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The Gemini-AALA (Australia, Asia, Latin America, Africa/Middle East) study evaluated the efficacy and safety of single-pill amlodipine/atorvastatin (Caduet) for the treatment of patients of diverse ethnicity with concomitant hypertension and dyslipidaemia. This was a 14-week, open-label study including patients from 27 countries across the Middle East, Asia-Pacific, Africa and Latin America. Eight dosage strengths of single-pill amlodipine/atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80 and 10/80 mg) were titrated to improve blood pressure and lipid control. Blood pressure and lipid goals were determined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines, respectively (blood pressure,140/90 or130/80 mm Hg; low-density lipoprotein cholesterol (LDL-C),4.1 to2.6 mmol l(-1) (160 to100 mgdl(-1))). Overall, 1649 patients received study medication. Most patients (91.4%) hador=1 cardiovascular risk factor (as defined by NCEP ATP III guidelines) in addition to hypertension/dyslipidaemia, and 61.7% had coronary heart disease/risk equivalent. At baseline, mean blood pressure was 146.6/88.3 mm Hg and LDL-C was 3.4 mmol l(-1) (130.2 mgdl(-1)). At week 14, 55.2% of patients reached both blood pressure and lipid goals, 61.3% reached blood pressure goal and 87.1% reached lipid goal (34.0% were at lipid goal at baseline). Mean blood pressure reduction was 20.2/11.4 mm Hg. For patients who were lipid-lowering drug naive at baseline, mean reduction in LDL-C was 41.0%. Treatment-related adverse events led to the discontinuation of 3.6% of patients. Single-pill amlodipine/atorvastatin therapy was well tolerated and effective for the reduction of blood pressure and lipids to recommended goals in patients from diverse ethnic backgrounds.

To examine the effects of dietary isoflavone supplementation with an extract from red clover on cognitive function in postmenopausal women.Thirty postmenopausal women aged greater than 60 years received either two tablets of an extract of aglycone isoflavones from red clover (each containing formononetin 25 mg, biochanin 2.5 mg and less than 1 mg of daidzein and genistein) for 6 months in a randomized, controlled clinical trial. Cognitive function tests were performed at baseline and at the end of isoflavone or placebo therapy.Isoflavone supplementation was associated with an apparent improvement in block design (a test of visual-spatial intelligence) compared to placebo (isoflavone +12%, placebo -3%; p = 0.03), no improvement in verbal memory compared to an improvement on placebo (isoflavone +1%, placebo +29%; p = 0.023) and a deterioration in digit recall compared to placebo (isoflavone -6%, placebo +12%; p = 0.029). However, these findings were not statistically significant when corrections were made for potential chance findings due to multiple comparisons.Isoflavone supplementation does not appear to have major short-term effects on cognitive function in postmenopausal women. However, further clinical trials are required to determine whether small effects or long-term effects on cognitive function occur during isoflavone supplementation.

Objectives: To assess the acceptability of the delivery of an isoflavone supplementation in the form of a powdered drink, and whether the supplementation of dietary isoflavones in this manner decreased the incidence of menopausal flushes. The secondary aims included assessment of other symptoms or parameters of estrogen deficiency and responses to isoflavones. Methods: A randomized, double-blind, placebo-controlled, parallel-group trial comprising 24 postmenopausal women with symptoms of estrogen deficiency was performed over a 12-week period. The women were randomized to receive a dietary beverage containing isoflavones or an isoflavone-free, isocaloric placebo preparation. Results: Although there was a high compliance rate among individual patients, there was a 25% withdrawal rate from the study in the active group. The incidence of complaints of bad taste tended to be higher in the active group (p = 0.07), and the total number of adverse events was significantly higher in this group (p < 0.001). There ...

The bioavailability of and pharmacodynamic responses to doxazosin, administered with and without food, were examined in a crossover study in 12 hypertensive subjects. The administration of doxazosin with food delayed its absorption by approximately 1 hour, reduced the maximum (peak) plasma drug concentration after single dose administration (Cmax) by 18%, and reduced the area under the plasma concentration-time curve (AUC) by 12%; however, these effects were not statistically significant. The acute fall in blood pressure following doxazosin administration was not significantly affected by food; however, there was a trend towards a lower incidence of complaints in this group. The effect of coadministration of food on the pharmacokinetic and pharmacodynamic responses to doxazosin are unlikely to be of clinical significance.

The aim of this study was to determine whether dietary supplementation with isoflavones from red clover affected ambulatory blood pressure and forearm vascular endothelial function in postmenopausal type 2 diabetic women.Sixteen postmenopausal type 2 diabetics treated with diet or oral hypoglycaemic therapy completed a randomized double-blind crossover trial of dietary supplementation with isoflavones from red clover (approximately 50 mg/day) for 4 weeks compared to placebo. Twenty-four-hour ambulatory blood pressure recordings and forearm vascular responses to acetylcholine, nitroprusside and L-nitromonomethylarginine (L-NMMA) were measured at the end of each treatment period.Mean daytime systolic and diastolic blood pressures were significantly lower during isoflavone therapy compared to placebo (-8.0 +/- 3.4 and -4.3 +/- 1.9 mmHg respectively, p0.05). The increase in forearm vascular resistance following L-NMMA was significantly greater during isoflavone supplementation (20.9 +/- 6.5) than placebo (3.7 +/- 2.9 arbitrary units, p0.05), suggesting an improvement in basal endothelial function. Plasma lipoproteins, glycated haemoglobin and forearm vascular responses to acetylcholine and nitroprusside did not differ significantly between isoflavone and placebo therapy.Isoflavone supplementation from red clover may favourably influence blood pressure and endothelial function in postmenopausal type 2 diabetic women.

To assess the acceptability of the delivery of an isoflavone supplementation in the form of a powdered drink, and whether the supplementation of dietary isoflavones in this manner decreased the incidence of menopausal flushes. The secondary aims included assessment of other symptoms or parameters of estrogen deficiency and responses to isoflavones.A randomized, double-blind, placebo-controlled, parallel-group trial comprising 24 postmenopausal women with symptoms of estrogen deficiency was performed over a 12-week period. The women were randomized to receive a dietary beverage containing isoflavones or an isoflavone-free, isocaloric placebo preparation.Although there was a high compliance rate among individual patients, there was a 25% withdrawal rate from the study in the active group. The incidence of complaints of bad taste tended to be higher in the active group (p = 0.07), and the total number of adverse events was significantly higher in this group (p0.001). There was no statistically significant difference in the incidence of flushes between the groups. There was no difference between the groups in Greene Menopause Symptom Scores, vaginal maturation value, levels of follicle stimulating hormone (FSH) or sex hormone-binding globulin (SHBG), or bone turnover markers.Powdered energy drinks are not commonly consumed in Australia and were poorly tolerated in this study. The high withdrawal rate and reporting of side-effects suggests that other methods of isoflavone delivery may be more appropriate in this culture, in future trials. At the dose used no benefit was seen in relief from menopausal symptoms, although for the sample size, the study could only have been expected to detect major differences between the groups.

Several recent studies have addressed issues including the optimum blood pressure target and differences between antihypertensive drug classes in reducing cardiovascular morbidity and mortality.To review the results of several recent and topical hypertension trials.There is remaining uncertainty about the optimal blood pressure target with the exception of diabetics in whom aggressive blood pressure reduction has been shown to be more effective in reducing morbidity and mortality than less aggressive reduction. It remains unclear whether there are differences between antihypertensive drug classes in their ability to reduce cardiovascular events. At least two studies have demonstrated that it is possible to achieve good blood pressure control in the majority of hypertensive patients if two or more antihypertensive drugs are used.

ACE inhibitors are valuable and effective drugs in the treatment of hypertension, heart failure, myocardial infarction and nephropathy. Angiotensin receptor antagonists, which have recently been introduced into clinical practice, have the potential to replace ACE inhibitor therapy in many patients.To review the mechanisms of action, indications and side effects of ACE inhibitors and angiotensin receptor antagonists and to highlight similarities and differences between the two drug classes.Angiotensin receptor antagonists have the theoretical advantage of being more effective in blocking the effects of angiotensin II at angiotensin type I receptors. The potential disadvantage of not potentiating bradykinin may be compensated by the unopposed action of angiotensin II on vascular angiotensin type II receptors, which appear to mediate similar beneficial cardiovascular effects to bradykinin. Angiotensin II receptor antagonists have a lower incidence of adverse effects than ACE inhibitors as they do not produce cough and appear much less likely to produce angioedema. Although ACE inhibitors are the most commonly prescribed antihypertensive drug class in Australia, they are underused for the treatment of heart failure and left ventricular dysfunction following myocardial infarction. Angiotensin receptor antagonists may become alternative therapies to ACE inhibitors in these disorders. However, at present they are only indicated for the treatment of hypertension.

Angiotensin converting enzyme (ACE) inhibitors are now widely used for the treatment of hypertension and heart failure. They are of particular value in treating hypertensive patients with left ventricular dysfunction, and in diabetics where they have been shown to delay the progression of diabetic nephropathy. Differences in the metabolism, pharmacokinetics, and pharmacodynamics between the various ACE inhibitors generally do not translate into significant clinical differences in the majority of patients. However, fosinopril may be the preferred ACE inhibitor in patients with significant renal dysfunction because of a reduced requirement for dosage reduction. The duration of action of ACE inhibitors is determined by two properties, the plasma half-life and the affinity of binding to tissue ACE. All of the ACE inhibitors (with the possible exception of captopril) can provide satisfactory 24-hour blood pressure control in the majority of patients with mild to moderate hypertension when given once daily. Lisinopril provides consistently better 24-hour control of blood pressure than either captopril or enalapril. Evidence for superior 24-hour blood pressure control over enalapril has not been as well established for the other ACE inhibitors. Captopril may be preferred for initiating therapy in patients with severe heart failure who are at risk of first dose hypertension because of its rapid onset of action and relatively short duration of action. There is evidence, however, that perindopril may have a low risk of first dose hypertension in heart failure because of its gradual onset of action. Long-acting ACE inhibitors may be preferable for chronic therapy of heart failure. All of the ACE inhibitors have a low incidence of adverse effects in both young and elderly patients, and there is no convincing evidence of differences in tolerability between the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Critical assessment of ACE inhibitors is an independent review of an important group of drugs widely used in the management of hypertension and heart failure. The paper is presented in two parts: Part 1 contains an overview of their action and their use in the treatment of hypertension. Part 2 focuses on the use of ACE inhibitors in heart failure and in pregnant women and in children.

We have previously reported a strong positive association between average day time and nighttime heart rate measured during 24 hour ambulatory blood pressure monitoring and usual alcohol intake.1 Acute alcohol consumption has been previously described to reduce ECG indices of vagal activity, and men who are severely dependent on alcohol have been reported to have significantly lower indices of cardiac vagal nerve activity than normal volunteers.2–5 We performed 24 hour ambulatory ECG monitoring and power spectral analysis of heart rate variability in apparently healthy middle aged men to examine the association between alcohol consumption, heart rate, and indices of heart rate variability. Twenty eight men aged 50 (9) years (range 33–68 years) who were free from clinically apparent alcohol related or cardiovascular diseases and receiving no medication were selected from volunteers responding to an advertisement in a local newspaper. The subjects’ blood pressures (128 (12)/75 (9) mm Hg), heart rate (72 (9) beats/min), body weight, and height were measured and their demographic details recorded. A detailed alcohol consumption history was taken by an experienced alcohol and other drugs nurse counsellor (JR). The information obtained included the duration that they had been consuming their current alcohol intake, the days of the week that they usually drank, and the amount of alcohol consumed …

The spontaneously hypertensive rat (SHR) is the most commonly used animal model of hypertension. For many years, it has been widely accepted that the most appropriate control strain is the Wistar-Kyoto (WKY) rat to which SHR rats are genetically related. However, recent concerns have been raised about genetic differences between the various colonies of SHRs and, in particular, genetic differences between colonies of WKY rats. It has been further emphasized that the only way to establish that a genetic trait is an etiological factor in the development of hypertension is through studies of F2 backcrosses between SHR and WKY rats. The present article details the history of the SHR and WKY strains and demonstrates why there is high likelihood of genetic variability between rats of both strains from different colonies around the world. It suggests that the WKY strain is not the most suitable for backcross studies because of the incidence of spontaneous hypertension and the somewhat higher levels of blood pressure in these rats. A central reference strain is proposed using SHRs inbred at Kyoto University, where brother/sister inbreeding has continued for more than 80 generations.

Reserpine (Fig. 1), an alkaloid derived from the roots of certain species of Rauwolfia, was isolated in 1952, and about 50 Rauwolfia alkaloids are known. Extracts of Rauwolfia, a plant genus belonging to the Apocynaceae family, were used by the Hindus for a variety of diseases including snake bites because of the resemblance of the roots to a snake (Rauwolfia serpentina). It was also used for the treatment of cardiovascular diseases, insomnia, and insanity (Weiner 1985). Reference to the medical use of Rauwolfia alkaloids appeared in the Western literature as early as 1563 (Bein 1956). In 1931 Sen and Bose reported in the Indian Medical Journal that the whole root could be used for the treatment of hypertension and psychosis. Widespread interest in their use for the treatment of hypertension, however, was aroused much later after Vakil (1949) published his findings on the use of Rauwolfia alkaloids in the British Heart Journal. Parental usage became popular for hypertensive emergencies but has a tendency to produce excessive sedation.

Guanethidine and related compounds have collectively been called adrenergic blocking drugs because their major pharmacological action is to prevent the release of noradrenaline from postganglionic neurons in response to sympathetic nerve stimulations. Guanethidine has other actions on catecholamine metabolism (see Sect. 2) and can cause significant tissue depletion of catecholamines. It does not, however, interfere with release of catecholamines from the adrenal medulla and does not produce parasympathetic blockade.

Ten normal volunteers consumed 80 g of ethanol per day or abstained from ethanol for 4 consecutive days prior to measurements of blood pressure, heart rate, vascular responsiveness to noradrenaline (NA) and angiotensin II (AII) infusions and sympathetic responsiveness to isometric handgrip exercise in an open, random order, crossed study. Supine systolic and diastolic pressures and heart rates, and erect systolic pressures rose significantly following ethanol. Vascular responsiveness to NA infusions was reduced in all subjects following ethanol, while responses to AII infusions did not show a consistent pattern of change. Plasma renin activity, plasma NA and adrenaline concentrations, and concentrations of the NA metabolite 3,4 dihydroxyphenylethylene glycol (DHPG) did not significantly differ following ethanol and control treatments. The rise in plasma NA following 2 min isometric handgrip at 50% of maximal effort was greater following ethanol (0.24 +/- 0.21 nM) than control (0.12 +/- 0.10 nM) but the difference did not reach statistical significance. The pressor effect of regular ethanol consumption and the reduced vascular reactivity to NA may both be the result of an increase in sympathetic activity that was not large enough to measurably alter resting plasma NA concentrations.

In chronic cardiac failure, various neurohumoral mechanisms are activated to sustain blood volume, blood pressure, and organ perfusion. Using the coronary artery ligation model of heart failure in the rat, we have measured changes in vasoactive hormone secretion and related these changes to salt and water status during a 1-month period. When compared with controls, rats with infarction had a marked rise in plasma atrial natriuretic peptide (294 +/- 59 vs. 79 +/- 10 pg/ml, p less than 0.001) although there was no increase in total exchangeable body sodium. Plasma renin activity and plasma aldosterone concentrations were the same for both rats with infarction and controls. Similarly, there were no significant differences in plasma arginine vasopressin, plasma osmolality, or plasma sodium concentration in rats with infarction. Ventricular norepinephrine levels were reduced in animals with infarction (p less than 0.01). Plasma atrial natriuretic peptide levels were raised in this model of chronic left ventricular failure. However, there was no salt retention and little stimulation of the renin-angiotensin-aldosterone system or vasopressin. The results suggest that high circulating atrial natriuretic peptide levels may prevent or limit salt and water retention, either directly or indirectly, by inhibiting the renin-angiotensin-aldosterone system.

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

Plasma levels of norepinephrine (NE) and the NE metabolite 3,4-dihydroxyphenylethylene glycol (DHPG) were measured simultaneously following sympathetic activation induced by standing, cold pressor testing and bicycle exercise at progressively increasing workloads in normal volunteers. Free DHPG and NE levels both increased with sympathetic activation, but free NE levels were a more sensitive index of change. In addition, plasma free NE levels more closely reflected the fall in heart rate following exercise than free DHPG. In contrast to free levels, conjugated DHPG and NE levels did not change significantly after exercise. Supine resting free DHPG/ NE ratios were always greater than 2·0, but fell progressively with increasing sympathetic activation because of a proportionately greater rise in NE than DHPG. The simultaneous measurement of plasma free DHPG and NE does not offer advantages over free NE levels as an index of sympathetic activity in man, but may be of use in the diagnosis of pheochromocytoma and in studies of NE metabolism.

Blood pressure and vascular reactivity to infusions of noradrenaline and angiotensin II (ANG II) were measured in 10 normotensive volunteers who had consumed 80 g alcohol per day for 4 days after a similar period of abstaining from alcohol. Supine systolic and diastolic blood pressure and heart rate, and erect systolic blood pressures rose significantly following alcohol. Vascular reactivity to noradrenaline decreased following alcohol, while reactivity to ANG II did not change in a consistent manner. Although plasma noradrenaline levels did not alter following alcohol, the decrease in vascular reactivity to noradrenaline may indicate down-regulation of alpha-receptors and provide indirect evidence that increased sympathetic activity contributes to the rise in blood pressure that follows regular, moderate alcohol consumption.

Neuropeptide (NPY) and norepinephrine (NE) concentrations were measured in the right ventricle (RV) of rats with cardiac failure resulting from coronary artery ligation. RV NE concentrations fell significantly in rats with infarcts while RV NPY concentrations were unaltered.

Normotensive male volunteers (n = 8) either abstained from ethanol for 4 days or consumed 66 g of ethanol per day in an open, crossed, random order study. Mean arterial pressures rose by an average of 5.4 mmHg following the ethanol phase of the study (P less than 0.001). Plasma noradrenaline (NA) concentration was higher during ethanol ingestion (P less than 0.01), principally because of a significant reduction in NA clearance of -1.51 l min-1 m-2 (P less than 0.05). In contrast, NA spillover or release rates did not significantly differ between the two study periods. Total plasma calcium levels were significantly lower (P less than 0.05) following the ethanol compared to the control period. These data do not appear to support the proposition that regular alcohol consumption raises blood pressure by producing a generalised increase in sympathetic activity.