Biomedical subjects

C A Hamilton

Publications and source records attributed to C A Hamilton.

At least 91 records · Page 5Linked to original sources

PubMed1992

Effects of endothelin upon blood pressure in normotensive rabbits and in perinephritis hypertension.

AIMS: The effects of endothelin upon blood pressure were investigated in normotensive and hypertensive rabbits. METHODS: Endothelin was injected intravenously into conscious animals and blood pressure was monitored. Groups were pretreated with vehicle, calcium antagonists, indomethacin to block prostaglandin release, or NG-nitro-L-arginine methyl ester (L-NAME) to block endothelium-derived relaxing factor (EDRF) production in order to study the mechanisms of action of endothelin in normotensive and hypertensive animals. RESULTS: Intravenous endothelin caused a rapid depressor response lasting less than 1 min followed by a prolonged pressor response. Calcium antagonists attenuated this pressor response. Hypertensive animals showed a greater sensitivity to calcium antagonists than normotensives. High concentrations of calcium antagonists abolished the pressor response, revealing a more prolonged depressor response lasting up to 5 min. Indomethacin pretreatment caused an apparent dose-related increase in pressor responses in all animals. L-NAME pretreatment enhanced responses in normotensives but caused no change or a decrease in these responses in hypertensive animals. Neither calcium antagonists, indomethacin or L-NAME modified the initial depressor response to endothelin. However when given together with nifedipine infusion, which abolished the pressor response, indomethacin and L-NAME decreased the duration of the depressor response. CONCLUSIONS: In conscious rabbits extracellular calcium influx is important in mediating pressor responses to endothelin. In normotensive rabbits endothelin apparently causes release of prostaglandin and EDRF modifying responses. In hypertensive rabbits, a role for prostaglandins but not EDRF was observed in modulating responses to endothelin. Thus, the measured response to endothelin is the sum of a number of effects, the relative importance of which may be altered in pathological conditions.

Animals↗

PubMed1991

Imidazole binding sites in rabbit kidney and forebrain membranes.

1. The binding of [3H]-clonidine, [3H]-idazoxan and [3H]-yohimbine to rabbit forebrain and kidney membranes was compared. 2. Yohimbine bound exclusively to adrenergic sites, idazoxan to non-adrenergic sites and clonidine to both non-adrenergic and adrenergic sites. 3. Differences were observed between the ligands not only in binding at adrenergic and non-adrenergic sites but also between the non-adrenergic binding of [3H]-clonidine and [3H]-idazoxan. 4. However, no tissue specific differences were found.

Animals↗

PubMed1991

Noradrenaline and endothelin-stimulated inositol phosphate formation in arterial smooth muscle from rabbits with perinephritis hypertension.

Total inositol phosphate (IP) formation was measured in the aorta and femoral artery from rabbits at 1, 2, and 6 weeks after kidney wrapping, at which times the mean arterial pressures were 88 +/- 4, 96 +/- 3 and 126 +/- 7 (control = 74 +/- 3) mmHg. Noradrenaline (10(-7)-10(-4) M)-stimulated IP formation was increased in the aorta and femoral artery from hypertensive rabbits at 2 weeks (e.g., aorta noradrenaline 10(-6) M sham = 105 +/- 14%, hypertensive = 164 +/- 20% of control). In contrast, endothelin-1-stimulated IP formation was unchanged at 2 weeks. Noradrenaline-stimulated IP formation was unchanged at 1 and 6 weeks. Basal IP formation was not significantly different in normotensive and hypertensive animals. In perinephritis hypertension, there is an alteration in phosphatidylinositol metabolism in arterial smooth muscle at the time when blood pressure is rising rapidly. This alteration may affect a specific phosphatidylinositol pool that is linked to the alpha-adrenoceptor but not to the endothelin-1 receptor.

Animals↗

PubMed1990

Differences in the regulation of [3H]idazoxan and [3H]yohimbine binding sites in the rabbit.

In vitro studies suggest that [3H]yohimbine binds to alpha 2-adrenoceptors while [3H]idazoxan binds preferentially at a non-adrenergic site. In order to compare in vitro with in vivo effects male New Zealand White rabbits received the following treatments: 5 days idazoxan 1.1 mg/kg per h, 10 days noradrenaline 46 micrograms/kg per h (intravenous infusion), 21 days amitriptyline 30 mg/kg per day (intraperitoneally) or vehicle. The effect of these treatments on the number of [3H]yohimbine and [3H]idazoxan binding sites was examined. Ten days noradrenaline infusion and 21 days amitripytyline treatment significantly reduced [3H]yohimbine binding in kidney and hindbrain membranes respectively, but had no significant effect on [3H]idazoxan binding. Five days idazoxan infusion significantly increased [3H]yohimbine binding in the forebrain, while a significant reduction in [3H]idazoxan binding sites in the kidney was observed. Thus differential regulation of the two binding sites was observed in vivo. These alterations in binding site number are consistent with the differing affinities of noradrenaline and idazoxan for the [3H]yohimbine and [3H]idazoxan binding sites previously observed in vitro and support the hypothesis that in the rabbit idazoxan binds preferentially at non-adrenergic sites while yohimbine binds to an alpha 2-adrenergic site. The idazoxan site may be an imidazoline type of receptor but further work, including functional studies, is required to substantiate this.

Adrenergic alpha-Agonists↗

PubMed1990

Inositol phosphate formation in arterial smooth muscle from rabbits with perinephritis hypertension.

Total inositol phosphate formation was measured in the aorta and femoral artery from rabbits at 1, 2 and 6 weeks after kidney wrapping, at which times the mean arterial pressures were 88 +/- 4, 96 +/- 3 and 126 +/- 7 mmHg against a control pressure of 74 +/- 3 mmHg. Noradrenaline-stimulated (10(-7) to 10(-4) mol/l) inositol phosphate formation was increased in the aorta and femoral artery from hypertensive rabbits at 2 weeks (aorta noradrenaline 10(-6) mol/l sham, 105 +/- 14%; hypertensive, 164 +/- 20% of control). Noradrenaline-stimulated inositol phosphate formation was unchanged at 1 and 6 weeks in the aorta. Endothelin-stimulated inositol phosphate formation was unchanged at 2 weeks. Basal inositol phosphate formation was not significantly different in normotensive and hypertensive animals. In perinephritis hypertension there is an alteration in phosphatidylinositol metabolism in arterial smooth muscle. This occurs at the time when the blood pressure is rising rapidly. This alteration may affect a specific phosphatidylinositol pool that is linked to the alpha-adrenoceptor but not to the endothelin receptor.

Animals↗

PubMed1990

Binding studies of platelet alpha 2- and lymphocyte beta 2-adrenoceptors in patients with cirrhosis.

Radioligand binding studies were performed on 10 patients with cirrhosis and 10 healthy subjects. Bmax and KD of platelet alpha 2-adrenoceptors, studied using [3H]-yohimbine, were similar in both groups (Bmax 24.9 vs 22.1 fmol/10(9) platelets, P = 0.47; KD 4.6 vs 5.5 nmol 1-1, P = 0.56). Bmax and KD of lymphocyte beta 2-adrenoceptors, studied using [125I]-iodocyanopindolol, were also similar in both groups (Bmax 24.0 vs 27.2 fmol mg-1 protein, P = 0.55; KD 49.6 vs 55.3 pmol 1-1, P = 0.65). In this model there is no evidence of adrenoceptor down-regulation in cirrhosis despite the increased sympathetic activity in this condition.

Adult↗

PubMed1990

Desensitization and down-regulation of brain alpha 2-adrenoceptors by centrally acting antihypertensive drugs.

Rabbits were treated with intravenous clonidine (8 mumol kg-1 day-1), guanabenz (20 mumol kg-1 day-1), rilmenidine (80 mumol kg-1 day-1) or vehicle via osmotic minipumps. After 6 days treatment mean arterial pressure (MAP), pressor responses to intravenous alpha-methyl noradrenaline and depressor responses to intracisternal clonidine were studied, and [3H]-yohimbine binding to forebrain and hindbrain examined in vitro. Clonidine, guanabenz and rilmenidine had similar effects on MAP and caused a similar attenuation of the depressor response to intracisternal clonidine, but only guanabenz attenuated pressor responses to intravenous alpha-methyl noradrenaline. Rilmenidine had no effect on [3H]-yohimbine binding to brain membranes. Clonidine treatment decreased binding in hindbrain while guanabenz treatment decreased binding in both fore- and hindbrain. Thus, the depressor effects of chronic treatment did not correlate with the effects on [3H]-yohimbine binding sites in rabbit brain suggesting that the blood pressure lowering effects of many centrally acting antihypertensive drugs are not necessarily dependent on binding to the alpha 2-adrenoceptor site labelled by [3H]-yohimbine.

Animals↗

PubMed1990

Noradrenaline sensitivity and calcium fluxes in arteries from rabbits with perinephritis hypertension.

1. Contractions of isolated vascular and cardiac preparations taken from rabbits with perinephritis (one kidney, one wrapped) hypertension were compared with those of preparations from control operated animals. 2. Significantly increased sensitivity to noradrenaline, which acts on alpha 1-adrenoceptors, was found in mesenteric arterial rings but not in aortic rings. The degree of hypersensitivity was the same in the presence and absence of cocaine, suggesting that there is no increase in uptake of noradrenaline into adrenergic nerves in this model of hypertension. In contrast to these agonist-induced contractions, no increased sensitivity was found to potassium chloride, suggesting that hypersensitivity is specific for receptor mediated rather than membrane potential mediated effects. 3. No hypersensitivity to noradrenaline was found in the isolated left or right atria, which suggests that the hypertension is associated with changes in excitation-contraction coupling in blood vessels but not in cardiac muscle. 4. Hypertension increased basal 45Ca uptake in the mesenteric artery but not in the aorta. However, there was no significant difference between preparations from normotensive and hypertensive rabbits in 45Ca uptake or efflux stimulated by noradrenaline or KCl. 5. Increased basal 45Ca uptake could contribute to the increased sensitivity to noradrenaline found in the mesenteric artery in rabbit perinephritis hypertension.

Angiotensin II↗

PubMed1989

Effects of short-term exposure to noradrenaline and adrenaline on adrenoceptor responses.

Adrenaline (0.05 and 1.5 mumol/kg per h) and noradrenaline (0.09 and 0.5 mumol/kg per h) were infused i.v. into conscious rabbits. Pressor responses to bolus doses of phenylephrine, alpha-methylnoradrenaline and chronotropic responses to isoprenaline were studied before and during infusion. Plasma adrenaline levels rose from 1.4 +/- 0.5 to 13 +/- 2 and 31 +/- 9 nM during the 0.05 and 1.5 mumol/kg per h infusions respectively while noradrenaline levels rose from 2.0 +/- 0.9 to 16 +/- 7 and 29 +/- 11 nM during the 0.09 and 0.5 mumol/kg per h noradrenaline infusions. Pressor responses to alpha-methylnoradrenaline were attenuated within 2.5 and 60 min during the higher and lower rates of adrenaline infusion respectively. Attenuation occurred within 10 min with the higher rate infusion of noradrenaline but no change was seen during the lower noradrenaline infusion. Chronotropic responses to isoprenaline were also reduced during the adrenaline infusions but not during noradrenaline infusion. In contrast no change was observed in phenylephrine pressor responses. These results suggest that short-term elevation in the levels of the endogenous catecholamines, noradrenaline and adrenaline, can cause desensitisation of alpha 2- and beta-adrenoceptors but not of alpha 1-adrenoceptors.

Animals↗

PubMed1989

Skeletal muscle beta 2-adrenoreceptors and the effect of adrenergic drugs on plasma potassium in perinephritis hypertension in rabbits.

1. It has been suggested that beta 2-adrenoreceptors in skeletal muscle regulate plasma potassium. The possibility that alterations in the function and/or density of these receptors occurs in perinephritis hypertension in rabbits was studied. 2. Intravenous infusion of adrenaline (0.2 micrograms kg-1 min-1) caused a fall in potassium while intravenous bolus injection of propranolol (0.75 mg kg-1) resulted in an increase in serum potassium which was of similar magnitude in both perinephritis hypertensive and sham-operated normotensive rabbits. 3. Binding studies with the radioligand [125I] cyanopindolol (ICYP) showed that there were no significant differences between the hypertensive and normotensive rabbits in the density (Bmax) or affinity (KD) of the skeletal muscle beta 2-adrenoreceptor. 4. The results suggest that function and density of skeletal muscle beta 2-adrenoreceptors are not altered in rabbits with perinephritis hypertension.

Animals↗

PubMed1989

Platelet cytosolic free calcium before and after antihypertensive treatment in perinephritis hypertension of the rabbit.

Cytosolic free calcium concentration ([Ca2+]i) in platelets has been reported to be elevated in human essential hypertension, to be positively correlated with blood pressure and to decrease with blood pressure reduction. However, some groups have been unable to confirm these findings in either humans or hypertensive rats. We have examined the relationship between platelet [Ca2+]i and blood pressure in the perinephritis model of hypertension in the rabbit. In addition, the effects of both acute and chronic treatment with verapamil or prazosin were studied. Mean arterial pressure, heart rate and platelet [Ca2+]i were measured before and after treatment. Platelet [Ca2+]i was measured by the Quin 2 fluorescence technique. Platelet [Ca2+]i was similar for the normotensive and hypertensive rabbits, and no correlation between platelet [Ca2+]i and blood pressure was observed. None of the antihypertensive treatments produced a lowering of platelet [Ca2+]i. Therefore we conclude that platelet [Ca2+]i is unlikely to be a universally useful index of ([Ca2+]i in vascular smooth muscle of resistance vessels.

Adrenergic alpha-Agonists↗

PubMed1989

Endothelin stimulates phosphatidylinositol hydrolysis in rat vascular smooth muscles.

The ability of endothelin to stimulate phosphatidylinositol hydrolysis in rings of rat aorta was studied. Endothelin 10(-8)-10(-5) mol/l caused increases of 200-1000% in inositol phosphate levels. However, physiological responses to endothelin have been reported in the concentration range 10(-10)-10(-8) mol/l. Thus phosphatidylinositol hydrolysis as measured in the present study does not correlate directly with functional responses. Phosphatidylinositol hydrolysis in response to endothelin was attenuated but not abolished by removal of endothelium. Attenuation of inositol phosphate production was also observed with time, consistent with the hypothesis that continuous exposure to the agonist can cause desensitization of the endothelin receptor.

Animals↗

PubMed1988

Idazoxan and brain alpha 2-adrenoceptors in the rabbit.

The effect of intravenous infusion of idazoxan on the depressor response to intracisternal clonidine 1 microgram/kg and on [3H]yohimbine binding in the fore- and hindbrain of the rabbit was examined. Idazoxan was infused either acutely (30 min) or chronically (5 days) at doses of 0.56 or 1.1 mg/h. Idazoxan 1.1 mg/h reduced the fall in blood pressure after clonidine. This attenuation of the depressor response was observed in the groups that were given the higher dose of idazoxan both acutely and chronically. The extent of attenuation was not modified by the duration of treatment. The low dose of idazoxan given acutely had no significant effect on the response to clonidine but the chronically infused group showed an enhanced response. A significant increase in the number of [3H]yohimbine binding sites (83%) was observed in the forebrain after 5 days infusion of 1.1 mg/h idazoxan with no change in the hindbrain. The lower dose of infusion did not cause any significant change in [3H]yohimbine binding in either brain region. Thus it appears that the susceptibility of the alpha 2-adrenoceptor binding sites to up-regulation by idazoxan may depend on the brain region observed.

Animals↗

PubMed1988

Alpha 1-adrenoceptor desensitisation.

The effects of intravenous infusion with phenylephrine on pressor responses to bolus doses of phenylephrine were examined in conscious rabbits. Four hours infusions failed to attenuate responses except in animals pretreated with phenoxybenzamine to eliminate the alpha 1-adrenoceptor reserve. However, the doses of phenylephrine required to attenuate responses were very large and were not well tolerated. Thus alpha 1-adrenoceptors in rabbit vascular smooth muscles are relatively resistant to in vivo agonist desensitisation compared to alpha 2- and beta-adrenoceptors.

Animals↗

PubMed1988

[3H]yohimbine and [3H]idazoxan bind to different sites on rabbit forebrain and kidney membranes.

The binding of the alpha 2-adrenoceptor ligands [3H]yohimbine and [3H]idazoxan to rabbit kidney and forebrain membranes was compared. The maximum number of [3H]yohimbine binding sites was higher than the number of [3H]idazoxan binding sites in forebrain and lower in kidney. Large differences were observed in the ability of noradrenaline, adrenaline, idazoxan, rauwolscine, yohimbine and WY 26392 to displace [3H]yohimbine and [3H]idazoxan from their binding sites. These data suggest that [3H]idazoxan and [3H]yohimbine bind to different sites on rabbit tissue membranes.

Animals↗

PubMed1988

Regulation of adrenergic receptor number following chronic noradrenaline infusion in the rabbit.

In order to study noradrenaline-induced regulation of alpha- and beta-adrenoceptors, groups of male New Zealand White rabbits (n = 8) were treated with intravenous noradrenaline (0.09 mumol/kg x h) or ascorbate (0.1%) for 10 days via osmotic minipumps implanted in the femoral vein, and the number of cardiac, lung and lymphocyte beta-adrenoceptors as well as renal and platelet alpha 2-adrenoceptors were determined. 1. The mean arterial blood pressure, heart rate and catecholamine levels were measured before commencing, and after 24 h and 10 days infusion. Circulating noradrenaline concentrations were elevated approximately 6-fold at 24 h and were sustained at these levels after 10 days administration of noradrenaline. There were no significant alterations in the blood pressure while a significant decrease in the heart rate was observed at 24 h. 2. Alpha 2-adrenoceptor density was assessed using [3H]-yohimbine. A significant decrease in the number of alpha 2-adrenoceptors in the kidney was observed following the 10 days infusion with noradrenaline. This down-regulation was in marked contrast to the lack of alteration in platelet alpha 2-adrenoceptor number and the platelet alpha 2-adrenoceptor mediated aggregatory response. 3. The density of beta-adrenoceptors in lymphocytes, heart and lung were quantified using (-)[125I]iodocyanopindolol (ICYP). The noradrenaline infusions caused significant reductions in beta-adrenoceptor number in the heart and lung (containing predominantly beta 1-adrenoceptors) but not in lymphocytes (possessing mainly beta 2-adrenoceptors). The KD-values (pM) for ICYP binding to heart and lung were also significantly decreased in the present studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

The effects of chronic administration of adrenaline on the function and number of adrenoceptors in the rabbit.

Chronic (10-day) intravenous infusions of adrenaline (0.05 mumol/kg/h) were given to rabbits via osmotic minipumps implanted at the femoral vein. Blood pressure, heart rate, and plasma catecholamine concentrations were measured five times during the period of infusion. Tenfold elevations in circulating adrenaline levels were achieved within 24 h of commencing infusion and maintained throughout the study. This increase in plasma adrenaline was not accompanied by significant changes in blood pressure or heart rate. Rabbits were killed after 10 days: blood was withdrawn for platelet aggregation studies. Kidney, heart, and lung were also collected and alpha 2-adrenoceptor number on platelets and kidney measured using [3H]yohimbine. Beta adrenoceptors on platelets, lymphocytes, heart, and lung were quantified using [125I]iodocyanopindolol. Adrenaline infusion led to a significant reduction in platelet aggregation responses to adrenaline (0.001-100 microM), together with a decrease in alpha 2-adrenoceptor number on platelets, but no significant decrease in kidney alpha 2-adrenoceptors. A significant decrease in the density of beta adrenoceptors on heart and lung membranes was observed with no reduction in platelet and lymphocyte beta-adrenoceptor number. Thus adrenaline-induced down-regulation of adrenoceptors in the rabbit was dependent on the location and subtype of adrenoceptor.

Adenosine Diphosphate↗

PubMed1988

Desensitization of vascular and platelet alpha 2-adrenoceptors in rabbits with perinephritis hypertension.

The effects of infusion of alpha-adrenoceptor agonists on blood pressure, pressor responses to bolus doses of agonists and to platelet aggregation were examined in rabbits with perinephritis hypertension and in sham-operated controls. Pressor responses to bolus doses and infusions of phenylephrine, an alpha 1-selective agonist, were greater in hypertensive rabbits. In contrast, responses to boluses but not infusions of alpha-methylnoradrenaline, a selective alpha 2-agonist, were increased in hypertensives. During alpha-methylnoradrenaline infusions pressor responses to bolus doses of alpha-methylnoradrenaline and the aggregatory response of platelets to adrenaline were attenuated in all rabbits, consistent with alpha 2-adrenoceptor desensitization. Attenuation and recovery were observed within minutes of commencing and ceasing infusion. The extent of attenuation and rate of change were generally increased in hypertensive animals. This could explain the apparent increase in pressor responses to bolus doses but not infusions of alpha-methylnoradrenaline in the hypertensive rabbits. It might also contribute to the lability in blood pressure observed in these animals.

Adrenergic alpha-Agonists↗