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Biomedical subjects

C A Hamilton

Publications and source records attributed to C A Hamilton.

At least 127 records · Page 7Linked to original sources
PubMed1985

Pharmacokinetic and pharmacodynamic studies with two alpha-adrenoceptor antagonists, doxazosin and prazosin in the rabbit.

The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]-prazosin from specific binding sites. However, the lower pA2 value for doxazosin at alpha 1-adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. The dose-related pressor effects of intravenous phenylephrine were used to assess vascular alpha 1-adrenoceptor antagonism in vivo. There was a close agreement between alpha 1-adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The alpha 1-adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. Studies using either radioligand binding or pressor responses to B-HT 920 showed that doxazosin did not show any significant affinity for the alpha 2-adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. Doxazosin has a longer terminal elimination half-life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. Following pharmacological 'autonomic blockade' and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through alpha 1-adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained alpha 1-adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has alpha 1-adrenoceptor blocking properties.

Adrenergic alpha-Antagonists↗
PubMed1984

Changes in brain alpha-adrenoceptors with increasing age in rabbits.

The effects of aging on rabbit brain alpha-adrenoceptor number was studied using radioligand binding techniques. The ligands [3H]prazosin and [3H]clonidine were used to examine binding to alpha 1 and alpha 2-adrenoceptors, respectively, in forebrain and hindbrain membranes from rabbits aged from 1 month to 3 years. Changes in specific [3H]clonidine binding were compared to changes in central alpha 2-adrenoceptor function as measured by the fall in blood pressure after intracisternal administration of clonidine. Both alpha 1- and alpha 2-adrenoceptor number decreased with age in the rabbit brain. The maximum fall in specific [3H]prazosin binding occurred in animals aged between 3 and 6 months. [3H]clonidine binding in forebrain was also reduced in 6-month-old animals but [3H]clonidine binding in hindbrain was only reduced in animals over 2 years old. Despite the reduction in [3H]clonidine binding no decrease in the in vivo response to centrally administered clonidine was observed in 2-year-old animals when compared to 3-month-old rabbits.

Aging↗
PubMed1984

The recovery of alpha-adrenoceptor function and binding sites after phenoxybenzamine. An index of receptor turnover?

The recovery of peripheral alpha-adrenoceptor function and binding sites was studied in male New Zealand white rabbits after treatment with the irreversible adrenoceptor antagonist phenoxybenzamine. Phenoxybenzamine (5 mg/kg) was administered intravenously and the animals studied 30 min to 12 days later. Pressor dose response curves to intravenous phenylephrine, noradrenaline and guanabenz were constructed in vivo in conscious animals. The contractile response of abdominal aorta and renal artery to phenylephrine and noradrenaline was examined in vitro and the recovery of specific prazosin and clonidine binding to spleen membranes investigated in radioligand binding studies. The half life (t 1/2) for recovery of maximum pressor response in vivo ranged from 0.9 +/- 0.2 days for phenylephrine to 1.4 +/- 0.1 days for guanabenz. The t 1/2 for recovery of ED50 was not significantly different to t 1/2 for recovery of maximum pressor response and ranged from 0.8 +/- 0.2 days for noradrenaline to 1.3 +/- 0.3 days for phenylephrine. Half life for recovery of maximum response and EC50 in the isolated tissues was similar to that obtained in vivo for recovery of pressor responses and ranged from 0.4 +/- 0.1 days for the EC50 of noradrenaline in the renal artery to 1.2 +/- 0.6 days for maximum response to phenylephrine in the abdominal aorta. The rate of recovery of specific clonidine binding did not differ significantly from the rate of recovery of pressor responses to the alpha 2-selective agonist guanabenz. t 1/2 for maximum number of specific clonidine binding sites, Bmax was 1.6 +/- 0.9 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

An analysis of the pressor responses to putative alpha 1 and alpha 2-adrenoreceptor agonists given intravenously to conscious rabbits.

The selectivity of a range of alpha 1 and alpha 2-adrenoreceptor agonists was examined in the conscious rabbit. In this preparation the pressor responses to BHT 920, BHT 933, guanabenz and alpha-methylnoradrenaline were attenuated by idazoxan but not by prazosin. The pressor responses to clonidine and noradrenaline were attenuated by both idazoxan and prazosin while the response to phenylephrine was only significantly attenuated by prazosin. Both an immediate pressor response and a later depressor response to clonidine was observed but there were no depressor components to either BHT 920 or BHT 933 responses. Pressor responses to guanabenz were attenuated on repeated dosing.

Adrenergic alpha-Agonists↗
PubMed1984

Pretreatment with aspirin does not influence the pressor response to alpha 2-adrenoceptor agonists in conscious rabbits.

It has proved relatively easy to demonstrate pressor responses mediated via alpha 2-adrenoceptors in-vivo and in whole blood perfused vascular beds, but not in in-vitro work. The possibility that platelet alpha 2-adrenoceptor activation, with subsequent release of vasoactive prostanoids, contributes to the pressor response to alpha 2-adrenoceptor agonists was investigated. The pressor response to the alpha 2-adrenoceptor agonist BHT 920 (Alefexole) was compared in rabbits pretreated with distilled water or aspirin (3 X 200 mg kg-1 by gavage). Aspirin pretreatment had no significant effect on responses to BHT 920; thus, prostanoid formation does not appear to be an important mechanism contributing to postsynaptic alpha 2-adrenoceptor activation.

Adrenergic alpha-Agonists↗
PubMed1983

RX781094, a new potent alpha 2 adrenoceptor antagonist. In vivo and in vitro studies in the rabbit.

1. RX781094 [2-(2-(1,4-benzodioxanyl))-2-imidazoline HCl] is a new alpha 2 adrenoceptor selective antagonist. Its effects on cardiovascular response "in vivo" before and after administration of alpha 1 and alpha 2 adrenoceptor agonists have been studied in conscious and anaesthetized rabbits. The affinity of RX781094 for alpha 1 and alpha 2 adrenoceptors has been investigated "in vitro" in radioligand binding studies. 2. Intravenous injection of RX781094 caused an immediate short lived pressor response which was attenuated by alpha 1 and alpha 2 adrenoceptor antagonists; it also caused a prolonged bradycardia. 3. Pretreatment with intravenous RX781094 inhibited the hypotensive response to both intravenous and intracisternal clonidine in a dose dependent manner. 4. RX781094 also showed a dose dependent inhibition of the acute pressor response to the alpha 2 adrenoceptor selective agonist guanabenz. 5. Pressor dose response curves to noradrenaline, a mixed alpha 1/alpha 2 adrenoceptor agonist were shifted to the right after RX781094 whereas those to the alpha 1 adrenoceptor agonist phenylephrine were unchanged. 6. RX781094 was more effective at displacing specifically bound 3H clonidine than 3H prazosin in membrane preparations from rabbit brain. 7. These observations are consistent with a selective alpha 2 adrenoceptor antagonist effect of RX781094 at central and peripheral adrenoceptors in the rabbit.

Adrenergic alpha-Agonists↗
PubMed1983

Peripheral alpha 1- and alpha 2-adrenoreceptor mechanisms in blood pressure control.

Peripheral alpha-adrenoreceptors can be characterized as alpha 1 or alpha 2, depending on their affinity for agonists and antagonists. Alpha 2-adrenoreceptors, probably located postsynaptically on smooth muscle of resistance vessels, contribute to the pressor responses to intravenously given norepinephrine. Studies with the noncompetitive alpha-adrenoreceptor antagonist phenoxybenzamine suggest that there are important differences in the regulation of the two types of receptors. The slower recovery alpha 1-adrenoreceptor binding sites and the more rapid recovery of responses suggest the presence of "spare" alpha 1- but not alpha 2-adrenoreceptors.

Adrenergic alpha-Agonists↗
PubMed1982

A postsynaptic location of alpha 2 adrenoceptors in vascular smooth muscle: in vivo studies in the conscious rabbit.

The rise in blood pressure after intravenous administration of a range of alpha-adrenoceptor agonists and the effect of alpha adrenoceptor antagonists was studied in groups of conscious rabbits. Phentolamine was equally effective at blocking the pressor response to the alpha 1 adrenoceptor agonist phenylephrine and the mixed alpha 1/alpha 2 adrenoceptor agonist noradrenaline. Phenoxybenzamine which acts preferentially on alpha 1 adrenoceptors and the more specific alpha 1 adrenoceptor antagonist prazosin were more effective against phenylephrine induced rises in pressure, while yohimbine and alpha yohimbine which preferentially act on alpha 2 adrenoceptors were more effective against noradrenaline. The immediate pressor response to intravenous injections of the alpha 2 adrenoceptor agonists clonidine and guanabenz was blocked more effectively by phentolamine than prazosin when doses which gave a postsynaptic location of both alpha 1 and alpha 2 adrenoceptors both of which mediate vasoconstrictor responses in vascular smooth muscle.

Adrenergic alpha-Agonists↗
PubMed1982

The effects of intravenous 6-hydroxydopamine on peripheral alpha-adrenoreceptors.

1 Peripheral alpha-adrenoreceptor-mediated responses were studied in conscious intact rabbits and in animals pretreated with intravenous 6-hydroxydopamine (50 mg/kg). 2 Treatment caused a large decrease in noradrenaline in plasma and peripheral tissue but only small falls in blood pressure. 3. There was a shift to the left in pressor dose-response curves to the alpha 1-adrenoreceptor agonist phenylephrine and the mixed alpha 1/alpha 2-adrenoreceptor agonist noradrenaline in 6-hydroxydopamine-pretreated animals. The alpha 1-adrenoreceptor antagonist prazosin was less effective at blocking the phenylephrine pressor response in these animals. 4 There was no change in pressor responses to the alpha 2-adrenoreceptor selective agonists clonidine and guanabenz and alpha-adrenoreceptor antagonists were equally effective at blocking this pressor response in 6-hydroxydopamine-pretreated and in intact rabbits. 5 In conscious animals 6-hydroxydopamine pretreatment causes alteration in responses mediated by postsynaptic alpha 1-but not postsynaptic alpha 2-adrenoreceptors. These changes may help maintain blood pressure in the 6-hydroxydopamine treated rabbits.

Animals↗
PubMed1982

The role of presynaptic alpha-adrenoceptors in the regulation of blood pressure in the conscious rabbit.

1 Changes in mean arterial pressure, heart rate and plasma noradrenaline after alpha-adrenoceptor blockade with several alpha-adrenoceptor antagonists have been studied in the conscious rabbit in order to investigate the possible role of presynaptic alpha-adrenoceptors in cardiovascular regulation. 2 Prazosin (0.05-2 mg/kg) and phentolamine (0.5-20 mg/kg) produced dose-dependent falls in mean arterial pressure and rises in plasma noradrenaline. These changes were related to the degree of postsynaptic alpha-adrenoceptor blockade determined by the pressor response to intravenous phenylephrine. 3 Similar changes in mean arterial pressure and plasma noradrenaline were observed after administration of the direct vasodilators hydralazine (1-10 mg/kg) and nitroprusside (2.5-55 microgram kg-1 min-1). 4 After baroreceptor deafferentation by sinoaortic denervation the falls in mean arterial pressure were much greater and the rise in plasma noradrenaline was markedly attenuated. 5 Yohimbine (1 mg/kg) increased mean arterial pressure and plasma noradrenaline but it was not possible to exclude the possibility that central nervous effects of yohimbine underlay the increased sympathetic activity. 6 The magnitude of the baroreflex response to changes in pressure make it unlikely that the functional significance of the presynaptic alpha-adrenoceptor can be readily determined by measurement of plasma noradrenaline in intact animals.

Animals↗
PubMed1980

Changes in blood pressure, heart rate, and sympathetic activity on abrupt withdrawal of tiamenidine (HOE 440) in essential hypertension.

A limitation of clonidine therapy is the syndrome of rebound hypertension and sympathetic overactivity after withdrawal. Ten patients, four male, six female, aged 28--64 years, with essential hypertension, were treated for one year with an imidazoline derivative, tiamenidine. Blood pressure fell from an average of 178/108 mm Hg pretreatment to 152/86 mm Hg after 1 year. Tiamenidine was then withdrawn in hospital, replaced by identical placebo under single blind conditions and observations made over 96 h. The study was interrupted in five patients (4 patients within 36 h) because blood pressure rose to greater than 30 mm Hg (systolic) or greater than 20 mm Hg (diastolic) above pretreatment values. For the group, blood pressure was maximal at 194/112 mm Hg, 18 h post withdrawal, significantly higher than pretreatment (p less than 0.005). Headache, tremor, flushing and insomnia were noted. Saliva production rose 100% at 24 h. Plasma noradrenaline rose within 24 h with an accompanying rise in urinary metanephrine and catecholamine excretion. Tiamenidine appears to share with other imidazolines rebound cardiovascular and autonomic effects following abrupt withdrawal.

Adult↗
PubMed1980

Sedative and cardiovascular effects of clonidine and nitrazepam.

Five healthy male subjects, aged 26 to 35 yr, received single oral doses of clonidine 0.3 mg, nitrazepam 20 mg, or placebo double-blind with an interval of at least 1 wk between each treatment. Clonodine induced a maximal fall in systo9lic blood pressure from 104.2 +/- 1.6 to 84.7 +/- 1.4 mm Hg (mean +/- SEM) after 3.5 hr and nitrazepam from 102.9 +/- 1.9 to 90.3 +/- 2.6 mm Hg after 1.0 hr while after placebo blood pressure rose steadily from 102.5 +/- 2.9 to 109.6 +/- 3.5 mm Hg at the end of the 8-hr study. Total sleep time increased from 90.3 +/- 2.5. min after placebo to 256.2 +/0 21.0 min after clonidine (p < 0.001) and 281.0 +/- 40.3 min after nitrazepam (p < 0.001). Stage I sleep increased from 49.7 +/- 11.2 to 76.9 +/- 10.2 min after clonidine and to 76.3 +/- 25.2 min after nitrazepam (p < 0.0), while the greatest increase was observed in stage II: 230.7 +/- 25.6 min after clonidine and 236.6 +/- 35.4 min after nitrazepam compared with only 48.5 +/- 15.8 min after placebo (p < 0.001). Plasma norepinephrine did not change after placebo but fell after nitrazepam from 0.28 +/- 0.04 to 0.14 +/- 0.02 ng/ml after 3 hr (p < 0.05) and after clonidine from 0.23 +/- 0.07 to 0.07 +/- 0.02 ng/ml after 2 hr (p < 0.01). Clonidine and nitrazepam both induced similar hypnotic and hypotensive effects with some evidence that this might be due to a reduction in sympathetic tone.

Adult↗
PubMed1980

Sequential changes in plasma noradrenaline during bicycle exercise.

1. Forearm venous plasma noradrenaline, heart rate and intra-arterial blood pressure were measured sequentially during and after upright bicycle exercise in five normotensive and six hypertensive patients. 2. Plasma noradrenaline increased significantly between 4 and 8 min during exercise. 3. On stopping exercise blood pressure and heart rate decreased rapidly whilst plasma noradrenaline increased in each subject to reach a maximum at a median time of 108 s after exercise. 4. Plasma noradrenaline decreased in five of six normotensive patients between the end of exercise and 2 min after exercise performed in the supine position. 5. Evidence in favour of a reflex increase in sympathetic activity after upright exercise is discussed.

Adult↗
PubMed1980

Erythrocytes catechol-O-methyltransferase activity and indices of sympathetic activity in man.

1. Erythrocyte catechol-O-methyltransferase was studied in a population sample of 147 subjects. 2. There was a wide interindividual variability of catechol-O-methyltransferase activity, which was not unimodally distributed. Catechol-O-methyltransferase activity was not influenced by blood pressure, age or sex, nor was it related to plasma noradrenaline or urinary catecholamines or metanephrines. 3. It is not likely that inactivation of noradrenaline by O-methylation at least by erythrocytes is an important mechanism determining plasma noradrenaline, let alone arterial pressure.

Adolescent↗
PubMed1980

Plasma noradrenaline concentration in essential hypertension during long-term beta-adrenoceptor blockade with oxprenolol.

1. Chronic beta-adrenoceptor blockade with oxprenolol causes elevation of plasma noradrenaline levels, as compared with placebo, despite a significant fall in blood pressure and pulse rate. 2. The plasma noradrenaline concentration is not influenced by the frequency of administration or the formulation of the drug. 3. Plasma noradrenaline levels are not correlated with the plasma concentration of the drug. 4. The changes in plasma noradrenaline concentrations support a peripheral rather than central mechanism of action of beta-adrenoceptor blockers in man.

Adult↗
PubMed1980

Guanfacine: effects of long-term treatment and withdrawal.

1. Guanfacine 3-6 mg daily lowered blood pressure in five essential hypertensives and also reduced saliva production. 2. Plasma and urinary noradrenaline values were significantly reduced throughout the 8-10 weeks of treatment. 3. On substitution of placebo tablets for guanfacine, blood pressure increased over a 2-4 d period to reach but did not significantly exceed pretreatment levels. 4. After withdrawal of guanfacine plasma noradrenaline standing was significantly higher than the pretreatment level (P < 0.05) after 4 days. Saliva production was significantly higher than the pretreatment level on day 3 and day 4 of withdrawal. 5. Guanfacine is an effective antihypertensive drug with a spectrum of actions similar to clonidine. However, in abrupt withdrawal blood pressure returned to the pretreatment level over a 2-4 d period.

Antihypertensive Agents↗