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)

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.

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.

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)

Abnormalities in the renin-angiotensin-aldosterone system in normotensive subjects with a positive family history of hypertension.

Non-hypertensive men with a positive family history of hypertension in two generations (N = 16) were compared with weight-matched (N = 13) and lean (N = 12) control groups with a negative family history of hypertension with respect to the activity of the renin-angiotensin-aldosterone system at baseline and during an oral glucose tolerance test. Blood pressure was measured phonographically after 30 min of semirecumbent rest and the oral glucose tolerance test was performed after a 10-h overnight fast with 100 g of glucose given orally. Blood samples were drawn from a peripheral catheter at baseline, 30 and 120 min after the glucose challenge. Systolic and diastolic blood pressures did not differ between subjects with a positive or a negative family history of hypertension. At baseline, blood glucose and plasma insulin were similar in the three groups while the group with a positive family history of hypertension had a significantly lower plasma renin activity (PRA) (0.85 +/- 0.09 compared with the weight-matched but not with the lean control group (1.36 +/- 0.13 and 1.06 +/- 0.15 ng AI.ml-1.h-1; p < 0.01 and NS, respectively). The PRA increased significantly after the glucose challenge in all groups (p < 0.01), while the plasma aldosterone concentration decreased after 30 min and then showed an increase at 120 min. The PRA response was less pronounced in the group with a positive family history of hypertension compared with the weight-matched and lean control groups (p < 0.05 and p < 0.01, respectively). Serum potassium did not change significantly in either group after the glucose challenge. Urinary sodium excretion was similar in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced left ventricular distensibility in normotensive men with a positive family history of hypertension.

Left ventricular (LV) morphology and function (echocardiography) were assessed in a population-derived sample of young normotensive men with a positive (PFH, n = 15) or negative (NFH, n = 29) family history of hypertension for at least two generations. Since subjects with PFH were overweight (mean weight, 89 kg), the control group was divided into one group with mild overweight (n = 15) and one lean control group (n = 14). Blood pressure, cardiac output, and calculated total peripheral resistance did not differ between the groups. LV mass was significantly increased (P < .05 to .01) in the two groups, with overweight, compared with the lean control group and in multivariate analysis body mass index (BMI), the primary determinant for LV mass (r = 0.63, P < .001). Neither LV contractility nor LV relaxation time index differed between the groups. Left ventricular distensibility (a/H ratio), which was moderately related to BMI, systolic blood pressure, and the renal vascular sensitivity to angiotensin II (r = 0.34, P < 0.03), was reduced compared with the control groups. This difference persisted after adjusting for BMI and blood pressure. The present study shows that in normotensive subjects with a positive family history of hypertension the increased LV mass was primarily dependent on weight, irrespective of heredity. However, the observed reduction in LV distensibility remained after adjusting for weight, suggesting that diastolic abnormalities may occur before hypertension in subjects likely to later develop the clinical condition.

Low-dose angiotensin II increases glucose disposal rate during euglycemic hyperinsulinemia.

To study the metabolic effects of angiotensin II we examined the glucose disposal rate and calf blood flow in healthy men (n = 39) during euglycemic hyperinsulinemia followed by a period with simultaneous angiotensin II infusion at a low dose (0.1 ng/kg/min). Angiotensin II infusion abruptly increased the glucose disposal rate significantly as compared with glucose disposal rate during euglycemic hyperinsulinemia only. There were no differences in blood glucose or plasma insulin between the euglycemic hyperinsulinemic and the angiotensin II infusion period. During hyperinsulinemia alone, blood pressure was unchanged while calf muscle blood flow increased significantly as compared with the baseline period, while during the angiotensin infusion the systolic blood pressure increased and calf blood flow decreased significantly as compared with the hyperinsulinemic period. We conclude that angiotensin II within physiological range stimulates insulin-mediated glucose uptake in healthy men. The mechanisms are, however, unclear, but changes in blood flow are probably not responsible for the observed effects.

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.

Blunted renal sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension.

The natriuretic and intra-arterial blood pressure response to an acute saline load (1000 mL 0.9% NaCl), was studied in normotensive young men with positive (n = 11) and negative (n = 21) family histories of hypertension. The age-matched (36 +/- 5 years) control group with negative family histories of hypertension was subdivided into two groups, one matched for body mass index (BMI) to the subjects with positive family histories of hypertension (n = 10), and another lean control group (n = 11). Baseline blood pressure was significantly higher in subjects with positive family histories of hypertension and in controls matched for BMI as compared with lean controls. Sodium excretion increased in all three groups during the saline infusion, while subjects with positive family histories of hypertension disclosed a diminished natriuretic response as compared with the two control groups. Systolic blood pressure increased significantly during the saline load in subjects with positive family histories of hypertension, while in subjects with negative family histories of hypertension, no significant change in blood pressure was observed. Plasma renin activity, angiotensin II, serum aldosterone, plasma noradrenaline, blood volume, and ouabain-sensitive erythrocyte sodium efflux rate constant did not differ between the three groups at baseline. A significant negative correlation was found between baseline sodium excretion and sodium efflux rate constant in subjects with positive family histories of hypertension. We conclude that the subjects with positive family histories of hypertension exhibit a blunted natriuretic and an exaggerated blood pressure response to an acute saline load as compared with the two control groups with negative family histories of hypertension. This could be of neuronal and/or hormonal origin.

Insulin sensitivity is more related to fat distribution than to heredity for hypertension in normotensive men.

The insulin-mediated glucose disposal rate was assessed during a euglycemic hyperinsulinemic clamp in 16 normotensive men (mean age, 41 +/- 5 years) with positive family histories of hypertension and mild overweight (PFHO) and in 25 men with negative family histories of hypertension (NFH). The control group was divided into one group with normal body weight ([NFHN] n = 11) and a second group with a similar degree of overweight ([NFHO] n = 14) as in the group with PFHO. Systolic and diastolic blood pressures were significantly greater in subjects with PFHO as compared with the NFHN group. Blood glucose and plasma insulin at baseline and during the insulin clamp did not differ between the three groups. Insulin sensitivity, expressed as the glucose disposal rate per total body weight, was significantly (P < .01) decreased in PFHO subjects (7.7 +/- 3.0 mg/kg/min) and in NFHO subjects (7.1 +/- 3.5 mg/kg/min) as compared with NFHN subjects (11.1 +/- 4.0 mg/kg/min). In multivariate analysis using body mass index, waist to hip ratio, and blood pressure as predictor variables, the waist to hip ratio was significantly related to both baseline plasma insulin (r = .70, P < .0001) and insulin sensitivity (r = -.71, P < .0001). In the present study, insulin sensitivity was related to body weight and fat distribution, whereas no difference was found regarding insulin sensitivity in subjects with or without positive family histories of hypertension.

Cerivastatin gender effect: sub-analyses of results from a multinational, randomised, double-blind study. Cerivastatin Study Group.

We previously reported the results of a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day and cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. Exploratory analysis in this study suggested a gender difference in the 0.4 mg group: mean low-density lipoprotein cholesterol (LDL-C) decreased by 44.4 +/- 8.9% in women, compared with a mean decrease of 37.0 +/- 0.9% in men (p < 0.046). This paper reports the results of further sub-analyses from this study. Overall in the per-protocol (PP) population, 71.5% (n = 73) of women taking cerivastatin 0.4 mg had an LDL-C decrease of > 40%, compared with 38.0% (n = 76) of men taking the same dose. In the cerivastatin 0.2 mg PP population, 34% (n = 17) of women had an LDL-C decrease of > 40%, compared with 19% (n = 18) of men. Mean LDL-C/HDL-C ratio decreased by 43% from baseline to the end of the study in the cerivastatin 0.4 mg PP group: -41.3% in males vs. -48.3% in females. In the cerivastatin 0.2 mg group, the decrease in LDL-C/HDL-C ratio from baseline to endpoint did not markedly differ between genders: -37.0% for males vs. -37.3% for females. Categorial analysis of the LDL-C/HDL-C ratio found that 90% of PP patients taking cerivastatin 0.4 mg, and 84% of PP patients taking cerivastatin 0.2 mg, had a low CHD risk (defined as a LDL-C/HDL-C ratio < or = 3) after 8 weeks of treatment. The 6th and 95th percentiles of the distribution of LDL-C reduction from baseline revealed that 90% of PP patients taking cerivastatin 0.4 mg had an LDL-C reduction of between 22% and 56%. The mean LDL-C reduction for this 90% subset of patients was 40.1%. The same analysis for PP patients taking cerivastatin 0.2 mg found that 90% had an LDL-C reduction of between 13% and 49%. The mean LDL-C reduction in this 90% subset of patients was 31.5%. Of the patients taking cerivastatin 0.4 mg and valid for treatment according to National Cholesterol Education Program (NCEP) criteria, 71% (149/211) achieved NCEP targets for LDL-C at Week 16.

Efficacy and safety of cerivastatin, 0.2 mg and 0.4 mg, in patients with primary hypercholesterolaemia: a multinational, randomised, double-blind study. Cerivastatin Study Group.

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4 mg. This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day with that of cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4 mg (n = 332) or 0.2 mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 +/- 0.7% from baseline in the 0.4 mg group, compared with a decrease of 31.5 +/- 0.9% in the 0.2 mg group (p < 0.0001). There was a significant gender difference in the 0.4 mg group: LDL-C decreased by 44.4 +/- 8.9% in women, compared with a decrease of 37.0 +/- 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 +/- 0.5% from baseline in the 0.4 mg group, compared with a decrease of 21.6 +/- 0.7% in the 0.2 mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4%) patients in the 0.4 mg group and five (3.1%) patients in the 0.2 mg group withdrew owing to adverse events. Cerivastatin 0.2 mg/day and 0.4 mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.

Family history and pathophysiological mechanisms of primary hypertension. Studies in non-hypertensive young men with positive and negative family histories of hypertension.

In an attempt to explore pathophysiological mechanisms relevant for the development for future primary hypertension, we investigated young normotensive men with positive family histories of hypertension (PFH) regarding blood pressure, body weight, systemic and renal haemodynamics as well as cardiovascular hormones and sodium homeostasis. Sixteen subjects with PFH and thirteen controls with negative family histories (NFH), matched for age and body weight were investigated at age 31 and after five years. Blood pressure and heart rate did not differ between the two groups at the first or follow-up examination. At follow-up body weight had increased and a positive correlation between blood pressure and body mass index was found in subjects with PFH, while subjects with NFH had unchanged blood pressure and body weight. Initially, intraerythrocyte sodium content was increased in subjects with PFH, however, at follow-up intraerythrocyte sodium content did not differ between the two groups. At follow-up systemic and renal haemodynamics and sodium homeostasis were investigated in fifteen subjects with PFH and in twenty-nine controls matched for age (36 +/- 5 year) and with NFH. The control group was divided into one group matched for body mass index (n = 15) and one group with normal body mass index (n = 14). Blood pressure and central venous pressure were measured during bolus injections of phenylephrine and during an acute saline/fluid load (1000ml 0.9% NaCl within 10 min). Renal haemodynamics and blood pressure were measured during low doses (0.1 and 0.5 ng/min/kg) continuous infusions of angiotensin II (AII). At baseline blood pressure, body weight and sodium excretion were higher in subjects with PFH and matched controls as compared with lean controls. Calf and forearm haemodynamics (pletysmography), plasma catecholamines, plasma renin activity, angiotensin II, aldosterone, blood volume and erythrocyte sodium efflux rate constant did not differ between the three groups. Circulating atrial natriuretic peptide was higher in subjects with PFH than in the two control groups. In subjects with PFH there was a negative correlation between renal sodium excretion at baseline and the ouabain-sensitive sodium efflux rate constant. During the acute saline/fluid load central venous pressure and systolic blood pressure increased more and venous vascular compliance (ml/mmHg/kg) was reduced in PFH. Atrial natriuretic peptide release and renal sodium excretion were blunted during saline/fluid load in subjects with PFH as compared with the two control groups. Renal blood flow and renal vascular resistance did not differ at baseline. Glomerular filtration rate was somewhat higher in PFH.(ABSTRACT TRUNCATED AT 400 WORDS)

Low-dose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide.

Blood pressure (BP) and metabolic variables were determined initially and after 1, 2, 4, 6 and 10 years' treatment in two groups of hypertensive men (n = 53 each) randomized to bendroflumethiazide 2.5-5 mg/day or propranolol 160-320 mg daily. There was no significant differences in BP or metabolic variables between the two groups at entry. BP was reduced to the same degree by both treatments. Five men in the propranolol group and one man in the thiazide group developed clinically overt diabetes during follow-up. Fasting blood sugar increased slightly but significantly though equally in both groups. Oral glucose tolerance was initially impaired to the same degree in both groups but improved significantly during treatment with both drugs. Fasting insulin increased slightly but to the same degree. While serum potassium decreased significantly in the thiazide group, the total body potassium was unchanged in this group. In the propranolol group, serum potassium rose, while total body potassium decreased significantly. Serum urate increased in both groups, though slightly more during thiazide treatment. One case of gout was found in each group. There was no difference in serum lipids between the two groups. The finding in this long-term trial indicate that in middle-aged men with mild to moderate hypertension a low-dose thiazide diuretic like bendroflumethiazide is as effective and safe an antihypertensive agent as the beta-blocker propranolol is and that it does not induce diabetes. The total clinical picture favors the retention of thiazide diuretics as a first choice drug in hypertension.

Relationship between sodium-lithium countertransport and insulin sensitivity in mild hypertension.

OBJECTIVES: To study the relationship between insulin sensitivity and sodium-lithium countertransport (Na(+)-Li+ CT) in mild, essential hypertension, and to investigate the effect of metformin and metoprolol, respectively. DESIGN: A double-blind, triple cross-over, placebo-controlled study over a total period of 18 weeks. SETTING. A hypertension out-patient clinic and research laboratory at Sahlgrenska University Hospital. SUBJECTS: Seventeen non-obese men with mild essential -hypertension and 17 weight-matched, healthy controls. INTERVENTIONS: Metformin 850 mg b.i.d., metoprolol CR 100 mg once daily and placebo were given during 18 weeks. Each treatment period was 6 weeks. A euglycaemic clamp was performed and erythrocyte Na(+)-Li+ CT measured after each 6-week treatment period. MAIN OUTCOME MEASURES: Insulin sensitivity, erythrocyte Na(+)-Li+ CT, their interrelation, and the effect of metformin and metoprolol CR on both variables, respectively. RESULTS: The hypertensive men tended to have an elevated Na(+)-Li+ CT compared with the control subjects (0.34 +/- 0.03 versus 0.26 +/- 0.02 mmol L-1 h-1, P < 0.1). Glucose disposal rate was similar, but plasma insulin levels higher (P < 0.05) among the hypertensives than the controls. Na(+)-Li+ CT exhibited a positive relationship to BMI (r = 0.53, P = 0.03) and a negative correlation to glucose disposal rate (r = -0.66, P = 0.008) in the hypertensive subjects. In multiple regression analysis, Na(+)-Li+ CT showed a significant correlation to glucose disposal rate only. In the control subjects, there was no relation between glucose metabolism and Na(+)-Li+ CT. Neither metformin nor metoprolol influenced Na(+)-Li+ CT, glucose disposal rate or plasma insulin. CONCLUSION: Erythrocyte Na(+)-Li+ CT seemed to be closely related to insulin-glucose metabolism in mild hypertension, but was not influenced by metformin or metoprolol.