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Biomedical subjects

R Massingham

Publications and source records attributed to R Massingham.

64 records · Page 4Linked to original sources
PubMed1972

The nature of the positive inotropic response of the isolated frog heart to theophylline and to iminazole.

1. The mechanism of the positive inotropic responses to theophylline and to iminazole has been examined in the frog heart.2. Both theophylline and iminazole caused positive inotropic effects which declined to control amplitude with time despite continued exposure to the drugs. The duration of the response to iminazole was always longer than that to theophylline.3. On washout of theophylline and iminazole the amplitude of heart beat slowly decreased to a value below that in the control period.4. The theophylline response was not prevented by phentolamine or by propranolol given separately or in combination.5. Theophylline potentiated the staircase and prolonged the post-stimulation potentiation phenomena when its own inotropic activity had subsided but iminazole reduced the staircase effect at this time.6. Theophylline, iminazole and 3 x [Ca(2+)](o) all increased the influx of (45)Ca into isolated ventricles. Theophylline increased but iminazole and 3 x [Ca(2+)](o) slightly reduced (45)Ca efflux.7. Total cell calcium changes were only detected in ventricles exposed for 15 min to 3 x [Ca(2+)](o) or theophylline (5 x 10(-3)M). After 60 min exposure to theophylline the total cell calcium was not significantly different from controls.8. It is concluded that the positive inotropic responses to theophylline and iminazole can be interpreted in terms of the increased calcium influx which they produce and that interpretation of effects in terms of their action on phosphodiesterase should be treated with reservation.

Animals↗
PubMed1971

Aortic reactivity and electrophysiology in normotensive rats, spontaneously hypertensive rats and rats made hypertensive with desoxycorticosterone plus salt.

The mechanical and electrophysiological activity of rings and strips of thoracic aortic smooth muscle taken from normotensive, DOCA-hypertensive and New Zealand spontaneously hypertensive (A.S. strain) rats have been compared. Aortae from A.S.-hypertensive rats developed less tension in the presence of noradrenaline and K+ than those isolated from normotensive and DOCA-hypertensive rats. Aortae from DOCA-hypertensive rats developed the same tension in response to K+ as normotensive rats but were less reactive to noradrenaline. Measurements of resting membrane potentials from the three groups of rats demonstrated that whereas normotensive and DOCA-hypertensive rats had similar resting membrane potentials, those from A.S.-hypertensive rats were significantly lower (P<0.001). It is suggested that the enhanced responsiveness of intact vascular beds in A.S.-hypertensive rats is a consequence of a change in the geometry of the blood vessels rather than an increase in the contractor response of the smooth muscle cells.

Animals↗
PubMedDate not supplied

Comparison of in vivo acute lethal potency and in vitro cytotoxicity of 48 chemicals.

The cytotoxicity of 48 compounds included in the MEIC (Multicenter Evaluation of In Vitro Cytotoxicity) list was determined in cultures of rat hepatocytes, McCoy, and MDBK cells. The average minimum concentration of each compound inducing cytotoxicity was measured in each cell type. The cytotoxicity values were then compared with published oral LD50 values for rats and mice. The logarithmic transformation of in vivo toxic doses and the corresponding in vitro cytotoxic concentrations showed a statistically significant correlation between the in vitro and in vivo values. The results show that an accurate in vivo LD50 dose could be predicted from in vitro data for at least 75% of the selected compounds. It is hoped that this finding will not only stimulate others to pursue in vitro technique but will eventually lead to elimination of the in vivo LD50 test.

Animal Testing Alternatives↗
PubMedDate not supplied

Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents.

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Preferential noradrenergic innervation of alpha-adrenergic receptors in vascular smooth muscle.

In the isolated perfused hindlimb preparation of the dog, pressor responses to norepinephrine (NE) are mediated by postsynaptic alpha 1- and alpha 2-adrenergic receptors. Results obtained using preferential alpha 1- and alpha 2-adrenergic receptor antagonists suggest that the alpha 1-subtype is predominantly innervated while both alpha 1- and alpha 2-adrenergic receptor subtypes in vascular smooth muscle are accessible to circulating agonists and antagonists. Preliminary studies in the isolated perfused cat spleen support these in vivo findings in the dog. In contrast to vascular smooth muscle, the cat nictitating membrane appears to contain only alpha 1-adrenergic receptors postsynaptically.

Animals↗
PubMedDate not supplied

Effects of the 5-hydroxytryptamine1A receptor agonists, 8-OH-DPAT, buspirone and flesinoxan, upon brain damage induced by transient global cerebral ischaemia in gerbils.

The effects of the 5-hydroxytryptamine1A agonists, 8-OH-DPAT, buspirone and flesinoxan, on the delayed hyperactivity and on the ensuing neuronal degeneration induced by transient global cerebral ischaemia, were studied. In normothermic, male Mongolian gerbils, subjected to 3 min bilateral carotid artery ligation, the locomotor activity was measured 1 day after ischaemia. The neuronal damage was quantified 7 days later using an image analysis system. Buspirone (3 and 10 mg/kg, i.p.) and flesinoxan (1 and 3 mg/kg, i.p.), administered twice a day for 3 days both in pre- and post-ischaemic conditions, failed to significantly protect the CA1 zone of the hippocampus against neuronal damage. In contrast, 8-OH-DPat (1 and 3 mg/kg, i.p.) significantly reduced the neuronal degeneration. All compounds abolished the hyperactivity but there was no correlation between this parameter and the extent of the reduction in neuronal damage. The ineffectiveness of buspirone and flesinoxan was not the result of too low a dose - as evidenced by the complete inhibition of hyperactivity with both compounds and by the appearance of a serotonin behavior syndrome with flesinoxan - but is possibly related to a partial agonist activity at the 5-hydroxytryptamine1A receptor, as reported for buspirone. Further studies are necessary to explain the differences between these agonists.

8-Hydroxy-2-(di-n-propylamino)tetralin↗