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Biomedical subjects

R Massingham

Publications and source records attributed to R Massingham.

At least 55 records · Page 3Linked to original sources
PubMed1981

In vitro studies on 6-fluoronoradrenaline at several peripheral sympathetic neuroeffector junctions.

A comparison of the effects of noradrenaline and 6-fluoronoradrenaline has been made at several peripheral sympathetic neuroeffector junctions. In the rat vas deferens preparation in the presence of 1 microM cocaine, 6-fluoronoradrenaline was found to be about 9 times more potent than noradrenaline as an agonist at presynaptic inhibitory alpha 2- adrenoceptors. In the rabbit aorta, 6-fluoronoradrenaline had approximately one tenth of the potency of noradrenaline in stimulating the postsynaptic alpha 1-adrenoceptors. Furthermore 6-fluoronoradrenaline, in contrast to previous reports, appears to be a substrate for the neuronal uptake process since exposure to cocaine potentiated the inhibition of the twitch response of the vas deferens by 6-fluoronoradrenaline. In addition, 6-fluoronoradrenaline increased the spontaneous outflow of radioactivity from rabbit pulmonary artery strips prelabelled with 3H-noradrenaline and this increase was blocked by cocaine (30 microM). These results demonstrate that 6-fluoronoradrenaline is a preferential alpha 2-adrenoceptor agonist which is a substrate for the neuronal uptake process in peripheral sympathetically innervated smooth muscle preparations.

Animals↗
PubMed1981

Pre- and postsynaptic alpha adrenoceptor selectivity studies with yohimbine and its two diastereoisomers rauwolscine and corynanthine in the anesthetized dog.

The selectivity of yohimbine and its two diastereoisomers rauwolscine and corynanthine for pre- and postsynaptic alpha adrenoceptors has been investigated in the anesthetized dog. Antagonism of the inhibitory effect of clonidine on the tachycardia produced by electrical stimulation of the ansa subclavia was used as a measure of presynaptic alpha-2 adrenoceptor blockade. Inhibition of the diastolic pressor response to phenylephrine in ganglion and beta blocked dogs was used as a measure of postsynaptic alpha-1 adrenoceptor blockade. All three of the isomers reduced, and at higher doses reversed, the inhibitory effect of clonidine Yohimbine and rauwolscine were equipotent in this respect and were approximately 100-fold more potent than corynanthine. However, all the isomers were equipotent as antagonists of the diastolic pressure response to phenylephrine. Yohimbine and rauwolscine were approximately 30 times more potent as alpha-2 adrenoceptor than alpha-1 adrenoceptor antagonists, whereas corynanthine was 10-fold more potent at alpha-1 adrenoceptors than at alpha-2 adrenoceptors. These results are in broad agreement with those previously reported from in vitro experiments showing yohimbine and rauwolscine to be preferential alpha-2 adrenoceptor antagonists and corynanthine to be a preferential alpha-1 adrenoceptor antagonist. It is concluded that the high affinity of the antagonists yohimbine and rauwolscine for alpha-2 adrenoceptors is responsible for their selectivity because at the level of blockade of postsynaptic alpha-1 adrenoceptors both isomers were equipotent with corynanthine.

Animals↗
PubMed1980

The role of presynaptic receptors in the cardiovascular actions of N,N-di-n-propyldopamine in the cat and dog.

Intravenous administration of N,N-di-n-propyldopamine (DPDA: 50 and 200 micrograms/kg/min, i.v.) produces hypotensive and bradycardic effects in anaesthetized cats and dogs. These effects were abolished by ganglionic blockade and antagonized by haloperidol or (SR)-sulpiride suggesting a neurogenic mechanism of action, mediated by specific dopamine receptors. The renal blood flow increases to DPDA in dogs were resistant to ganglionic blockade indicating some activity at postsynaptic vascular dopamine receptors. Studies with DPDA in vivo administered via the intravertebral and intravenous routes suggested a peripheral site of action for the hypotensive effects of this compound. In vitro, in isolated perfused cat spleens prelabeled with 3H-noradrenaline, DPDA (0.01--1 microM) produced a concentration-dependent inhibition of tritium release elicited by nerve stimulation at 1 Hz which was selectively antagonized by 1 microM (SR)-sulpiride implicating presynaptic inhibitory dopamine receptors in the mediation of this effect. In isolated rabbit splenic arteries, contracted by prostaglandin-F2 alpha, dopamine,ADTN (2-amino-6,7-dihydroxytetrahydronaphthalene) and apomorphine produced concentration-dependent relaxations while DPDA exhibited only weak postsynaptic dopamine-like effects. In vivo DPDA reduced, in a frequency dependent manner, the end organ responses to sympathetic nerve stimulation in the cat nictitating membrane and in the dog renal vascular bed. Both effects were mediated through activation of presynaptic inhibitory dopamine receptors by DPDA. In conclusion these results suggest a predominantly presynaptic agonist effect for DPDA in vitro and a similarly important action in vivo, mediated mainly via dopamine receptors. Furthermore evidence is presented which suggests that pre- and postsynaptic dopamine receptors may differ in their pharmacological properties and that presynaptic dopamine receptors could be important target receptors in the development of novel antihypertensive drugs.

Animals↗
PubMed1980

Presence of postsynaptic alpha 2-adrenoreceptors of predominantly extrasynaptic location in the vascular smooth muscle of the dog hind limb.

1. In the autoperfused hind limb of the dog prazosin (10 microgram/kg intravenously) markedly antagonized responses to lumbar sympathetic stimulation, whereas responses to injected noradrenaline were largely unaffected. 2. In beta-adrenoreceptor- and ganglion-blocked animals, the hind limb pressor responses to phenylephrine were antagonized to a greater degree by prazosin than responses to injected noradrenaline. 3. Rauwolscine, a selective alpha 2-adrenoreceptor-blocking agent, antagonized responses to the alpha 2-adrenoreceptor agonist guanabenz, but not those to phenylephrine. 4. Hind limb pressor responses to noradrenaline were significantly inhibited by rauwolscine and further reduced by prazosin. 5. These results demonstrate that in this vascular bed alpha 1- and alpha 2-adrenoreceptors are located postsynaptically. Furthermore the results suggest that neuronally released noradrenaline acts mainly upon alpha 1-adrenoreceptors, whereas exogenous noradrenaline acts upon alpha 1- and alpha 2-adrenoreceptors. 6. It is suggested that this selectivity of prazosin in blocking the vasoconstriction to neuronally-released noradrenaline may in part explain the effectiveness of this drug as an antihypertensive agent.

Adrenergic alpha-Antagonists↗
PubMed1980

Lack of correlation between presynaptic inhibition of noradrenaline release and end organ responses during nerve stimulation.

1 LD 3098 (cirazoline) is an imidazoline derivative, possessing agonist properties at alpha-adrenoceptor sites.2 When transmitter release was measured directly as tritium overflow from perfused cat spleen preparations, prelabelled with [(3)H]-noradrenaline, LD 3098 was found to be 10 times more selective for presynaptic than for postsynaptic alpha-adrenoceptors.3 In addition, in this preparation, LD 3098 appears to induce a postsynaptic sensitization to the transmitter released by nerve depolarization because under conditions in which [(3)H]-noradrenaline overflow decreased, there was a paradoxical potentiation in the response to nerve stimulation. This potentiation also occurred with a concentration of LD 3098 that did not per se affect stimulation-evoked [(3)H]-noradrenaline release or the basal perfusion pressure of the spleen.4 Both the reduction in (3)H-transmitter release induced through activation of alpha-presynaptic adrenoceptors and the potentiation of the responses to nerve stimulation were concentration-dependent phenomena.5 In pentobarbitone anaesthetized dogs, the heart rate response to low frequency ansa-subclavia stimulation was not affected by LD 3098. Whilst the alpha(1) mediated increase in blood pressure responses to injected noradrenaline and tyramine was significantly potentiated by LD 3098, the beta(1)-mediated heart rate responses to these injected amines were not modified in the presence of LD 3098.6 Thus it is possible that the failure to detect any presynaptic effects with LD 3098 when transmitter release is measured indirectly at the level of the postsynaptic responses is due to end organ sensitivity changes.7 These findings emphasize that caution is necessary when assessing presynaptic alpha-adrenoceptor effects through end organ responses to nerve stimulation both in vitro and in vivo and the need for measurements of transmitter overflow as well as adequate postsynaptic controls in such experiments.

Animals↗
PubMed1975

A comparsion of the effects of prazosin and hydrallazine on blood pressure, heart rate and plasma renin activity in conscious renal hypertensive dogs.

Prazosin, a novel antihypertensive agent, and hydrallazine have been compared in renal hypertensive dogs. I.v. prazosin (0.1 mg/kg) produced greater falls in blood pressure than hydrallazine (1 mg/kg i.v.) but, in contrast to hydrallazine, did not cause any significant alteration in heart rate or plasma renin activity in these animals. When given orally, prazosin (0.1 mg/kg) produced falls in blood pressure equivalent to those observed with i.v. hydrallazine (1 mg/kg) again without significant tachycardia or plasma renin activation.

Animals↗
PubMed1973

The ionic composition of aortic smooth muscle from A.S.-hypertensive rats.

The Na(+), K(+) and Ca(2+) content of plasma and aortic vascular smooth muscle from normotensive and A.S.-hypertensive rats have been compared. There was no significant difference in the plasma concentrations of Na(+), K(+) and Ca(2+), or the Na(+), K(+) and water content or (3)H-inulin space of aortic tissue in the two groups.There was a marked increase in the amount of Ca(2+) in the aortae taken from the hypertensive animals as compared with the normotensive animals (P<0.01).

Animals↗