Biomedical subjects

S A Doggrell

Publications and source records attributed to S A Doggrell.

At least 73 records · Page 4Linked to original sources

PubMed1992

Effects of (+/-)-, (+)- and (-)-celiprolol on the rat left atria and portal vein.

Differing effects of (+/-)-celiprolol at beta-adrenoceptors have been reported. The effects of (+/-)-, (+)- and (-)-celiprolol on the contractile responses of the rat left atria and portal vein have therefore been studied. (+/-)-Celiprolol did not augment the responses of the atria to electrical stimulation and is therefore not an agonist at beta 1-adrenoceptors. Prolonged treatment with (+/-)-celiprolol attenuated the contractile activity of the vein and this effect was blocked by ICI 118,551 and is therefore mediated by agonism at beta 2-adrenoceptors. The pA2 values for (+/-)-, (+)- and (-)-celiprolol at the beta 1-adrenoceptors of the atria were 8.0, 6.0 and 8.6, respectively. On the protal vein, (+/-)- and (-)-celiprolol produced non-parallel rightward shifts of log isoprenaline attenuation curves with a reduction in isoprenaline maximum responses. This effect of (+/-)-celiprolol on the vein was not due to slowly reversible antagonism, as the inhibitory effect of (+/-)-celiprolol was readily reversible.

Adrenergic beta-Antagonists↗

PubMed1992

The effects of labetalol and dilevalol on isolated cardiovascular preparations of the guinea-pig and rat.

Differing effects of labetalol and dilevalol on cardiovascular preparations have been reported. I have studied the effects of labetalol and dilevalol on the contractile responses of the rat and guinea-pig left atria and rat portal vein. On the guinea-pig left atria low concentrations of labetalol (> or = 10(-8) M) and of dilevalol (> or = 10(-7) M) inhibited to a small extent the responses to electrical cardiac stimulation, which is indicative of membrane stabilizing activity. Labetalol (> or = 3 x 10(-8) M) and dilevalol (> or = 10(-8) M) caused surmountable antagonism of the isoprenaline responses of the atria and the pA2 values were 8.60 and 8.98 at the beta 1-adrenoceptors of the rat left atria and 7.90 and 8.31, respectively, on the guinea-pig left atria which has functional beta 1- and beta 2-adrenoceptors. Labetalol and dilevalol (both at > or = 10(-7) M) attenuated the spontaneous contractile activity of the rat portal vein and the attenuation to labetalol at 10(-6) M was abolished by ICI 118,551 which illustrates that the labetalol-induced attenuation is beta 2-adrenoceptor mediated. The isoprenaline attenuation responses of the portal vein were inhibited by labetalol and dilevalol (both at > or = 10(-7) M) and the pA2 value for the labetalol at beta 2-adrenoceptors was 7.59. It is concluded that labetalol and dilevalol are beta 1-adrenoceptor selective antagonists.

Animals↗

PubMed1991

Effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the rat left atria and portal vein.

1. The effects of (+/-)- (+)- and (-)-metoprolol, (+/-)- (+)- and (-)-pindolol, (+/-)-mepindolol and (+/-)-bopindolol on the beta 1-adrenoceptor mediated responses of the rat left atria and the beta 2-adrenoceptor mediated responses of the rat portal vein to isoprenaline have been determined. 2. Racemic and (-)-metoprolol were selective beta 1-adrenoceptor antagonists. (+)-Metoprolol was devoid of beta-adrenoceptor antagonistic activity. 3. Racemic and (-)-pindolol were potent and (+)-pindolol was a modest beta-adrenoceptor antagonist. 4. (+/-)-Mepindolol and (+/-)-bopindolol were apparently competitive antagonists of the isoprenaline beta 1-adrenoceptor mediated responses of the rat left atria but non-competitive antagonists of the isoprenaline beta 2-adrenoceptor mediated responses of the rat portal vein. 5. It is suggested that (+/-)-mepindolol and (+/-)-bopindolol are slowly dissociating beta-adrenoceptor antagonists and the non-competitive antagonism can only be detected on tissues with modest receptor reserves for maximum responses to isoprenaline.

Adrenergic beta-Antagonists↗

PubMed1990

Assessment of the beta 2 adrenoceptor and Ca2+ channel-blocking activity of drugs with the rat portal vein.

The rat portal vein has spontaneous mechanical activity. The effects of beta-adrenoceptor agonists and antagonists and verapamil alone and together on this mechanical activity have been determined. Isoprenaline, but not dobutamine, attenuated the contractile activity. Three successive challenges to isoprenaline produced identical attenuation curves. The responses to isoprenaline were antagonized by propranolol, metoprolol, and ICI 118,551, and the pA2 values, derived by Schild analysis, were 9.12, 6.78, and 9.33, respectively. Thus, the rat portal vein contains predominantly beta 2-adrenoceptors. Verapamil attenuated the contractile activity of the rat portal vein, and this attenuation was not altered by the presence of propranolol at 10(-5) M. The potencies of isoprenaline and propranolol were not altered by the presence of a 30% attenuation of the contractile activity with verapamil at 10(-7) M. Thus, the rat portal vein may be used to determine the potencies of drugs as beta 2-adrenoceptor antagonists and as voltage dependent calcium channel blockers. In addition, the potency of drugs as beta 2-adrenoceptor antagonists on the rat portal vein may be determined in the presence of some voltage dependent calcium channel blockade.

Animals↗

PubMed1990

The membrane stabilizing and beta 1-adrenoceptor blocking activity of (+)- and (-)-propranolol on the rat left atria.

1. The membrane stabilizing and beta 1-adrenoceptor blocking activities of (+)- and (-)-propranolol have been determined using the rat left atria. 2. (+)- And (-)-propranolol have membrane stabilizing activity. Thus a low concentration of (-)-propranolol, 10(-8) M, and a higher concentration of (+)-propranolol, 10(-6) M, inhibited the responses to electrical stimulation. A high concentration of (+)- and (-)-propranolol, 10(-5) M, also inhibited the maximal combined response to electrical stimulation and isoprenaline. 3. As competitive beta 1-adrenoceptor antagonists, (-)-propranolol was over a 100 times more potent than (+)-propranolol.

Adrenergic beta-Antagonists↗

PubMed1990

Effects of bromoacetylalprenololmenthane (BAAM), an irreversible beta-adrenoceptor antagonist, on the rat isolated left atria and portal vein.

1. The effects of treatment with bromoacetylalprenololmenthane (BAAM), an irreversible beta-adrenoceptor antagonist, for 30 min on the contractile responses of the rat left atria and portal vein have been determined. 2. On the electrically driven rat left atria, BAAM at 10(-5) M followed by a 60-min wash-out caused parallel rightward shifts of the isoprenaline response curves with no reduction in the maximal response to isoprenaline. 3. Treatment of the atria with BAAM at 3 x 10(-5) M caused non-parallel rightward shifts of isoprenaline response curves with a reduction in the maximum response to isoprenaline. The KA (dissociation constant) for isoprenaline at beta 1-adrenoceptors was 7.3 x 10(-7) M. Calculation of receptor occupancy demonstrated that in order to produce a maximal response of the rat left atria, isoprenaline had to occupy 12% of the beta 1-adrenoceptors. 4. Treatment of the atria with higher concentrations of BAAM (greater than or equal to 6 x 10(-5) M) caused a non-specific action, the reduction of the response to electrical stimulation. 5. On the rat portal vein, BAAM at 3 x 10(-7)-3 x 10(-6) M followed by a 45-min wash-out had no effect on the spontaneous contractile activity, caused non-parallel rightward shifts of isoprenaline response curves with a depression of the isoprenaline maximum responses. Using data derived from experiments with 3 x 10(-7), 10(-6) and 3 x 10(-6) M BAAM, the KA for isoprenaline at beta 2-adrenoceptor was 6.4, 3.7 and 7.7 x 10(-7) M and the calculated receptor occupancy was that in order to produce a maximal response of the rat portal vein, isoprenaline had to occupy 14, 21 and 12%, respectively of the beta 2-adrenoceptors. 6. The present study with the rat left atria and portal vein has shown that it is possible to determine treatments with BAAM that produce no non-specific actions and consequently BAAM may be used as an experimental tool in KA and receptor occupancy determinations in these tissues.

Adrenergic beta-Antagonists↗

PubMed1990

The effects of (+/-)-, (+)- and (-)-celiprolol and bromoacetylalprenololmentane at the beta-adrenoceptors of rat isolated cardiovascular preparations.

The effects of (+/-)-, (+)- and (-)-celiprolol and of bromoacetylalprenololmentane (BAAM, an irreversible beta-adrenoceptor antagonist) on the contractile responses of the electrically driven rat right ventricle strip to isoprenaline and on the relaxant responses of the rat aorta to procaterol, have been studied. Racemic and (-)-celiprolol or BAAM treatment of the ventricle produced non-parallel rightward shifts of the isoprenaline response curves with a reduction in the maximal response. Sotalol produced parallel rightward displacements of the procaterol response curves of the aorta with no effect on the maximal relaxations. Racemic and (+)- and (-)-celiprolol or BAAM treatment of the aorta produced non-parallel rightwards shifts of the procaterol relaxant curves with a reduction in the maximal relaxation. The BAAM data was used to demonstrate that the KA (dissociation constant) for isoprenaline at beta 1-adrenoceptors was 1.46 x 10(-7) M and for procaterol at beta 2-adrenoceptors was 2.34 x 10(-5) M. Calculation of receptor occupancy demonstrated that to produce a maximal response of the rat right ventricle, had to occupy 87% of the beta 1-adrenoceptors. Likewise, for a maximal response of the rat aorta, procaterol had to occupy 81% of the beta 2-adrenoceptors. It is suggested that the use of tissues with small beta-adrenoceptor reserves has shown that (+/-)- and (-)-celiprolol are slowly dissociating, rather than readily reversible, beta-adrenoceptor antagonists.

Adrenergic beta-Antagonists↗

PubMed1990

Relaxant and beta 2-adrenoceptor blocking activities of (+/- )-, (+)- and (-)-pindolol on the rat isolated aorta.

The KCl contracted rat aorta is relaxed by procaterol, (+/- )-, (+)- and (-)-pindolol. The relaxations to procaterol, but not to (+/- )-pindolol, were prevented by ICI 118,551 at 10(-6) M. The relaxations to (+/- )-pindolol are, therefore, not due to beta-adrenoceptor agonism. At 10(-7) M ICI 118,551, (+/- )-, (+)- and (-)-pindolol were beta 2-adrenoceptor antagonists as they inhibited the relaxant responses of the aorta to procaterol.

Adrenergic beta-Antagonists↗

PubMed1989

Hyperpolarizing action of cromakalim on the rat aorta.

Cromakalim alone at 1 microM had no effect and at 10 microM hyperpolarized the rat aorta. The rat aorta was depolarized by KCl (20 mM), noradrenaline (0.3 microM) and 5-hydroxytryptamine (1 microM). In the presence of depolarization with KCl, noradrenaline or 5-hydroxytryptamine, cromakalim at 1 and 10 microM hyperpolarized the rat aorta. Thus the antispasmogenic actions of modest concentrations of cromakalim is compatible with potassium channel opening.

5-Hydroxytryptophan↗

PubMed1989

The effects of atriopeptin and angiotensin on the rat right ventricle.

1. Atriopeptin had no effect, whereas angiotensin increased the force of the electrically stimulated ventricle muscle. 2. Atriopeptin and angiotensin had no effect on the combined response to muscle stimulation and isoprenaline. 3. Following incubation of the ventricle with [3H]noradrenaline, atriopeptin and angiotensin had no effect on the spontaneous or nerve-evoked outflow of radioactivity.

Angiotensin II↗

PubMed1989

The inability of the rat aorta to relax to acetylcholine does not imply lack of a functional endothelium only.

1. The inability of blood vessels to relax to acetylcholine is often used as the sole test of endothelial removal. 2. Following blotting of the intimal surface of the rat aorta with filter paper, the tissue did not relax to acetylcholine and the contractions to alpha 2-adrenoceptor agonists and to the lower concentrations of noradrenaline, adrenaline, phenylephrine and KCl were enhanced. 3. However the responses to the higher concentrations of noradrenaline, adrenaline, phenylephrine and KCl were reduced. 4. These results show that blotting with filter paper destroys the endothelium and some smooth muscle.

Acetylcholine↗

PubMed1989

Atenolol, bufuralol and prizidilol are dual antagonists of the responses of the electrically driven rat right ventricle strip to isoprenaline.

1. Procaine, a membrane stabilizer, depresses the maximal responses of the electrically driven rat right ventricle to isoprenaline. 2. Esmomol is a competitive beta-adrenoceptor antagonist as it causes parallel rightward shifts of isoprenaline response curves. 3. Atenolol, bufuralol and prizidilol were dual antagonists of the responses to isoprenaline. 4. The competitive component of the dual antagonism (parallel rightward shift of response curve) is due to beta-adrenoceptor antagonism whereas the noncompetitive component (depression of isoprenaline maximal response) is probably due to membrane stabilization. 5. This membrane stabilizing activity of beta-adrenoceptor antagonists may be clinically relevant.

Adrenergic beta-Antagonists↗

PubMed1989

The effects of beta-adrenoreceptor antagonists on the force responses of the electrically driven rat right ventricle strip to isoprenaline.

1. The force of the electrically driven rat right ventricle strip is increased by isoprenaline but not by procaterol, a beta 2-adrenoceptor agonist. The effects of some beta-adrenoreceptor antagonists on the responses of the strip to isoprenaline have been determined. 2. Metoprolol (a beta 1-adrenoreceptor-selective antagonist) at 3 x 10(-8)-3 x 10(-7) moll-1 and ICI 118,551 (a potent beta 2-adrenoreceptor-selective antagonist) at 10(-7)-10(-6) moll-1 had no effect on maximum responses to isoprenaline and caused parallel rightward shifts of the isoprenaline response curves. The pA2 values for metoprolol and ICI 118,551 were 7.86 and 7.40, respectively. Thus the isoprenaline responses of the rat right ventricle strip are due to stimulation of beta 1-adrenoreceptors. 3. Metoprolol at 10(-6) moll-1 acted as a dual antagonist of the responses of the ventricle strip to isoprenaline causing parallel rightward shifts of the concentration-response curves which was due to beta 1-adrenoreceptor antagonism and a depression of the maximum response to isoprenaline which was probably due to membrane stabilizing activity. 4. Low concentrations of (+/-)-pindolol (10(-8) moll-1), (+)-pindolol (10(-7) moll-1), (-)-pindolol (10(-8) moll-1) and mepindolol (10(-10) moll-1) had no effect on isoprenaline maximum responses and caused parallel rightward shifts of isoprenaline response curves. Both (+/-)- and (-)-pindolol at 10(-7) moll-1, mepindolol at 10(-9)-10(-7) moll-1 and bopindolol at 10(-9)-10(-7) moll-1 reduced the isoprenaline maximum responses and caused non-parallel rightward shifts of the isoprenaline response curves. 5. BAAM (an irreversible beta-adrenoreceptor antagonist) treatment (3 x 10(-6) moll-1) for 30 min followed by 60 min washout reduced the isoprenaline maximum responses and caused a non-parallel rightward shift of the isoprenaline response curve. The kA (dissociation constant) for isoprenaline was 1.10 x 10(-6) moll-1. Calculation of receptor occupancy demonstrated that in order to produce a maximal response of the rat right ventricle strip, isoprenaline had to occupy 73% of the beta 1-adrenoreceptors. 6. The use of the rat right ventricle strip, a tissue with a small beta 1-adrenoreceptor reserve for isoprenaline, allows a definitive characterization of reversible (e.g. metoprolol) and irreversible (e.g. BAAM) beta 1-adrenoreceptor antagonists. It is suggested that (+/-)- and (-)-pindolol, mepindolol and bopindolol may be slowly dissociating beta 1-adrenoreceptor antagonists.

Adrenergic beta-Antagonists↗

PubMed1988

Simultaneous assessment of membrane-stabilizing and beta-adrenoceptor blocking activity of drugs with the rat isolated left atria.

Three consecutive challenges of the rat isolated left atria with electrical stimulation and then electrical stimulation and isoprenaline were made. The responses to electrical stimulation decreased and the responses to isoprenaline increased with consecutive challenges such that the maximal combined response to electrical stimulation and isoprenaline remained constant. The sensitivity (pD2) to isoprenaline decreased with successive challenges. Thus, in studies of the effects of drugs on the responses to electrical stimulation and isoprenaline, it is necessary to perform parallel experiments with untreated atria to monitor changes in the responses unrelated to the addition of drug. Analysis of the effects of procaine, metoprolol, and propranolol on the responses to electrical stimulation and/or isoprenaline demonstrated distinct contractile manifestations of beta-adrenoceptor blocking and membrane stabilizing activity. The beta-adrenoceptor blocking activity of metroprolol at 10(-7) M and propranolol (3 X 10(-9)-10(-6) M) consisted of parallel rightward shifts of the concentration-response curves to isoprenaline alone. There were three components to the membrane-stabilizing action of drugs: first, there was a decrease in the responses to electrical stimulation alone, which was observed with procaine at greater than or equal to 10(-4) M and propranolol at greater than or equal to 3 X 10(-9) M, second, there was a small parallel rightward shift of concentration-response curve to isoprenaline alone with metoprolol at 10(-6) M and propranolol at 3 X 10(-6) M (that the inhibitory effects of metoprolol at 10(-6) M or propranolol at 3 X 10(-6) M are greater than can be explained by beta-adrenoceptor blockade only may be detected either by determining pA2 values from the formula pA2 = pAx + log(x - 1) or by Schild analysis); third, the highest concentrations of procaine (3 X 10(-4) M) and propranolol (10(-5) M) tested decreased the maximal combined response to electrical stimulation and isoprenaline.

Adrenergic beta-Antagonists↗

PubMed1988

No evidence for the differential antagonism of the initial fast and secondary slow contractile responses of the rat portal vein to phenylephrine, 5-hydroxytryptamine or methacholine.

1. The present study was to ascertain whether drugs cause differential antagonism of the initial fast and secondary slow contractile responses to phenylephrine, 5-HT and methacholine of the rat portal vein. 2. Cocaine (5 x 10(-6) M) had no effect on the responses to methacholine. Cocaine potentiated the initial fast but not the secondary slow responses to phenylephrine suggesting that neuronal uptake limits the initial fast but not the secondary slow response to phenylephrine. Cocaine reduced the maximal responses to 5-HT suggesting that the responses to high concentrations of 5-HT are due, in part, to the release of noradrenaline. 3. In the presence of cocaine, idazoxan had no effect on responses to phenylephrine or 5-HT and prazosin had no effect on responses to 5-HT. Prazosin (3 x 10(-9)-10(-8) M) inhibited the responses to phenylephrine causing similar parallel rightward shifts of the concentration-response curves to the initial fast and secondary slow responses. 4. In the presence of cocaine, mianserin (10(-9)-10(-8) M), cyproheptadine, (10(-10)-10(-9) M), methysergide (10(-8) M), ketanserin (10(-10)-10(-9) M) and Ly 53857 (at 10(-9)-10(-8) M) had similar inhibitory effects on the initial fast and secondary slow responses to 5-HT, namely a parallel rightward displacement of the concentration-response curves. 5. Atropine (less than or equal to 10(-7) M) and pirenzepine less than or equal to 10(-6) M) had no effect on the responses to phenylephrine and 5-HT, but caused similar parallel rightward shifts of the concentration-response curves to both responses to methacholine. 6. The results of this study provide no evidence for differential antagonism of the initial fast and secondary slow responses of the rat portal vein to phenylephrine, 5-HT or methacholine.

Adrenergic alpha-Antagonists↗

PubMed1988

Relaxant and beta 2-adrenoceptor blocking activities of labetalol, dilevalol, amosulalol and KF-4317 on the rat isolated aorta.

The KCl-contracted rat aorta is relaxed by labetalol, dilevalol, amosulalol and KF-4317. These relaxations are not reversed by ICI 118,551 at 10(-6) M and, therefore, are not due to beta-adrenoceptor agonism. At 10(-7) M, labetalol, dilevalol, amosulalol and KF-4317 were beta 2-adrenoceptor antagonists as they inhibited the relaxant responses of rat aorta to procaterol.

Adrenergic beta-Agonists↗

PubMed1987

Effects of (+)- and (-)-amosulalol on the rat isolated right ventricle.

The effects of (+)- and (-)-amosulalol on the spontaneous and nerve stimulation-evoked outflow of radioactivity following loading of the rat right ventricle with [3H]noradrenaline and on the contractions evoked either by nerve stimulation or by isoprenaline are reported. The spontaneous outflow of radioactivity was increased by (+)- and (-)-amosulalol at 10(-5) M by a cocaine- and idazoxan-insensitive mechanism. (+)-Amosulalol at 10(-5) M and (-)-amosulalol at 10(-6)-10(-5) M increased the nerve-evoked outflow of radioactivity. The ability of (+)-amosulalol to increase outflow was reduced by cocaine and idazoxan, whereas the ability of (-)-amosulalol to increase outflow was unaltered by cocaine but abolished by idazoxan pretreatment. This suggests that (-)-amosulalol but not (+)-amosulalol, at 10(-6) M is an alpha 2-adrenoceptor antagonist and that (+)- but not (-)-amosulalol, at 10(-5) M, inhibits the neuronal uptake process for noradrenaline. (-)-Amosulalol was a more potent inhibitor of the contractile responses evoked by nerve stimulation than (+)-amosulalol. The contractile responses of the electrically driven direct muscle stimulated right ventricle to isoprenaline were inhibited by (+)-amosulalol at 10(-6) M and (-)-amosulalol at 3 X 10(-8)-10(-6) M. (-)-Amosulalol (pA2 = 7.9) was 100 times more potent than (+)-amosulalol (pA2 = 5.9) as a beta 1-adrenoceptor antagonist. In addition, the maximal responses to isoprenaline were reduced by the higher concentrations of (-)-amosulalol tested (10(-7)-10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1987

Differential antagonism of the initial fast and secondary slow contractile responses of the rat isolated aorta to 5-hydroxytryptamine by mianserin and ketanserin.

1 The rat isolated aorta is contracted by 5-hydroxytryptamine (5-HT) with an initial fast and secondary slow response. The secondary slow responses were greater than the initial fast. The effects of antagonists (prazosin, idazoxan, phentolamine, dihydroergotamine, methysergide, cyproheptadine, mianserin and ketanserin) on these initial fast and secondary slow contractile responses to 5-HT were studied. 2 Prazosin and idazoxan at 10(-7)M had no effect on responses to 5-HT. Thus all concentrations of 5-HT contract the aorta by stimulating receptors distinct from alpha-adrenoreceptors. 3 Phentolamine, dihydroergotamine, methysergide and cyproheptadine had similar inhibitory effects on the initial fast and secondary slow responses to 5-HT. Phentolamine at 10(-6)M caused parallel, whereas dihydroergotamine (10(-9)-10(-8)M), methysergide (10(-9)-10(-8)M) and cyproheptadine (3 X 10(-11)-10(-8)M) caused non-parallel rightward shifts of the concentration-response curves. 4 Mianserin and ketanserin had greater inhibitory effects on the initial fast than secondary slow responses. Mianserin (10(-9)-10(-7)M) caused a non-parallel and parallel rightward shift of the concentration-response curves to the initial fast and secondary slow responses to 5-HT, respectively. Ketanserin (10(-8)-10(-7)M) produced non-parallel rightward shifts of the concentration-response curves. 5 One possible explanation of these results is that the rat aorta has no spare 5-HT2 receptors and that in inhibiting responses to 5-HT: (a) phentolamine is a competitive antagonist, (b) mianserin and ketanserin are slowly dissociating antagonists, and (c) dihydroergotamine, methysergide and cyproheptadine are irreversible antagonists. Furthermore, the competitive and irreversible antagonists have similar effects on initial fast and secondary slow responses to 5-HT, whereas the slow dissociating antagonists (mianserin and ketanserin) have a greater inhibitory effect on the initial fast than secondary slow response.

Animals↗