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To determine if the increased risk of cardiovascular disease in patients with lower socioeconomic status could be explained by higher prevalence of known risk factors including hypertension or whether there was an independent effect of deprivation.

The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)–lowering.

To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized study.

ObjectiveTo identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide (HCTZ) 12.5 mg, and are well tolerated, in lowering systolic blood pressure (SBP) in patients with isolated systolic hypertension (ISH).

BackgroundSecondary prevention of stroke with antihypertensive drugs is now standard practice, but it is unclear how soon after a cerebrovascular event antihypertensive therapy should be initiated or re-started. Due to impaired cerebral autoregulation, changes in systemic blood pressure may be reflected in cerebral perfusion, especially in hypertensive patients immediately post-stroke. Conversely, early initiation in hospital may better assure continued long-term treatment. We have investigated the effect of the angiotensin II receptor antagonist (ARA) losartan on mean arterial blood pressure (MABP), global and focal cerebral blood flow (CBF), and glomerular filtration rate (GFR) in hypertensive patients 2–7 days after stroke.

Endothelial dysfunction, believed to underlie the structural changes of atherosclerosis, is a systemic phenomenon. Despite this, the radial artery has been considered as devoid of atherosclerosis and is commonly used as a conduit in coronary artery bypass grafting (CABG). Recently, histological study has shown intimal hyperplasia and other structural changes consistent with early atherosclerosis in the radial artery. The objective of the present study was to determine if structural changes in the radial artery could be detected invivo in patients with coronary atherosclerosis. Using high resolution echo-tracking, measurements of radial artery internal diameter, wall thickness and wall cross-sectional area were made in 25 patients awaiting CABG and in 20 controls. Digital and brachial blood pressures were also recorded. Mean arterial pressures did not differ between the patient and control groups. All measures of wall thickness were greater in the patient than the control group. Neither current arterial pressures nor past history of hypertension correlated with wall thickness. Using a model of analysis of covariance, coronary artery disease was the best single predictor of intima-media thickness, R2 = 48%, n = 44, P< 0.0005. We concluded that increased radial artery wall thickness can be demonstrated invivo in patients with coronary atherosclerosis. This is a novel observation which seems to be independent of blood pressure, and is consistent both with the hypothesis of systemic endothelial dysfunction leading to systemic structural changes and also to the recent histological evidence for atherosclerotic changes in this vessel.

Highly sensitive enzymatic assays, microdissection techniques, and histochemical methods were used to investigate the effects of blunt trauma on rabbit spinal cord serotonin, norepinephrine, and dopamine concentrations. Within 5 minutes after trauma, norepinephrine and serotonin in gray matter decreased considerably at the lesion center. In white matter, norepinephrine decreased or was unchanged, but at the lesion edges serotonin increased. No changes in dopamine concentration were detected. Substantial changes in monoamines do occur after spinal cord trauma and serotonin may play a role in injury development.

Animal studies, while generally showing loss of endothelium-dependent responses after an elevation in plasma cholesterol, have provided conflicting reports with regard to recovery of function after normalisation of cholesterol level. Therefore, we assessed changes in vascular function after a period of hypercholesterolaemia and the subsequent effect of normalisation of cholesterol levels. Contractile responses to phenylephrine (PE) and endothelium-dependent relaxation in response to carbachol were examined in thoracic aorta from New Zealand White rabbits (NZW) fed a 0.3% cholesterol diet for 20 weeks, from NZW fed a 0.3% cholesterol diet for 20 weeks, followed by standard diet for 20 more weeks, and from their respective age-matched controls. Cholesterol levels were increased in rabbits receiving the 0.3% cholesterol diet (12.7 ± 3.2 mM;0.5 ± 0.1 mMcontrol) and returned to normal when standard diet was reintroduced (0.8 ± 2.0 mM). Contractile responses were not affected by the period of hypercholesterolaemia. Carbachol-induced relaxation of a submaximal PE contraction was impaired after the period of hypercholesterolaemia (Emax69 ± 9%; 95 ± 3% age-matched control); the effect was reversed after reintroduction of standard diet (Emax79 ± 6%; 82 ± 2% age-matched control). Our results demonstrate that endothelium-dependent relaxation is impaired after a long-term 0.3% cholesterol diet. Furthermore, after reintroduction of a normal diet, there is no further impairment of endothelium-dependent relaxation and endothelium function improves.

We conducted pharmacodynamic studies in man with a specific α2-adrenoceptor agonist BHT-933. The study involved nine male normotensive volunteers each of whom received BHT-933 5 mg or placebo in random order. BHT-933 significantly lowered systolic and diastolic blood pressure (BP) in supine and standing positions, the greatest effect occurring 3–4 h following drug administration. Supine values: placebo 116/73; BHT-933 99/64. Standing values: placebo 114/79: BHT-933 92/67. Heart rate was uninfluenced by BHT-933 even at the time of maximum fall in BP. Plasma noradrenaline concentration in the supine position was significantly reduced: placebo 2.5 ± 0.8 nmol/L: BHT-933 1.7 ± 0.6. The haemodynamic changes accompanying Valsalva's manoeuvre and cold pressor test were uninfluenced by BHT-933. All subjects experienced sedation and dry mouth following BHT-933 with a time course similar to that of the fall in BP. These results are consistent with an effect of BHT-933 on BP control through an action on α2-receptors at the level of the brainstem.

We conducted pharmacodynamic studies with a new vasodilator, MDL-899. Following initial dose-ranging studies we studied eight male normotensive volunteers, each of whom received, orally, 10 mg MDL-899 or placebo in double-blind random order. MDL-899 significantly lowered standing blood pressure, the maximal effect occurring 3–6 h following drug administration. There was a significant increase in heart rate in both supine and standing positions, maximal 6–8 h postdose. Supine plasma noradrenaline concentrations were greater following MDL-899, with the greatest difference present 4 h after drug administration. Plasma renin concentrations were greater following MDL-899. Six of our subjects were also given 10 mg MDL-899 together with 100 mg atenolol, in an additional study. Atenolol increased the hypotensive effect and attenuated the tachycardia following MDL-899 alone. Side effects following MDL-899 administration included headache, lightheadedness, and tachycardia. These were reduced following atenolol coadministration. The haemodynamic profile of MDL-899 suggests that this drug acts as a direct arteriolar vasodilator in man. The observed increase in heart rate is likely mediated by reflex activation of the sympathetic nervous system.

The biological effects of dose-dependent inhibition of renin have rarely been extensively studied after oral (p.o.) dosing in humans. We studied remikiren (Ro42–4892), a selective renin inhibitor, in normal volunteers after activation of the renin-angiotensin system (RAS) based on salt depletion. Twelve normal men (28 ± 9 years, 77 ± 10 kg), comprising three consecutive dose panels of 4 subjects, received four treatments, double-blind and randomised 2 weeks apart: panel I, placebo (P). or 30. 100. and 300 mg. remikiren: panel II. placebo or 300. 600 mg, 1,000; panel III, placebo or 30, 600, and 1,000 mg. The RAS was activated by 40 mmol/day sodium diet plus frusemide (40 mg BDS), for 3 days before each study day. Data (mean ± SD) were examined by repeated-measures analysis of variance (ANOVA). RAS activation was confirmed by 24-h urinary sodium excretion (screen, 142 ± 74 mmol/24 h: prestudy, 66 ± 33. 59 ± 41, 78 ± 4. 73 ± 30 mmol/24 h) and increase in plasma renin activity (PRA) (screen, 0.8 ± 0.3 ng AI/ml/h; before dosing. P, 6.5 ± 3.1: 30 mg. 8.2 ± 3; 100 mg. 9.4 ± 5.7: 300 mg. 6.5 ± 2.4; 600 mg. 5.2 ± 2: 1,000 mg. 6.2 ± 4.4 ng AI/ml/h). PRA was reduced in dose dependently (mean minimal activity: 30 mg 1.4 ± 1.2: 100 mg. 1.6 ± 1: 300 mg, 0.1 ± 0.1,600 mg, 0.1 ± 0.1:1,000 mg, 0.01 ± 0.02), and active renin was increased (mean maximal active renin; 30 mg. 182 ± 186; 100 mg. 185 ± 83: 300 mg. 252 ± 240; 600 mg. 262 ± 100, 1.000 mg. 1.417 ± 2.008 pg/ml). Maximal effects were noted soon after dosing for PRA (30 mg. 1.1 ± 0.3: 100 mg. 1 ± 0; 300 mg. 1 ± 0; 600 mg. 1.3 ± 0.4; 1.000 mg. 1.3 ± 0.4 h) but slower for increase in active renin (30 mg. 4.6 ± 1.3. 100 mg. 3 ± 1.4; 300 mg. 1.8 ± 1.6: 600 mg. 2.8 ± 1.5; 1,000 mg. 3.4 ± 1.4 h). Despite evidence of biochemical effect, supine blood pressure (BP) was not significantly affected by active treatment. Erect BP did show a significant decrease from pretreatment values, but only after 1,000 mg remikiren 1 h after dosing (P. baseline, 116 ± 12/68 ± 7: 1 h, 112 ± 8/65 ± 7; 1.000 mg. baseline, 114 ± 12/65 ± 7; 1 h, 96 ± 9/50 ± 18). Drug concentrations showed a wide dose-related spectrum of mean maximal concentrations (30 mg. 1.07 ± 1.64; 100 mg, 2.17 ± 1.38; 300 mg. 28.88 ± 16.95; 600 mg. 67.76 ± 36.06: 1.000 mg. 136.9 ± 156 ng/ml). Values for Tmaxwere generally observed soon after dosing and were not clearly dose related (30 mg. 0.5 ± 0.5; 100 mg. 0.56 ± 0.77; 300 mg, 0.66 ± 0.51: 600 mg. 0.44 ± 0.11; 1,000 mg. 0.94 ± 0.63 h). Remikiren is enzymatically active after p.o. administration in humans in a dose-dependent manner. Only the dose of 1.000 mg reduced BP in salt-deplete subjects. Haemodynamic effects are therefore demonstrable but are slight, dissociated from RAS inhibition in blood, despite confirmed activation of the RAS. BP changes parallel the pharmacokinetic profile. The latter is unlikely to permit once daily dosing with 24-h effect. Higher doses and or controlled-release p.o. formulations or alternative routes of administration would be required to achieve antihypertensive efficacy. Owing to the selective nature of renin inhibition, a separate profile of efficacy and response in hypertensive patients is unlikely.

Risks associated with hypertension: Hypertension is a major factor in haemorrhagic and atherothrombotic stroke. Reduction of blood pressure reduces stroke risk by up to 40 in all hypertensive populations. Many older patients who would benefit from antihypertensive therapy are currently not adequately treated.

We investigated the effects of the xanthine oxidase (XO)/hypoxanthine (HX) free radical (FR) generating system on the relaxant properties of aortic rings from New Zealand White rabbits. This system generates superoxide anions, hydroxyl radicals, and H2O2. We wished to identify which of these species is responsible for impairment of vascular function. After obtaining dose-response curves to phenylephrine (PE) and carbachol or sodium nitroprusside (SNP), we exposed rings to the FR generating system or H2O2for 30 min, either with or without a range of potentially protective agents. Doseresponse curves to carbachol or SNP were then repeated. Exposure to the XO/HX system impaired endotheliumdependent, carbachol-induced relaxation. The hydroxyl radical scavengers mannitol, N-(2-mercaptopropionyl)-glycine (MPG), and captopril offered no protection. Superoxide dismutase (SOD) increased the impairment of response, catalase provided partial protection, and a combination of SOD and catalase completely prevented impairment of the response. H2O2mimicked the effects of XO/HX system. H2O2appears to be the primary species involved in mediating the toxic effects of the XO/HX FR generating system, but the superoxide anion is probably responsible for some of the loss of relaxation and a role for intracellular generation of hydroxyl radicals cannot be excluded

There is evidence that responses mediated via α adrenoceptors are dependent on calcium fluxes and it has been suggested that the α2adrenoceptor is particularly associated with the increased entry of extracellular calcium ions, which is preferentially antagonised by calcium channel blocking drugs. This study investigates in normotensive men the effects of calcium antagonism with verapamil and the dihydropyridine nisoldipine on the pressor responses to adrenergic and nonadrenergic vasoconstriction. Phenylephrine and alphamethylnoradrenaline were intravenously infused to assess respectively α1, and α2adrenoceptor-mediated peripheral vascular responsiveness and angiotensin II was used to assess nonadrenergic responsiveness. After 4 days oral treatment, both verapamil and nisoldipine significantly attenuated the responses to angiotensin II with three- to fivefold rightward shifts of the mean pressor dose–response curves. Rightward shifts of comparable magnitude were obtained for phenylephrine but with alphamethylnoradrenaline, although the overall trend was similar, only nisoldipine caused a significant twofold rightward shift. These data demonstrate, in humans, that peripheral vascular adrenergic responses mediated via both α1and α2adrenoceptors are affected by calcium channel blocking drugs. There was no evidence that this effect was specifically linked to the α2adrenoceptor.

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke1–3and several mendelian traits featuring stroke have been described4,5. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed6,7. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes8as well as an increased sensitivity to experimentally induced focal cerebral ischaemia9,10. Rubattu et al.11performed a genome-wide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1–3. Of these, STIR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors11. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.

Because both verapamil and prazosin act on peripheral vascular smooth muscle and undergo extensive first-pass metabolism, the possibility of dynamic and kinetic interactions with their concurrent use was investigated. The acute hemodynamic effects of oral prazosin (1 mg), oral verapamil (160 mg), and their combination were evaluated in eight men with normotension. The kinetics of both drugs, alone and in combination, were also assessed. Verapamil did not change blood pressure or heart rate, but prazosin induced a fall in blood pressure, particularly on standing (lowest systolic pressure was 98 mm Hg). The combination of prazosin and verapamil had an earlier, longer, and greater hypotensive effect that was maximal 4 hr after dosing, with a standing systolic pressure of 89 mm Hg. Increases in heart rate were less after the combination (maximum of 102 bpm) than after prazosin alone (maximum of 112 bpm), although there were greater falls in blood pressure with the combination than with prazosin alone. Increases in plasma catecholamine and aldosterone levels and plasma renin activity were greatest with the combination. No differences were found in the kinetics of verapamil when combined with prazosin, but the combination affected prazosin kinetics, with increases in peak prazosin concentrations and AUC. Our data suggest that the greater hypotensive activity of the combination results at least in part from a kinetic interaction that enhances the bioavailability of prazosin, but it is possible that a dynamic interaction at the level of vascular smooth muscle or compensatory cardiac activity also plays a role.

Captopril inhibits the metabolism of endogenous opioids in vitro and potentiates their effects in vivo. We examined the hypothesis that endogenous opioids contribute to the actions of captopril in man. The acute cardiovascular and autonomic effects of oral captopril, intravenous naloxone, and their combination were examined in eight healthy men with normotension in a double-blind, placebo-controlled study of a Latin squares design. Naloxone altered neither blood pressure nor heart rate. There were significant falls in systolic blood pressure during captopril dosing alone, but there was no fall in blood pressure during combination therapy. Heart rates were higher during the combination than during captopril alone. The combination caused sedation, but neither captopril nor naloxone alone had any behavioral effects. Modification of the acute circulatory effects of captopril by naloxone suggests a role for endogenous opioids in the responses to converting enzyme inhibition. The sedation caused by the combination raises the possibility that captopril may exert central nervous actions in man.

The imidazoline derivative idazoxan, which has been shown to be a potent, selective α2-adrenoceptor antagonist, was injected intravenously to eight men with normotension. There was a transient small increase in blood pressure and a decrease in heart rate within 20 min of injection, with a slight increase in plasma norepinephrine levels. These effects are consistent with antagonism of prejunctional α2-adrenoceptors. In response to infusions of the relatively selective α2-adrenoceptor agonist α-methylnorepinephrine, the pressor dose-response curve shifted to the right with idazoxan. These data provide evidence for receptors with α2-adrenoceptor characteristics on resistance vessels in man. In vitro platelet aggregation studies provide further evidence of selective α2-adrenoceptor antagonism by idazoxan, with greater potency and affinity than α-yohimbine. These observations are consistent with both pre-and postjunctional peripheral α2-adrenoceptors in man and provide further support that idazoxan is a selective α2-adrenoceptor antagonist.

Initiation of prazosin therapy may be complicated by the first-dose response of acute postural hypotension and tachycardia. The effects of β-blocker on the responses to oral prazosin were studied in eight normotensive men. After 1 mg oral prazosin there was a marked postural fall in blood pressure to a lowest mean standing systolic pressure of 88 ± 7 mm Hg (\[xmacr] ± SD), associated with a tachycardia of 117 ± 13 bpm, and an increase in mean plasma norepinephrine concentration to 9.6 ± 7.9 nmole/l. There was a linear relationship (r = 0.93) between plasma prazosin concentration and hypotensive effect. Concurrent propranolol 80 mg or primidolol 100 mg (a cardioselective β-blocker) increased the severity and duration of the postural hypotensive response, with lowest mean systolic blood pressure (BP) of 79 ± 7 and 75 ± 9 mm Hg. There was no effect on the orthostatic release of norepinephrine but there was attenuation of the postural tachycardia. Concurrent β-adrenergie blocking therapy, selective or nonselective, intensifies the immediate postural hypotensive response to the initial oral dose of prazosin.Clinical Pharmacology and Therapeutics (1981) 29, 303–309; doi:10.1038/clpt.1981.40

Blood pressure, heart rate and responses to a range of autonomic reflex tests were studied in 10 normotensive male volunteers following 7 days of regular alcohol consumption (0.8 gkg per day) or 7 days of abstaining from alcohol in a crossed, random order, open study. Systolic and diastolic pressures were significantly higher following alcohol intake than the alcohol-free control period (mean rise of 3.0 mmHg systolic and 3.1 mmHg diastolic, P< 0.05 and P< 0.01, respectively). Regular alcohol consumption attenuated the rise in blood pressure during isometric exercise and hand immersion in ice water, but did not affect blood pressure or heart rate responses to bicycle exercise. Resting, supine plasma noradrenaline levels, increases in noradrenaline levels during sympathetic activation and vagal reflexes (standing to lying test, diving reflex and Valsalva manoeuvre) did not differ significantly between the alcohol and control phases of the study. These findings support previous evidence that regular alcohol consumption decreases adrenoceptor mediated cardiovascular reactivity. However, the relationship between this effect and the rise in blood pressure that follows regular, moderate alcohol consumption remains unclear.

The capacity of endothelin-1 to induce severe reductions in cerebral blood flow and ischaemic neuronal damage was assessed in anaesthetised rats. Endothelin-1 (25 μl of 10−7–10−4M) was applied to the adventitial surface of an exposed middle cerebral artery and striatal blood flow assessed by the hydrogen clearance technique. Endothelin-1 induced severe dose-dependent reductions in cerebral blood flow (e.g., minimum CBF at 10−5Mof 9 ± 11 ml 100 g−1min−1compared to 104 ± 22 ml 100 g−1min−1with vehicle, p< 0.05), which persisted for at least 60 min at each concentration of endothelin-1. Application of endothelin-1 to the middle cerebral artery produced dose-dependent ischaemic brain damage (e.g., volume of damage of 65 ± 34 mm3at 10−5Mcompared to 0.22 ± 0.57 mm3for vehicle, p< 0.01). These data demonstrate that endothelin-1 is capable of reducing blood flow to pathologically low levels and provide a new model of controlled focal ischaemia followed by reperfusion.

This study investigated the cardiac responses and pharmacokinetics following the acute and chronic administration of verapamil in 14 middle-aged and elderly patients with ischemic heart disease (age range 42–76 years). There were small significant reductions in heart rate during chronic treatment, but there were no significant effects on the PR intervals following either single intravenous administration or after 4 weeks continued treatment. Left ventricular ejection fractions at rest or exercise were not significantly changed following either acute intravenous (rest 33%; exercise 38%) or chronic oral dosing with verapamil (rest 35%; exercise 43%) when compared with placebo (rest 34%; exercise 42%). There were no independent age-related effects on these indices of cardiac function, nor on apparent liver blood flow, nor on blood pressure and heart rate. The plasma clearance of verapamil was reduced from 1.3 1/min after acute dosing to 0.8 1/min during chronic treatment, but there was no significant independent age-related effect. The results of this study suggest that middle-aged and elderly patients with ischemic heart disease do not show enhanced cardiovascular responses to low doses (5 mg intravenously and 80 mg tid orally) of the calcium antagonist drug, verapamil.

This review of new antihypertensive drugs concentrates on an exciting new class of antihypertensive agents, the orally active angiotensin II receptor antagonists, and their potential role in the management of hypertension. These drugs have been evaluated within the last year or so to determine their efficacy and safety as blood-pressure-lowering agents and to unravel the role of the renin-angiotensin system in the pathophysiology of hypertension. In addition, renin inhibitors have undergone further clinical trials in hypertension. The use of angiotensin-converting enzyme inhibitors for the treatment of symptomatic heart failure of all grades has become established since the publication of the report of the Studies of Left Ventricular Dysfunction (SOLVD) group and the Vasodilator Heart Failure Trial-ll (V-HeFT-ll) study. The role of newer β-blocking agents and novel formulations of drug delivery that have been applied to calcium antagonists in particular are discussed. The section on new approaches to hypertension treatment focuses on isolated systolic hypertension and hypertension in the elderly.

We have studied several factors that may cause hypertension in renal transplant recipients. Cardiac output measurements suggest that hypertension is maintained by an increase in total peripheral resistance. Plasma noradrenaline concentration was significantly higher in both normotensive and hypertensive patients than in matched normal subjects. Plasma noradrenaline rose significantly in response to headup tilt in normotensive, but not in hypertensive, patients. Resting plasma renin activity was significantly higher in both groups of patients than in normal subjects, but there was no relationship between plasma renin activity and blood pressure. Plasma renin activity did not change in response to headup tilt or isoprenaline infusion in the patients. The rise in arterial pressure during noradrenaline infusion was significantly greater in hypertensive than in normotensive patients. Regression analysis showed a significant relationship between the combination of total exchangeable sodium and the rise in mean arterial pressure during noradrenaline infusion with resting mean arterial pressure.

Sodium nitroprusside infused intravenously into conscious rabbits lowered blood pressure and raised heart rate and plasma noradrenaline. Acute beta blockade with propranolol, 2 mg/kg/hr i.v. for 2 hr, increased resting plasma noradrenaline and did not change the hypotensive effects of nitroprusside or the rise in plasma noradrenaline but attenuated the increase in heart rate. Chronic treatment with propranolol, 2 mg/kg twice daily for 3 weeks, did not modify the cardiovascular or reflex effects of nitroprusside. However, bilateral sinoaortic denervation augmented the hypotensive effect of nitroprusside and abolished both the heart rate and plasma noradrenaline responses to the vasodilator. The fall in blood pressure after nitroprusside is therefore attenuated by baroreflex mechanisms, which did not appear to be mediated by beta adrenoceptors or by withdrawal of vagal tone but could involve alpha-receptor-mediated vasoconstriction. Propranolol does not lower noradrenaline or modify the increase in noradrenaline after sodium nitroprusside.

The hypokalaemic response to adrenaline and the involvement of β-adrenoceptors and Na+-K+pumps were investigated in control rabbits and animals chronically pretreated with adrenaline. The hypokalaemic response to acute intravenous infusion of adrenaline was significantly reduced when rabbits were chronically pre-treated with adrenaline for 10 days. Chronic pretreatment of rabbits with adrenaline significantly reduced the densities for [125]cyanopindolol and [3H]ouabain binding sites in skeletal muscle and heart. Furthermore, there was a strong positive correlation (r = 0.97, p < 0.001) between the Bmaxfor ICYP and [3H]ouabain, in the rabbit heart. Ouabain-sensitive 86Rb uptake and the activity of 3-O-methylfluorescein phosphate phosphatase were user to assess the function of the Na+-K+pump in skeleta and cardiac muscle. There was no significant difference it these functional indices of the Na+-K+pump betweer the control and adrenaline-pretreated animals, in skeleta or cardiac muscle. Thus, downregulation of the [3H]ouabain binding sites did not appear to be accompa nied by reduced function of the Na+-K+pump. Additional investigations are required to confirm further the dissociation between the function of the pump and the ouabain binding sites.

Aging has been reported to alter the responsiveness of β-receptors, but there have been few comparable studies of α-receptors. This study compares in six young and six healthy elderly subjects the haemodynamic effects of the α1-antagonist prazosin and the pressor responses to the α1-agonist phenylephrine. Prazosin orally lowered erect (but not supine) blood pressure in both groups by a similar amount between 2 and 6 h after dosing. Maximal falls in systolic pressure were 19.5 ± 15.7 and 29.3 ± 11.4 mm Hg (mean ± SD) in young and old, respectively. There was a significant difference in the associated heart rate response: in the young group mean heart rate increased to 103 beats/min, but there was no corresponding increase in the elderly group, which had a mean heart rate of 80 beats/min. Following the intravenous infusion of increasing doses of phenylephrine, log dose—response curves were derived, and the dose required to raise mean arterial pressure by 20 mm Hg (PD20) was compared. The mean PD20, was significantly different in the two groups: 2.5 ± 1.6 in the young, compared to 4.6 ± 2.3 μg/kg/min in the elderly, indicating reduced pressor responsiveness in the elderly. However, no significant difference was apparent when pressor responsiveness was determined following the administration of prazosin. Thus, while there is no evidence of an age-related increase in the sensitivity of α-adrenoceptor-mediated vaso-constriction, the data are not inconsistent with an age-related reduction in responsiveness to α-adrenoceptor activation.

Captopril (SQ 14 225) was administered to normotensive, sodium-replete volunteers in order to investigate the relationships between its haemodynamic effects and effects on sympathetic activity, the renin—angiotensin—aldosterone system, and plasma-converting enzyme activity. Following the administration of captopril (25 mg) orally, mean arterial pressure fell (supine 89.1 ± 5.9 to 81.1 ± 3.3 mm Hg, p < 0.01: erect 98.5 ± 5.5 to 87.4 ± 6.7 mm Hg, p < 0.01) but heart rate did not change. Plasma noradrenaline rose; plasma renin activity and angiotensin I concentration rose, while angiotensin II and aldosterone fell; plasma-converting enzyme was inhibited for 6 h. The extent of blood pressure reduction and converting enzyme inhibition was closely correlated (r = 0.92, p < 0.001). Plasma captopril concentration was directly related to converting enzyme inhibition in an in vitrostudy using plasma from the same subjects. In the absence of a convenient assay of captopril, converting enzyme may be used as an index of captopril concentration in the further study of kinetic and dynamic relationships.

Pharmacodynamic and pharmacokinetic interactions have been reported when an a,-antagonist is combined with a calcium antagonist. We evaluated the clinical usefulness of the combination of nifedipine (20 mg twice daily, b.i.d.) and doxazosin (2 mg once daily, o.d.) in hypertensive patients in whom blood pressure (BP) control was suboptimal after doxazosin (group A) or nifedipine (group B) as monotherapy and investigated the underlying kinetic and dynamic interactions, including changes in vascular responsiveness to i.v. infusions of angiotensin II (ANGII) and phenylephrine (PE). The combination was well tolerated and associated with further significant reductions in BP. After 4 weeks of combined therapy, average supine BP over 8 h was 122/77 in group A and 137/80 in group B as compared with 140/86 and 150/88 mm Hg, respectively, during monotherapy placebo. The combination attenuated both phenylephrine and ANG-induced pressor responses: e.g., the mean PD15values (dose of agonist required to increase systolic BP by 15 mm Hg) for group A at 1.5–3 h were 3.5 μg/kg/min for PE and 7.5 ng/kg/min for ANGII as compared with 2.9 and 2.3, respectively, during treatment with doxazosin and placebo. There was no evidence of a significant kinetic interaction between the two drugs and, in particular, addition of nifedipine had no effect on the steady-state kinetics of doxazosin. In conclusion, doxazosin and nifedipine are an effective antihypertensive combination in patients who require treatment with more than one drug..ab

Internal mammary arteries (IMA) and saphenous veins (SV) are vessels currently used in human coronary artery bypass surgery. In addition to late complications, the vessels may develop spasm perioperatively. We studied isolated IMA and SV from patients undergoing coronary artery bypass graft to reproduce in vitro the phenomenon of vasospasm. Vascular rings were constricted with phenylephrine in a classic organ bath. The effects of two vasodilator agents, milrinone and sodium nitroprusside (SNP), on phenylephrine precontracted vessels and as a pretreatment to reverse or prevent the contraction, respectively, were studied. When added to a precontracted vessel, milrinone had the same vasorelaxant effect as SNP in artery rings (EC50: 7.4 × 10-7± 0.8 × 10-7vs. 5.9 × 10-7± 0.8 × 10-7M, milrinone vs. SNP). In veins, milrinone was less effective in relaxing the rings than SNP (EC50: 15 × 10-7± 3 × 10-7vs. 1.5 × 10-7± 0.1 × 10-7M, milrinone vs. SNP, p < 0.05). If milrinone or SNP was added as a pretreatment, using the EC50values, the inhibitory effect of milrinone on phenylephrine-induced contractions was greater in arteries than in veins (71 ± 4 vs. 36 ± 11 inhibition of maximum contraction to phenylephrine, artery vs. vein, p < 0.05). In arteries, milrinone caused a greater inhibitory effect than SNP (71 ± 4 vs. 52 ± 9 inhibition, milrinone vs. SNP, p < 0.05), but similar inhibition in veins (36 ± 11 vs. 42 ± 16, milrinone vs. SNP). These results suggest that milrinone could be useful in preventing IMA spasm and, to a lesser extent, SV spasm, but not in reversing established spasm of an artery.

Prazosin, doxazosin, and trimazosin are structural analogues with relatively selective peripheral α1-adrenoceptor antagonist properties. The relationships between the pharmacokinetics and pharmacodynamics for these three drugs have been studied following acute intravenous administration in normotensive subjects. The mean terminal elimination half-life (± SD) for prazosin was 2.0 ± 0.4 h, and that for trimazosin was comparable at 3.1 ± 0.3 h, whilst the mean terminal elimination half-life for doxazosin was significantly longer at 9.4 ± 1.5 h. The clearance of prazosin (mean, 327 ± 78 ml/min) was greater than that of both doxazosin (139 ± 30 ml/min) and trimazosin (67 ± 29 ml/min). The hypotensive effects of prazosin and doxazosin were fitted to an integrated pharmacokinetic-pharmacodynamic model with similar resulting values for the parameter describing responsiveness. The pharmacodynamic profile of trimazosin was subjected to similar analysis and was most appropriately fitted to a model incorporating an effect compartment associated with both parent drug and its major metabolite 1-hydroxy trimazosin.

The effects of enalapril maleate and its lysine analogue, lisinopril, on reflex control of heart rate after acute and chronic administration were examined in 10 normotensive males. Both drugs reduced blood pressure without change in heart rate after acute dosing and after seven days. Both drugs impaired the vagally mediated early cardiac acceleration associated with lying down (standing to lying test). A similar effect was observed following edrophonium. After lisinopril bradycardia induced by facial immersion (diving reflex) was significantly attenuated. Edrophonium similarly attenuated the bradycardia. Both these reflexes are parasympathetically mediated. Neither drug altered heart rate or blood pressure changes following Valsalva's manoeuvre and the cold pressor test. Plasma noradrenaline was unchanged. Absence of reflex tachycardia with blood pressure reduction by converting enzyme inhibitors may be related to increased parasympathetic activity either centrally or peripherally wihout impairment of baroreflexes or sympathetic function.

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 ± 7mmHg against a control pressure of 74 ± 3 mmHg. Noradrenaline-stimulated (10-7to 10-4m-ol/l) inositol phosphate formation was increased in the aorta and femoral artery from hypertensive rabbits at 2 weeks (aorta noradrenaline 10-6mol/l sham, 105 ± 14; hypertensive, 164 ± 20 of control). Noradrenaline-stimulated inositol phoshate formation was unchanged at 1 and 6 weeks in the aorta. Endothelin-stimulated inositol phoshate formation was unchanged at 2 weeks. Basal inositol phoshate 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 α -adrenoceptor but not to the endothelin receptor.

This study investigates the potential utility of a drug concentration-effect modelling approach to predict the long-term response to antihypertensive treatment with enalapril. Concentration-effect relationships were characterized in 13 subjects following a single dose of enalapril (20 mg) and for each individual the derived parameters were used to predict the steady-state blood pressure profile. The predicted responses (before dosing and 4 h after dosing) were in close agreement with the responses observed after 6 weeks. In individual patients, the observed and predicted blood pressure profiles over a 12 h period were compared. In six of the 13 subjects, there were statistically significant (P< 0.05) prediction errors. However, in all but one of these patients the error was < 10, and for the group as a whole the mean prediction error was small and not statistically significant ( — 0.6 ±.1 mmHg). The kinetic-dynamic parameters derived from observations of the first dose were used to simulate steady-state responses to several alternative doses and dose frequencies. A regimen of 10 mg twice daily increased the ratio of blood pressure at trough-to-peak response to 75 ±5 compared to 33± 16 when 20 mg was given once daily. In addition, a twice-daily regimen reduced the coefficient of variation of the hourly average blood pressure. Thus, concentration-effect parameters derived from the first dose response to enalapril have potential not only for predicting long-term antihypertensive response, but also for optimizing dosage regimens for individual patients.

Oral and intravenous trimazosin, a quinazoline derivative, resulted in a significant reduction in blood pressure of normal subjects, particularly when the subjects rose from a supine position to standing. This hypotensive effect was maximal between 4 and 6 hr after dosing and was accompanied by a significant increase in heart rate. The responses to intravenous infusions of phenylephrine indicated that trimazosin had significant, selective, peripheral α1-antagonist properties. Kinetic analysis showed oral bioavailability of 63%, a clearance rate of 66 ml/min, and a terminal elimination t½ of approximately 3 hr. The correlation between drug levels and hypotensive effect was significantly improved by inclusion of the concentrations of trimazosin's major metabolite, 1 -hydroxy-trimazosin (CP 23445), particularly for the period of maximum effect. Our data show that acute administration of trimazosin is associated with a fall in blood pressure, an increase in heart rate, and a significant degree of α1-antagonism and that the overall hypotensive effect may in part be mediated by an active metabolite. It seems 1-hydroxy-trimazosin is a likely candidate for this role, but it is not clear whether this metabolite also has significant α-adrenoceptor antagonist properties.Clinical Pharmacology and Therapeutics (1984) 35, 156–160; doi:10.1038/clpt.1984.21

(1) When incremental infusions of drugs that increase blood pressure are given to human subjects to assess “pressor responsiveness,” only the lower part of the sigmoid dose-response curve can be obtained. (2) Fitting a quadratic function does not involve discarding data points, which is usually the case with a linear fit, and it provides a more satisfactory fit to the lower part of a sigmoid dose-response curve. (3) In the presence of a competitive antagonist, a pressor dose-response curve will be shifted to the right. In this situation the dose-response curves obtained before and after treatment with antagonist should be fitted simultaneously to a quadratic model in which the parallel shift is one of the parameters. (4) The use of quadratic fitting is illustrated by reference to clinical experiments to obtain the following three curves for drugs that modify peripheral alpha adrenoceptors: norepinephrine pressor response curves after placebo and doxazosin, an alpha1antagonist; norepinephrine pressor response curves after placebo, labetalol, and medroxalol (drugs with combined alpha 1 and beta blocking properties); and phenylephrine pressor response curves before and after prazosin. (5) Fitting a quadratic function is the appropriate initial step in the analysis of pressor dose-response curves in man.Clinical Pharmacology and Therapeutics (1982) 32, 450–458; doi:10.1038/clpt.1982.188

The effects of the xanthine oxidase/hypoxanthine free radical generating system on endothelium dependent and independent relaxation were compared in aortic rings from New Zealand white rabbits and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits with mild atherosclerosis. Studies were carried out in young (3 months) and mature (18 months) animals. Plasma cholesterol levels were significantly higher in both 3 and 18 month WHHL animals. Endothelium independent relaxation to SNP did not differ between groups. However, the attenuation of relaxation to carbachol after xanthine oxidase/hypoxanthine treatment tended to be less in WHHL. This reached significance at 18 but not 3 months. We propose that this could be due to increases in levels of endogenous scavenger enzymes in these WHHL rabbits.

1. The responsiveness of a-receptors was compared in six young and six healthy elderly subjects by evaluating the haemodynamic effects of the a, antagonist prazosin and the pressor responses to the a, agonist phenylephrine. 2. Oral prazosin (1 mg) lowered erect (but not supine) blood pressure in both groups by a comparable amount: in young and old groups the respective maximal falls in systolic pressure were 19.5 ± 15.7 and 29.3 ± 11.4 mmHg (mean ± sd) and for diastolic pressure the maximal falls were 13 ± 13.3 and 18 ± 11.1 mmHg. 3. This similar fall in blood pressure occurred in association with a significantly different heart rate response: in the young group mean heart rate increased to 103 beats/min but there was no corresponding increase in the elderly group, which had a mean heart rate of 80 beats/min. 4. Log dose-response curves were derived from incremental intravenous infusions of phenylephrine, and the doses required to raise mean arterial pressure by 20 mmHg (PD20) were compared: the mean PD20 was significantly different in the two groups: 2.5 ± 1.6 in the young compared with 4.6 ± 2.3 µg min-1 kg-1 in the elderly, consistent with reduced pressor responsiveness in the elderly. 5. No significant difference in PD20 was apparent when pressor responsiveness was determined after prazosin, but the elderly required a significantly smaller increase in phenylephrine dosage to overcome prazosin's a-receptor-blocking effects. 6. Although there is no evidence of an age-related increase in the sensitivity of a-adrenoceptor-mediated vasoconstriction, the results are not inconsistent with an age-related reduction in a-adrenoceptor responsiveness.

The ability of endothelin to stimulate phosphatidylinositol hydrolysis in rings of rat aorta was studied. Endothelin 10-8-10-5mol/l caused increases of 200–1000 in inositol phosphate levels. However, physiological responses to endothelin have been reported in the concentration range 10-10-10-8mol/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.

Conscious male beagle dogs were given constant intravenous infusions of noradrenaline for 14 days, four receiving 125 ng/kg/min and four 250 ng/kg/min. Before, during and after these infusions dose-response studies were done in which additional noradrenaline was infused at 500, 1000 and 2000 ng/kg/min, each rate for 1 h. Blood samples were taken before and during infusions for measurement of haematocrit and plasma concentrations of noradrenaline, active renin, angiotensin II, aldosterone, sodium and potassium. Fourteen-day infusion of noradrenaline at 125 ng/kg/min did not raise blood pressure significantly though infusion at 250 ng/kg/min did, but for the first week of infusion only. Heart rate decreased significantly at both rates. Arterial pressure fell markedly and significantly on stopping infusion. Mean plasma concentrations of renin, angiotensin II and aldosterone tended to be lower during prolonged infusion of noradrenaline, but only the fall of renin during the second week was significant in one group of dogs. Noradrenaline at higher rates significantly raised blood pressure and increased plasma concentrations of renin and angiotensin II. Plasma aldosterone concentration did not rise significantly, perhaps because plasma potassium concentration decreased; in support of this theory changes of plasma aldosterone correlated with changes of plasma potassium but not with changes of angiotensin II. The rise in arterial pressure during dose-response studies was related to the increase of plasma noradrenaline. Prolonged infusion of noradrenaline did not alter the dose-response relation between plasma noradrenaline concentration and arterial pressure.

The effects of infusion of α-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 α1selective agonist, were greater in hypertensive rabbits. In contrast, responses to boluses but not infusions of α-methylnoradrenaline, a selective α2-agonist, were increased in hypertensives. During α-methylnoradrenaline infusions pressor responses to bolus doses of α-methylnoradrenaline and the aggregatory response of platelets to adrenaline were attenuated in all rabbits, consistent with α2-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 α-methylnoradrenaline in the hypertensive rabbits. It might also contribute to the lability in blood pressure observed in these animals.

To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters.

Single doses of the angiotensin converting enzyme (ACE) inhibitor quinapril were administered to salt replete normotensive men to investigate pharmacokinetics and dose responses. Maximal ACE inhibition was produced by the 2.5, 5, and 20 mg doses (but not by 0.5 mg), but there was evidence of dose-dependency only for the duration of ACE inhibition. Quinaprilat was detectable in plasma up to 72 hours after all doses and the terminal phase half-life was calculated at 26 ± 7 hours. Although there were dose-related increases in area under the curve (AUC), the relationships between dose and both AUC and maximum concentration were nonlinear. These findings suggest that quinapril displays the same prolonged terminal phase half-life that is characteristic of other ACE inhibitor drugs. The failure of doses above 2.5 mg to produce any further increase in the magnitude of ACE inhibition is consistent with an maximum effect dose-response relationship, with the obvious implication that higher doses will increase only the duration not the magnitude of response.

This study investigates concentration-effect relationships in nine patients who had essential hypertension treated with prazosin. Antihypertensive responsiveness was determined for each individual patient in terms of millimeters of mercury of blood pressure reduction per nanogram per milliliter of plasma prazosin concentration. The principal findings were that there was significant attenuation of antihypertensive responsiveness, from 11.5 mm Hg per nanogram per milliliter after the first dose to 8.7 mm Hg per ng/ml after 1 week of treatment with prazosin. Correspondingly, there was significant attenuation of the degree of α1-antagonism as assessed by the pressor response to intravenous phenylephrine. However, there was no significant further attenuation of either assessment during continued treatment for up to 3 months. These findings suggest that after an early adaptation, which occurs within the first week of treatment, there is no long-term attenuation of the antihypertensive effect of prazosin. Despite this initial adaptive change, the magnitude of the long-term antihypertensive effect of prazosin was predictable from the first dose response in individual patients.