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Opening of potassium channels can cause hyperpolarization and relaxation of vascular smooth muscle cells. The aim of this work was to investigate the contribution of potassium channel activation to vasorelaxation in internal thoracic artery taken from patients undergoing coronary artery bypass graft surgery. Relaxations to carbachol and sodium nitroprusside were studied in isolated rings of internal thoracic artery in the absence and presence of nitric oxide synthase inhibitors and potassium channel blockers. The nitric oxide synthase inhibitors Nω-nitro-⌊-arginine methyl ester and NG-monomethyl-⌊-arginine abolished relaxations to carbachol. Relaxations to both carbachol and sodium nitroprusside were attenuated in the presence of raised extracellular potassium and the potassium channel blockers charybdotoxin, iberiotoxin and tetraethylammonium. Neither apamin nor glibenclamide modified relaxation. ODQ (1H-[1,2,4]oxadiazolol-[4,3a] quinoxalin-1-one), an inhibitor of soluble guanylate cyclase, abolished relaxation to carbachol in rings from some but not all subjects. These results suggest that potassium channel opening may make a small contribution to endothelium-dependent vasorelaxation in internal thoracic artery. The potassium channels had characteristics consistent with those of large-conductance calcium-dependent potassium channels.

1. The effects of 300 µg of oral clonidine on blood pressure, heart rate, plasma noradrenaline and adrenaline concentrations were studied in seven tetraplegic subjects with physiologically complete cervical spinal cord transections. 2. Clonidine did not significantly change resting blood pressure during the 8 h of the study. Resting heart rate fell. Resting plasma noradrenaline and adrenaline concentrations, when measured 2 h after clonidine, were not significantly lower. 3. Urinary bladder stimulation resulted in a marked rise in blood pressure accompanied by an elevation in plasma noradrenaline but not adrenaline. The hypertensive response to bladder stimulation was substantially reduced by clonidine, the maximum suppression occurring 2–4 h after administration of the drug. The plasma noradrenaline response to bladder stimulation, when measured 2 h after clonidine, was significantly lower than the response before clonidine. In two tetraplegic subjects with indwelling catheters the rise in intravesical pressure caused by bladder stimulation was unchanged by clonidine. 4. The pressor response to intravenous noradrenaline in two tetraplegic subjects and to intravenous phenylephrine in a further two tetraplegic subjects was unchanged by clonidine. 5. Clonidine may have additional antihypertensive effects which occur independently of actions in the brain. These effects may be exerted by an action either on sympathetic neurones in the spinal cord or on presynaptic a-adrenoreceptors in the periphery.

1. We measured sodium-lithium countertransport, sodium-hydrogen exchange and membrane microviscosity in 48 individuals with familial hypercholesterolaemia, 33 subjects with hypertriglyceridaemia and 54 normolipaemic controls. Full lipid profile, blood pressure, body mass index, fasting glucose and insulin levels were also measured. 2. Subjects with hypertriglyceridaemia had higher blood pressure, body mass index, fasting glucose and insulin levels than normal controls. 3. Vmax of the sodium-lithium countertransport was elevated in the hypertriglyceridaemic group compared with controls. Across the whole group loge triacylglycerols correlated with Vmax of the sodium-lithium countertransport. There was no difference in sodium-lithium countertransport Km between the groups. 4. Sodium-hydrogen maximal proton efflux rate (Vmax) and Km were not different between the three groups. There were no correlations between sodium—hydrogen exchange and sodium—lithium countertransport parameters. 5. Microviscosity as measured by diphenylhexatriene was reduced at the core of the membrane in subjects with hypertriglyceridaemia compared with those with familial hypercholesterolaemia or normolipaemic controls, suggesting an alteration in membrane structure. 6. Changes in sodium transport in hyperlipidaemia may be mediated by changes in membrane structure resulting in altered protein conformation or turnover.

1. Blood pressure and heart rate responses to head-up tilt, standing, the Valsalva manoeuvre, sustained handgrip and cutaneous cold were measured in 27 haemodialysis patients (10 of whom had episodes of haemodialysis-induced hypotension) and 15 control subjects to assess autonomic nervous function. Plasma nor-adrenaline levels were measured at rest and during head-up tilt. 2. Mean resting supine blood pressure, heart rate and plasma noradrenaline levels were higher in haemodialysis patients than in the control subjects. There was no fall in blood pressure during head-up tilt or standing. The ratio of the R-R intervals of the thirtieth and the fifteenth heart beat after standing (30: 15) was lower in the patients; this may be related to their higher resting heart rate. Head-up tilt raised plasma noradrenaline levels in both groups. Heart rate responses to the Valsalva manoeuvre were similar in the patients and control subjects. 3. Systolic blood pressure and heart rate responses to sustained handgrip were similar in both groups. Diastolic and mean blood pressure changes, however, were lower in the patients. The blood pressure and heart rate responses to cutaneous cold were similar in the patients and control subjects. 4. We conclude that generalized autonomic nervous dysfunction does not appear to cause haemodialysis-induced hypotension in patients with chronic renal failure on maintenance haemodialysis.

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.

1. Plasma noradrenaline concentrations were similar in normotensive and hypertensive outpatients, but were significantly lower in laboratory control subjects. 2. Standing plasma noradrenaline concentrations were similar in all three groups. 3. Urinary vanillyl mandelic acid, catecholamines and metanephrines were also similar in the normotensive and hypertensive groups. 4. Laboratory controls, possibly because of familiarity with the techniques of sphygmomanometry and blood sampling, may attain a ‘basal’ resting level of sympathetic nervous discharge more readily and rapidly than subjects who are unfamiliar with such procedures. 5. After orthostatic stimulation by standing for 2 min, the activity of the sympathetic nervous system, as determined by pulse rate and plasma noradrenaline concentrations, was similar in the three groups, despite the lower starting values in the laboratory staff. 6. The absence of differences in plasma noradrenaline or urinary catecholamine and metabolite concentrations does not support the hypothesis of excessive sympathetic nervous activity in essential hypertension.

1. An improved approach for the determination of plasma [3H]noradrenaline ([3H]NA) kinetics in man is described, incorporating the extraction of plasma [3H]catechols on alumina and separation of [3H]NA from [3H]dihydroxymetabolites by high-performance liquid chromatography (HPLC). 2. After a 30 min intravenous infusion, [3H]NA accounted for 57.2 ± 13.2% of the radioactivity recovered by the procedure, while the dihydroxymetabolites 3,4-[3H]dihydroxyphenylethylene glycol ([3H]DHPG) and 3,4-[3H]dihydroxymandelic acid ([3H]DOMA) accounted for 32.3 ± 11.5% and 4.9 ± 6.0% respectively. After 90 min of constant infusion the proportion due to [3H]NA fell to 44.4 ± 10.4%, while that due to [3H]DHPG rose to 45.9 ± 9.5% because of an increase in the amount of [3H]DHPG at the later time. 3. Plasma [3H]NA radioactivity rose rapidly during the constant infusion and usually reached a plateau by 30 min. However, in individual subjects large variations in plasma [3H]NA radioactivity occurred during the course of the infusion, implying rapid and variable changes in plasma [3H]NA clearance. 4. The inclusion of a step to separate [3H]NA from [3H]dihydroxymetabolites is necessary if the aim is to determine plasma [3H]NA kinetics, as a large proportion of the radioactivity recovered from plasma on alumina is due to the presence of these metabolites.

1. The effect of intravenous infusion of catecholamines and related drugs on human platelet α2-adrenoceptor number and function was investgated. 2. Short (60–120 min) infusions of catecholamines with α2 agonist activity in vivo produced attenuation of the platelet responses to adrenaline in vitro. This desensitization was specific for the adrenaline induced aggregatory response. 3. The maximum number of [3H]yohimbine binding sites on platelets was not altered by adrenaline infusion. 4. The ability of adrenaline to reduce platelet cyclic AMP levels was significantly reduced after the infusions. 5. Acute infusions of α2-adrenoceptor agonists may alter the coupling of the platelet α2-adrenoceptor to adenylate cyclase.

1. Omeprazole, a substituted benzimidazole, is a potent inhibitor of gastric acid secretion which is currently being evaluated in patients with peptic ulcer and Zollinger-Ellison syndrome. 2. Drugs which possess an imidazole nucleus have previously been shown to inhibit cortisol release from the adrenal cortex, secondary to inhibition of mitochondrial cytochrome P-450 dependent hydroxylation reactions. 3. In a double-blind placebo-controlled crossover study in healthy male volunteers, omeprazole (60 mg daily for 7 days) did not alter basal cortisol levels. The peak cortisol response to ACTH stimulation was significantly reduced. Cortisol levels 60 min after ACTH were 824 ± 27 nmol/l on omeprazole (mean ± sem), and 929 ± 35 on placebo (P < 0.005). 4. In vitro, omeprazole caused a concentration-dependent inhibition of ACTH-stimulated cortisol release from isolated bovine adrenal cells (ED50 = 20 μg/ml). This was associated with a decrease in deoxycortisol synthesis. Therefore, unlike some other imidazole-containing drugs, the inhibitory effects of omeprazole are not entirely due to steroid 11 β-hydroxylase inhibition. 5. Substantial inhibition occurred at omeprazole concentrations which are higher than plasma levels normally achieved in clinical use. However, impairment of adrenocortical function may occur in patients on long-term high dose omeprazole treatment for Zollinger-Ellison syndrome.

1. The effects of alcohol (0.9 g/kg) compared with placebo (400 ml of orange juice) on plasma noradrenaline and 3,4-dihydroxyphenylethylene glycol levels, and on erect and supine blood pressures and heart rates, were studied in eight normal male volunteers. 2. Alcohol caused a rise in noradrenaline levels that commenced approximately 30 min after drinking and lasted about 4h. In contrast, 3,4-dihydroxyphenylethylene glycol levels fell immediately after alcohol administration and remained low for at least 6h. Acute alcohol administration alters noradrenaline catabolism, and may have a dual effect of increasing noradrenaline release and decreasing noradrenaline clearance. 3. Alcohol caused a transient rise in erect and supine blood pressures that preceded the rise in plasma noradrenaline. Thereafter erect blood pressures fell compared with control. This fall was associated with a progressive rise in both supine and erect rates, and reached a maximum several hours after the maximum levels of blood alcohol. 4. The major effect of acute alcohol administration is to lower blood pressure and induce a reflex tachycardia. Changes in noradrenaline and 3,4-dihydroxyphenylethylene glycol levels did not readily explain changes in blood pressure or heart rate, suggesting that alcohol induced changes in noradrenaline metabolism occur largely independent of changes in blood pressure and heart rate.

1. α2-Adrenoceptors on blood platelets have been widely used as a model for α-adrenoceptors in less accessible tissues. 2. The effect of oestrogen (200 μg/day intramuscularly) on α2-adrenoceptor number and function was studied in immature female rabbits. α2-Adrenoceptor number was measured in whole platelets, and membrane preparations of forebrain, hindbrain, spleen and kidney by radioligand binding. α2-Adrenoceptor function was examined by measuring platelet aggregation in vitro and circulatory responses to selective α2-adrenoceptor agonists in vivo. 3. Oestrogen treatment resulted in a significant decrease in platelet α2-adrenoceptor number and function. However, no changes were observed either in receptor number in other tissues or in responses to α2-agonists in vivo. 4. The results suggest that oestrogen modulation of rabbit platelet α2-adrenoreceptor number and function may be different from that of brain, kidney and spleen. Caution should be exercised in extrapolating results from platelets to α-adrenoceptors at other sites.

1. Captopril (50 mg orally) produced a significant fall in systolic and diastolic blood pressure in six normotensive sodium replete subjects, without a rise in heart rate. 2. On captopril, there was no change in the expected normal increase in heart rate on standing. Supine plasma noradrenaline was not reduced by captopril and normal postural increases were maintained. 3. Atropine (0.04 mg/kg i.v.) reduced the difference in blood pressure change between captopril and placebo. 4. Facial immersion in water produced a bradycardia. This change was abolished by atropine and attenuated both by captopril and edrophonium (10 mg i.V.), a cholinesterase inhibitor. 5. Lying down after 6 min standing produced an immediate transient tachycardia, which was abolished by atropine and attenuated by captopril. 6. Blood pressure and heart rate rose after a cold pressor test on both captopril and placebo. 7. The tachycardia during the Valsalva manoeuvre was inhibited by edrophonium and to a lesser extent by captopril. The effects of captopril and edrophonium were additive. 8. Parasympathetic activity of captopril may contribute to its haemodynamic profile.

1. Preliminary studies in healthy normotensive subjects with a selective α2−adrenoceptor antagonist 2 − {2 − (1,4 − benzodioxanyl)} − 2 − imidazoline (RX781094) in a dose of 0.2 μg/kg intravenously are described. 2. There was a transient increase in blood pressure, and plasma noradrenaline, 10–20 min after dosing and an associated reduction in heart rate. These observations are consistent with blockade of peripheral presynaptic α2−adrenoceptors in man. 3. The pressor responses to α−methylnoradrenaline, which has relatively selective agonist effects on α2−adrenoceptors, were markedly attenuated between 0.5 and 3.0 h after dosing (dose ratio > 20). 4. The pressor responsiveness to intravenous phenylephrine, a selective α1−adrenoceptor agonist, was only slightly reduced (dose ratio 1.7 ±0.8), as was the blood pressure rise after intravenous noradrenaline (dose ratio 1.7 ± 0.7). 5. The differential effects on the agonist pressor responses are consistent with antagonism by RX781094 of post−junctional α2−adrenoceptors on vascular smooth muscle.

1. Adrenaline was infused intravenously in nine normal volunteers to plasma concentrations similar to those found after myocardial infarction. This study was undertaken on three occasions after 5 days' treatment with placebo or the β-adrenoceptor antagonists, atenolol or timolol. 2. Adrenaline increased the systolic pressure by 11 mmHg, decreased the diastolic pressure by 14 mmHg, and increased the heart rate by 7 beats/min. These changes were prevented by atenolol. However, after timolol the diastolic pressure rose (+19 mmHg) and heart rate fell (− 8 beats/min). 3. Adrenaline caused the corrected QT interval (QTc) to lengthen (0.36 ± 0.02 s to 0.41 ± 0.06 s). No significant changes were found in the QTc when subjects were pretreated with atenolol or timolol. 4. The serum potassium fell from 4.06 to 3.22 mmol/l after adrenaline. Serum potassium fell to a lesser extent to 3.67 mmol/l after atenolol and actually increased to 4.25 mmol/l after timolol. Adrenaline-mediated hypokalaemia appears to result from the stimulation of a β2-adrenoceptor linked to membrane Na+/K+-ATPase causing potassium influx.

1. The 24 h urinary excretion of free 4-hydroxy-3-methoxyphenylethylene glycol (HMPG), HMPG conjugated as glucuronide and HMPG conjugated as sulphate was determined in nine healthy volunteer subjects and six patients with phaeochromocytoma. In both groups of subjects most (97%) HMPG was in the conjugated form. 2. Although patients with phaeochromocytoma excreted five- to ten-fold the amounts of each of the forms of HMPG excreted by the control subjects the ratio of these different forms of HMPG to each other did not differ significantly between the groups. 3. In cerebrospinal fluid and brain about 80% of HMPG was free and of the conjugated HMPG in these two tissues most was in the glucuronide form. 4. It is concluded from these data that both HMPG sulphate and HMPG glucuronide have a substantial peripheral origin and that measurements of their urinary excretion cannot be used as an index of brain catecholamine turnover.

1. A Workshop on a-Adrenoceptors was held at Loch Lomond, Scotland in July 1984. Forty participants from different disciplines in the pharmacological, biochemical, physiological and clinical fields considered the questions: (i) How many subtypes of a-receptor do we need at present? (ii) What are the activation steps set in motion by a-adrenoceptors? (iii) What are the physiological roles of a-adrenoceptors in circulatory control? (iv) What are the pathophysiological roles and how can a-receptors be manipulated in disease? 2. This paper reviews the major points which arose and is intended as a guide to the papers in this Supplement.

1. Agonist regulation of platelet a2-adrenoceptors was examined in human volunteers after acute elevations of adrenoceptor agonist and during chronic elevation of plasma catecholamines in two patients with phaeochromocytoma. 2. Platelet a2-adrenoceptor number was measured by radioligand binding ([3H]yohimbine) and a2-adrenoceptor function measured by turbidimetric platelet aggregation. 3. Short term infusion of adrenoceptor agonists with a2 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. 4. The changes in platelet response were not accompanied by changes in a2-adrenoceptor number. 5. It is proposed that a process of receptor inactivation occurs during desensitization and this is responsible for the dynamic regulation of platelet responses.

1. By the sequential administration of a1- and a2-blockers it can be shown, in the pithed rabbit, that the dose/pressor response curve to noradrenaline consists of two separate curves, one for each receptor. a2-mediated responses predominate at low doses and a1-mediated responses predominate at high doses. Pressor responses to sympathetic nerve stimulation have, similarly, an a2 component at low frequencies and a dominant a1-mediated response at high frequencies: a residual response is resistant to combined a1- plus a2-blockade. 2. This a-blocker-resistant pressor nerve response was further analysed in the pithed rat and was found to be partly susceptible to a,ß-methylene ATP, which densitizes purinergic responses. However, reserpine pretreatment produced a greater reduction of nerve-mediated pressor responses than did a-blockade, suggesting that part of the ‘a-blocker resistant’ response might be adrenergic. 3. It is concluded that sympathetic vasopressor nerve transmission is mediated for the greater part by a1- and a2-adrenoceptors but that there is evidence for contributions from non-a-adrenergic and ‘purinergic’ elements. An even greater proportion of the responses to circulating catecholamines is attributable to the a-receptors with a relatively small but significant ‘resistant’ component.

1. The relationship between a-adrenoceptor number and response has been studied in rabbits under a range of physiological and pathological conditions. 2. The effects of irreversible a-adrenoceptor blockade, maturation, ageing, oestrogen treatment, adrenaline infusion, perinephritis hypertension and sinoaortic denervation on a-adrenoceptor number and response were examined. 3. a-Adrenoceptor number was measured by radioligand binding. [3H]Prazosin and [3H]clonidine were used as ligands to measure a1- and a2-adrenoceptor number in spleen and [3H]yohimbine to measure a2-adrenoceptor number on platelets. Responses in vivo were studied by examining the pressor responses to a range of a-adrenoceptor agonists. The functional response of platelets was examined in vitro by using the aggregatory response to adrenaline. 4. Reductions in a2-adrenoceptor ligand binding were consistently accompanied by equivalent reductions in a2-adrenoceptor-mediated responses. In contrast large reductions in [3H]prazosin binding were observed with little or no change in a1-adrenoceptor-mediated responses. 5. These results would be consistent with a large receptor reserve for a1-adrenoceptors but few if any spare a2-adrenoceptors in the vasculature or on platelets. 6. Increased responses to both a1- and a2-adrenoceptor agonists were observed in animals with sinoaortic denervation and to a1-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.

1. The autonomic and local control of the circumflex coronary bed evoked through acute rises in aortic pressure (aortic balloon inflation) was analysed in conscious, normotensive and hypertensive dogs in complete heart block with ventricles paced at 100 beats/min. 2. In normotensive dogs there was an initial rise (6–12 s) in circumflex conductance preceding a fall in conductance as aortic pressure increased and was sustained. The initial rise, but not the later fall, in circumflex conductance was partly due to a cholino-receptor and partly due to a-adrenoreceptor mechanisms. Local constrictor mechanisms were responsible for the later fall in conductance. 3. The initial cholinoreceptor component of the rise in circumflex conductance is initiated through arterial baroreflex mechanisms. 4. The initial autonomic mechanisms regulating circumflex conductance appear to be absent in renal hypertension. 5. The absence of the transient autonomic rise in circumflex flow and conductance in response to rapid elevations in aortic pressure in certain forms of hypertension, e.g. during tachyarrhythmias and behavioural disturbances, may result in myocardial ischaemia when it is least appropriate.

1. Plasma noradrenaline was measured in groups of rats up to 4 weeks after application of a renal artery clip. 2. When renal artery clipping was accompanied by contralateral nephrectomy (one-kidney model) plasma noradrenaline was significantly higher in hypertensive rats than in sham-operated control rats at 7, 14 and 28 days. 3. Plasma noradrenaline was not altered at any time examined in the two-kidney model (unilateral clip and contralateral kidney left in situ). 4. Neurogenic mechanisms mediated by the peripheral sympathetic nervous system appear to participate in the development of one-kidney renovascular hypertension, but do not play a significant role in the two-kidney model.

1. The effect of the calcium antagonist nifedipine on the pressor and aldosterone responses to angiotensin II was studied in six normal subjects. 2. Blood pressure, pulse rate and plasma aldosterone, potassium and cortisol were measured during paired consecutive infusions of angiotensin II (5, 10 and 20 ng min-1 kg-1) on two separate occasions. Nifedipine (20 mg by mouth) was given, 30 min before the second set of infusions. 3. After nifedipine there were reciprocal changes in supine resting blood pressure (-7 mm Hg) and pulse rate (+18 min-1) and a significant decrease in the pressor response to angiotensin II (P < 0.05; Wilcoxon signed rank test). 4. Basal levels of aldosterone were not changed by nifedipine, but the response to angiotensin II was significantly attenuated (P < 0.05). Nifedipine had no effect on plasma potassium or cortisol. 5. Transmembrane movement of calcium is involved in the aldosterone response to angiotensin II in man. Calcium antagonists may lower blood pressure via decreased adrenal responsiveness to angiotensin II as well as by peripheral vasodilatation.

1. Blood volume, total exchangeable sodium and the effects of head-up tilt on plasma noradrenaline were studied in 10 normotensive and 11 hypertensive renal transplant recipients. The blood pressure and heart rate responses to infused noradrenaline and isoprenaline were measured. 2. Blood volume and total exchangeable sodium were significantly greater in hypertensive than in normotensive patients. 3. Resting plasma noradrenaline was significantly higher in both groups of transplantees than in normal subjects, but was similar in normotensive and hypertensive patients. 4. Plasma noradrenaline rose in normotensive but not hypertensive patients in response to head-up tilt. 5. The rise in blood pressure in response to infused noradrenaline was significantly greater in hypertensive than in normotensive transplantees. Both groups of patients showed similar responses to infused isoprenaline. 6. Extracellular fluid volume expansion associated with increased a-receptor sensitivity to noradrenaline may contribute to hypertension in renal transplant recipients.

1. A single oral dose of clonidine hydrochloride (300 µg) lowered systolic blood pressure by 20 ± 2 mmHg and diastolic blood pressure by 15 ± 2 mmHg in seven healthy normotensive subjects. 2. Resting supine plasma noradrenaline concentration fell from 2·42 ± 0·47 nmol/l before dosing to a minimum of 0·59 ± 0·18 nmol/l at 6 h. The value subsequently rose and was not significantly different from that before the dose at 12 h. There was a significant reduction in urinary free catecholamine excretion in the first 12 h after dosing. 3. Resting supine plasma renin activity before dosing was 0·95 ± 0·16 pmol of angiotensin I h-1 ml-1 of plasma and rose significantly after clonidine to 3·50 ± 0·39 pmol of angiotensin I h-1 ml-1 of plasma at 6 h. By 12 h plasma renin activity had returned to control values. 4. When the same subjects were studied on a control, drug-free, day under the same conditions, there was no significant change in blood pressure or plasma noradrenaline. Although plasma renin activity rose during this control day, it was significantly lower than after clonidine. 5. In normotensive subjects single doses of clonidine lower blood pressure and are associated with a reduction of sympathetic nervous activity. Delayed elevation of plasma renin activity may be secondary to the fall in blood pressure. There is no evidence for an overshoot of sympathetic activity after a single dose of clonidine.

1. Plasma noradrenaline concentrations and dopamine ß-hydroxylase activity have been measured at various stages in the development of hypertension in the one-kidney Goldblatt rat (unilateral renal arterial constriction and contralateral nephrectomy). 2. Although plasma noradrenaline concentrations were significantly elevated from control values at 7, 14 and 28 days, plasma dopamine ß-hydroxylase activity was not significantly different from control values except at 24 h. 3. These findings suggest that peripheral sympathetic activity is increased in the one-kidney Goldblatt model of experimental hypertension but that plasma dopamine ß-hydroxylase activity is a poor index of this increase. 4. Both the rise in blood pressure and the rise in plasma noradrenaline concentrations were prevented by pretreatment with intracisternal 6-hydroxydopamine, suggesting that the increased sympathetic activity is at least in part centrally mediated.

1. Haemodynamic and hormonal responses to infused angiotensin II were studied in conscious salt-deplete dogs during infusion of D-glucose or losartan (DuP753/MK954). 2. Mean arterial pressure (118±13mmHg) fell rapidly after losartan (60 min 106±18 mmHg) with a rise in heart rate (107±16 beats/min) from baseline (98±17 beats/min). Pressor responses to angiotensin II during D-glucose infusion (6 ng min−1 kg−1, 99±10 mmHg; 18 ng min−1 kg−1, 140±15 mmHg; 54 ng min−1 kg−1, 157±12 mmHg; 162 ng min−1 kg−1, 178±14 mmHg) showed a parallel shift during losartan infusion with very similar pressures in response to higher rates of angiotensin II infusion (54 ng min−1 kg−1,108 ± 17 mmHg;162 ng min−1 kg−1 138±14 mmHg; 486 ng min−1 kg−1, 155±14 mmHg; 1458 ng min−1 kg−1, 177 ± 12 mmHg). Losartan caused a fall in baseline systemic vascular resistance. Despite the similar mean arterial pressure, the rise in systemic vascular resistance after angiotensin II during D-glucose infusion (162 ng min−1 kg−1, 8065± 1967 dyn s cm−5) was reduced during losartan infusion (1458 ng min−1 kg−1, 6645 ±1720 dyn s cm−5. Losartan caused a small rise in cardiac output related to a rise in heart rate and increased stroke volume. Pressure infusions of angiotensin II caused a fall in cardiac output during D-glucose infusion, which was blocked during losartan infusion. The rise in heart rate in response to angiotensin II was similar during both D-glucose and losartan infusion, but with higher absolute values during losartan alone. There was a linear relationship between heart rate and the plasma concentration of angiotensin II, which was unaffected by losartan. Pulmonary pressure was marginally elevated by losartan, related to the rise in cardiac output, and was much less sensitive to angiotensin II infusion, rising only at the highest rate of infusion during both D-glucose and losartan infusion. 3. Losartan infusion alone caused a rise in plasma angiotensin II concentration with a fall in aldosterone concentration. During pressor infusions the measured angiotensin II concentrations suggested that losartan increased the clearance of angiotensin II. 4. Losartan has complex effects on cardiovascular function. The pressor response of mean arterial pressure to angiotensin II shows competitive inhibition, but this marks subtle effects on cardiac output and heart rate, in addition to systemic vascular resistance. In addition to elevating endogenous angiotensin II and suppressing aldosterone, losartan may enhance clearance of infused angiotensin II.

1. The blood pressure, heart rate, hormonal and pressor responses to constant rate infusion of various doses of the angiotensin (type 1) receptor antagonist Losartan (DuP 753/MK 954) were studied in the conscious salt-deplete dog. 2. Doses in the range 0.1–3 μmin−1 kg−1 caused no change in blood pressure, heart rate or pressor response to angiotensin II (54 ng min−1kg−1), and a dose of 10 μgmin−1 kg−1 had no effect on blood pressure, but caused a small fall in the pressor response to angiotensin II. Infusion of Losartan at 30 μmin−1 kg−1 for 3 h caused a fall in mean blood arterial pressure from baseline (110.9 ± 11.2 to 95.0 ± 12.8 mmHg) and a rise in heart rate (from 84.6 ± 15.1 to 103 ± 15.2 beats/min). Baseline plasma angiotensin II (42.5 ± 11.8 pg/ml) and renin (64.5 ± 92.7 μ-units/ml) concentrations were already elevated in response to salt depletion and rose significantly after Losartan infusion to reach a plateau by 70 min. The rise in mean arterial blood pressure after a test infusion of angiotensin II (35.3 ± 11.6 mmHg) was reduced at 15 min (11.8 ± 6.8 mmHg) by Losartan and fell progressively with continued infusion (3 h, 4.3 ± 3.3 mmHg). The peak plasma angiotensin II concentration during infusion of angiotensin II was unaffected by Losartan, but the rise in plasma angiotensin II concentration during infusion was reduced because of the elevated background concentration. Noradrenaline infusion caused a dose-related rise in mean blood arterial pressure (1000 ngmin−1kg−1, +19.9 ± 8 mmHg; 2000ngmin−1 kg−1, +52.8 ± 13.9 mmHg) with a fall in heart rate (1000 ng min−1 kg−1, −27.9 ± 11.5 beats/min; 2000 ng min−1 kg−1, −31.2 ± 17.3 beats/min). During Losartan infusion the 1000 but not the 2000 ng min−1 kg−1 noradrenaline infusion caused a greater rise in mean arterial blood pressure and a greater fall in heart rate. The fall in heart rate tended to decrease with continued infusion of Losartan. Plasma catecholamine concentrations were unaffected by Losartan. In a further study, higher doses of Losartan (100, 300 and 1000 μg min−1 kg−1; 30 min) produced greater falls in mean arterial blood pressure also with a rise in heart rate and complete blockade of the pressor effect of infused angiotensin II. Some animals became disturbed at the highest dose. 3. Losartan produces rapid dose-related falls in blood pressure and a rise in heart rate and renin release with elevation of plasma angiotensin II. Pressor responses to angiotensin II are reduced at intermediate doses and are eliminated at high doses. Losartan does not appear to inhibit angiotensin II clearance from the plasma and may in some way increase it.

1. The intra-arterial blood pressure responses to Valsalva's manoeuvre and postural change were investigated as indices of cardiovascular reflex activity in seventeen Parkinsonian patients on maximally tolerated doses of l(-)-dopa (levodopa) and repeated in nine patients on levodopa with an extracerebral decarboxylase inhibitor, l-alpha methyldopahydrazine. The results were compared with control pretreatment responses. 2. There was significant impairment of the pressor response to Valsalva's manoeuvre on levodopa, which returned to control values after the addition of l-alpha methyldopahydrazine. 3. The systolic, diastolic and mean arterial pressures measured in a horizontal position during treatment with levodopa, with and without l-alpha methyldopahydrazine, were significantly lower than pretreatment values. 4. It is concluded that the impairment of baroreflex function by levodopa is mediated, at least in part, at the periphery. In contrast, mechanisms operating within the central nervous system contribute to the lowering of blood pressure recorded in the horizontal position in patients receiving levodopa.

1. Cardiovascular reflex activity has been studied in thirty Parkinsonian patients, none of who had received levodopa or sympatholytic drugs. 2. Changes in blood pressure and pulse rate in response to Valsalva's manoeuvre and head-up tilt were investigated by intra-arterial recording. 3. Cardiovascular reflex function deteriorated with advancing age, but there was no correlation with either the duration or the severity of the Parkinsonism. 4. These results are discussed in relation to previous reports of hypotension in Parkinsonism.

1. Depletion of brain catecholamines by injection of 6-hydroxydopamine (6-OH D) into the cisterna magna in rabbits significantly diminished the rise in arterial pressure following the wrapping of both kidneys in cellophane, 6-OHD treated animals having a mean arterial pressure of 100 mmHg at 6 weeks after wrapping, compared with 122 mmHg in control animals. 2. In rabbits with established cellophane perinephritis hypertension, intracisternal 6-OHD significantly lowered the arterial pressure from 124 to 103 mmHg. 3. The pressor response to intraventricular angiotensin (100 ng) was decreased in normotensive rabbits pretreated with intracisternal 6-OHD from a pressure rise of 20 mmHg in 1 min to 10 mmHg in 1 min.

1. Mean supine plasma noradrenaline was lower in 12 male laboratory staff (0·24 ± 0·02 µg/l) than similarly normotensive out-patients (0·44 ± 0·07 µg/l). 2. In 164 non-medical hospital staff, plasma noradrenaline increased with age in white males only. 3. Plasma noradrenaline was significantly higher in women than men. 4. There was no relationship between supine blood pressure and plasma noradrenaline in normotensive or hypertensive subjects.

1. Sinoaortic deafferentation in the rat leads to increased blood pressure and heart rate. 2. Early increases in tyrosine hydroxylase activity both in brain stem and hypothalamus suggest that increased noradrenaline synthesis may contribute to the development of neurogenic hypertension. 3. After 4 weeks, phenylethanolamine-N-methyltransferase activity was reduced in the hypothalamus. 4. Noradrenaline- and adrenaline, but not dopamine-containing neurones may participate in regulation of sympathetic efferent activity.

1. Blood samples were obtained simultaneously from femoral artery and vein, pulmonary artery and antecubital vein at rest and during isometric and dynamic exercise in six patients during cardiac catheterization and plasma noradrenaline was measured radioenzymatically. 2. Analysis of variance indicated that differences between vascular sites were not significant, whereas differences between patients (P < 0·001) and differences between activities (P < 0·001) were significant. 3. Mean systemic arterial concentrations tended to be lower than pulmonary arterial concentrations during each activity, although the difference was not significant. 4. We conclude that forearm venous plasma noradrenaline concentrations are representative of those from other sites.

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.

1. Two studies were performed to elucidate the role of opioids in blood pressure control in man. 2. Study 1: nine normal subjects, 18–32 years, received in a randomized single blind manner, volume matched infusions of a Met-enkephalin analogue (DAMME) 0.5 mg, naloxone 0.2 mg/kg or saline. Blood pressure, heart rate and plasma noradrenaline were determined supine and after a 5 min, 70° head-up tilt at 0, 3/4, 2, 3, 4, 5 and 6 h. 3. Study 2: seven subjects, after baseline recordings of blood pressure and heart rate received six incremental infusions of sodium nitroprusside, 1.5–7.5 µg min-1 kg-1. They then received DAMME or naloxone and the nitroprusside infusions were repeated between 3 and 4 h. There was a significant linear relationship between fall in mean arterial pressure and rise in heart rate in each case and the slope was used as an index of baroreflex sensitivity. 4. Neither naloxone nor DAMME influenced supine blood pressure or heart rate. Blood pressure after head-up tilt was significantly (analysis of variance) decreased by DAMME for up to 5 h but not by naloxone, the effect being most marked at 3 h: systolic (mean ± sd), placebo 110 ± 6, naloxone 106 ± 10, DAMME 96 ± 16 (P< 0.02); diastolic (mean ± sd), placebo 78 ± 7, naloxone 79 ± 5, DAMME 67 ± 8 (P < 0.01). The increases in heart rate and plasma noradrenaline on tilting after DAMME were not significantly different from values with placebo or naloxone. The 3 h values for heart rate were: placebo 87 ± 16, naloxone 88 ± 19, DAMME 89 ± 23 (P > 0.1); for plasma noradrenaline (nmol/l): placebo 6.0 ± 2.2, naloxone 5.8 ± 1.9, DAMME 6.0 ± 1.9 (P > 0.1). 5. Naloxone significantly increased the slope (beats per min/mmHg) of the regression relationship from a mean of 1.8 ± 0.07 to 3.0 ± 1.3 (P < 0.05), and DAMME reduced the slope from 2.7 ± 1.7 to 1.2 ± 0.5 (P < 0.05). 6. We conclude that endogenous opioids modulate baroreflex function in man.

1. A highly specific and sensitive assay based on stable isotope dilution and mass fragmentography has been developed to measure clonidine in plasma. 2. Plasma half-lives of clonidine ranged from 6·9 to 9·4 h in five normotensive subjects. 3. Plasma clonidine concentration correlated with reduction in salivary flow and degree of sedation but not with change in blood pressure.