Advanced chronic kidney disease, cardiovascular events and the effect of diabetes: data from the Atherosclerosis and Folic Acid Supplementation Trial.

BACKGROUND: End-stage kidney disease registry data have reported increased mortality in patients with diabetes as compared with those without. Here we examine whether diabetes is independently associated with an increased risk of major cardiovascular events and death in patients with advanced chronic kidney disease (CKD). METHODS: Data from 315 participants with CKD in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) were assessed. Primary end-points were fatal or non-fatal cardiovascular events, including myocardial infarction, stroke, unstable angina, coronary revascularisation and peripheral vascular events assessed both jointly and separately using Cox-proportional hazard models. RESULTS: Twenty-three per cent reported diabetes. Median follow up was 3.6 years. In those with diabetes, an increased risk for major cardiovascular events was observed, crude hazard ratio (HR) 2.87 (95% confidence interval (CI) 2.11-3.90). After adjustment for age, gender, smoking, systolic blood pressure, body mass index, past ischaemic heart disease and use of preventive therapies, diabetes was associated with an HR of 1.83 (1.28-2.61) for major cardiovascular events. The risk for peripheral vascular events was also increased, adjusted HR 6.31 (2.61-15.25). For all-cause death, major coronary and stroke events, the risk in those with diabetes was not significantly increased (all-cause death, adjusted HR 1.31 (95% CI 0.80-2.14); major coronary events, adjusted HR 1.26 (95% CI 0.64-2.49); and major stroke events, adjusted HR 1.28 (95% CI 0.55-2.99)). CONCLUSIONS: Diabetes significantly increases the risk of major cardiovascular events, especially peripheral vascular events in patients with advanced CKD. Trials of multifactorial management of cardiovascular risk factors are required to determine if outcomes for this population may be improved.

Exchanges across land-water-scape boundaries in urban systems: strategies for reducing nitrate pollution.

Conservation in urban areas typically focuses on biodiversity and large green spaces. However, opportunities exist throughout urban areas to enhance ecological functions. An important function of urban landscapes is retaining nitrogen thereby reducing nitrate pollution to streams and coastal waters. Control of nonpoint nitrate pollution in urban areas was originally based on the documented importance of riparian zones in agricultural and forested ecosystems. The watershed and boundary frameworks have been used to guide stream research and a riparian conservation strategy to reduce nitrate pollution in urban streams. But is stream restoration and riparian-zone conservation enough? Data from the Baltimore Ecosystem Study and other urban stream research indicate that urban riparian zones do not necessarily prevent nitrate from entering, nor remove nitrate from, streams. Based on this insight, policy makers in Baltimore extended the conservation strategy throughout larger watersheds, attempting to restore functions that no longer took place in riparian boundaries. Two urban revitalization projects are presented as examples aimed at reducing nitrate pollution to stormwater, streams, and the Chesapeake Bay. An adaptive cycle of ecological urban design synthesizes the insights from the watershed and boundary frameworks, from new data, and from the conservation concerns of agencies and local communities. This urban example of conservation based on ameliorating nitrate water pollution extends the initial watershed-boundary approach along three dimensions: 1) from riparian to urban land-water-scapes; 2) from discrete engineering solutions to ecological design approaches; and 3) from structural solutions to inclusion of individual, household, and institutional behavior.

Vasoconstrictor role for vasopressin in experimental heart failure in the rabbit.

Vasopressin's role as a vasoconstrictor in chronic heart failure, was examined in rabbits with adriamycin cardiomyopathic congestive heart failure. Chronic adriamycin treatment resulted in a decrease in cardiac output (829 +/- 38-610 +/- 36 ml/min, P less than 0.005) and blood pressure (83 +/- 2-76 +/- 3 mmHg, P less than 0.01), and an increase in peripheral resistance (8,377 +/- 381-10,170 +/- 657 dyn-s-cm-5, P less than 0.05). Plasma renin activity (4.7 +/- 0.6-10.9 +/- 2.8 ng angiotensin I/ml X h) and norepinephrine (0.7 +/- 0.1-1.3 +/- 0.2 pmol/ml, P less than 0.05) increased while plasma vasopressin levels did not change. Vasopressin infusion, however, produced significantly greater increases in peripheral resistance in animals with heart failure than in controls. Moreover, a specific vasopressin vascular antagonist reduced blood pressure (7 +/- 3%) and peripheral resistance (14 +/- 4%) and increased cardiac output (10 +/- 3%) in animals with heart failure but had no cardiovascular effects in normal rabbits. These results suggest that vascular sensitivity to vasopressin is increased in heart failure, and that it contributes significantly to the increased afterload in heart failure despite normal plasma levels. In this model of severe, chronic heart failure the sympathetic, renin-angiotensin, and vasopressin systems all appear to be activated.

Overweight women with polycystic ovary syndrome have evidence of subclinical cardiovascular disease.

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and the metabolic syndrome. There are no adequate data demonstrating significantly increased cardiovascular disease (CVD) mortality. In the absence of clinical outcome studies, surrogate markers of early CVD can provide insight into early CVD. OBJECTIVE: The aim of this study was to clarify whether overweight women with PCOS have an increased prevalence of cardiovascular risk factors and early CVD, compared with age- and body mass index-matched controls, to determine the contribution of PCOS per se to CVD status. DESIGN AND PATIENTS: This was a case control study of 100 overweight women with PCOS and 20 subjects of similar body mass index and age. MAIN OUTCOME MEASURES: Noninvasive markers of early CVD [carotid intimal media thickness, pulse wave velocity (PWV), and brachial arterial flow-mediated vasodilation] were measured. Metabolic parameters studied included insulin, glucose, C-reactive protein, lipids, and androgens. RESULTS: Subjects with PCOS had elevated testosterone (2.5 +/- 0.2 vs. 1.3 +/- 0.1 nmol/liter), dehydroepiandrosterone sulfate (4.9 +/- 0.3 vs. 3.6 +/- 0.4 mmol/liter), fasting insulin (19.6 +/- 1.4 vs. 6.8 +/- 0.8 microU/ml), and homeostasis model assessment of IR (4.1 +/- 0.3 vs. 1.3 +/- 0.2), compared with controls. In addition, those with PCOS had elevated cholesterol (5.1 +/- 0.1 vs. 4.6 +/- 0.2 mmol/liter) and triglycerides (1.4 +/- 0.1 vs. 0.9 +/- 0.1 mmol/liter), whereas there were no differences in either C-reactive protein or 24-h ambulatory blood pressure parameters. Subjects with PCOS also had increased arterial stiffness (PWV, 7.4 +/- 0.1 vs. 6.6 +/- 0.2 m/sec) and endothelial dysfunction (flow-mediated vasodilation, 9.8 +/- 0.4 vs. 13.3 +/- 0.9), compared with controls. There was no difference in mean intimal media thickness between the groups. Stepwise regression in PCOS subjects showed that IR and lipids were independent predictors of PWV. CONCLUSION: Overweight women with PCOS have increased cardiovascular risk factors and evidence of early CVD, compared with weight-matched controls, potentially related to IR.

Vascular dysfunction and metabolic parameters in polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and the metabolic syndrome; however, the cardiovascular (CV) manifestations of PCOS remain unclear. OBJECTIVE: The objective of this study was to examine the relationships between IR, metabolic parameters, androgens, and markers of early CV disease in PCOS. DESIGN: We conducted an observational study examining noninvasive markers of early CV disease in women with PCOS including structural [carotid intimal media thickness (IMT)] and functional measures (arterial function with pulse wave velocity and endothelial function with brachial arterial flow-mediated vasodilation). Metabolic parameters included insulin and glucose during an oral glucose tolerance test and lipid and androgen levels. SETTING: Participants were recruited from the general community. PATIENTS: Eighty overweight women with PCOS who were nonsmokers and not on oral contraceptives or other medications known to affect IR participated in the study. RESULTS: Stepwise regression analysis showed that after adjustment for age and body mass index, IMT was significantly correlated with blood pressure (BP) load (P = 0.03) and inversely with dehydroepiandrosterone sulfate (DHEAS) (P = 0.01). After correction for androgen status, IMT was correlated with fasting glucose and area under curve (AUC) insulin. Flow-mediated vasodilation was inversely related to lipids (P = 0.02), whereas pulse wave velocity was related to BP (P < 0.001), AUC insulin (P = 0.04), and AUC glucose (P = 0.035). CONCLUSION: In overweight women with PCOS, insulin resistance and BP interacted negatively with arterial structural and functional measures. DHEAS correlated inversely with arterial structure, suggesting possible cardioprotective effects of endogenous DHEAS in women with PCOS. Additional research is needed to clarify these findings.

Use of radial artery applanation tonometry and a generalized transfer function to determine aortic pressure augmentation in subjects with treated hypertension.

OBJECTIVES: The purposes of this study were to investigate the use of radial artery applanation tonometry and a generalized transfer function for the assessment of central aortic pressure augmentation in subjects taking commonly used antihypertensive agents (angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, Ca2+ antagonists, diuretic therapy). BACKGROUND: Applanation tonometry of the radial artery with a generalized transfer function has been proposed as a means of assessing central aortic blood pressure. Recently, a commercial apparatus based on this technique has become available; we therefore examined the effect of a generalized transfer function on derived central aortic pressure compared with measured brachial blood pressures and also investigated the potential of this technique to assess the influence of differing drug therapy. METHODS: Two hundred and sixty-two hypertensive patients on stable medication were studied using the PWV Medical Blood Pressure Analysis System (version 2, DAT-1). RESULTS: In univariate analysis, augmentation index showed association with age, sex, height and heart rate. In multivariate analysis, diastolic blood pressure and age (positively), height and heart rate (negatively) and sex were significantly associated. After adjustment for these variables, pressure augmentation was not associated with any antihypertensive treatment investigated. Linear relationships were demonstrated between brachial blood pressures and corresponding central pressures derived by transfer function methods. CONCLUSIONS: Our findings suggest that if adjustment for central-peripheral pressure difference is necessary, simple linear relationships may be sufficient. Age, heart rate and height but not the class of antihypertensive medication affected the degree of pressure augmentation observed using this technique.

Hormone replacement therapy in postmenopausal women protects against smoking-induced changes in vascular structure and function.

OBJECTIVES: The purpose of this study was to investigate the role of hormone replacement therapy (HRT) in postmenopausal women who smoke. BACKGROUND: Hormone replacement therapy appears to afford cardiovascular protection in postmenopausal women; however, in high risk individuals, specifically smokers, this has not been adequately studied. This question was addressed in a cross-sectional study of arterial structure, function and plasma lipids in postmenopausal smokers and nonsmokers. METHODS: Vascular ultrasound was performed in two age-matched groups of postmenopausal women, 70 on HRT (35 smokers) and 70 control subjects not on HRT (35 smokers). Indexes of arterial structure (carotid intima-media thickness [IMT]) and vascular function (systemic arterial compliance [SAC]) and lipid profiles were measured. RESULTS: Participant characteristics were similar in the two groups. Smokers on HRT, compared with smoking control subjects, had lower cholesterol (6.0+/-0.2 vs. 6.8+/-0.3 mmol/liter, p = 0.03) and more favorable mean values for IMT (0.64+/-0.02 vs. 0.74+/-0.03 mm, p = 0.007) and SAC (0.41+/-0.03 vs. 0.32+/-0.03 U/mm Hg, p = 0.03). Nonsmokers on HRT compared with nonsmoking control subjects had lower total cholesterol (5.7+/-0.2 vs. 6.5+/-0.2 mmol/liter, p = 0.02) and low density lipoprotein cholesterol (3.4+/-0.2 vs. 4.4+/-0.3 mmol/liter, p = 0.01). Mean IMT and SAC values in nonsmokers on HRT and control subjects were not significantly different. Multiple regression demonstrated significant correlation between HRT status and both IMT and SAC, in smokers and in those with increased cholesterol. In nonsmokers and those with lower cholesterol, HRT status was not significantly correlated with vascular parameters. CONCLUSIONS: In postmenopausal women who smoke there may be a beneficial effect of long-term estrogen therapy on indexes of arterial structure and function as surrogate markers of cardiovascular disease. Long-term controlled studies are needed to confirm these findings.

Vasopressin and angiotensin II contribute equally to the increased afterload in rabbits with heart failure.

STUDY OBJECTIVE: Vasopressin, like angiotensin, has both vasoconstrictor and fluid retaining properties and therefore may make an important contribution to the pathogenesis of low output congestive heart failure. The study aimed to examine the relative importance of the renin-angiotensin system and vasopressin in an animal model of heart failure. DESIGN: The acute haemodynamic effects of vasopressin receptor blockade with a selective antagonist, d(CH2)5DAVP (AVPA) (30 micrograms.kg-1) and angiotensin converting enzyme inhibition with captopril (1 mg.kg-1) were compared. The effect of combined blockade (ie, vasopressin receptor antagonist + angiotensin converting enzyme inhibitor) was also examined. EXPERIMENTAL MATERIAL: Rabbits, 2.5-3.5 kg, with doxorubicin induced cardiomyopathy and heart failure (n = 20) were used. There were 15 controls. MEASUREMENTS AND MAIN RESULTS: Both AVPA and captopril produced significant increases in cardiac output (11% and 13% respectively) and falls in peripheral vascular resistance (21% and 17% respectively). Inhibition of the two vasoconstrictor systems was additive and resulted in a fall in peripheral vascular resistance to levels found in normal animals. CONCLUSIONS: Vasopressin and angiotensin II make equal contributions to the raised peripheral vascular resistance observed in this model of heart failure. Vasopressin inhibition may be useful in the treatment of heart failure either alone or as an adjunct to angiotensin converting inhibition.

Myocardial and peripheral catecholamine responses to acute coronary artery constriction before and after propranolol treatment in the anaesthetised dog.

The left anterior descending coronary artery was constricted for eight minutes on two occasions in 13 anaesthetised open-chest dogs. One group (n = 8) was studied before and afer 1 mg . kg-1 propranolol intravenously; a second group (n = 5) served as controls. Simultaneous blood samples were drawn from arterial and coronary sinus catheters for measurement of lactate and catecholamine concentrations. In controls, coronary artery constriction resulted in a reproducible fall in fractional myocardial lactate extraction and an increase in left atrial pressure, but caused no significant changes in blood pressure, heart rate or plasma concentrations of noradrenaline, adrenaline, or dopamine. In the treated group, heart rate was reduced but blood pressure was the same after propranolol; both remained unchanged during constriction and after release. The fall in fractional lactate extraction was abolished by propranolol. Arterial noradrenaline increased significantly after propranolol, fell during constriction and rose again after release. A similar trend was observed in coronary sinus noradrenaline. Reversible myocardial ischaemia is not associated with peripheral or myocardial release of catecholamines. Pre-treatment with propranolol appears to exert a protective effect on the myocardium even during reversible ischaemia. Although peripheral noradrenaline levels are increased after propranolol, this increase is not maintained during coronary artery constriction.

Regional blood flow effects of dopexamine versus enalaprilat during propofol anaesthesia in rabbits with experimental chronic heart failure.

OBJECTIVE: Chronic congestive heart failure (CHF) was induced in rabbits with doxorubicin in order to evaluate: (1) haemodynamic and regional blood flow responses to propofol anaesthesia; (2) modification of these cardiovascular responses with background intravenous infusions of enalaprilat or dopexamine. METHODS: Rabbits received either doxorubicin, 2 mg.kg-1 weekly intravenously for seven weeks (CHF, n = 6), or saline (controls, n = 6). Doppler flow probes were implanted on the ascending aorta, left renal artery, and lower abdominal aorta. In three separate studies propofol was infused for 40 min periods at 0.6 and then 1.2 mg.kg-1.min-1 after background infusions of either saline, enalaprilat (0.2 mg.kg-1 + 0.003 mg.kg-1.min-1), or dopexamine (0.008 mg.kg-1.min-1). RESULTS: In normal rabbits propofol (1.2 mg.kg-1.min-1) reduced mean arterial pressure from awake control by 33(SEM 3)%, cardiac output by 24(4)%, and hindlimb blood flow (HBF) by 10(2)%, but did not change renal blood flow. In rabbits with CHF, although resting mean blood pressure was lower, propofol did not alter blood pressure or hindlimb blood flow, but renal blood flow was reduced by 37(6)%. CONCLUSIONS: Both enalaprilat and dopexamine increased renal blood flow in the control and CHF groups. Enalaprilat caused marked hypotension during anaesthesia in the CHF group. Dopexamine increased mean arterial pressure, heart rate, and hindlimb blood flow during anaesthesia in controls, but not in CHF.

Cardiovascular responses to graded treadmill exercise during the development of doxorubicin induced heart failure in rabbits.

STUDY OBJECTIVE: The aim was to examine the haemodynamic and humoral responses to graded treadmill exercise, serially during the development of congestive heart failure. DESIGN: Doxorubicin (1 mg.kg-1) was given to rabbits twice weekly intravenously over 8 weeks to induce a low output congestive cardiomyopathy. Treadmill exercise at 8 and 16 m.min-1 was performed at weeks 0, 2, 4, 6, 7, and 8. During each exercise study, continuous recordings were made of cardiac output, mean arterial pressure, and heart rate, and central venous blood was sampled at rest and during the last 10 s of exercise for plasma noradrenaline and plasma renin activity. EXPERIMENTAL MATERIAL: Six cross-bred English rabbits, mean weight 2.6 kg, received doxorubicin treatment; three control rabbits received vehicle injection. MEASUREMENTS AND MAIN RESULTS: Over the first 2 weeks, resting haemodynamic variables and responses to exercise were normal in all rabbits. Thereafter, doxorubicin treated rabbits had progressive falls in resting cardiac index and mean arterial pressure, and rises in resting heart rate and systemic vascular resistance. The normal increases in cardiac index and mean arterial pressure with exercise were progressively attenuated, despite an increase in resting and exercising heart rate. The resting levels of plasma noradrenaline and plasma renin rose after the fourth week of doxorubicin treatment. Throughout the experiment, exercise consistently raised plasma noradrenaline and renin, but the exercising levels of both hormones increased as heart failure progressed. Four of the six doxorubicin treated rabbits became exhausted in the final run and there was an intense rise in systemic vascular resistance. CONCLUSIONS: In this rabbit model of chronic heart failure, sympathetic vasoconstrictor drive is greater than normal at rest, and is greatly exaggerated during exercise. It is suggested that this abnormal response to exercise results from a combination of failure of arterial pressure to reach the elevated set point of the arterial baroreflex, increased afferent input from exercising muscles due to their underperfusion, and increase in central command due to muscle fatigue.

Differential renal function during angiotensin converting enzyme inhibition in renovascular hypertension.

Renal function was measured sequentially in 32 patients with proven renovascular hypertension who were treated with the oral angiotensin converting enzyme inhibitor captopril. Renal function was assessed by serial measurement of serum creatinine. Six patients showed acute rises in serum creatinine concentration compatible with acute renal failure. Acute renal failure was confined to those patients with stenosis to a solitary kidney (transplant or native, occurring in 3 of 8 patients) or bilateral renal artery stenosis (occurring in 3 of 13 patients). No rise in serum creatinine concentration was observed in 11 patients with unilateral renal artery stenosis during long-term angiotensin converting enzyme inhibitor therapy. Acute renal failure during angiotensin converting enzyme inhibitor therapy was not related to the degree of blood pressure fall or the plasma angiotensin II level. Eleven patients with renovascular hypertension were followed prospectively with estimation of renal function by 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance (determined by computer analysis of scintillation camera renography). In six patients with unilateral renal artery stenosis, total 99mTc-DTPA clearance and serum creatinine level remained constant following angiotensin converting enzyme inhibitor therapy, while in five patients with bilateral renal artery stenosis 99mTc-DTPA clearance fell from 40 +/- 9 to 27 +/- 5 ml/min (p less than 0.05). Split renal function studies revealed that 99mTc-DTPA clearance fell in most kidneys with stenosed arteries during angiotensin converting enzyme inhibition, including the stenosed kidney from patients with unilateral renal artery stenosis (16 stenosed kidneys studied; change in Tc-DTPA clearance, -7.5 +/- 2.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary soy has both beneficial and potentially adverse cardiovascular effects: a placebo-controlled study in men and postmenopausal women.

To address the cardiovascular effects of dietary soy containing phytoestrogens, we measured blood pressure (BP), lipids, vascular function (systemic arterial compliance and pulse wave velocity), and endothelial function (flow-mediated vasodilation) in a randomized, double-blind trial. Two hundred thirteen healthy subjects (108 men and 105 postmenopausal women), 50-75 yr old, received either soy protein isolate (40 g soy protein, 118 mg isoflavones) or casein placebo for 3 months. There were 34 withdrawals (16%), with 179 subjects (96 men and 83 women) completing the protocol. After intervention in the soy group, compared with casein placebo, urinary phytoestrogens increased, accompanied by a significant fall in BP reflected by the BP model (P < 0.01) encompassing mean change (+/-SEM) in systolic (-7.5 +/- 1.2 vs. -3.6 +/- 1.1 mm Hg, P < 0.05), diastolic (-4.3 +/- 0.8 vs. -1.9 +/- 0.7 mm Hg, P < 0.05), and mean BP (-5.5 +/- 1 vs. -0.9 +/- 1 mm Hg, P < 0.008). In the lipid model, soy induced greater changes, compared with placebo (P < 0.001). On individual analysis, significant contributors included a reduction in the low- to high-density lipoprotein ratio (-0.33 +/- 0.1 vs. 0.04 +/- 0.1 mmol/L, P < 0.05) and triglycerides (-0.2 +/- 0.05 vs. -0.01 +/- 0.05 mol/L, P < 0.05) and an increase in Lp(a) lipoprotein (+/- 95% confidence interval) [42 (range, 17-67) vs. 4 (range, -22-31) mg/L, P < 0.05], whereas total, low-density lipoprotein, and high-density lipoprotein cholesterol improved in both groups; but no treatment effect was demonstrated. The arterial functional model demonstrated no difference between groups; although again, overall function improved in both groups. On individual analysis, peripheral PWV (reflecting peripheral vascular resistance) improved with soy (P < 0.01), whereas flow-mediated vasodilation (reflecting endothelial function) declined (in males only), compared with casein placebo (P < 0.02). No effect of treatment on the hypothalamic-pituitary-gonadal axis was noted in males or females. In normotensive men and postmenopausal women, soy improved BP and lipids but, overall, did not improve vascular function. Potential adverse effects were noted, with a decline in endothelial function (in males only) and an increase in Lp(a). Further research in hypertensive and hyperlipidemic populations is needed.

Hemodynamic study of short- and long-term isradipine treatment in patients with chronic ischemic congestive heart failure.

The acute hemodynamic effects of isradipine on cardiac performance, at rest and during exercise, were examined in nine male patients aged 37 to 69 years with congestive heart failure due to ischemic heart disease. The effects of 10 mg oral isradipine were maximal after two to three hours with significant decreases in blood pressure as well as in systemic and pulmonary vascular resistances, and an increase in cardiac output. There were no significant changes in heart rate or pulmonary capillary wedge pressure. For the same 50-watt bicycle workload pre- and post-drug, the addition of isradipine was associated with lower systemic and pulmonary vascular resistances (systemic vascular resistance, 805 +/- 70 versus 975 +/- 70; p less than 0.01; pulmonary vascular resistance, 144 +/- 27 versus 207 +/- 35 dynes.sec.cm-5; p less than 0.01), and lower pulmonary artery pressures (54 +/- 6/23 +/- 3 versus 66 +/- 7/27 +/- 3 mm Hg; p less than 0.01) during exercise. In a double-blind 12-week trial, body weight decreased during isradipine treatment (71.6 to 68.9 kg; p less than 0.01), but there were no significant changes in exercise duration, radionuclide ejection fraction, or cardiothoracic ratio, and no serious side effects were encountered. These results suggest that isradipine is worthy of further evaluation in long-term treatment of chronic ischemic congestive heart failure.

Comparison of felodipine extended release and conventional tablets in essential hypertension using ambulatory blood pressure monitoring.

Two formulations of felodipine, conventional and extended release (ER) tablets, were compared in a double-blind, crossover study of patients whose blood pressure was not being controlled using metoprolol 100 mg once daily. Nineteen patients with a supine diastolic blood pressure greater than or equal to 95 mmHg after 4 weeks of taking metoprolol and placebo were randomly assigned to felodipine conventional (5 mg twice a day) or ER (10 mg once daily) for 4 weeks. A 2-week washout period was then followed by 4 weeks of treatment with the alternative formulation. Metoprolol once daily was taken concomitantly throughout the study. Clinic blood pressure was measured at 0 h (i.e. 12 h after the last dose of conventional, and 24 h after the last ER felodipine dose), and then 2 and 5 h after the following dose had been taken. Ambulatory blood pressure and the heart rate were monitored over 24 h using an Accutracker (Suntech Medical Instruments, Raleigh, North Carolina, USA). During the final treatment, both felodipine formulations caused similar substantial falls in supine blood pressure compared with pressures prior to randomized treatment. The falls in clinic blood pressures (systolic/diastolic) were similar with the conventional and ER formulations at all time points, i.e. 0 h (21/13; 19/11 mmHg), 2 h (39/18; 36/18 mmHg) and 5 h (30/12; 35/11 mmHg) after the morning dose was taken. Both formulations also produced similar falls in blood pressures over 24 h and during the daytime (21/12; 20/12 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of activated neurons in the rabbit brain following a volume load.

Immunohistochemical detection of the protein, Fos, was used to identify neurons in the brain activated following a volume load. The plasma expanders, Haemaccel and 6% dextran, were infused intravenously in conscious rabbits for 60 min. Compared to control animals both stimuli significantly increased right atrial pressure but had no effect on blood pressure. Heart rate was significantly elevated with dextran only. Volume expansion with Haemaccel also reduced renal sympathetic nerve activity by about 50% from the pre-infusion resting level. Ninety minutes after the start of the infusion, the rabbits were perfusion fixed and the distribution of Fos-positive cell nuclei was examined. Following Haemaccel infusion there were significant increases in the number of Fos-positive cell nuclei in the organum vasculosum of the lamina terminalis, parvocellular paraventricular nucleus and in specific rostrocaudal levels of the nucleus tractus solitarius and ventrolateral medulla. Following dextran similar effects were observed in the medulla but Fos-positive cell nuclei were not significantly elevated above controls in the forebrain. After Haemaccel or dextran areas such as the supraoptic nucleus, the magnocellular paraventricular nucleus, the bed nucleus of the stria terminalis, diagonal band of Broca and amygdala either did not produce Fos or were not consistently different from the control group. The results suggest that specific brain regions, that are known to be important in cardiovascular control, are activated by a volume load. These areas are likely to play an important role in the reflex responses initiated by that particular stimulus.

Crossover comparison of atenolol, enalapril, hydrochlorothiazide and isradipine for isolated systolic systemic hypertension.

The benefit of antihypertensive therapy in reducing cardiovascular morbidity and mortality associated with isolated systolic hypertension has now been established by the Systolic Hypertension in the Elderly Program. However, there is little information about the relative effectiveness of different drug regimens in this condition. This study compared the efficacy and tolerability of 50 mg of atenolol, 10 mg of enalapril, 25 mg of hydrochlorothiazide and 2.5 mg of isradipine in the treatment of isolated systolic hypertension. After a 3-week placebo run-in phase, 24 subjects were randomized into a 4-period double-blind crossover study by use of an orthogonal latin square design. Treatment periods were of 6 weeks' duration with titration to a higher dose after 4 weeks in those not reaching goal blood pressure (BP). Each active treatment was followed by a 3-week placebo washout. Casual clinic and 24-hour ambulatory BP (Accutracker II) were measured at the end of each treatment phase. Routine biochemistry was also performed after the placebo run-in, at the end of each active treatment phase, and after the placebo run-out. Of the 24 subjects entered (mean age 72.3 years, 38% men) 20 completed the whole study. Mean +/- standard deviation of supine clinic and daytime ambulatory BP on entry were 181/79 +/- 21/9 mm Hg and 165/82 +/- 23/15 mm Hg, respectively. All drugs reduced mean casual and ambulatory BP significantly relative to placebo but only hydrochlorothiazide and enalapril produced a consistent hypotensive effect throughout the entire 24-hour period. Isradipine and enalapril exhibited a relatively greater effect on reducing systolic BP than either hydrochlorothiazide or atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal and blood pressure responses to tilting in beta-blocked essential hypertension treated with felodipine or prazosin.

A study was carried out of 22 patients with essential hypertension who were treated with metoprolol (100 mg/day) and placebo for 4 weeks. Felodipine (n = 11) or prazosin (n = 11) were then added in increasing doses (felodipine 5, 10, 20 mg bid; prazosin 1, 2, 4 mg bid) for 2 weeks until a diastolic blood pressure of less than or equal to 90 mm Hg was achieved. Acute haemodynamic and hormonal responses to 80 degrees tilting (measurements after 4 minutes' tilt) were obtained immediately prior to randomisation to felodipine or prazosin, and after 6 to 8 weeks of treatment. At randomisation, 80 degrees tilt produced no change in blood pressure and only a small increase in pulse rate. There was no significant change in the plasma renin-angiotensin system, vasopressin or adrenaline concentrations. Plasma noradrenaline concentration rose in response to 80 degrees tilt. Following substitution of felodipine (n = 11) or prazosin (n = 11) for placebo, and continuation of metoprolol, blood pressure fell. 80 degrees tilt caused no change in the plasma renin-angiotensin system, vasopressin or adrenaline concentration. Plasma noradrenaline concentration rose in response to tilt, as before. Felodipine is an effective antihypertensive agent when used with metoprolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Components of blood pressure variability in the elderly and effects on sample size calculations for clinical trials.

This study investigated components of blood pressure variability in the elderly using both ambulatory blood pressure monitoring (ABPM) and casual clinic blood pressure measurement. These were then used to determine sample size requirements for clinical trials of different design scenarios in the elderly. Twenty-six elderly subjects not receiving antihypertensive medication were recruited from general practices and seen on four occasions at weekly intervals. On each occasion of blood pressure was measured in the clinic using a standard mercury sphygmomanometer and then for 24 h using a noninvasive ambulatory monitoring device. The between subject and between subject/within occasion components of blood pressure variability were determined by analysis of variance and used to calculate to sample size requirements for parallel and crossover trials respectively. The between subject variance of mean blood pressure was 1/3 greater with clinic readings, except within a subgroup of subjects who had isolated systolic hypertension (ISH). Increasing the number of readings or occasions on which measurement was performed in a parallel group trial only reduced the variability substantially when the number of subjects involved was small. With crossover designs, the between subject component of variance is eliminated resulting in substantial reduction in sample size. Whereas 60 subjects with ISH would be required to detect a 10 mm Hg difference in systolic blood pressure between two treatments in a parallel design using casual readings, only 18 are required with a crossover trial. If ABPM is used the number of subjects required are 54 and 14, respectively. Reducing variability with ABPM involves a trade-off between the increased number of readings available with the technique against the highly uniform and standardized conditions used to determine clinic blood pressures. ABPM appears most useful as a strategy for reducing sample size in parallel group trials involving small numbers of subjects measured on one occasion.

Suppression of noradrenaline spillover by the dopamine prodrug gamma-L-glutamyl-L-dopa: a central effect?

The DA prodrug gamma-L-glutamyl-L-dopa (gludopa) has a high degree of renal selectivity with 2-step conversion to DA in the kidney. The effects of gludopa, with and without DA-2 receptor blockade, on renal and total noradrenaline (NA) spillover, were studied in two groups of rabbits. Eight rabbits received gludopa infusion (25 and 100 micrograms/kg/min and 8 received an infusion of gludopa and DA-2 receptor antagonist, YM-09151 (50 micrograms/kg i.v.). Renal and total NA spillover rates were measured by 3H-NA tracer method before and after gludopa infusion. Brain NA, DA, gludopa and L-dopa content were measured after gludopa infusion in 5 rabbits; control values for tissue catecholamine and drug levels were obtained in 5 untreated rabbits. Gludopa infusion markedly increased kidney DA content (300-fold) and DA excretion (6000-fold) but had little effect on plasma DA. It produced a dose-related fall in mean (+/- SEM) renal NA spillover (21.6 +/- 3.7 to 10.6 +/- 2.7, 7.2 +/- 2.7 ng/min, p < 0.01). Even greater falls were observed in total NA spillover after gludopa (43.1 +/- 10.2 to 19.7 +/- 3.4, 9.4 +/- 1.8 ng/min, p < 0.01). DA-2 receptor antagonism had no influence on the effects of gludopa on either renal or total NA spillover. Significant amounts of gludopa were detected in the brain after drug infusion (0.28 +/- 13 nmol/g brain tissue). Gludopa, a putative renal selective dopamine prodrug with effects mediated via DA-1 receptors also significantly inhibits both renal and extra-renal NA spillover. This effect is not a DA-2 effect but may be mediated centrally.