasoconstriction was due to activation of alpha 1-adrenoceptors and that it was partly counteracted by a vasodilator component due to activation of beta-adrenoceptors. In the presence of propranolol, idazoxan or reduction of the concentration of Ca2+ in the perfusing solution from 2.5 to 0.63 mM significantly reduced responses to sympathetic nerve stimulation, indicating that a component of the vasoconstrictor response was due to activation of alpha 2-adrenoceptors. Forskolin, which increases cyclic AMP levels independently of beta-adrenoceptors, reduced responses to sympathetic nerve stimulation to a greater extent in the presence than in the absence of propranolol and this effect was additive with that of prazosin but not idazoxan. It is concluded that activation of beta-adrenoceptors inhibits the component of responses to sympathetic nerve stimulation due to activation of alpha 2-adrenoceptors because of an inhibitory effect of cyclic AMP on Ca2+ channels linked to alpha 2-adrenoceptors.

Adenylyl Cyclases↗
PubMed1990

Effects of the alpha 2-adrenoceptor agonist UK14304 on pressor responses in pithed rats.

1. Intravenous infusions of UK14304 (0.3-10 micrograms/kg per min) in pithed rat produced dose-dependent pressor responses which were not affected by prazosin (10 micrograms/kg) but were reduced by yohimbine (0.3 mg/kg). 2. Pressor responses to noradrenaline (0.1 micrograms/kg), phenylephrine (1 micrograms/kg) and vasopressin (10 mU/kg) were enhanced during infusions of UK14304 (0.03-1 micrograms/kg per min). Likewise, pressor responses to spinal sympathetic stimulation were enhanced during infusions of low concentrations of UK14304 (0.03-0.3 microgram/kg per min) but were reduced during infusion of a higher concentration of UK14304 (10 micrograms/kg per min). 3. After administration of yohimbine (0.3 mg/kg) or the calcium channel blocking drug diltiazem (infused at 50 micrograms/kg per min), pressor responses to noradrenaline and UK14304 were reduced, and responses to noradrenaline during infusion of UK14304 were not enhanced. 4. Prazosin (10 micrograms/kg) revealed a secondary depressor component in the response to sympathetic stimulation which is due to beta-adrenoceptor activation, since it was abolished by ICI 118551 (0.3 mg/kg). In the presence of ICI 118551 plus prazosin, pressor responses to sympathetic stimulation were enhanced during infusions of UK14304. 5. The depressor response to nitroprusside and the depressor component of responses to sympathetic stimulation after prazosin were enhanced during infusions of UK14304 at concentrations that increased the blood pressure. 6. The findings show that alpha 2-adrenoceptor activation enhanced the pressor responses to sympathetic nerve stimulation, noradrenaline, phenylephrine and vasopressin in the pithed rat and beta-adrenoceptor activation produced depressor responses which increased with increasing blood pressure.

Adrenergic alpha-Agonists↗
PubMed1990

Mechanisms of the effects of endothelin on responses to noradrenaline and sympathetic nerve stimulation.

1. The effects of endothelin (0.1-1 nmol/L) and the phorbol ester, phorbol 12-myristate 13-acetate (PMA, 0.1-100 nmol/L) have been studied on vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline in the rabbit isolated ear artery. 2. Endothelin (0.1 nmol/L) significantly enhanced the biphasic response of the arteries to a prolonged period of sympathetic nerve stimulation (2 Hz for 60 s). Both the component of the response attributable to mobilization of intracellular calcium (phasic response) and the component due to the influx of extracellular calcium (tonic response) were enhanced. 3. PMA (0.1 and 0.3 nmol/L), which activates protein kinase C, enhanced vasoconstrictor responses to noradrenaline but a higher concentration of PMA (100 nmol/L) inhibited responses to noradrenaline. 4. It is concluded that the enhancement of responses to sympathetic nerve stimulation and noradrenaline produced by endothelin may be due to facilitation of the influx of extracellular calcium and to the activation of protein kinase C.

Animals↗
PubMed1990

Responses of rat isolated intestinal segments to stimulation of perivascular mesenteric nerve fibres.

1. Isolated preparations of segments of rat jejunum were set up for isotonic recording of the activity of the longitudinal smooth muscle and the extrinsic nerve supply running with the mesenteric blood vessels was stimulated for 30-s periods at 0.5-20 Hz. 2. Contractions were regularly elicited during periods of stimulation at 0.5-2 Hz, and were usually elicited during stimulation at 5 Hz, but relaxations were usually elicited during stimulation at 10 and 20 Hz. On cessation of the period of stimulation, a secondary contraction occurred in most preparations regardless of whether the primary response during the period of stimulation had been a contraction or a relaxation. 3. Tetrodotoxin (0.9 microM) abolished responses during periods of stimulation and the secondary contraction. 4. The relaxations were mimicked by noradrenaline and were abolished by blockade of alpha- plus beta-adrenoceptors but were not affected by hexamethonium, indicating that they are attributable to stimulation of postganglionic noradrenergic fibres. 5. The contractions were mimicked by acetylcholine and were abolished by atropine and hexamethonium, suggesting that they are attributable to stimulation of preganglionic cholinergic nerves: they were also abolished in the presence of capsaicin, indicating that sensory neuropeptide-containing nerve fibres may be involved. 6. The secondary contraction that usually occurred on cessation of stimulation was still present after blockade by atropine or capsaicin of the contractions occurring during stimulation. It was also present after blockade by propranolol and phentolamine of the relaxations occurring during stimulation, and was not affected by indomethacin.

Animals↗
PubMed1990

Effects of omega-conotoxin GVIA on autonomic neuroeffector transmission in various tissues.

1. The effects of omega-conotoxin GVIA (conotoxin), a potent inhibitor of neuronal N-type Ca2+ channels, have been examined on responses to stimulation of noradrenergic, cholinergic and non-adrenergic, non-cholinergic (NANC) nerves in a range of isolated tissues to investigate the role of conotoxin-sensitive Ca2+ channels in neurotransmission. 2. Contractions elicited by field stimulation of noradrenergic nerves in rat and mouse anococcygeus muscles, rabbit ear artery and rat vas deferens (epididymal portion) were inhibited by conotoxin. Responses to noradrenaline, and to adenosine triphosphate in the vas deferens, were not affected. 3. Positive chronotropic responses to field stimulation of noradrenergic nerves were inhibited by conotoxin in rat and mouse atria, but responses to noradrenaline and tyramine were not affected. 4. The stimulation-induced release of noradrenaline was inhibited by conotoxin in the rabbit ear artery and in rat and mouse atria. 5. Relaxations in response to stimulation of the noradrenergic perivascular mesenteric nerves were reduced or abolished by conotoxin in rat and rabbit jejunum. The response to noradrenaline in rat jejunum was not affected. 6. Contractions elicited by stimulation of cholinergic nerves were inhibited by conotoxin in rat jejunum and mouse ileum (perivascular mesenteric nerves), and in guinea-pig taenia caeci (field stimulation). Responses to acetylcholine in rat jejunum and mouse ileum were not affected. 7. Contractions elicited by stimulation of the cholinergic plus NANC pelvic nerves were inhibited by conotoxin in rabbit colon, and to a lesser extent in guinea-pig colon. The stimulation-induced contraction of the guinea-pig colon was inhibited by conotoxin by a greater proportion in the presence than in the absence of atropine. Responses to acetylcholine were not affected in the rabbit colon but were slightly reduced in the guinea-pig colon. 8. Relaxations in response to field stimulation of NANC nerves were inhibited by conotoxin in guinea-pig taenia caeci and rat gastric fundus strips, and in rat anococcygeus muscle when the tone was raised by guanethidine but not when it was raised by carbachol. The relaxations produced by sodium nitroprusside in the rat gastric fundus and anococcygeus were not affected. 9. Contractions of the rat bladder elicited by stimulation of the peri-urethral nerves, which are NANC- and cholinergically mediated, were relatively insensitive to inhibition by conotoxin. The response were almost completely abolished by tetrodotoxin. 10. The conotoxin-induced inhibitions of responses to nerve stimulation developed slowly and persisted after removal of conotoxin. The responses were almost completely abolished by tetrodotoxin. 10. The conotoxin-induced inhibitions of responses to nerve stimulation developed slowly and persisted after removal of conotoxin. 11. The inhibitory effect of conotoxin was inversely proportional to the frequency of stimulation (in several preparations) and to the Ca2+ concentration in the bathing solution (in rat vas deferens). These observations suggest that the inhibition by conotoxin of the Ca2+ influx required for excitation-secretion coupling in autonomic nerve terminals is not absolute, and can be overcome by repeated stimulation or by raising the Ca2 + concentration.

Animals↗
PubMed1989

The effect of endothelin on noradrenergic transmission in rat and guinea-pig atria.

Pre-and postjunctional effects of 10 nM endothelin have been studied in rat and guinea-pig spontaneously beating isolated atria. Endothelin increased the rate and force of contraction of atria from both species, but decreased the positive inotropic and chronotropic responses to stimulation of intramural sympathetic nerves by approximately 60% in rat and by 10-15% in guinea-pig atria. The stimulation-induced release of noradrenaline from either rat or guinea-pig atria was not significantly changed by endothelin.

Animals↗
PubMed1989

Prejunctional inhibition of non-adrenergic non-cholinergic transmission in the rat anococcygeus muscle.

The muscarinic agonist McN-A-343 did not affect the tone or nitroprusside-induced relaxations of the rat anococcygeus, but inhibited non-adrenergic non-cholinergic (NANC) relaxations. Atropine, pirenzepine and gallamine blocked the McN-A-343 inhibition of NANC relaxations. Agonists of alpha 1-(methoxamine) or alpha 2-adrenoceptors (clonidine, rilmenidine) increased tone and reduced NANC relaxations. Carbachol also increased tone but produced a greater reduction of NANC relaxations. The findings suggest that activation of prejunctional muscarinic receptors on NANC terminals inhibits transmitter release, but there is no evidence for prejunctional alpha-adrenoceptors.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1989

Neuropharmacological effects of nicotine in relation to cholinergic mechanisms.

Studies with nicotine have, from the outset, been of fundamental importance for the elucidation of physiological mechanisms. However, many nicotinic cholinoreceptors do not appear to subserve a physiological role, at least within the present framework of knowledge. The main challenge in the immediate future is to determine the functional role of nicotinic cholinoceptors in the CNS. This knowledge will not only add to the physiological mechanisms that have been unravelled as a result of studies with nicotine, but will also provide a major contribution to the understanding of tobacco use.

Acetylcholine↗
PubMed1989

Inhibition of sympathetic neurotransmission by the opioid delta-receptor agonist DAMA in the pithed rat.

1. The effects of [D-Ala2,Met5]enkephalinamide (DAMA), an analogue of [Met5]-enkephalin that acts selectively on opioid receptors of the delta-subtype, were studied on pressor responses elicited by sympathetic stimulation in pithed rats. 2. Intravenous injections of bolus doses of 0.1 mg/kg and 0.3 mg/kg of DAMA did not affect either the basal blood pressure or pressor responses to noradrenaline. 3. Pressor responses elicited either by electrical stimulation of the spinal sympathetic outflow or by stimulation of sympathetic ganglion cells with the muscarinic agonist McN-A-343 were reduced by DAMA. 4. Naloxone (1 mg/kg + 0.5 mg/kg per h) had no significant effect on the basal blood pressure or on pressor responses to spinal sympathetic stimulation, but antagonised the inhibitory effect of DAMA. 5. These results indicate that activation of opioid delta-receptors on sympathetic vasomotor nerve terminals can inhibit noradrenergic neurotransmission.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1989

Paradoxical effects of endothelin on cardiovascular noradrenergic neurotransmission.

1. Pre- and postjunctional effects of endothelin (1-10 nmol/L) have been studied in the rabbit isolated ear artery and in rat isolated atria. 2. Endothelin produced concentration-dependent increases in arterial perfusion pressure, and had positive chronotropic and inotropic effects in rat atria. 3. Vasoconstrictor responses of the arteries to sympathetic nerve stimulation were reduced by 1 nmol/L endothelin and abolished by 10 nmol/L endothelin. In rat atria, the chronotropic responses to nerve stimulation were markedly reduced by 10 nmol/L endothelin. 4. In rabbit ear artery, vasoconstrictor responses to noradrenaline were enhanced by 1 nmol/L endothelin, but were reduced by 10 nmol/L endothelin. In rat atria, endothelin reduced the chronotropic response to isoprenaline. 5. Endothelin (10 nmol/L) increased the stimulation-induced release of radioactivity in arteries and atria labelled with [3H]-noradrenaline by 91% and 23%, respectively. 6. The pre- and postjunctional effects of endothelin persisted in both arterial and atrial preparations for at least 30 min after its removal.

Animals↗
PubMed1989

Does suppression of responsiveness to beta-adrenoceptor activation explain the enhancement of vasoconstrictor responses by alpha 2-adrenoceptor agonists?

1. The alpha 2-adrenoceptor agonist TL99, in concentrations that had no other observable effect, enhanced constrictor responses to phenylephrine in perfused segments of the rat tail artery. 2. Vasoconstrictor responses to phenylephrine were also enhanced by propranolol (0.3 mumol/L). 3. Vasoconstrictor responses to phenylephrine in the presence of propranolol were further enhanced by TL99 (10 nmol/L). 4. The enhancement of vasoconstrictor responses by alpha 2-adrenoceptor agonists is not due to the removal of a counteracting vasodilator component produced by activation of beta-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1989

Amplification by serotonin of responses to other vasoconstrictor agents in the rat tail artery.

1. A low concentration of serotonin (3 nmol/L), which did not exert a direct vasoconstrictor action, amplified the responses to certain other vasoconstrictor agents (alpha 1-adrenoceptor agonists, KCl, ATP and vasopressin) in isolated perfused segments of the rat tail artery. 2. Low concentrations of serotonin (0.3 and 1 nmol/L) amplified vasoconstrictor responses to sympathetic nerve stimulation, but higher concentrations of serotonin (10 and 30 nmol/L) produced vasoconstriction and reduced responses to sympathetic nerve stimulation. 3. The calcium channel blocking drug diltiazem (1 and 10 mumol/L) produced concentration-dependent reductions of vasoconstrictor responses to phenylephrine. The amplifying effect of serotonin on responses to phenylephrine was attenuated by 1 mumol/L and abolished by 10 mumol/L diltiazem, and was also abolished in a Ca2+-free medium. 4. Ketanserin (10 nmol/L) antagonized the vasoconstrictor action of serotonin and, to a lesser extent, the vasoconstrictor actions of phenylephrine and noradrenaline. It abolished the amplifying effect of a low concentration of serotonin on responses to noradrenaline and phenylephrine. 5. The amplification of vasoconstrictor response in the rat tail artery by serotonin appears to be due to activation of receptors of the 5-HT2 subtype which are coupled to an increase in Ca2+ influx into the vascular smooth muscle cells.

Animals↗
PubMed1989

Facilitation of noradrenaline release by isoprenaline in rat isolated atria does not involve angiotensin II formation.

1. Rat isolated atria were incubated with 3H-noradrenaline and the intramural sympathetic nerves were stimulated at 2 Hz for 60 s. The stimulation-induced (SI) efflux of radioactivity was used as an index of release of transmitter noradrenaline. 2. Isoprenaline (0.1 mumol/L) alone did not increase noradrenaline release. Cocaine (30 mumol/L) produced a 73% increase in the stimulation-induced release of noradrenaline. In the presence of cocaine, isoprenaline enhanced noradrenaline release by 22%. 3. In the presence of cocaine, both angiotensin I (0.3 mumol/L) and angiotensin II (0.3 mumol/L) produced almost two-fold enhancements in the SI release of noradrenaline. 4. Captopril (5 mumol/L) blocked the facilitatory effect of angiotensin I on noradrenaline release but did not alter that of isoprenaline. 5. Saralasin (0.1 mumol/L) reduced the facilitatory effect of angiotensin II on noradrenaline release but did not alter that of isoprenaline. 6. The findings indicate that the facilitation of noradrenaline release by isoprenaline in rat atria is not mediated by local formation of angiotensin II.

Angiotensin I↗