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Background We have previously shown that tissue Doppler assessments of left ventricular (LV) diastolic function predict cardiac events in a hypertensive population over a period of 4 years (1). These out-performed traditional echocardiographic measures in a well-treated hypertensive population. Purpose We aimed to test whether tissue Doppler assessment of LV diastolic function would predict cardiovascular (CV) mortality in the Hypertension Associated Cardiovascular Disease sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Methods ASCOT was a multicentre randomised trial with a 2x2 factorial design (2). Inclusion criteria for the study included hypertension and three other CV risk factors, including male sex and age over 55. Protocols, including for echocardiography, have been detailed previously (2, 3). This study comprised the 519 patients recruited to the St Mary's Hospital site of the ASCOT study, who were followed for 19 years with mortality flagged by the Office for National Statistics. We have used all reported deaths on or before 31st January 2019. CV deaths include deaths due to coronary heart disease (CHD), stroke and other CV causes. Echocardiography was performed one year after blood pressure control. mean tissue Doppler E' was calculated as the average of septal, lateral and inferior wall measurements over three cycles. The ratio of the transmitral Doppler E wave velocity and the composite mean of E' was used to calculate E/E' ratio. Statistical analysis was performed using Python including multivariable Cox proportional hazards regression. A two-sided P-value Results After a median of 19 years, 317 patients survived (mean age at baseline 60.7y, 38 female) and 202 did not (mean age 68.1y, 30 female). Twenty-three deaths were due to CHD, 11 were due to stroke, 27 were due to other CV causes, and 76 were due to cancer. Baseline characteristics were not significantly different between those who survived to follow up and those who did not. Unadjusted analysis showed a strong association between CV mortality and E' (HR=0.74, p The association between CV mortality and E/E' was attenuated but persisted after adjusting for age and sex (HR=1.12, p=0.01) and after adjusting for age, sex and systolic BP (HR=1.11, p=0.04). There was a weak association between all-cause mortality and both E/E' and E', which was null after adjusting for age and sex. Figure 1 shows unadjusted Kaplan Meier survival curves for E'. Conclusions Tissue Doppler E' velocity and E/E' predicted 19-year cardiovascular mortality in a hypertensive population independent of age, sex and systolic blood pressure. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The HACVD substudy was supported by an investigational grant by Pfizer International, New York, NY, USA. The principal funding source for ASCOT was Pfizer, New York, NY, USA, additional funding was also provided by Servier Research Group, Paris, France, and Leo Laboratories, Copenhagen, Denmark.

To evaluate, in hypertensive patients, whether the metabolic syndrome is a better predictor of new-onset diabetes compared with impaired fasting glucose, obesity or its other individual components alone, or collectively.Cox models were developed to assess the risk of new-onset diabetes associated with the metabolic syndrome after adjusting for a priori confounders (age, sex, ethnicity and concomitant use of non-cardiovascular medications), its individual components and other determinants of new-onset diabetes. Area under receiver operator curves using the metabolic syndrome or models of impaired fasting glucose were compared, and the ability of these models to correctly identify those who (after 5-years of follow-up) would or would not develop diabetes was assessed.The metabolic syndrome adjusted for a priori confounders and its individual components, and further adjusted for other determinants, was associated with significantly increased risk of new-onset diabetes [1.19 (1.00-1.40), P = 0.05 and 1.22 (1.03-1.44), P = 0.02, respectively]. The discriminative ability of the metabolic syndrome model [area under receiver operating curve: 0.764 (0.750-0.778)] was significantly better than the model of impaired fasting glucose [0.742 (0.727-0.757)] (P0.001). The metabolic syndrome correctly allocates the risk of new-onset diabetes in a significantly higher proportion of patients (62.3%) than impaired fasting glucose status (37.7%) (P0.001). The presence of both the metabolic syndrome and impaired fasting glucose were associated with an approximately 9-fold (7.47-10.45) increased risk of new-onset diabetes. Among normoglycaemic patients, the metabolic syndrome was also associated with significantly increased risk of new-onset diabetes, after adjusting for BMI and a priori confounders [1.66 (1.29-2.13)].Both impaired fasting glucose and the metabolic syndrome predict the risk of new-onset diabetes; however, the metabolic syndrome is a better predictor than impaired fasting glucose in assigning the risk of new-onset diabetes in hypertensive patients, and among those with normoglycaemia.

Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as80% of days covered), compared with low adherence to drug (50% of days covered) in terms of risk of events and long-term economic consequences.Open-label follow up of a randomised placebo-controlled trial in hypertensive patients.Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period.Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs).Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

To investigate whether reduction in blood pressure has a beneficial effect on left ventricular diastolic function, we investigated 20 hypertensive patients with evidence of diastolic dysfunction at baseline and at 3 and 6 months after initiation of captopril therapy. Two-dimensional echocardiography was used to determine left ventricular mass index and Doppler ultrasound to assess diastolic function. Fifteen of the 20 patients had a significant reduction in blood pressure at 3 and 6 months and left ventricular mass index remained unchanged during the study period. Despite reduction in blood pressure, no difference in isovolumic relaxation time, early and atrial filling velocities or their ratio was observed. Our results suggest that a direct relationship between blood pressure and left ventricular diastolic function does not exist and that other factors such as alterations in muscle or collagen composition of the left ventricle may be more important in determining abnormal diastolic function in hypertension.

The effect of antihypertensive therapy on regression of left ventricular hypertrophy and left ventricular diastolic function was investigated in 25 hypertensive patients for up to 18 months after initiation of treatment. Left ventricular mass index was calculated by two-dimensional echocardiography and left ventricular diastolic function assessed by transmitral pulsed doppler ultrasound. Significant reduction in left ventricular mass index was observed after 9 months of treatment. Only 13 patients had a reduction in mass greater than the intraobserver variability of the technique. There was no change in doppler indices of left ventricular diastolic function. In 7 patients who were studied for a further 9 months after regression had occurred there was still no appreciable difference in left ventricular diastolic function. These findings indicate that there is no direct relation between left ventricular mass and abnormal left ventricular diastolic function.

Since 1960 we have diagnosed phaeochromocytoma (paraganglioma) in 10 children. The cases include a 15 year old girl who over a three year period presented with multiple paragangliomata and an associated malignant carotid body tumour. All children were hypertensive, eight of 10 presenting with severe headaches. Diagnosis was based on finding a raised urinary vanillylmandelic acid excretion and plasma noradrenaline concentration. In addition six of eight children were hypercalcaemic with raised plasma calcitonin concentrations; plasma parathyroid hormone concentrations were high in two of seven and four out of eight children had raised plasma renin activities on presentation. No child, however, was found to have a multiple endocrine neoplasia syndrome. Despite the introduction of newer techniques for the detection of catecholamine producing tumours we found that selective arteriography and venous catecholamine sampling were superior for tumour localisation compared with ultrasound scanning, computed tomography, and metaiodo-benzyl-guanidine (MIBG) scanning.

Increased intima-media thickness of the common carotid artery predicts increased risk of myocardial infarction and stroke. Preliminary evidence suggests that a decrease in blood pressure (BP) is associated with diminished wall thickness. It is not known if all classes of anti-hypertensive agents have similar protective effects. In this double-blind parallel-group clinical trial, 69 previously untreated patients with hypertension were allocated randomly to 1 year of treatment with either amlodipine (5-10 mg daily) or lisinopril (5-20 mg daily). Doxazosin and bendrofluazide were added if required to achieve BP control. After 12 months of treatment, clinic BP, ambulatory BP and cardiac mass were reduced similarly by the two treatment regimens. Common carotid artery intima-media thickness decreased by 0.048 mm (95% confidence intervals -0.066, -0.031 mm) in the amlodipine-treated group, but decreased by only 0.027 mm (-0.046, -0.007 mm) in the lisinopril-treated group (P0.05 for difference between treatments). Common carotid artery lumen diameter declined significantly only in patients treated with lisinopril [amlodipine, -0.02 mm (-0.14, 0.10 mm); lisinopril, -0.21 mm (-0.32, -0.11 mm); P0.02], while intima-media area declined similarly in the two treatment groups [amlodipine -1.32 mm(2) (-1.91, -0.74 mm(2)), lisinopril -1.26 mm(2) (-1.80, -0.72 mm(2)); not significant]. The results confirm that a decrease in BP causes regression of structural changes in the carotid artery in hypertensive patients. The nature of the structural regression differed markedly between the two treatment regimens, in spite of similar decreases in BP. The calcium channel blocker induced greater regression of common carotid artery intima-media thickness than the angiotensin-converting enzyme inhibitor. However, carotid artery wall mass, as indicated by intima-media area, was reduced to a similar extent by the two treatments. It remains to be established whether such differences confer a prognostic advantage.

1. Human isolated subcutaneous arteries were mounted in a myograph and isometric tension measured. In some experiments, intracellular calcium [Ca(2+)]i was also measured using fura-2. 2. Angiotensin II (100 pM - 1 microM) increased [Ca(2+)]i and tone in a concentration-dependent manner. The effects of angiotensin II (100 nM) were inhibited by an AT1-receptor antagonist, candesartan (100 pM). 3. Ryanodine (10 microM), had no effect on angiotensin II-induced responses, but removal of extracellular Ca(2+) abolished angiotensin II-induced rise in [Ca(2+)]i and tone. Inhibition of Ca(2+) entry by Ni(2+) (2 mM), also inhibited angiotensin II responses. The dihydropyridine, L-type calcium channel antagonist, amlodipine (10 microM), only partially attenuated angiotensin II responses. 4. Inhibition of protein kinase C (PKC) by chelerythrine (1 microM), or by overnight exposure to a phorbol ester (PDBu; 500 nM) had no effect on angiotensin II-induced contraction. 5. Genistein (10 microM), a tyrosine kinase inhibitor, inhibited angiotensin II-induced contraction, but did not inhibit the rise in [Ca(2+)]i, suggesting that at this concentration it affected the calcium sensitivity of the contractile apparatus. Genistein did not affect responses to norepinephrine (NE) or high potassium (KPSS). 6. A selective MEK inhibitor, PD98059 (30 microM), inhibited both the angiotensin II-induced contraction and rise in [Ca(2+)]i, but had no effect on responses to NE or KPSS. 7. AT1 activation causes Ca(2+) influx via L-type calcium channels and a dihydropyridine-insensitive route, but does not release Ca(2+) from intracellular sites. Activation of tyrosine kinase(s) and the ERK 1/2 pathway, but not classical or novel PKC, also play a role in angiotensin II-induced contraction in human subcutaneous resistance arteries.

To test the primary hypothesis that a newer antihypertensive treatment regimen (calcium channel blocker +/- an angiotensin converting enzyme inhibitor) is more effective than an older regimen (beta-blocker +/- a diuretic) in the primary prevention of coronary heart disease (CHD). To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterolor = 6.5 mmol/l.Prospective, randomized, open, blinded endpoint trial with a double-blinded 2 x 2 factorial component.Patients were recruited mainly from general practices.Men and women aged 40-79 were eligible if their blood pressure wasor = 160 mmHg systolic oror = 100 mmHg diastolic (untreated) oror = 140 mmHg systolic oror = 90 mmHg diastolic (treated) at randomization.Patients received either amlodipine (5/ 10 mg) +/- perindopril (4/8 mg) or atenolol (50/ 100 mg) +/- bendroflumethiazide (1.25/2.5 mg) +K+ with further therapy as required to reach a blood pressure ofor = 140 mmHg systolic and 90 mmHg diastolic. Patients with a total cholesterol ofor = 6.5 mmol/l were further randomized to receive either atorvastatin 10 mg or placebo daily.Non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD).19 342 men and women were initially randomized, of these 10297 were also randomized into the lipid-lowering limb. All patients had three or more additional cardiovascular risk factors.The study has 80% power (at the 5% level) to detect a relative difference of 20% in CHD endpoints between the calcium channel blocker-based regimen and the beta-blocker-based regimen. The lipid-lowering limb of the study has 90% power at the 1% level to detect a relative difference of 30% in CHD endpoints between groups.

Potency and efficacy, duration of action, organ-specific effects and tolerability are the main considerations when choosing among antihypertensive therapies. Candesartan has been shown in in vitro animal models to bind insurmountably to the angiotensin II type 1 (AT1) receptor, thus providing effective blockade of all the major negative cardiovascular effects of angiotensin II. Its binding characteristics differentiate candesartan from other AT1-receptor blockers. Candesartan cilexetil has been found to produce a predictable and pronounced dose-dependent decrease in blood pressure, with placebo-like tolerability even at the highest doses studied. In comparison with the standard 50-mg dose of losartan, candesartan cilexetil, 16 mg, was significantly more effective in suppressing the renin-angiotensin system and in reducing trough diastolic blood pressure. Pooled results from placebo-controlled trials also indicate that candesartan cilexetil has equivalent efficacy to irbesartan. In addition, the extent of blood pressure lowering by candesartan cilexetil has been shown to be similar to that of agents in the other major classes of antihypertensive drugs, and to be effective in combination therapy with diuretics and calcium channel blockers. Candesartan cilexetil combines 24-h blood pressure lowering with placebo-like tolerability and is therefore an important advance in antihypertensive therapy.

Hypertension is a heterogeneous disease and this is reflected in the marked variability in response to monotherapy. Co-administering antihypertensive therapies has several theoretical benefits, namely enhanced efficacy, improved tolerability, increased compliance and, in some cases, potentially beneficial changes in biochemical variables associated with increased cardiovascular risk, such as improvements in lipid profiles. alpha 1-Blockers, such as doxazosin, have several favourable properties which should be advantageous when used with other agents. Their mechanism of action is complementary to that of each of the other four main groups of antihypertensive drugs and, in each case, enhanced efficacy has been observed when alpha 1-blockade has been added to monotherapy with other drug classes. Synergistic effects have been seen when an alpha 1-blocker is administered together with either a calcium channel blocker or angiotensin-converting enzyme inhibitor. While alpha 1-blockers induce regression of left ventricular hypertrophy, the possibility of enhanced effects during multiple therapy has not been explored. alpha 1-Blockers exert positive effects on lipids (limited data suggest that they are able to reverse the deleterious lipid effects of diuretics and beta-blockers) and exert neutral or positive effects on glucose homeostasis. Further studies are needed to determine whether alpha 1-blockers can alleviate the adverse effects of beta-blockers or diuretics on glucose homeostasis. alpha 1-Blockers, when given concomitantly with other antihypertensive drugs, are well tolerated, conferring advantages with respect to patient compliance. The current data favour the use of alpha 1-blockers as an additional component of antihypertensive therapy, but further studies are needed to address the metabolic and end-organ effects of such treatment regimens.

1. Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2. Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT2 selective antagonist, PD123319, was without effect on responses to AII. The effects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3. Mechanical removal of the endothelium; pre-incubation with Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or pre-incubation with BQ 485, an endothelin antagonist; had no significant effect on contractions induced by AII. 4. Our results suggest AII contracts human isolated resistance arteries by an action on AT1 receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT1 antagonists without sacrificing assumptions regarding the competitive nature of binding of these antagonists.

Objective To determine the effects of single-session transurethral microwave treatment (TUMT) on human prostatic alpha-1 adrenoreceptor density in patients with symptomatic bladder outlet obstruction caused by benign prostatic hyperplasia. Patients and methods Radioligand-binding assays using 3H-prazosin were performed on prostatic tissue obtained from 25 patients, 10 of whom had received a single TUMT whilst the remaining 15 patients had not, and acted as controls. Prostatic tissue was obtained by cold-punch biopsy immediately before transurethral resection of the prostate from 20 patients (10 following microwave treatment and 10 controls) and from a further five patients at the time of retropubic prostatectomy; these five patients again had undergone TUMT. There were no statistically significant differences in several variables between the groups except for the weight of resected tissue, which was greater for the patients undergoing retropubic prostatectomy. Differences in the maximum receptor density (Bmax) and dissociation constant (Kd) were analysed statistically using the Mann–Whitney U-test because the data were non-parametric. Results Binding was saturable and a single class of high-affinity binding sites was identified in all cases. In the control group, the mean and 95% confidence interval (CI) alpha-1 adrenoreceptor density (Bmax) was 96.4 (82.7–110.1) fmol/mg and the mean (95% CI) dissociation constant (Kd) was 0.56 (0.37–0.74) nmol/L. In those patients who had undergone TUMT, the mean Bmax was significantly lower at 71.3 (58.6–84.7) fmol/mg (P < 0.02) but the Kd of 0.56 (0.20–1.14) mmol/L was identical to that in the control group. Conclusions Single-session TUMT, using a non-irrigated catheter, causes a significant reduction in prostatic alpha-1 adrenoreceptor density in the region of the prostate subjected to maximum heating. This may represent one possible mechanism of action by which microwave treatment exerts its beneficial effects.

Several studies have recently been published which have raised doubts over the long-term safety of calcium channel blockers (CCB). These have included retrospective case control studies in hypertension and meta-analyses of small scale studies in unstable angina and myocardial infarction (MI). Most of the reports were primarily concerned with the use of the short acting dihydropyridine nifedipine. Despite wide media coverage of these reports, the results are by no means irrefutable and, because of the nature of the studies themselves, are open to several criticisms. Calcium channel blockers are currently being evaluated in large-scale, prospective, randomised controlled studies, but results are unlikely to be available within the next few years. Meanwhile, the consensus view seems to be that short acting dihydropyridines should in general be avoided and have no place in the management of unstable angina and post MI. In the setting of stable angina, long acting dihydropyridines should generally be used in conjunction with a beta-blocker. In hypertensive patients, long acting dihydropyridines may be used as alternative antihypertensive agents in patients in whom the first line agents (diuretics and beta-blockers) are poorly tolerated, contra-indicated or ineffective.

The aim of this multicenter, randomly allocated, double-blind, parallel-group study was to evaluate the equivalence of three fixed-dose combination drugs in mild to moderate hypertension: perindopril + indapamide (4 + 1.25 mg), captopril + hydrochlorothiazide (50 + 25 mg) and enalapril + hydrochlorothiazide (20 + 12.5 mg).After a single-blind, 4-week, placebo run-in phase, 527 patients (mean +/- SD age 54.5 +/- 1.2 years) with a supine diastolic blood pressure of 101.2-101.7 mmHg were randomly assigned to one of the three treatments for 8 weeks. The main evaluation criteria were diastolic blood pressure and serum potassium concentration. Equivalence was assessed on an intention-to-treat basis, using Schuirmann's method, which involves performing two one-tailed statistical tests on the data. Thirty-five patients were withdrawn from the study but there were no differences between groups in the reasons for withdrawal.Diastolic blood pressure decreased by between 13.1 and 14.2 mmHg in the three groups. The 90% confidence intervals for the differences between perindopril + indapamide and the other treatments were -1.1, +1.7 mmHg for captopril + hydrochlorothiazide and -0.4, +2.6 mmHg for enalapril + hydrochlorothiazide. Schuirmann's test was highly statistically significant (P0.001 for perindopril + indapamide versus captopril + hydrochlorothiazide; P0.002 for perindopril + indapamide versus enalapril + hydrochlorothiazide), so that the two one-sided hypotheses that the treatments were not equivalent were rejected at the nominal level of alpha = 0.05. Similarly, the safety of the treatments was equivalent in terms of serum potassium. The 90% confidence intervals of the differences between perindopril + indapamide and the other treatments were -8.7, -1.6% for captopril + hydrochlorothiazide (P = 0.004) and -1.5, +2.7% for enalapril + hydrochlorothiazide (P0.001).We conclude that the safety and efficacy of perindopril + indapamide, captopril + hydrochlorothiazide and enalapril + hydrochlorothiazide were equivalent after 8 weeks of treatment in patients with mild to moderate hypertension.

Thiazide diuretics are widely used to treat hypertension, but their use is associated with impaired glucose tolerance. We propose that the diabetogenic action of thiazides may be due to their ability to open calcium-activated potassium (KCa) channels in pancreatic beta-cells.

An increased carotid intima-media thickness (IMT) has been found to be associated with a number of cardiovascular risk factors such as age, hypertension, cigarette smoking, hypercholesterolaemia and left ventricular hypertrophy. Our objective was to assess whether carotid intima-media thickness in hypertensive patients could be reduced by antihypertensive therapy.13 hypertensive patients, 10 previously untreated, were examined using carotid ultrasonography and echocardiography at baseline and then at 8 weeks and 39 weeks after commencement of antihypertensive therapy with ramipril and the second-line addition of felodipine.By the end of the study significant regression of IMT (0.1(0.05-0.16) mm, F-value 10.2, P0.01) and left ventricular mass index had occurred (25(10.7-39.3) g/m2, F-value 9.7, P0.01). The reduction in IMT was significantly related to the reduction in mean arterial pressure, r = 0.55, P = 0.05).Antihypertensive therapy with ramipril and felodipine causes regression of IMT in hypertensive patients, probably chiefly through blood pressure reduction. Large prospective studies are required to assess whether a reduction in IMT results in a reduction in morbidity and mortality.

It has been suggested that the increased incidence of sudden death in hypertensive patients, particularly those with left ventricular hypertrophy, may be casually related to the increased number and complexity of ventricular arrhythmias that have been demonstrated in these patients. The objective of the present study was to assess some of the factors which might be responsible for these arrhythmias.One hundred and three untreated subjects were divided into four groups on the basis of blood pressure and echocardiographic measurements: hypertensive patients with left ventricular hypertrophy (n = 38), hypertensive patients without left ventricular hypertrophy (n = 16), patients with borderline or white-coat hypertension (n = 26) and normotensive subjects (n = 23). Each subject underwent two-dimensional and Doppler echocardiography, 12-lead electrocardiogram examination, 12-lead electrocardiogram exercise stress testing, 24-h ambulatory blood pressure monitoring and 24-h Holter monitoring. A further 17 hypertensive patients with left ventricular hypertrophy who were on long-term antihypertensive therapy were also investigated in the same manner and compared with untreated hypertensive patients with left ventricular hypertrophy who were matched for age, sex and race.Untreated hypertensive patients, even with left ventricular hypertrophy, had a low prevalence of frequent or complex arrhythmias (seven out of 80 patients with Lown score 2+). In contrast, hypertensive patients with left ventricular hypertrophy on long-term antihypertensive therapy had a significantly greater prevalence of complex arrhythmias than untreated patients with left ventricular hypertrophy (eight out of 17 treated patients compared with two out of 17 untreated patients with Lown score 2+).Hypertensive patients with left ventricular hypertrophy who had received long-term antihypertensive therapy were found to have a high prevalence of complex ventricular arrhythmias, which was in contrast to untreated hypertensive patients, even those with left ventricular hypertrophy. This may reflect the consequences on the left ventricle of long-term antihypertensive treatment. If complex ventricular arrhythmias are implicated in the excess of sudden deaths in hypertensive patients, this might be an important factor.

The aim was to investigate the involvement of polyamines in the development of cardiovascular hypertrophy in a rat angiotensin II infusion model of hypertension.Rats were chronically infused with a low dose of angiotensin II (83 ng.min-1.rat-1) or vehicle by osmotic minipumps. The polyamine content of the cardiovascular organs and liver was measured by HPLC, and the blood pressure of conscious rats was determined by a tail cuff method. The mesenteric arterial beds were perfusion fixed in situ and medial and luminal cross sectional areas were determined by computer assisted planimetry. Cardiac hypertrophy was assessed by determination of ventricular:body weight ratios.Angiotensin II infusion caused an increased concentration of polyamines in the ventricles and aorta within hours of beginning the infusion, and within days in the mesenteric arteries. Polyamine content of the liver was unaffected. Hypertrophy of the myocardium and mesenteric arteries in association with the increased blood pressure was evident.A low dose of angiotensin II stimulates an early biochemical marker of growth, the polyamines, in cardiovascular tissues but not in the liver. The increase in tissue polyamines is associated with cardiovascular hypertrophy and the development of hypertension.

The objectives in managing the hypertensive patient are to reduce or reverse the risks of cardiovascular morbidity and mortality, that are known to be associated with higher levels of arterial pressure. Given the overwhelming evidence from the intervention trials (discussed previously) that the lowering of blood pressure by drugs is associated with a reduction in the incidence of stroke and coronary heart disease events, such objectives are realistic.

The retinal vasculature is an accessible region of the microcirculation in humans which undergoes change in essential hypertension. In this study we have examined the effect of nifedipine and glyceryl trinitrate (GTN) on retinal blood flow velocities. Retinal blood flow was measured in 11 subjects using colour Doppler ultrasound. Nifedipine (10 mg orally) or glyceryl trinitrate (0.3 mg, GTN) was given after 30 minutes recumbancy. Systolic retinal arterial blood flow velocity (SRV), diastolic retinal arterial blood flow velocity (DRV), retinal resistive index (RI), SBP, DBP were measured at -10, 0, 5, 10, 15, 20 and 25 minutes following drug administration. Nifedipine significantly increased SRV (peak effect at 15 minutes) but by 25 minutes SRV did not differ significantly from pre-drug values. Nifedipine did not significantly affect DRV, RI, SBP or DBP. GTN significantly increased both SRV and DRV, although both tended to fall towards pre-drug values by 25 minutes. RI, SBP nor DBP were not significantly altered by GTN. Both nifedipine and GTN transiently increase blood flow velocity in the central retinal artery although at the doses used neither agent affected BP or RI. Doppler ultrasound measurement of retinal arterial blood velocity may be a useful technique in the investigation of the retinal microcirculation in essential hypertension.

Hypertension is associated with structural changes in the vascular system and in the heart. This study has examined the relationships between carotid artery intima-media thickness and other risk factors in 52 untreated patients (20 hypertensive). Carotid intima-media thickness was measured bilaterally using a Duplex doppler ultrasonic scanner. In the hypertensive individuals the left ventricle was examined by echo-cardiography and the left ventricular mass index determined. There was a significant association between age and IMT, and both SBP and DBP and IMT. The IMT in the hypertensive group was significantly larger than in the normotensive group and in the hypertensive subjects there was a positive association between left ventricular mass index and IMT. There was no significant difference in calculated media stress between the normotensive and hypertensive groups, probably due to a small increase in carotid intima-media area combined with a small reduction in carotid lumen diameter. Hypertension is associated with a thickening of the intima-media of the carotid artery and an increase in left ventricular mass. Whether these changes in cardiac and arterial structure are in response to similar influences remains to be established.

The involvement of calcium and potassium channels in mediating the vascular actions of hydrochlorothiazide, indapamide and cicletanine were investigated in guinea pig small vessels mounted on the Mulvany myograph. Hydrochlorothiazide (10 microM) and cicletanine (10 microM) were weak calcium antagonists shifting the calcium dose-response curve half a log unit to the right. Indapamide was a far more potent inhibitor, a 10 microM concentration shifting the calcium dose-response curve 3 log units to the right and reducing maximal calcium contraction by 72% (P.001). Relaxations to hydrochlorothiazide and cicletanine were reduced in the presence of charybdotoxin, a blocker of calcium-activated potassium channels (KCa). Maximal relaxation induced by hydrochlorothiazide (30 microM) was reduced by 91% and cicletanine-induced relaxation by 63%. In the presence of iberiotoxin, a more selective KCa inhibitor, maximal hydrochlorothiazide and cicletanine-induced relaxations were reduced by 73 and 60%, respectively. Neither drug's action was affected by incubation with glibenclamide, which inhibits ATP-sensitive K+ channels. Incubation with glibenclamide, charybdotoxin or iberiotoxin had no effect on the indapamide-induced relaxation. These results show differences in the involvement of ion channels in the acute vasorelaxation produced by these drugs. Hydrochlorothiazide and cicletanine-induced relaxations appear to be mediated via KCa, whereas indapamide is a potent calcium antagonist.

The effect of amlodipine, a dihydropyridine calcium antagonist which is largely ionized at physiological pH, was studied in human resistance arteries. Resistance arteries were isolated from subcutaneous fat and isometric force measured in a myograph. Amlodipine inhibited depolarization-induced contractions in a time- and concentration-dependent manner. The potency of amlodipine was markedly increased by depolarization of the resistance arteries by a physiological saline containing high potassium (40 mM) during exposure to amlodipine. The onset and offset of amlodipine-induced inhibition in these arteries was slow, but concentration dependent. Depolarization markedly increased the rate of onset of inhibition. The increase in potency of amlodipine under depolarized conditions could largely be accounted for by the increased rate of association of the drug. Possible use-dependence of amlodipine was also examined in comparison with verapamil. The efficacy of both verapamil and amlodipine was increased in vessels which were repeatedly depolarized compared with vessels which were only activated once. This effect was more marked for verapamil than for amlodipine. The action of amlodipine in human resistance arteries is slow, shows marked voltage-dependence and, to a lesser degree, some use-dependence. These properties may be important in understanding the action of amlodipine in vivo.

Small resistance arteries were isolated from human subcutaneous fat and omentum and studied using a myograph. Endothelin-1 induced a concentration-dependent contraction in both type of arteries. In subcutaneous arteries preincubation with calcium antagonists partially inhibited responses to endothelin-1. The effectiveness of the calcium antagonists was nisoldipinenimodipineverapamil = flunarizinediltiazem. In omental arteries nimodipine and diltiazem had no significant effect on endothelin-1-induced contraction and removal of extracellular calcium also had little effect on responses to endothelin-1. The role of influx of extracellular calcium through voltage operated calcium channels in endothelin-1-induced contraction appear to differ between subcutaneous and omental resistance arteries.

In human subcutaneous resistance arteries in-vitro, the relaxation produced by the novel furopyridine compound cicletanine (30 μm) was inhibited by 51% (P < 0·0001) in the presence of 20 μm of the cyclo-oxygenase inhibitor indomethacin. Maximal cicletanine-induced relaxation was reduced by both the cyclo-oxygenase inhibitor mefenamic acid and the relatively specific blocker of prostacyclin synthetase, tranylcypromine by 55% (P < 0·0005) and 43% (P < 0·01), respectively. The potassium channel blocker, glibenclamide (100 μm), did not affect the relaxation produced by cicletanine but did inhibit the relaxation produced by the potassium channel blocker cromakalim (P < 0·0001). Cromakalim-induced relaxation was inhibited in the presence of indomethacin; relaxation induced by cromakalim (30 μm) was reduced by 22% (P < 0·02). The relaxation produced by the hypotensive agonists sodium nitroprusside, hydrochlorothiazide, bumetanide and nicardipine was unaffected by incubation with indomethacin. The results suggest that the vascular eicosanoid system, specifically prostacyclin, may be involved in the mechanism of the acute vasodilator action of cicletanine. Although at high doses, cicletanine is a diuretic, in this model it did not act like either a thiazide or a loop diuretic. The acute vasodilator action of the thiazide diuretic, hydrochlorothiazide was a novel finding of this study. Cromakalim showed a reduced response in the presence of indomethacin suggesting an involvement of the eicosanoid system in its mechanism of action.

We present a case in which a patient, having already sustained an episode of malignant hypertension, was subsequently found to have an underlying Conn's adenoma. Ablation of the adenoma improved control of her hypertension. When a second adenoma developed in her remaining adrenal gland, control of her hypertension deteriorated.

The relationship of left ventricular (LV) filling to the clinical and echocardiographic characteristics of 51 patients with untreated hypertension (borderline hypertension n = 17, essential hypertension n = 34) was investigated using two-dimensional echocardiography and Doppler ultrasound. Twenty-five patients had evidence of abnormal LV filling. Linear regression analysis revealed weak but significant correlations of LV filling with age (r = -0.53; P less than 0.0001), systolic blood pressure (r = -0.38; P less than 0.006), LV septal wall thickness (r = -0.44; P less than 0.0001) and LV mass index (r = -0.33; P less than 0.02). There was no association between LV filling and sex, race, heart rate or LV posterior wall thickness or cavity dimension. After stepwise regression analysis, age was found to be the only independent variable associated with LV filling, indicating that the other variables were dependent on age. This study suggests that a) abnormal LV filling is a frequent observation in hypertension b) LV filling is more dependent on age than blood pressure or LV size and c) other pathophysiological factors, so far undetermined, must contribute to the development of these abnormalities.

Hyperglycaemia, a raised fibrinogen, an increased serum triglyceride and a reduced HDL-cholesterol are common metabolic features of non-insulin dependent diabetes mellitus (NIDDM). Hypertension is frequently associated with NIDDM, however the influence of antihypertensive therapy on these combined factors in the diabetic is at present unclear. In a double-blind placebo-controlled crossover study in 20 stable NIDDM subjects with hypertension, the metabolic effects of 6 weeks' treatment with the alpha-blocker, doxazosin, was compared with treatment with the beta-blocker, atenolol. Similar and significant reductions in BP were produced by both drugs. Significant increases in weight, HbA1, apoprotein B, serum triglyceride and cholesterol/HDL ratio were observed with atenolol therapy. Doxazosin therapy was associated with opposite patterns of changes in fasting glucose, lipids and lipoproteins but only for serum triglyceride was difference between treatments significant. Fibrinogen was not altered by either treatment. Conclusions from this study indicate; 1) adrenergic mechanisms may be an important influence on glucose homeostasis and lipid metabolism in NIDDM and 2) the beta-blocker, atenolol, has a small adverse effect on weight, glycaemic control and the atherogenic lipid profile, whereas the alpha-blocker, doxazosin, has no such effect and may, in part, correct the disturbances of lipoprotein metabolism characteristic of NIDDM.

The effects of a DAi dopamine receptor selective agonist, fenoldopam, were examined on human blood vessels. Fenoldopam relaxed precontracted human arteries in vitro from brachial, cerebral, cervical, colic, coronary, lumbar, pulmonary, renal and splenic sites. Fenoldopam failed to relax uterine or external iliac arteries or saphenous vein segments. These effects of fenoldopam were not endothelium dependent, but were antagonised by the selective DAi receptor antagonists, SCH 23390, (+)-butaclamol, and (R)- more than (S)-sulpiride. The effect of fenoldopam may involve cyclic adenosine monophosphate. These studies indicate the presence of DAi receptors on a variety of large isolated human arteries.

Blood was collected simultaneously from the left ventricle and pulmonary artery in 12 patients undergoing routine cardiac catheterisation and was analysed for noradrenaline concentrations at rest, during, and after isometric stress (hand grip). Moderate isometric exercise resulted in a significant rise in plasma noradrenaline with a return to basal values 10 minutes after discontinuing the grip test. There were no significant differences in noradrenaline levels between the left ventricular and pulmonary arterial samples either at rest or during exercise. Three patients with evident left ventricular dysfunction had the highest plasma noradrenaline concentrations, in contrast to the much lower levels in 2 patients on beta-blockers and in 1 patient with a normal heart. As moderate isometric effort results in an important increase in noradrenaline level, this form of exercise could be dangerous in subjects suffering from ischaemic heart disease or in those with impaired left ventricular function since these patients are particularly susceptible to arrhythmias.

Summary The present study shows that different racial groups (black and white) living in a similar environment have different levels of blood pressure. Furthermore the same ethnic group living in a dissimilar environment also has different blood pressure distributions: thus it seems that both genetic (racial) and environmental factors influence the levels of arterial pressure. The data presented also reveal that there are racial differences in certain biochemical correlates of blood pressure, namely plasma renin activity and plasma noradrenaline concentration, and it is suggested that these observations may underline differing pathogenetic mechanisms for blood pressure elevation in blacks and whites.

These studies have investigated the effect of endothelin-1 (ET-1) on human resistance vasculature in vivo and in vitro. ET-1 was infused via the brachial artery and forearm blood flow (FBF) measured by venous occlusion plethysmography. Isolated resistance vessels were studied in a myograph. ET-1 (10 pmol-10 nmol/min, i.a.) reduced forearm blood flow. Endothelin-1-induced forearm vasoconstriction was slow to recover following washout. ET-1 (10 pM-10 nM) contracted isolated human subcutaneous and omental resistance vessels. Contractile responses to ET-1 were sustained and washout recovery was slow. Responses to ET-1 displayed marked tachyphylaxis. Calcium channel blockers and removal of extracellular calcium failed to completely abolish responses to ET-1 in vitro.

As part of a longitudinal study of migrants who move from a subsistence farming rural society to Nairobi, blood pressures and associated factors were measured in cross sectional studies of members of the Luo tribe in their traditional rural environment and in the urban environment of Nairobi. Blood pressures in Nairobi correlated with duration of urban residence. In the rural area men showed a negligible rise in blood pressure with age, and both sexes showed a significantly smaller rise than in the urban area. Although mean weights of the rural group were smaller, this did not account for all the urban/rural differences in blood pressures. Nevertheless, mean urinary sodium concentration and sodium ratios (sodium/potassium and sodium/creatinine) were significantly higher in the urban group whereas mean urinary potassium concentration and potassium/creatinine ratio were significantly lower. Perhaps the ratio of sodium to potassium in the diet contributes to the different blood pressure profiles of these two populations.

Celiprolol is reported to be a new cardioselective beta blocker with novel ancillary properties including vasodilator effects. The purpose of this study was to investigate whether celiprolol possesses a direct vasodilatory effect on human vasculature in vivo and in vitro. We studied the in vivo effects of intra-arterial celiprolol (1-100 micrograms/min i.a.) on forearm blood flow (FBF). Forearm blood was measured by venous occlusion plethysmography. Possible vasorelaxant actions of celiprolol on human vascular smooth muscle were studied using segments of isolated human saphenous vein in vitro. The effect of celiprolol was investigated on resting tone or noradrenaline induced tone. Possible alpha 2-adrenoceptor antagonist effects of celiprolol were assessed using celiprolol as an antagonist of BHT933 induced constriction. Celiprolol was without significant effect on FBF and failed to relax isolated saphenous vein segments preconstricted with noradrenaline. The weak alpha 2-adrenoceptor antagonist action of celiprolol was demonstrable in human saphenous vein. This study does not provide evidence for a direct vasodilatory effect of celiprolol on human vasculature.

A longitudinal study has shown that migrants from a remote Kenyan low-blood pressure (BP) community living in an urban environment had significantly higher BPs than a cohort of matched, nonmigrant controls. Selective migration was thought to be the likely explanation for this observation, but the BPs of 90 males studied prior to migration were almost identical to those found in the age-matched rural based controls studied in the low-BP community from which they came (120.9/59.0 mm Hg vs 120.5/60.1 mm Hg). Hence, in view of these premigration data supported by other evidence from the Kenyan Luo Migrant Study, it appears that the higher BP levels of the Luo migrants are not due to selective migration but are consequent upon environmental changes, including changes in electrolyte intake, which occur rapidly after migration.