The effect of metformin on adipose tissue metabolism and peripheral blood flow in subjects with NIDDM.

OBJECTIVE: To examine the effect of metformin on net lactate and glycerol release in NIDDM subjects, we used abdominal subcutaneous microdialysis combined with 133Xe clearance. Skeletal muscle blood flow (MBF) was assessed simultaneously both before and after metformin treatment. RESEARCH DESIGN AND METHODS: Nine male patients with NIDDM (age 53 +/- 2 years [mean +/- SE]; BMI 30.2 +/- 1.4 kg/m2; body fat 23.0 +/- 2.6 kg; diabetes duration 4.6 +/- 1.5 years; six of nine receiving sulfonylurea treatment) were recruited into an open study. They were studied after an overnight fast, both before and after 1 week of additional treatment with 500 mg metformin three times daily. Nine weight- and age-matched nondiabetic subjects served as a control group. RESULTS: Postabsorptive net subcutaneous lactate release increased (149 +/- 50 vs. 475 +/- 127 nmol.100 g-1.min-1, P < 0.05) whereas plasma lactate was unchanged after metformin treatment in the NIDDM patients. The net decrease of glycerol release 90 min after an oral glucose tolerance test was more pronounced (110 +/- 30 vs. 199 +/- 20 nmol.100 g-1.min-1, P < 0.05) after metformin treatment. Both adipose tissue blood flow (ATBF) (1.5 +/- 0.1 vs. 2.3 +/- 0.2 ml.100 g-1.min-1, P < 0.01) and MBF (3.2 +/- 0.4 vs. 4.2 +/- 0.5 ml.100 ml-1.min-1, P < 0.05) increased after metformin treatment. CONCLUSIONS: In this open study, postabsorptive net lactate release in abdominal subcutaneous adipose tissue was clearly increased in NIDDM patients after metformin treatment. Basal ATBF as well as MBF was improved after metformin treatment. Whether this reflects enhanced metabolic control or is a drug-specific effect remains to be established.

Importance of dietary salt in the hemodynamic adjustment to weight reduction in obese hypertensive men.

Twenty-three moderately obese middle-aged men with previously untreated hypertension (World Health Organization classification 1-2) were evaluated to assess the effects on blood pressure (BP) of a diet restricted in energy (fats and carbohydrates) but unrestricted in sodium (Group 1) compared to a diet restricted in energy and sodium (Group 2). The patients were randomly allocated to either of the two groups and were comparable in age, sex, weight, and BP. The same energy- and sodium- restricted diet was given to both groups, but the intake of Group 1 (n = 13) was supplemented with dietary sodium. The average urinary output for Group 1 was 192 +/- 39 mmol/24 hr at baseline and 200 +/- 56 mmol/24 hr during the diet. For Group 2 (n = 10), which remained on the initial diet, urinary sodium excretion changed from 188 +/- 53 mmol/24 hr at baseline to 97 +/- 32 mmol/24 hr (p less than 0.001). Intraarterial BP, cardiac output (CO), plasma volume, circulating norepinephrine (NE), and urinary NE were measured at baseline and at the end of the dieting periods. Before the dietary sodium supplement while on the initial diet, the patients in Group 2 showed a reduction in body weight from 97.3 +/- 10.5 kg to 88.6 +/- 9.9 kg (p less than 0.001). Heart rate (HR) and urinary NE output were significantly reduced in comparison with baseline, but intraarterial BP was unchanged. No change in cardiopulmonary blood volume, CO, or stroke volume (SV) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactivity to norepinephrine and effect of sodium on blood pressure during weight loss.

Eighteen moderately obese middle-aged men with untreated mild hypertension were randomized to two groups and placed on a low energy diet regimen for 9 to 11 weeks. In Group I (n = 10) the amount of sodium chloride in the diet maintained the urinary sodium excretion at the predieting level. Mean body mass was reduced by 9.1 +/- 0.7 (SEM) kg. Mean intra-arterial pressure showed no significant change. There were significant decreases in heart rate (p less than 0.05) and urinary norepinephrine excretion (p less than 0.05) but not in plasma concentration of norepinephrine. In Group II (n = 8) energy as well as sodium intake was restricted, with a 95 +/- 22 mmol/24 hour reduction of urinary sodium excretion. Body mass decreased by 9.3 +/- 1.1 kg, and mean arterial pressure decreased by -18.9 to -4.3 mm Hg (95% confidence interval). There were also significant reductions in heart rate (p less than 0.001) and plasma norepinephrine concentrations (p less than 0.01) but not in urinary norepinephrine excretion. The pressor response (mean arterial pressure) to norepinephrine infusion at different dose rates was significantly elevated (p less than 0.05) in Group I during dieting in comparison with baseline. The blood pressure response to norepinephrine during dieting in patients in Group II was not changed from baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased response to physical and mental stress in men with hypertensive parents.

Blood pressure and heart rate responses to isometric handgrip exercise were studied at age 31 and after 5 years in young nonhypertensive men with positive family histories of hypertension (n = 13) and in those with negative family histories of hypertension (n = 13) for two generations to test whether subjects with positive family histories established a pattern of increased blood pressure and heart rate responses during the 5-year follow-up period. At follow-up the response to mental stress (Stroop's color word test) was also studied. Baseline blood pressure and heart rate at rest did not differ, initially or at follow-up, between the groups. At the initial examination, absolute blood pressure levels were significantly higher during isometric handgrip exercise just before exhaustion in subjects with positive family histories. At follow-up the absolute blood pressure level (p < 0.001) and the blood pressure responses (p < 0.01-0.001) were found to be significantly increased during handgrip exercise in subjects with positive family histories compared with subjects with negative family histories. In subjects with positive family histories the diastolic blood pressure response was significantly higher (p < 0.01) at follow-up than initially and was significantly related (r = 0.70, p < 0.01) to changes in baseline diastolic blood pressure during the follow-up period. In subjects with negative family histories the systolic blood pressure response was somewhat lower at follow-up than initially. During the mental stress test, the blood pressure response was significantly greater in subjects with positive than with negative family histories.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of energy-restricted diet on sympathetic muscle nerve activity in obese women.

Twenty obese women aged 45-65 years with borderline hypertension were allocated randomly to either a group with an energy-restricted diet or to a control group. Body weight, blood pressure, urinary sodium, and urinary excretion of norepinephrine and plasma volume were recorded. Resting muscle sympathetic nerve activity was measured in the peroneal nerve by tungsten microelectrodes and expressed as bursts per minute. These measurements were repeated after 3 days of semistarvation and after a body weight reduction of 7% while each patient's weight was in a steady state. After 3 days of semistarvation, only body weight was reduced, whereas after the long-term energy intake restriction, there were reductions of body weight (79.9 +/- 3.4 versus 74.1 +/- 3.4 kg; p less than 0.001), diastolic blood pressure (93 +/- 3 versus 86 +/- 4 mm Hg; p = 0.01), and muscle sympathetic nerve activity (49 +/- 2 versus 42 +/- 3 bursts/min; p less than 0.05). Other variables were unchanged. There were no changes in body weight, blood pressure, or muscle sympathetic nerve activity in the control group. We conclude that body weight decrease in obesity results in a reduction of blood pressure that is at least partially caused by a reduction of sympathetic vasoconstrictor activity.

Increased waist/hip ratio, metabolic disturbances, and family history of hypertension.

To test whether nonhypertensive subjects with a two-generation positive family history of hypertension (PFH) are characterized by disturbed glucose metabolism, 16 men (38 +/- 6 years old) with PFH and 25 subjects matched for age and with negative family histories of hypertension (NFH) were recruited. Blood pressure; serum lipids; erythrocyte transmembrane sodium transport; and the glucose, plasma insulin, and C-peptide responses to an oral glucose tolerance test were investigated. Subjects with PFH had higher blood pressure, body weight, body mass index (BMI), waist/hip ratio (WHR), and abdominal sagittal diameter than subjects with NFH. Baseline blood glucose, plasma insulin, serum lipids, and transmembrane sodium transport did not differ between the two groups. Blood glucose levels at 90 and 120 minutes after oral glucose were significantly higher in subjects with PFH than in controls. Blood glucose adjusted for BMI and WHR at 90 minutes was significantly related to a PFH. Plasma insulin level at 90 minutes during the glucose load was significantly higher in subjects with PFH. In multivariate analysis, WHR was significantly related to baseline blood pressure, insulin, and cholesterol, whereas BMI was significantly associated with the insulin response to the oral glucose tolerance test. Transmembrane sodium transport was significantly related to blood pressure only. In conclusion, subjects with PFH are characterized by increased body weight and BMI, increased visceral fat accumulation, and an altered blood glucose response to an oral glucose load. It was also shown that WHR was related to blood pressure and that BMI was more related to cholesterol and response to glucose loading than a PFH was.

Renal and hemodynamic effects of isradipine in essential hypertension.

Twenty-three men with essential hypertension participated in a double-blind placebo-controlled study with a crossover design to evaluate the long-term (nine weeks) effects of isradipine on central and renal hemodynamics. Isradipine as monotherapy was titrated from 2.5 to 5 and then to 7.5 mg twice daily. At the end of the crossover periods, cardiac output (dye-dilution) and intraarterial blood pressure were assessed. Compared with placebo, isradipine reduced ambulatory blood pressure from 174/104 to 154/91 (p less than 0.001), whereas the heart rate was unchanged. The reduction of blood pressure was entirely due to a reduction (36 percent; p less than 0.001) of the peripheral resistance. The baroreceptor sensitivity did not change (RR intervals during infusion of phenylephrine) but, with isradipine, the setpoint was shifted to lower blood pressure levels. Renal plasma flow (para-amino hippurate clearance) increased (465 versus 391 ml/minute; p less than 0.05), but glomerular filtration rate ([51Cr]ethylenediaminetetraacetic acid clearance) did not change. Hence, the filtration fraction decreased. With isradipine, there was a post-dose increase in natriuresis (0.45 to 0.34 mmol/minute; p = 0.06). Side effects were mild.

Weight reduction versus antihypertensive drug therapy in obese men with high blood pressure: effects upon plasma insulin levels and association with changes in blood pressure and serum lipids.

OBJECTIVES: First, to compare dietary and antihypertensive drug treatment in obese men with mild hypertension with respect to effects upon insulin, glucose, lipid metabolism and blood pressure. Second, to test the hypothesis that in the diet group changes in blood pressure and serum lipid concentration were associated with changes in plasma insulin concentration. DESIGN: A 6-week run-in period followed by random assignment to either diet or drug treatment, lasting for 1 year. Blood pressure measurements were performed blind after 5 and 45 min rest, and during isometric exercise. Plasma insulin and blood glucose concentrations were measured before and after an oral glucose load. SETTING: Outpatient clinic in a city hospital. PATIENTS: Sixty-four men aged 40-69 years with a body mass index > or = 26 kg/m2 and with a diastolic blood pressure of 90-104 mmHg when untreated were recruited (screening after an advertisement in a newspaper). Exclusion criteria were diabetes mellitus, organ damage secondary to hypertension and diseases that may have interfered with compliance and the interpretation of results. Sixty-one patients completed the study. INTERVENTIONS: Dietary treatment was based upon weight reduction and sodium restriction. Drug treatment used a stepped-care approach with atenolol as first choice drug. MAIN OUTCOME MEASURES: Absolute reductions in blood pressure, plasma insulin, blood glucose, serum lipid concentration and the waist:hip circumference ratio. RESULTS: Mean body weight decreased in the diet group and increased in the drug-treatment group. Plasma insulin concentrations, the waist:hip circumference ratio and serum lipid profile improved in the diet group compared with the drug group. Blood pressure control was significantly better in the drug group. In the diet group the changes in mean arterial pressure after 5 min rest and serum triglyceride levels correlated with changes in plasma insulin concentrations independent of changes in body mass index or body weight. CONCLUSIONS: Diet treatment was inferior to drug treatment in controlling hypertension, but superior in lowering plasma insulin concentrations and improving the serum lipid profile. The hypothesis of a relation between changes in blood pressure, serum triglycerides and plasma insulin was supported.

Blood pressure control and haemodynamic adaptation with the dihydropyridine calcium antagonist isradipine: a controlled study in middle-aged hypertensive men.

Twenty-three middle-aged men (59 +/- 2 years) with sustained, essential hypertension (WHO Stage II) and with diastolic blood pressure exceeding 100 mmHg during a run-in placebo month were included in a trial designed to assess the clinical and haemodynamic effects of isradipine, a novel dihydropyridine calcium antagonist. The study was double-blind with a placebo-controlled crossover design. Isradipine as monotherapy was titrated in three, 3-week periods in doses of 2.5, 5 and 7.5 mg twice daily, or as apparently identical placebo capsules. A 3-week placebo wash-out period separated the two phases of the study. Clinical characteristics were followed during each treatment phase and an invasive haemodynamic examination was performed on the last day of the final active or placebo dose. In the haemodynamic investigation, cardiac output was measured using a dye-dilution technique and blood pressure via a catheter in the brachial artery. Plasma renin activity (PRA) was assessed by radio-immunoassay of generated angiotensin I and arterial noradrenaline concentrations using high-performance liquid chromatography (HPLC). Baroreceptor sensitivity was calculated from R-R intervals of the ECG and beat-to-beat systolic blood pressure during increasing bolus injections of phenylephrine. During optimal therapy with isradipine (7.5 mg twice daily), highly significant decreases in supine systolic (from 174 +/- 4 to 154 +/- 3 mmHg) and diastolic blood pressures (from 104 +/- 2 to 91 +/- 1 mmHg) were observed. Heart rate was unchanged (79 +/- 3 versus 81 +/- 2 beats/min) during chronic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of weight reduction versus antihypertensive drug treatment: a comparative, randomized, 1-year study of obese men with mild hypertension.

The aim of the study was to compare cardiovascular effects of weight reduction and sodium restriction with antihypertensive drug treatment in obese middle-aged men with mild hypertension in an open randomized trial lasting for 1 year, preceded by a 6-week run-in period. In the diet group (n = 31), weight decreased by 7.8 kg and salt intake by 2 g/day. In the other group (n = 30), treatment was structured with atenolol as the first line drug. The differences in antihypertensive response were highly significant when measured as casual blood pressure, with drug treatment being favoured. Echocardiographic estimations of left ventricular morphology and function showed no difference in effects between the two treatment modalities. Further analyses showed that the presence of previous antihypertensive treatment was modulating the effect of intervention on left ventricular mass. The response to treatment in plethysmographic estimations of resistance at maximal dilatation in the forearm did not differ between the groups. We conclude that drug treatment was superior to the diet regimen in controlling hypertension, that no differences were observed in effects on cardiovascular structure and that previous antihypertensive treatments seems to be a potent confounding factor that should be taken into consideration in future studies.

Reduced venous compliance in normotensive men with positive family histories of hypertension.

OBJECTIVE: To test the hypothesis of reduced venous compliance and increased cardiovascular responses to volume expansion and alpha-agonist stimulation. METHOD: Non-hypertensive healthy young men with positive (PFH) and negative family histories of hypertension were investigated regarding peripheral haemodynamics and changes in central venous pressure (CVP) and arterial blood pressure in response to graded doses of phenylephrine and acute i.v. fluid volume loading (1000 saline solution in 10 min). The control group was divided into one group matched for body mass index to PFH subjects (NFHO) and one lean control group (NFHN). RESULTS: Supine blood pressure was higher in PFH and NFHO subjects compared with NFHN subjects, whilst CVP was similar in the three groups at baseline. No significant differences in calf or forearm haemodynamics or blood volume were observed between the three groups. Cardiovascular responses to bolus doses of phenylephrine did not differ between the three groups. Saline infusion significantly increased CVP and systolic blood pressure, and effective vascular compliance (change in blood volume: CVP ratio) was reduced in PFH subjects. CONCLUSION: PFH subjects have decreased effective vascular compliance and altered arterial blood pressure responses to acute increases in vascular fluid volume. This may result from multiple factors such as increased venous vascular tone, structural reduction of venous distensibility and/or an altered neurohormonal response to increased CVP.

Adrenaline infusion in man increases muscle sympathetic nerve activity and noradrenaline overflow to plasma.

This study was conducted to determine if muscle sympathetic nerve activity (MSA) and/or the neuronal release of noradrenaline per impulse are modulated by adrenaline in the physiological plasma concentration range. We gave step-wise infusions of adrenaline (0.05-0.6 nmol/kg per min) to 10 healthy young men and measured: intra-arterial blood pressure; heart rate; central venous pressure (CVP); efferent MSA (microneurography in the peroneal nerve); arterial (brachial artery) and femoral venous plasma concentrations of noradrenaline, and the spillover of noradrenaline to arterial and venous plasma (radiotracer infusion). The infusion of adrenaline caused a fall in diastolic blood pressure and tachycardia, and was associated with increases in MSA and noradrenaline spillover. These observations suggest that part of the adrenaline-induced increase in transmitter release is due to enhanced nerve impulse activity, but such a conclusion rests on the absence of diffusion limitations from the site of noradrenaline infusion into the blood stream. After termination of adrenaline infusion the tachycardia and elevated plasma noradrenaline levels persisted, but these changes were probably due mainly to a profound increase in nerve activity. Concurrently, there was a reduction in CVP which may have triggered the increase in efferent sympathetic nerve activity. Infusions of adrenaline did not influence the clearance of noradrenaline from arterial plasma, but the fractional extraction over the leg was moderately reduced, indicating that more arterial noradrenaline is recovered in venous plasma during adrenaline infusion. The present data suggest that the reasons for the adrenaline-induced increase in noradrenaline release are complex, but they are consistent with the hypothesis that stress levels of adrenaline enhance sympathetic nerve activity, and that circulating adrenaline may modulate both haemodynamic and neural responses to stress.

Resting and volume-stimulated circulating atrial natriuretic peptide in young normotensive men with positive family histories of hypertension.

Normotensive young men (36 +/- 5 years old) with positive family histories of hypertension (n = 11) and age-matched controls (n = 21) with negative family histories of hypertension were examined. The control group was divided into one group matched for body mass index with those subjects with positive family histories (n = 10) and one group with normal body mass index (n = 11). Blood pressure, central venous pressure (CVP), plasma atrial natriuretic peptide (ANP) and serum aldosterone were examined at a baseline and during an acute volume load with 1000 ml saline solution. Subjects with positive family histories and controls matched for body mass index had a higher blood pressure at baseline than controls with normal body mass index. CVP and serum aldosterone did not differ between the three groups, while sodium intake and plasma concentrations of ANP were significantly higher in subjects with positive family histories. During volume loading, CVP increased significantly more in subjects with positive family histories as compared with the two control groups. A blunted response to ANP was observed during volume loading in subjects with positive family histories, while subjects in the two control groups demonstrated comparable and significant increases in circulating ANP. Serum aldosterone, however, decreased during volume loading in all three groups, with no difference between the groups. We conclude that normotensive subjects with positive family histories are characterized by increased basal concentrations of ANP and exhibit a blunted response to an acute volume load.(ABSTRACT TRUNCATED AT 250 WORDS)

Calf muscle haemodynamics and the renin-angiotensin-aldosterone system in normotensive subjects with a familial predisposition to hypertension: changes during increased salt intake.

Blood pressure, plethysmographically determined muscle blood flow in the calf at rest and during maximal dilatation, plasma renin activity, angiotensin II and plasma and urinary aldosterone were determined in normotensive men with a positive family history of hypertension (n = 17) and in an age- and weight-matched control group (n = 15) during usual sodium intake and after four weeks of increased salt intake. On normal salt intake resting muscle blood flow was significantly lower and resting resistance and resting vascular tone significantly higher in those with a positive family history, reflecting a stronger smooth muscle contraction of the resistance vessels in the calf at rest. Flow and resistance at maximal dilatation did not differ between the groups, indicating no difference in the structural design of the resistance vessels in the calf. Plasma angiotensin II and urinary aldosterone were not significantly different between the two groups. Plasma renin activity was, however, significantly higher in those with a positive family history which might be interpreted as increased renal sympathetic activity in the genetically predisposed subjects. After four weeks of increased salt intake no significant changes were noted in blood pressure, muscle blood flow and resistance at rest or at maximal dilatation in either of the two groups. Plasma renin activity and angiotensin II decreased significantly in both groups after 10 days of increased salt but tended to return to normal values at the end of the fourth week. Plasma aldosterone and urinary aldosterone excretion were equally and significantly decreased in both groups giving no evidence for an inadequate suppression of aldosterone in subjects genetically predisposed to hypertension.

Haemodynamic and haemorheological effects of hypervolaemic haemodilution in men with primary hypertension.

The haemorheological disturbances observed in primary hypertension arise mainly from haemoconcentration, which leads to an elevation of blood and plasma viscosity and increased aggregation of red blood cells (RBCs). We evaluated the rheological properties of blood and central haemodynamic indices in 13 men with untreated primary hypertension (WHO stage I and II), during a baseline period and after intravenous infusion of 1000 ml of 0.9% NaCl (within 12-15 min). The rheological properties studied were: whole blood viscosity (WBV), plasma viscosity (PV), haematocrit (HCT) and plasma fibrinogen concentration (PF). The central haemodynamic indices were: mean intra-arterial blood pressure (MAP), central venous pressure (CVP), cardiac index (CI), stroke volume index (SVI), total peripheral resistance index (TPRI) and the vascular hindrance index (VHI). Plasma renin activity (PRA) and plasma noradrenaline concentration (P-NA) were also measured. Volume expansion with saline caused haemodilution as expressed by a fall in HCT (P less than 0.001), WBV (P less than 0.001) and PV (P less than 0.01). At the same time, CVP, MAP and VHI increased (P less than 0.05) while PRA decreased (P less than 0.05) and P-NA remained unchanged. Mean values of the cardiac index (CI) and stroke volume index (SVI) did not change significantly. We did not observe any significant relationship between haemodynamic and haemorheological parameters, during baseline or between their respective changes after the infusion. The results indicate that although hypervolaemic haemodilution produced by saline infusion in hypertensive patients may improve blood flow properties (HCT, WBV, PV), blood pressure (BP) is not reduced; rather the converse is true. The reduction in HCT and hence the improved blood rheology, did not affect calculated vascular resistance. Thus, correction of WBV does not acutely normalize BP in primary hypertension.

Central haemodynamics, baroreceptor sensitivity and alpha 1-adrenoceptor-mediated vascular reactivity during weight-stable sodium restriction in obese men with hypertension.

Ten obese men (20-40% overweight) with previously untreated arterial hypertension (WHO stages I and II) were examined before and during sodium-restricted isocaloric diets. The mean (+/- s.d.) daily sodium excretion was reduced from 199 +/- 65 to +/- 25 mmol/24 h. Intra-arterial blood pressure (BP), cardiac output (CO), plasma volume, circulating and urinary noradrenaline (NA), plasma renin activity (PRA) and urinary aldosterone were measured. Vascular reactivity was assessed with intravenous bolus injections of 50, 100 and 200 micrograms phenylephrine, and baroreflex sensitivity was assessed with the R-R interval response to pressure elevations on electrocardiogram. Significant reductions in systolic BP from 163 +/- 18 to 147 +/- 17 mmHg and in diastolic BP from 97 +/- 7 to 88 +/- 9 mmHg occurred during salt restriction. Blood pressure reductions were correlated with changes of urinary sodium excretion (r = 0.71; P less than 0.05). No significant changes in CO, heart rate (HR) or stroke volume (SV) were observed; therefore, BP reduction was secondary to the fall in total peripheral resistance (TPR) from 21.8 +/- 4.1 to 19.0 +/- 4.1 units (P = 0.05). Plasma volume, as well as total blood volume, was not affected by the moderate sodium restriction, but PRA rose from 0.71 +/- 0.1 to 0.87 +/- 0.1 micrograms angiotensin 1/ml per h (P less than 0.05). Urinary aldosterone was increased from 32 +/- 12 to 54 +/- 9 nmol/24 h. No change in venous or arterial concentrations of NA or of urinary NA was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Felodipine. A calcium-inhibiting vasodilator in refractory hypertension.

12 patients with primary hypertension not adequately controlled on combined treatment with diuretics, beta-adrenergic blocking drugs and hydralazine were included in the study. The patients were hospitalised and hydralazine discontinued. The diuretic and beta-blocking medication was given about 1 hour prior to the short term experiments and, following baseline measurements, an oral solution of felodipine (0.075-0.1 mg/kg) was ingested. Cardiac output was measured (dye dilution technique) and continuous monitoring of intra-aortic blood pressure (brachial artery) was performed. In 10 patients, changes in renal plasma flow (para-aminohippuric acid clearance) and glomerular filtration rate (51Cr-EDTA-clearance) were followed over a short period, and in 6 patients repeated after 5 to 7 months. Plasma renin activity (radioimmunoassay of angiotensin I) was followed, as was plasma concentration of felodipine. A significant hypotensive response was seen only 15 minutes after intake of felodipine. The maximal response occurred after 30 minutes when mean arterial blood pressure was reduced by 24% (from 132 to 102 mm Hg). There was a linear relationship between the change in mean arterial blood pressure and log plasma concentration of felodipine. Cardiac output increased from 5.1 +/- 1.5 to 6.6 +/- 2.6 L/min (p less than 0.01), partly because of increased heart rate from 56 +/- 7.9 to 65 +/- 9.5 beats/min (p less than 0.01) and partly due to increased stroke volume from 93 +/- 25 to 103 +/- 34 ml/beat (p less than 0.05). Renal plasma flow increased significantly (p less than 0.05) from 343 +/- 138 ml/min to 391 +/- 154 ml/min and 400 +/- 149 ml/min, while glomerular filtration rate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Felodipine in combination with a beta-blocker and a diuretic in chronic treatment of patients with refractory primary hypertension.

The acute antihypertensive effects of the dihydropyridine calcium antagonist, felodipine, were investigated in 12 male patients aged 43 to 64 years with uncontrolled blood pressure on combined treatment with a thiazide diuretic, a beta-blocker and hydralazine. Central and renal haemodynamics were monitored after acute oral administration (0.075 mg/kg) of felodipine in combination with the beta-blocker and diuretic. Six patients were continued on long term oral felodipine (mean dose 20 +/- 24 mg/day) in combination with the other drugs for 6 to 18 months. Ambulatory blood pressure was measured repeatedly and renal function re-examined once during long term felodipine therapy. In the 6 patients on long term therapy, systolic blood pressure was reduced from 190 +/- 17 to 149 +/- 24 mm Hg and diastolic blood pressure from 116 +/- 12 to 89 +/- 14mm Hg (p less than 0.001). No significant change in heart rate was observed (65 +/- 4 vs 62 +/- 10 beats/min). Renal plasma flow significantly increased from 284 +/- 97 to 425 +/- 131 ml/min/m2 (p less than 0.01) but glomerular filtration rate was unchanged (72 +/- 20 vs 80 +/- 22 ml/min/m2). Hence, the filtration fraction was significantly reduced and normalised in all patients (0.26 +/- 0.04 vs 0.20 +/- 0.03) [p less than 0.05]. Bodyweight was unchanged. It is concluded that felodipine is a highly potent vasodilator with a favourable effect on renal function and is suitable for long term therapy in patients with severe primary hypertension.

Candesartan cilexetil and renal hemodynamics in hypertensive patients.

This randomized, double-blind, placebo-controlled crossover study evaluated the effects of the angiotensin II type 1 (AT1)-receptor blocker candesartan cilexetil on renal blood perfusion and glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg. After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo, candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min(-1) (95% CI, 0.01; 0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, -0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.

Increased systemic and renal vascular sensitivity to angiotensin II in normotensive men with positive family histories of hypertension.

Normotensive young men (mean age 36 years) with positive (PFH) (n = 13) and negative (n = 29) family histories of hypertension were investigated in order to study systemic and renal hemodynamics at baseline conditions and during infusion of low doses (0.1 and 0.5 ng/min/kg) of angiotensin II (AII). The control group with negative family histories of hypertension was subdivided into one group matched for body mass index (n = 15) to subjects with PFH, and one lean control group (n = 14). Baseline blood pressure and sodium intake, measured as urinary excretion, were higher in PFH and in matched controls than in the lean control group. At baseline, renal blood flow (para-aminohippurate clearance) did not differ significantly among the three groups, while glomerular filtration rate (inulin clearance) was higher in PFH than in matched controls. Both doses of angiotensin II infusion increased the blood pressure significantly in PFH. In matched controls a small increase in blood pressure was seen with the highest dose only, while no change in blood pressure was observed in the lean control group. In PFH both doses of AII infusion caused diminished renal blood flow (P less than .01) and increased renal vascular resistance (P less than .001). The two control groups remained unchanged with both AII doses. These results could indicate that normotensive subjects with positive family histories of hypertension are characterized by an increased sensitivity to AII in the systemic and renal circulation as compared with subjects with negative family histories of hypertension.