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S A Doggrell

Publications and source records attributed to S A Doggrell.

At least 91 records · Page 5Linked to original sources
PubMed1986

On the assessment of the beta-adrenoceptor blocking activity of propranolol using the rat isolated right ventricle.

Two methods for determining pA2 values, the Schild regression and the use of the formula pA2 = pAx + log(x - 1), have been reassessed. The effects of propranolol on the contractile responses of the rat isolated right ventricle to isoprenaline were studied. The inhibitory effect with the lower concentrations of propranolol tested (3 X 10(-9) -10(-7) M) was solely competitive. Thus there was a parallel dextral displacement of the concentration-response curves to isoprenaline with no depression of the maximal responses. Dual antagonism was observed with the higher concentrations of propranolol tested (10(-6) and 3 X 10(-6) M), thereby showing a parallel displacement of the concentration-response curve to the lower concentrations of isoprenaline with a depression of the maximal responses. Without analysis of data for individual concentrations of propranolol on concentration-response curves to isoprenaline, Schild regression did not clearly illustrate that the antagonism was not solely competitive with the higher concentrations of propranolol. We suggest that data for individual concentrations of antagonist should always be analyzed to ascertain whether there has been a parallel shift of the concentration-response curves to agonist prior to determining pA2 values.

Adrenergic beta-Antagonists↗
PubMed1986

M1 and M2-muscarinic receptors in the epididymal half of the rat vas deferens.

The inhibitory effects of atropine and pirenzepine (nonselective and M1-selective antagonists, respectively) on the contractile responses of the epididymal half of the rat vas deferens to methacholine included a depression of the maximal response. In the presence of pirenzepine, atropine was a competitive antagonist of the responses to methacholine. However in the presence of atropine, pirenzepine remained a non-competitive inhibitor of the response. It is suggested that low concentrations of methacholine predominantly stimulate M2-receptors and that at high concentrations, methacholine also stimulates M1-receptors.

Animals↗
PubMed1986

The effects of KF-4317, a novel combined alpha- and beta 1-adrenoreceptor antagonist, on the rat isolated right ventricle and aorta.

The effects of KF-4317 on the accumulation of radioactivity from [3H]-noradrenaline, and on the subsequent spontaneous and noradrenergic nerve-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition the effects of KF-4317 on the contractions of the electrically-driven directly muscle stimulated rat right ventricle to isoprenaline and of the rat isolated aorta to phenylephrine and 5-hydroxytryptamine are reported. KF-4317 at 1 microM had no effect on the ability of the rat right ventricle to accumulate radioactivity from [3H]-noradrenaline. The spontaneous outflow of radioactivity, following loading of the ventricle with [3H]-noradrenaline, was increased by KF-4317 at 1 microM by a cocaine-insensitive mechanism. KF-4317 at 1 microM had no effect on the noradrenergic nerve-evoked outflow or radioactivity, and therefore is not an alpha 2-adrenoreceptor antagonist, but reduced the associated contractile response probably mainly by acting as an antagonist at postjunctional beta 1-adrenoreceptors. KF-4317 caused a parallel rightward shift of the concentration-response curve of the electrically-driven directly muscle stimulated rat right ventricle to isoprenaline. However the inhibitory effect, X9.0 and X237.2 in the presence of 0.1 and 1 microM KF-4317, was not closely concentration-related. At 1 microM, KF-4317 also depressed the maximum responses to isoprenaline. This suggests that in addition to beta 1-adrenoreceptor antagonism, KF-4317 probably exerts membrane stabilizing activity. The responses of the rat isolated aorta to phenylephrine were inhibited in a non-concentration related manner by KF-4317.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1985

Modification by desipramine of the effects of alpha-adrenoceptor antagonists on the contractile responses of the trisected rat vas deferens.

Desipramine at 10(-7) M inhibited the neuronal uptake of noradrenaline and at 10(-6) M was also a alpha 1-adrenoceptor blocker. Desipramine potentiated and inhibited the responses of the epididymal and other portions to field stimulation, respectively, probably because the increased concentration of noradrenaline in the synapse was stimulating postjunctional alpha 1- and prejunctional alpha 2-adrenoceptors, respectively. Qualitatively the effects of prazosin, phentolamine and yohimbine on responses to added noradrenaline and to field stimulation were consistent with their being alpha 1-selective, nonselective and alpha 2-selective adrenoceptor antagonists. Quantitatively the effects of phentolamine and/or yohimbine on fast and slow responses to field stimulation and the modification of these effects by desipramine were dependent on the portion of vas, the response, the frequency of stimulation and the concentration of desipramine used.

Adrenergic alpha-Antagonists↗
PubMed1985

The effects of amosulalol, a novel combined alpha- and beta-adrenoreceptor antagonist, on the rat isolated right ventricle and aorta.

The effect of amosulalol on the accumulation of radioactivity from [3H]-noradrenaline and on the subsequent spontaneous and nerve stimulation-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition the effect of amosulalol on the contractions of the electrically-driven directly muscle stimulated rat right ventricle to isoprenaline and of the rat isolated aorta to phenylephrine and 5-hydroxytryptamine are reported. Amosulalol at 10(-6)M did not prevent the accumulation of radioactivity from a solution containing [3H]-noradrenaline. The spontaneous outflow of radioactivity, following loading of the ventricle with [3H]-noradrenaline, was increased by amosulalol at 10(-6)M by a cocaine- and idazoxan- insensitive mechanism. The nerve stimulation-evoked outflow of radioactivity was increased by amosulalol (10(-6)M), cocaine (10(-5)M) and idazoxan (10(-7)M). The ability of amosulalol to increase nerve-evoked outflow was maintained in the presence of cocaine but prevented by pretreatment with idazoxan. This suggests that amusulalol is an alpha 2-adrenoreceptor antagonist. The contractile response of the electrically-driven directly muscle stimulated right ventricle to isoprenaline were inhibited by amosulalol at 10(-7) and 10(-6)M with apparent pA2 values of 7.5 and 8.1, respectively. It is suggested that amosulalol at 10(-6)M may have an action additional to beta 1-adrenoreceptor antagonism on the right ventricle. The contractile responses of the rat aorta to phenylephrine were inhibited by amosulalol at 10(-7) and 10(-6)M with a pA2 of 8.6 which was independent of concentration. Amosulalol also reduced the magnitude of the maximal responses of the aorta to 5-hydroxytryptamine.

Adrenergic alpha-Antagonists↗
PubMed1985

Comparison of the effects of labetalol and SCH 19927, the R1R isomer of labetalol, on the rat isolated right ventricle and aorta.

The effects of labetalol and its R1R isomer, SCH 19927, on the accumulation of radioactivity from [3H]-noradrenaline, and on the subsequent spontaneous and nerve-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition, the effect of these agents on the contractions of the electrically-driven rat right ventricle to isoprenaline and of the rat isolated aorta to phenylephrine and 5-hydroxytryptamine are reported. Labetalol and SCH 19927 (both at 10(-6)M) inhibited the accumulation of radioactivity from [3H]-noradrenaline by 26 and 37%, respectively. The spontaneous outflow of radioactivity, following loading of the ventricle with [3H]-noradrenaline, was increased by labetalol and SCH 19927 (both at 10(-6)M) by a cocaine and idazoxan-insensitive mechanism. The nerve-evoked outflow of radioactivity was increased by labetalol and SCH 19927 (both at 10(-6)M). The ability of labetalol and SCH 19927, to increase nerve-evoked outflow was maintained in the presence of cocaine (10(-5)M) or idazoxan (10(-7)M) but reversed in the presence of cocaine and idazoxan. It is suggested that labetalol and its R1R isomer act both to inhibit neuronal uptake of noradrenaline and as antagonists at prejunctional alpha 2-adrenoreceptors. Labetalol and SCH 19927 reduced the contractile responses associated with the nerve-evoked outflow of radioactivity probably mainly by acting as antagonists at postjunctional beta 1-adrenoreceptors. The contractile responses of the electrically-driven rat right ventricle to isoprenaline were inhibited by labetalol and SCH 19927. SCH 12297 (pA2 = 8.9) was 4 times more potent than labetalol (pA2 = 8.3) as a beta 1-adrenoreceptor antagonist. The ability of labetalol and SCH 19927 at greater than or equal to 10(-7)M to depress maximal responses to isoprenaline may represent membrane stabilizing activity. The contractile responses of rat aorta to phenylephrine were inhibited by labetalol and SCH 19927. Labetalol (pA2 = 7.5) was 4X more potent than SCH 19927 (pA2 = 6.9) as an alpha 1-adrenoreceptor antagonist. SCH 19927 and labetalol had no effect on contractile responses to 5-hydroxytryptamine.

Animals↗
PubMed1985

Postjunctional effects of mianserin and its metabolites on the rat isolated anococcygeus muscle.

After rat isolated anococcygeus muscle had been treated with 6-hydroxydopamine to abolish noradrenergic transmission, the effects of mianserin and its metabolites alone on tone and on the contractile responses to methacholine and phenylephrine were studied. Mianserin (greater than or equal to 3 X 10(-5) M) and 8-hydroxymianserin (greater than or equal to 3 X 10(-6) M), but not desmethylmianserin and mianserin-N-oxide, induced contractions. The contractions to mianserin were not altered by phentolamine, atropine, cyproheptadine, ouabain and verapamil but were reduced in tissues treated with indomethacin. Thus the responses to mianserin may, in part, be mediated by the synthesis of prostaglandins. Mianserin (10(-5) M) and 8-hydroxymianserin (10(-7)-10(-5) M) potentiated, mianserin-N-oxide had no effect, and desmethylmianserin (10(-7)-10(-5) M) inhibited methacholine-induced contractions. The inhibition of responses to phenylephrine was concentration-related with desmethylmianserin (10(-7)-10(-5) M) and mianserin-N-oxide (10(-6)-10(-5) M) but not with mianserin or 8-hydroxymianserin (10(-7)-10(-5) M). The effects of mianserin and its metabolites on responses to methacholine and phenylephrine were similar in the absence and presence of indomethacin. These results suggest that mianserin and 8-hydroxymianserin increase the tissue's sensitivity to methacholine by an action at the level, or distal to, the muscarine receptor. In addition to blocking alpha 1-adrenoceptors, mianserin and 8-hydroxymianserin may have another postjunctional action at, or beyond, the alpha 1-adrenoceptor.

Animals↗
PubMed1985

Cocaine potentiates the responses to methacholine and noradrenaline in the rat vas deferens.

The ability of cocaine (10 microM) to potentiate the contractile responses of the epididymal half of the rat vas deferens to methacholine was reversed by prazosin. Prazosin also partially reversed the ability of cocaine to increase the spontaneous overflow of 3H following loading of the tissue with [3H]noradrenaline. We suggest that cocaine potentiated the responses to methacholine by stimulating, directly or indirectly, alpha 1-adrenoceptors.

Animals↗
PubMed1984

Effects of the (+/-)-, (+)- and (-)-forms of propranolol, timolol and metoprolol on noradrenergic transmission in the rat isolated right ventricle.

The effects of the (+/-)-, (+)- and (-)-forms of propranolol, timolol and metoprolol on noradrenergic transmission have been studied in the rat isolated right ventricle. (+)- And (-)-propranolol (10(-5) M) inhibited the accumulation of radioactivity from [3H]-noradrenaline. The decline in the spontaneous outflow of radioactivity, following loading of the tissue with [3H]-noradrenaline, was reduced by (+)- and (-)-propranolol (10(-5) M), (+)-timolol (10(-5) M), (-)-timolol (10(-6) - 10(-5) M) and (+)-metoprolol (10(-5) M). (+)-Propranolol, (+)-timolol (10(-6) M) and (+)- and (-)-metoprolol (10(-5) M) increased the decline in outflow of radioactivity evoked by field stimulation in the absence, but not in the presence, of lignocaine (10(-4) M), probably by decreasing nerve excitability. The ability of (-)-propranolol (10(-5) M) to increase the decline in evoked outflow was also reduced in the presence of lignocaine. (+)-Propranolol, (+)-timolol and (-)-metoprolol reduced the contractile response to field stimulation by a similar percentage in the absence or presence of lignocaine. The ability of (-)-propranolol and (+)-metoprolol (10(-5) M) to reduce contractile responses was decreased and abolished, respectively, by the addition of lignocaine. Evoked-outflow was not altered but contractile responses were inhibited by (-)-timolol (10(-7) - 10(-5) M) and (-)-metoprolol (10(-5) M). Contractile responses to isoprenaline were not altered by (+)-propranolol, (+)-timolol (10(-7) M) and (+)-metoprolol (10(-7) - 10(-6) M). (+)- Or (-)-propranolol (10(-7) M) and (+)-timolol (10(-6) M) had no effect on the rate of beating to isoprenaline but reduced the force whereas (+/-)-metoprolol (10(-7) M) had no effect on the force but reduced the rate of beating. The rate of beating and force responses to isoprenaline were reduced by (+/-)-, (+)-, (-)-propranolol (10(-6) M), (+/-)- or (-)-timolol (10(-7) - 10(-6) M), (+/-)-metoprolol (10(-6) M) and (-)-metoprolol (10(-7) - 10(-6) M). The data suggest that, in the rat isolated right ventricle, the (+)-isomers are active constituents of (+/-)-propranolol and (+/-)-timolol but not of (+/-)-metoprolol.

Animals↗
PubMed1983

The effects of iprindole on noradrenergic transmission in the rat anococcygeus muscle.

The effects of iprindole on the contractile responses to field stimulation and to exogenously applied agents have been studied in the rat anococcygeus muscle. In addition the effects on the spontaneous overflow of 3H and that induced by field stimulation (following preloading of the tissue with [3H]-noradrenaline) are reported. Iprindole (10(-7)-5 X 10(-6) M) had no effect on the contractile responses to acetylcholine. Iprindole at 10(-7) or 10(-6) M was equieffective in potentiating the contractile responses to either field stimulation or to noradrenaline. With a higher concentration of iprindole (5 X 10(-6) M) the potentiation was greater. The responses to oxymetazoline were potentiated and inhibited by iprindole at 10(-8) and 10(-7) M, respectively. Iprindole at 10(-6) M potentiated the responses to tyramine. The effects of iprindole at 10(-7) and 5 X 10(-6) M on the responses to field stimulation and to noradrenaline were not altered by the presence of ouabain (5 X 10(-5) M), neostigmine (10(-6) M) or yohimbine (10(-7) M). In the presence of desipramine (10(-6) M), iprindole at 10(-7) M potentiated the contractile responses to field stimulation and to noradrenaline. The higher concentrations of iprindole (10(-6) and 5 X 10(-6) M) inhibited the contractile responses to field stimulation and to noradrenaline in the presence of desipramine. Iprindole (10(-7) M) had no effect on the relaxant responses to field stimulation. Iprindole at 10(-7) or 10(-6) M had no effect on the spontaneous overflow of 3H or that induced by field stimulation at 2 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

On the assessment of the potency of antagonists using the rat isolated anococcygeus muscle.

The conditions required for assessing the potencies of antagonists of muscarinic and at alpha-adrenoceptors have been examined using contractility studies with the rat anococcygeus muscle. Physostigmine (5 X 10(-7) M) and atropine (10(-8)-10(-7) M) had no effect on the responses to noradrenaline. The responses to acetylcholine were potentiated by physostigmine and inhibited by atropine. Physostigmine and atropine increased the slopes of the concentration-response curves to acetylcholine. In the presence of physostigmine, atropine at 10(-8) M inhibited the responses without altering the slopes of the concentration-response curves to acetylcholine. The responses to acetylcholine were potentiated by cocaine (greater than 10(-6) M) and inhibited by phentolamine (10(-6) M). Cocaine (10(-6) - 5 X 10(-6) M) potentiated and phentolamine (10(-7) - 10(-6) M) inhibited the responses to noradrenaline. The slopes of the concentration-response curves to noradrenaline were increased by cocaine at 5 X 10(-6) M, but not at 10(-6) - 2 X 10(-6) M, and by phentolamine. In the presence of cocaine (10(-6) M), phentolamine (10(-7) - 5 X 10(-7) M) inhibited the responses and increased the slopes of the concentration-response curves to noradrenaline. These results illustrate that, in the rat anococcygeus muscle, it is possible to assess the potency of muscarinic antagonists with the method described. However, in this tissue, alpha-adrenoceptor blocking activity cannot be determined with noradrenaline as the agonist in the presence of cocaine.

Acetylcholine↗
PubMed1983

Effects of amitriptyline, desipramine and mianserin on noradrenergic transmission in the rat isolated right ventricle.

The effects of amitriptyline, desipramine and mianserin on the accumulation of radioactivity from [3H]-noradrenaline, and on the subsequent spontaneous and field stimulation-evoked outflow of radioactivity have been investigated in the rat isolated right ventricle. In addition the effect of these agents on contractions produced by isoprenaline or by field stimulation are reported. Amitriptyline, desipramine (both at greater than or equal to 10(-8) M) and mianserin at greater than or equal to 10(-7) M inhibited the accumulation of radioactivity from [3H]-noradrenaline. The decline in the spontaneous outflow of radioactivity, following loading of the tissue with [3H]-noradrenaline, was not altered by amitriptyline, desipramine or mianserin. Rauwolscine, amitriptyline, desipramine and mianserin (all at 10(-6) M) reduced or reversed the decline in outflow of radioactivity evoked by field stimulation at 5 Hz. Desipramine had no additional effects in the presence of cocaine (10(-5) M) and amitriptyline and mianserin had no further effect in the presence of cocaine and rauwolscine. The effect of desipramine probably represents inhibition of neuronal uptake and that of amitriptyline and mianserin blockade of neuronal uptake and prejunctional alpha 2-adrenoreceptors. The rate of beating in the presence of isoprenaline (10(-6) M) was reduced by amitriptyline (10(-7) M), desipramine (10(-6) M) and mianserin (10(-7)--10(-6) M). Higher concentrations of the antidepressants greatly reduced or abolished the rate and force of beating in the presence of isoprenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗
PubMed1982

The effects of cocaine and lignocaine on the rat right ventricle in vitro.

1 The effects of cocaine and lignocaine on the contractile responses to field stimulation and to exogenously applied agents, in the absence of other stimuli, have been investigated in the rat right ventricle using methods we have recently described (Doggrell & Vincent, 1981a). In addition the effects of 3H accumulation from (-)-[3H]-noradrenaline and on the spontaneous and field stimulation-induced overflow of 3H, following preloading of the tissue with (-)-[3H]-noradrenaline, are reported. 2 Cocaine, but not lignocaine, inhibited the accumulation of 3H from (-)-[3H]-noradrenaline. The spontaneous overflow of 3H, following preloading of the tissue with (-)-[3H]-noradrenaline was not altered by cocaine, 10 microM, or lignocaine, 100 microM. 10 microM Lignocaine had no effect on the overflow of 3H evoked by field stimulation at 5Hz. Lignocaine, 100 microM, increased and cocaine, 1 and 10 microM, reduced the decline in evoked release of 3H. This effect of lignocaine probably represents a decrease in nerve excitability and that of cocaine inhibition of neuronal uptake of noradrenaline. 3 Cocaine, 1 microM, reduced the rate of beat response to tyramine, 1 microM, alone probably by inhibiting the neuronal uptake process. 4 Cocaine, 1 and 10 microM, had no effect on the contractile responses to field stimulation (at 2 and/or 5 Hz). The rate of beat (-)-noradrenaline or (-)-isoprenaline, 1 microM, alone was decreased by cocaine, 10 microM. Lignocaine, 10 microM, reduced the force of contractions to field stimulation at 5 Hz and the responses to (-)-noradrenaline or (-)-isoprenaline alone. It is suggested that the inhibitory effects of cocaine and lignocaine on responses to (-)-isoprenaline in the rat right ventricle are due to a decreased postjunctional membrane excitability. The inability of 10 microM cocaine to potentiate contractile responses to endogenous or exogenous (-)-noradrenaline as a consequence of the inhibition of neuronal uptake is also probably due in part to decreased post-junctional excitability of the right ventricle.

Animals↗
PubMed1981

Cholinergic component of the excitatory response in the rat anococcygeus muscle.

The effects of neostigmine and atropine on the excitatory response of the rat anococcygeus muscle to field stimulation have been studied. The excitatory responses were inhibited and abolished by 0.1 and 3 micro M phentolamine, respectively. Neostigmine, 1 micro M, by itself and in the presence of 0.1 micro M phentolamine potentiated responses. In the presence of 3 micro M phentolamine neostigmine restored responses to 1-20 HZ. Atropine, 1 micro M by itself, in the presence of neostigmine (1 micro M), and in the presence of neostigmine and phentolamine (0.1 micro M) inhibited the response. Hexamethonium, 100 micro M, had no effect on responses to field stimulation or to exogenously applied (-)-noradrenaline. Responses to (-)-noradrenaline were not altered by neostigmine or atropine. It is suggested that there is a cholinergic component to the excitatory response to field stimulation in the rat anococcygeus muscle.

Acetylcholine↗