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Biomedical subjects

C A Hamilton

Publications and source records attributed to C A Hamilton.

At least 109 records · Page 6Linked to original sources
PubMed1987

Rapid and reversible desensitisation of vascular and platelet alpha 2 adrenoceptors.

The effects of intravenous infusion with the alpha2 adrenoceptor selective agonist alpha methylnoradrenaline on pressor responses to alpha adrenoceptor agonists, alpha2 adrenoceptor mediated platelet aggregation and adenylate cyclase were examined in conscious rabbits. Pressor responses to alpha methylnoradrenaline but not phenylephrine were decreased in a dose dependent manner during methylnoradrenaline infusion at all times examined. Recovery of these responses after stopping infusion was dependent on both the dose infused and the duration of the infusion. Alpha methylnoradrenaline infusion resulted in a dose and time dependent decrease in the pro-aggregatory response of platelet to adrenaline without any significant change in the response to ADP or in the number of [3H]yohimbine binding sites. The ability of PGE1 to stimulate adenylate cyclase was not influenced by alpha methylnoradrenaline infusions. However, reversal of this stimulation by adrenaline was decreased by relatively long (30 min) infusions of the highest dose of alpha methylnoradrenaline examined. It is concluded that alpha methylnoradrenaline infusions resulted in desensitisation of all the alpha2 adrenoceptor mediated responses examined. However the time course for the desensitisation apparently differed according to the response examined.

Adrenergic alpha-Agonists↗
PubMed1987

The effects of calcium antagonists on blood pressure and responses to alpha-adrenoceptor agonists in hypertensive rabbits.

The effects of the calcium antagonists verapamil and nifedipine on mean arterial blood pressure, heart rate and pressor responses to a range of alpha-adrenoceptor agonists were examined in male normotensive New Zealand white rabbits and in rabbits with perinephritis hypertension. Verapamil and nifedipine caused a greater fall in mean arterial pressure in hypertensive compared to normotensive rabbits both when the fall was expressed as an absolute and as a percentage change. Effects on heart rate were similar in normotensive and hypertensive animals. Pressor responses to phenylephrine were attenuated by nifedipine and verapamil in normotensive and hypertensive rabbits. Pressor responses to alphamethyl noradrenaline were also attenuated by nifedipine, but pressor responses to BHT 920 were not significantly altered by either calcium antagonist in normotensive or hypertensive rabbits at the dose used. Thus the calcium antagonists had a greater effect on alpha 1 - than alpha 2-adrenoceptor mediated responses in both normotensive and hypertensive rabbits. Hypertensive animals showed an increased responsiveness to phenylephrine and alphamethyl noradrenaline but not BHT 920 compared to normotensives. This difference remained after treatment with both the calcium antagonists.

Adrenergic alpha-Agonists↗
PubMed1986

Changes in rabbit platelet alpha and beta adrenoceptor number and platelet aggregation.

Treatment with phenoxybenzamine caused a decrease in the number of alpha but not beta adrenoceptor ligand binding sites on platelets from male rabbits and thus a decrease in the ratio of alpha/beta adrenoceptor number. This was accompanied by decreased aggregation both in the presence and absence of propranolol. In contrast in female rabbits maturation and oestrogen treatment resulted in a decrease in both alpha and beta adrenoceptor ligand binding and no change in the alpha/beta adrenoceptor ratio or in the aggregatory response of the platelets to adrenaline in the absence of propranolol.

Animals↗
PubMed1986

Desensitization of platelet alpha 2-adrenoceptors after short term infusions of adrenoceptor agonist in man.

The effect of intravenous infusion of catecholamines and related drugs on human platelet alpha 2-adrenoceptor number and function was investigated. Short (60-120 min) infusions of catecholamines with alpha 2 agonist activity in vivo produced attenuation of the platelet responses to adrenaline in vitro. This desensitization was specific for the adrenaline induced aggregatory response. The maximum number of [3H]yohimbine binding sites on platelets was not altered by adrenaline infusion. The ability of adrenaline to reduce platelet cyclic AMP levels was significantly reduced after the infusions. Acute infusions of alpha 2-adrenoceptor agonists may alter the coupling of the platelet alpha 2-adrenoceptor to adenylate cyclase.

Adolescent↗
PubMed1986

Studies on alpha 2-adrenoceptors in rabbits with perinephritis hypertension.

Increased responses to intravenous injections of the full alpha 2-adrenoceptor agonists, alpha-methyl noradrenaline and noradrenaline, were observed in conscious rabbits with perinephritis hypertension. However, responses to the partial agonist, BHT 920, and the antagonist, idazoxan, were unchanged. These increased responses to noradrenaline and alpha-methyl noradrenaline did not appear to be related to the alpha 1- or beta-adrenoceptor activity or to altered clearance of the agonists. The pro-aggregatory response of platelets from hypertensive rabbits and normotensive rabbits to adenosine diphosphate (ADP) was similar, but the sensitivity of platelets from hypertensive rabbits to the adrenaline potentiation of the pro-aggregatory response was increased. This was not related to changes in the number of alpha 2-adrenoceptor binding sites or to changes at platelet beta-adrenoceptors. In contrast the aggregatory responses to the partial agonist, guanabenz, were similar in normotensive and hypertensive animals. In rabbits with perinephritis hypertension responses to phenylethanolamines (full agonists at the alpha 2-adrenoceptor) were increased in vivo in the conscious animal and in vitro in platelets, whereas responses to imidazolines which are partial agonists were similar in normotensive and hypertensive animals. These differences may be related to alterations in the coupling of alpha2-adrenoceptor activation to response in the hypertensive rabbits.

Adrenergic alpha-Agonists↗
PubMed1986

The cardiovascular effects of trimazosin and prazosin in the rabbit.

The cardiovascular effects of trimazosin, a quinazoline derivative similar in structure to prazosin, were investigated and compared with prazosin in the rabbit. Radioligand binding to cerebral membranes showed that trimazosin has roughly 100-fold less affinity for the alpha 1-adrenoceptor. This was further supported by its lower pA2 derived from phenylephrine contractile responses in isolated thoracic aorta preparations. Trimazosin is less extensively distributed and has a lower clearance from whole blood than prazosin although their whole blood elimination half-lives are comparable. In addition, although it is a less potent alpha 1-adrenoceptor antagonist in vivo, its peripheral vascular depressor effect tends to be greater than prazosin. Trimazosin at the dose used and under the conditions of study did not reverse the peripheral pressor effect of angiotensin II or B-HT920 but at higher concentrations, unlike prazosin, it relaxed the K+ contracted thoracic aorta. In addition, following pharmacological autonomic blockade and treatment with prazosin in vivo, trimazosin caused a further depressor response. A similar though shorter lasting non-alpha 1-receptor mediated action was also observed with prazosin. 1-Hydroxytrimazosin (CP23445), the major metabolite of trimazosin in man, showed little affinity for either the alpha 1- or alpha 2-adrenoceptor from radioligand binding studies. In addition to alpha 1-adrenoceptor antagonism, trimazosin may exert an additional direct vasodilator effect in rabbits.

Adrenergic alpha-Antagonists↗
PubMed1985

A comparison of alpha 2-adrenoceptor regulation in brain and platelets.

Functional responses and alpha 2-adrenoceptor radioligand binding were studied in brain and platelets of rabbits under a variety of circumstances. The effects of oestrogen treatment and maturation were studied in female rabbits and of aging and amitriptyline treatment in male rabbits. No correlation was found between changes in brain and platelets either in response or alpha 2-adrenoceptor ligand binding under any of the conditions examined.

Aging↗
PubMed1985

The effects of phenoxybenzamine on specific binding and function of central alpha-adrenoceptors in the rabbit.

We have studied the effects of phenoxybenzamine, an irreversible alpha-adrenoceptor antagonist on the binding of the alpha-adrenoceptor ligands [3H]prazosin and [3H]clonidine to rabbit brain membranes. Where possible changes in binding were related to changes in central alpha-adrenoceptor function. Phenoxybenzamine showed a similar alpha 1/alpha 2-adrenoceptor selectivity in the brain to that previously reported in the periphery. Much higher doses were required to reduce specific clonidine binding and to interfere with the hypotensive response to intracisternal clonidine than to reduce specific prazosin binding. Recovery of binding site number of both alpha 1- and alpha 2-adrenoceptor selective ligands was slower than in peripheral tissues (heart and spleen). Recovery was log linear and the half time (t1/2) for recovery of the maximum number of specific prazosin and clonidine binding sites in forebrain was 10.8 +/- 2.6 days and 6.1 +/- 0.1 days and in hindbrain 13.3 +/- 3.1 days and 4.6 +/- 1.8 days, respectively. t1/2 for recovery of the in vivo hypotensive response to intracisternal clonidine was 2.7 +/- 1.0 days. Recovery of this response was attenuated by treatment with the inhibitor of protein synthesis, 5-fluorouracil. This suggests that recovery after phenoxybenzamine in brain, as in the periphery, may depend at least in part on synthesis of new receptor protein. The recovery of brain adrenoceptor number after phenoxybenzamine may be an index of receptor turnover and is much slower in brain than in heart and spleen.

Animals↗
PubMed1985

The effects of sexual maturation on alpha-adrenoceptors in female rabbits.

alpha-Adrenoceptor number and function were examined in brain, platelets, and other peripheral tissues of young (2-3 months) and mature (6-8 months) non pregnant female rabbits. alpha1-Adrenoceptor number was significantly higher in forebrain, hindbrain, spleen and heart of mature rabbits. alpha2-Adrenoceptor number, on the other hand, was found to be significantly lower in platelets, forebrain and spleen but not changed in hindbrain and kidney of mature animals compared to young females. There was a significant reduction in platelet aggregation with maturation. However, no change in in vivo pressor or depressor responses to alpha-adrenoceptor agonists was observed in vivo.

Adrenergic alpha-Agonists↗
PubMed1985

Maternal and fetal platelet responses and adrenoceptor binding characteristics.

Paired blood samples were obtained from mothers (venous) and babies (cord venous blood) at the time of delivery by caesarean section under epidural anaesthetic. Fetal platelets failed to aggregate in response to adrenaline in vitro although adrenaline could potentiate the threshold response to adenosine diphosphate (1 microM). Fetal platelet responses to collagen and 8 Arg vasopressin did not differ significantly from maternal responses. Maternal and fetal platelets also showed similar inhibition of aggregation after activation of adenylate cyclase (PGE1 and parathormone), in contrast to the inhibition of adenylate cyclase by adrenaline. Alpha 2 adrenoceptors were investigated using [3H] yohimbine binding receptor number and were reduced modestly but significantly on fetal compared to maternal platelets. The failure of fetal platelet aggregation in response to adrenaline appears to be related to a failure of receptor coupling and may represent a delayed maturation of fetal platelet alpha receptors or a response to increased circulating catecholamines during birth.

Adenosine Diphosphate↗
PubMed1985

alpha-Adrenoceptor regulation in vivo and in vitro in the rabbit.

The relationship between alpha-adrenoceptor number and response has been studied in rabbits under a range of physiological and pathological conditions. The effects of irreversible alpha-adrenoceptor blockade, maturation, ageing, oestrogen treatment, adrenaline infusion, perinephritis hypertension and sinoaortic denervation on alpha-adrenoceptor number and response were examined. alpha-Adrenoceptor number was measured by radioligand binding. [3H]Prazosin and [3H]clonidine were used as ligands to measure alpha 1- and alpha 2-adrenoceptor number in spleen and [3H]yohimbine to measure alpha 2-adrenoceptor number on platelets. Responses in vivo were studied by examining the pressor responses to a range of alpha-adrenoceptor agonists. The functional response of platelets was examined in vitro by using the aggregatory response to adrenaline. Reductions in alpha 2-adrenoceptor ligand binding were consistently accompanied by equivalent reductions in alpha 2-adrenoceptor-mediated responses. In contrast large reductions in [3H]prazosin binding were observed with little or no change in alpha 1-adrenoceptor-mediated responses. These results would be consistent with a large receptor reserve for alpha 1-adrenoceptors but few if any spare alpha 2-adrenoceptors in the vasculature or on platelets. Increased responses to both alpha 1- and alpha 2-adrenoceptor agonists were observed in animals with sinoaortic denervation and to alpha 1-adrenoceptor agonists in rabbits with perinephritis hypertension. These increases in response were not accompanied by increases in radioligand binding and may be related to alterations in the coupling of receptor activation to end-organ response.

Adrenergic alpha-Agonists↗
PubMed1985

Acute and chronic regulation of alpha 2-adrenoceptor number and function in man.

Agonist regulation of platelet alpha 2-adrenoceptors was examined in human volunteers after acute elevations of adrenoceptor agonist and during chronic elevation of plasma catecholamines in two patients with phaeochromocytoma. Platelet alpha 2-adrenoceptor number was measured by radioligand binding [( 3H]yohimbine) and alpha 2-adrenoceptor function measured by turbidimetric platelet aggregation. Short term infusion of adrenoceptor agonists with alpha 2 activity caused reductions in the platelet response to adrenaline in vitro; conversely an increase in activity was observed postoperatively in two patients after removal of phaeochromocytoma. The changes in platelet response were not accompanied by changes in alpha 2-adrenoceptor number. It is proposed that a process of receptor inactivation occurs during desensitization and this is responsible for the dynamic regulation of platelet responses.

Adolescent↗
PubMed1985

Alpha-adrenoceptor changes after oestrogen treatment in platelets and other tissues in female rabbits.

alpha 2-Adrenoceptors on blood platelets have been widely used as a model for alpha-adrenoceptors in less accessible tissues. The effect of oestrogen (200 micrograms/day intramuscularly) on alpha 2-adrenoceptor number and function was studied in immature female rabbits. alpha 2-adrenoceptor number was measured in whole platelets, and membrane preparations of forebrain, hindbrain, spleen and kidney by radioligand binding. alpha 2-Adrenoceptor function was examined by measuring platelet aggregation in vitro and circulatory responses to selective alpha 2-adrenoceptor agonists in vivo. Oestrogen treatment resulted in a significant decrease in platelet alpha 2-adrenoceptor number and function. However, no changes were observed either in receptor number in other tissues or in responses to alpha 2-agonists in vivo. The results suggest that oestrogen modulation of rabbit platelet alpha 2-adrenoreceptor number and function may be different from that of brain, kidney and spleen. Caution should be exercised in extrapolating results from platelets to alpha-adrenoceptors at other sites.

Animals↗
PubMed1985

Pharmacokinetic interaction of propoxyphene with ethanol.

In order to study the effects of ethanol on the pharmacokinetics of propoxyphene, six healthy male volunteers were each given (1) propoxyphene 65 mg p.o. preceded by 1 h by ethanol 0.9 g/kg lean body weight and followed for 7.5 h by ethanol dosed to maintain breath ethanol at 800-1000 mg/l; and (2) propoxyphene 65 mg p.o. with orange juice in the same volume and frequency as ethanol. Ethanol did not induce any significant changes in apparent t 1/2 or Cmax of propoxyphene or norpropoxyphene. The average norpropoxyphene/propoxyphene ratio decreased by a mean 36%.

Adult↗
PubMed1985

Plasma catecholamines and modes of delivery: the relation between catecholamine levels and in-vitro platelet aggregation and adrenoreceptor radioligand binding characteristics.

Catecholamines were measured in maternal venous, and mixed umbilical cord blood. Maternal catecholamines were significantly (P less than 0.01) reduced by epidural analgesia with a 36% reduction in noradrenaline and a 33% reduction in adrenaline. Fetal catecholamines were elevated at birth with a 3-8 fold increase in noradrenaline but not adrenaline during spontaneous vaginal delivery. The lowest fetal catecholamines were obtained in the group delivered under epidural analgesia; lower plasma catecholamines were not associated with adverse respiratory effects. Fetal platelets showed impaired alpha 2-adrenoceptor function with absent aggregatory responses to adrenaline in vitro. The defect in platelet function was unlikely to be related to changes in the number of fetal platelet alpha-receptors or to changes in receptor affinity for adrenaline, as fetal platelets failed to aggregate to adrenaline from deliveries with high and low cord blood catecholamines.

Adult↗
PubMed1985

Recovery of alpha-adrenoreceptor mediated responses and binding site number after intravenous benextramine in the rabbit.

The densities of [3H]-prazosin and [3H]-clonidine binding sites were determined in spleen and brain membrane preparations from rabbits treated 1 to 48 h previously with benextramine (5 mg/kg). In other rabbits pressor responses to phenylephrine and BHT 920 were examined 1 to 72 h after benextramine administration. After benextramine there was a reduction in the density of both [3H] prazosin and [3H] clonidine binding sites in spleen and a non-parallel shift in pressor dose response curves to selective alpha 1- and alpha 2-adrenoreceptor agonists. Recovery of in vivo responses and binding site densities were relatively slow. No reduction in the maximum density of either [3H] prazosin or [3H] clonidine binding sites in brain was found after intravenous administration of benextramine. It is concluded that after intravenous administration benextramine binds irreversibly to peripheral alpha 1- and alpha 2-adrenoreceptors in the rabbit but fails to cross the blood brain barrier in appreciable quantities and bind to central alpha-adrenoreceptors. Recovery of in vivo responses was more rapid than that previously observed after alpha-adrenoreceptor blockade with phenoxybenzamine. The longer time course of recovery after phenoxybenzamine may be a result of redistribution of this lipophilic drug from fat.

Adrenergic alpha-Agonists↗