Stroke and coronary heart disease in treated hypertension -- a prospective cohort study over three decades.

OBJECTIVE: To compare cardiovascular mortality and morbidity in middle-aged hypertensive men with initially nonhypertensive men derived from the same random population sample, and to study stroke morbidity in these men in relation to cardiovascular risk factors during 25-28 years of follow-up. DESIGN: Prospective, population-based observational study in men where the main intervention effort was directed towards treatment of hypertension in a special outpatient clinic. SUBJECTS AND METHODS: A total of 754 hypertensive men aged 47-55 years at screening were compared with 6740 men with normal blood pressure. The hypertensive men got stepped care treatment with either beta-blockers, thiazide diuretics, or combination treatment including vasodilating agents during the whole observational period. Data on cause-specific mortality and morbidity, and all cause mortality were obtained from patient files and the national registers on mortality and hospital admissions respectively. MAIN OUTCOME MEASURES: Baseline and change of cardiovascular risk factors during the first 15 years of follow-up and all cause mortality, and mortality and morbidity from stroke and coronary heart disease during 25-28 years. RESULTS: Treated hypertensive men had their blood pressure reduced with 21/15 mmHg during the first 5 years of the study and mean blood pressure levels were then rather constant. A minor reduction of serum cholesterol was also observed and a significant reduction in the prevalence of smoking. Treated hypertensive men suffered a substantial increased incidence of cardiovascular complications that escalated during the latter course of the study. Their total incidence of stroke was doubled; they had 50% more myocardial infarctions (MIs); mortality from coronary heart disease was doubled and all cause mortality was increased by a third, compared with nonhypertensive. In multiple regression analysis the incidence of stroke was significantly related to smoking and diabetes at entry and in time-dependent Cox's regression analysis it was significantly related only to smoking. There was no relationship observed between achieved systolic or diastolic blood pressure and the risk of stroke or MI nor was there any relationship between the change in blood pressure and such cardiovascular complications. CONCLUSION: In spite of a substantial reduction of their blood pressure, treated hypertensive middle-aged men had a highly increased risk of stroke, MI and mortality from coronary heart disease compared with nonhypertensive men of similar age. The increased risk of cardiovascular complications escalated during the latter course of the study.

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.

Candesartan Cilexetil, 16 mg, Provides a Greater Antihypertensive Effect than Losartan, 50 mg, in Patients with Mild to Moderate Hypertension.

Candesartan is a new angiotensin II type 1 (AT 1 ) receptor blocker, which binds tightly to and dissociates slowly from the AT 1 -receptor. These binding characteristics underpin the long duration of action and antihypertensive efficacy of candesartan, and help to differentiate it from losartan, which was the first AT 1 -receptor blocker to be approved for the treatment of hypertension. This study compared the antihypertensive effect and tolerability of candesartan cilexetil, 8 or 16 mg once daily, with that of placebo and of losartan, 50 mg once daily, in patients with mild to moderate primary hypertension. The dose of 50 mg for losartan was chosen, as this is the dose usually recommended; higher doses do not seem to result in further reductions in blood pressure. Men and women, aged 20-80 years, with primary hypertension and a sitting diastolic blood pressure (DBP) of 95-114 mmHg at the end of a 4-week placebo run-in period, were randomized to once-daily, double-blind treatment with candesartan cilexetil, 8 mg ( n = 82), candesartan cilexetil, 16 mg ( n = 86), losartan, 50 mg ( n = 84), or placebo ( n = 85) for 8 weeks. Blood pressure was measured 6 and 24 h after dosing, i.e. at the times of peak and trough effects, respectively. Differences among treatments in changes in blood pressure from randomization to the end of the study were assessed by analysis of variance. Patients were defined as having responded to treatment if sitting DBP was 90 mmHg or below at week 8 or if sitting DBP had been reduced by more than 10 mmHg from baseline to week 8. The proportion of responders in each treatment group was 15% for placebo, 46% for losartan, 50 mg, 50% for candesartan cilexetil, 8 mg, and 57% for candesartan cilexetil, 16 mg. The reduction in sitting DBP at trough (the primary effect variable) was significantly greater in patients treated with candesartan cilexetil, 16 mg, than in patients treated with losartan, 50 mg (see Table). In addition, both doses of candesartan cilexetil had a trough-to-peak ratio of approximately 1.0, compared with 0.7 for losartan. Both candesartan cilexetil and losartan were well tolerated, with the incidence of adverse events similar to placebo in both treatment groups. Overall, the most common new-onset adverse events reported were headache and respiratory infection, both of which are common in this type of patient population. In conclusion, candesartan cilexetil, 8 or 16 mg once daily, is an effective and well-tolerated antihypertensive treatment, with a trough-to-peak ratio close to 1.0. Candesartan cilexetil, 16 mg once daily, produces a significantly greater reduction in blood pressure than losartan, 50 mg once daily.

Improved efficacy with maintained tolerability in the treatment of primary hypertension. Comparison between the felodipine-metoprolol combination tablet and monotherapy with enalapril. Swedish Multicentre Group.

In this multicentre, double-blind, parallel-group study, 120 out-patients with mild to moderate primary hypertension were randomised, after a 4-week single-blind placebo run-in period, to a combination tablet of felodipine-metoprolol 5/50 mg (Logimax, Mobloc, Astra) once daily or enalapril 10 mg once daily. If blood pressure (BP) remained suboptimally controlled after 4 weeks (supine diastolic BP >90 mm Hg 24-h post dose), the dose was doubled for a further 4 weeks. After 8 weeks felodipine-metoprolol reduced supine BP significantly more than enalapril (19.7/12.0 mmHg and 11.1/7.2 mm Hg, respectively). The mean differences in change in BP between treatments were 8.6/4.8 mm Hg in favour of felodipine-metoprolol (P = 0.001/P <0.001). A statistically significant difference to the advantage of felodipine-metoprolol was also seen in standing BP. Even though the dose was increased in a larger proportion of patients in the enalapril group (61%) than in the felodipine-metoprolol group (40%), fewer enalapril-treated patients achieved adequate BP control (41% vs 63% on felodipine-metoprolol, P <0.05). Both treatments were well tolerated. Three patients treated with felodipine-metoprolol and four with enalapril discontinued treatment due to adverse events. A similar number of patients reported adverse events in each treatment group. In conclusion, a combination tablet of felodipine-metoprolol 5/50-10/100 mg once daily reduced BP more effectively than enalapril 10-20 mg once daily 24 h post dose. The result was expected, but a more important observation was that both treatments were tolerated to a similar degree. Obviously, a considerable BP reduction may be well tolerated, as was the main purpose to demonstrate in this study.

Candesartan cilexetil in hypertension: effects of six weeks' treatment on haemodynamics, baroreceptor sensitivity and the renin-angiotensin-aldosterone system.

The effects of the angiotensin II receptor blocker candesartan cilexetil on systemic and forearm haemodynamics and baroreceptor sensitivity were evaluated in this randomized, placebo-controlled, double-blind, crossover study. After a 4-week placebo run-in period, 22 patients with essential hypertension (diastolic blood pressure 100-114 mmHg) were randomized to receive either candesartan cilexetil 16 mg or placebo once daily for 6 weeks. At the end of each period, 24 h after the last dose, invasive haemodynamic assessments were performed. Simultaneously, the plasma renin activity and plasma concentrations of angiotensin II, aldosterone and catecholamines were measured. Compared to placebo, candesartan cilexetil significantly reduced mean arterial pressure by 8 mmHg (95% CI: 2.6; 12.3), while cardiac output, stroke volume and heart rate were unchanged. Forearm vascular resistance was reduced by 1 mmHg x ml(-1) x L x min (CI: 0.3; 2.3). The baroreceptor sensitivity was not influenced, but a change in the set-point was noted. Plasma renin activity and angiotensin II concentrations were increased, while the aldosterone concentration was significantly reduced. Plasma catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with candesartan cilexetil 16 mg o.d. induced systemic and forearm vasodilatation and a reduction in blood pressure without compromising cardiac performance. The plasma concentration of aldosterone was reduced.

Acute effects of candesartan cilexetil (the new angiotensin II antagonist) on systemic and renal haemodynamics in hypertensive patients.

OBJECTIVES: This study was performed to assess the acute effects of the new angiotensin II antagonist, candesartan cilexetil, on systemic and renal haemodynamics in patients with sustained essential hypertension [diastolic blood pressure (DBP) 95-114 mmHg]. METHODS: After 4 weeks of placebo treatment, systemic and renal haemodynamics were investigated in 17 patients with a mean age of 62 years and a mean systolic and diastolic blood pressure of 170/98 mmHg, just before (baseline) and for 4 h after administration of a single oral dose of candesartan cilexetil, 16 mg. Plasma concentrations of candesartan (the active compound formed from the pro-drug candesartan cilexetil), angiotensin II (Ang II), as well as plasma renin activity (PRA), were measured before and after dosing. RESULTS: At 2, 3 h and 4 h after dosing with candesartan cilexetil, systolic blood pressure (SBP) and DBP, as well as mean arterial pressure (MAP), were significantly lower than at baseline. The mean reduction in MAP 4 h after dosing was 8.8 mmHg (-6.5%). This effect was due to a fall in total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and cardiac output (CO) were virtually unchanged. After 4 h there was a marked reduction in renal vascular resistance (RVR) of 0.0273 mmHg x ml(-1) x min (-16%), resulting in an increased renal plasma flow of 64.9 ml x min(-1) (14%). The glomerular filtration rate was increased by 7.75 ml x min(-1) (8%), and the filtration fraction (FF) was not significantly changed. There was no apparent relationship between the changes observed in systemic and renal haemodynamic variables and plasma concentrations of candesartan. Plasma renin activity increased over the study period, but in general the patients had low PRA. Changes in plasma concentrations of angiotensin II were inconsistent between patients. CONCLUSION: A single oral tablet of candesartan cilexetil, 16 mg, induced systemic and renal arterial vasodilatation and blood pressure reduction, without compromising renal perfusion or filtration or affecting cardiac performance. Plasma renin activity which was low in general, increased over the study period, but changes in plasma concentrations of angiotensin II were inconsistent.

Tolerability of a modern antihypertensive agent: candesartan cilexetil.

Tolerability and not efficacy is the limiting factor for long-term successful antihypertensive treatment. Since the discontinuation rate of first line antihypertensives may be as high as 50-60% over six months, it is important to develop new agents with an improved efficacy/tolerability ratio. Candesartan cilexetil is particularly promising in this respect. Candesartan is a potent and selective angiotensin II type 1 (AT1) receptor blocker that binds selectively and tightly (insumontable binding) to the receptor. Candesartan is not associated with any increased risk of cough or angiodema. It is an orally effective vasodilator that does not cause reflex tachycardia or first dose hypotension or orthostatic hypotension. In the dose range from 4-16 mg, once daily candesartan cilexetil is not associated with any dose-dependent adverse events and it is equally well tolerated in men and women and by older (> 65 years) and younger (< 65 years) patients. Furthermore, the drug has no adverse effect on glucose homeostasis or plasma lipid profile. In a double-blind comparison with losartan 50 mg od, candesartan cilexetil 16 mg once daily was significantly more effective in lowering the diastolic blood pressure at the end of the 24 h dose interval but was equally well tolerated. In meta-analyses of clinical trials, candesartan cilexetil showed a tolerability profile comparable to that of placebo therapy.

Does treated primary hypertension lead to end-stage renal disease? A 20-year follow-up of the Primary Prevention Study in Göteborg, Sweden.

BACKGROUND: Hypertension is reported to be one of the most common causes of end-stage renal disease (ESRD) in Europe and in the United States. However, the frequency with which treated primary hypertension leads to renal failure is not known. The majority of patients with ESRD have hypertension. Whether this is the cause or the consequence of the impaired renal function is often not possible to establish. METHODS: To determine if treated primary hypertension can lead to ESRD, we studied the development of serum creatinine levels in 686 white hypertensive men, recruited from a random third of the male population aged 47-55 years living in Göteborg, Sweden (n=9998; 7495 participants). At entry and during 20 years follow-up, all signs of kidney disease, secondary hypertension, or increase in blood pressure were investigated. Records of patients with a serum creatinine value > or = 130 micromol/l at any time during the observation period were thoroughly studied to ascertain the cause of the impaired renal function. RESULTS: A serum creatinine level above 130 micromol was seen in 8.9% (61/686) of the treated hypertensives during the 20 years of follow-up. An underlying renal disorder was found in 7.2% (49/686) of the patients; renoparenchymal disease (2.2%), renovascular disease (1.5%), diabetic nephropathy (1.2%) or a urological disease (1.6%). Only 1.7% (12/686) of the hypertensives showed a moderate progressive increase in serum creatinine of unknown cause. The serum creatinine in this group was 133+/-8 micromol/l (mean+/-SD; range 124-144) after 15 years and 139+/-7 micromol/l (range 132-151) after 20 years. Thus, none of these patients aged 66-71 years had developed ESRD or a clinically important reduction in renal function. CONCLUSION: The main finding in this population-based study of white middle-aged men with primary nonmalignant hypertension was that long-term antihypertensive treatment was not associated with development of end-stage renal disease or even an abnormal progressive decline in kidney function.

Cost-effectiveness of felodipine-metoprolol (Logimax) and enalapril in the treatment of hypertension.

We present results from a Swedish retrospective cost-effectiveness analysis of felodipine-metoprolol (Logimax) and enalapril in hypertension. In the 8-week trial, the average reduction of diastolic blood pressure (DBP) and the share of patients reaching target DBP were both significantly greater in the felodipine-metoprolol group. Cost of treatment (costs of drugs and physician visits) was somewhat higher in the felodipine-metoprolol group. After 8 weeks, an extra 4.8 mmHg reduction and an additional 22% of patients reaching target DBP were achieved with felodipine-metoprolol at the extra cost of SEK 19 (Swedish kronor, $US I=SEK 7.90). The incremental cost per mmHg reduction and per patient reaching target DBP was calculated at SEK 4 and SEK 86, respectively. Average cost-effectiveness ratios showed that the costs per mmHg reduction and per patient reaching target DBP after 8 weeks were 40 and 34% lower in the felodipine-metoprolol group, respectively. In conclusion, felodipine-metoprolol is cost-effective in the treatment of hypertension.

Survival in treated hypertension: follow up study after two decades.

OBJECTIVE: To compare survival and cause specific mortality in hypertensive men with non-hypertensive men derived from the same random population, and to study mortality and morbidity from cardiovascular diseases in the hypertensive men in relation to effects on cardiovascular risk factors during 22-23 years of follow up. DESIGN: Prospective, population based observational study. SUBJECTS AND METHODS: 686 hypertensive men aged 47-55 at screening compared with 6810 non-hypertensive men. The hypertensive men were having stepped care treatment with either beta adrenergic blocking drugs, thiazide diuretics, or combination treatment. Mortality, morbidity, and adverse effects were registered at yearly examinations and from death certificates. MAIN OUTCOME MEASURES: All cause mortality and cause specific mortality. RESULTS: Treated hypertensive men had significantly impaired probability of total survival as well as survival from coronary heart disease and stroke. All cause mortality as well as coronary heart disease and stroke mortality were very similar in hypertensive men and normotensive men during the first decade, but increased steadily thereafter despite continuous good blood pressure control. Smoking, signs of target organ damage, and high serum cholesterol levels, but not blood pressure at screening, were significantly related to the incidence of coronary heart disease during follow up. In time dependent Cox's regression analysis, the incidence of coronary heart disease was significantly related only to serum cholesterol concentrations in the study. Cancer mortality was almost similar in treated hypertensive men (61/686, 8.9%) and non-hypertensive men (732/6810, 10.8%). CONCLUSION: Treated hypertensive men had impaired survival and increased mortality from cardiovascular disease compared with non-hypertensive men of similar age. These differences were observed during the second decade of follow up. During an observation period of 22-23 years-about 15 000 patient years-hypertensive men receiving diuretics and beta blockers had no increased risk of cancer or non-cardiovascular disease.

Minimal influence of blood flow on interstitial glucose and lactate-normal and insulin-resistant muscle.

To study the regulation of the interstitial glucose concentration in skeletal muscle, nine control subjects and nine older and overweight non-insulin-dependent diabetes mellitus (NIDDM) subjects with extreme insulin resistance were investigated with microdialysis in the medial femoral muscle before and during a euglycemic insulin clamp. After an overnight fast, arterial plasma glucose concentration was 4.9 +/- 0.1 and 8.5 +/- 0.6 mmol/l (P < 0.001), respectively. The arterial-interstitial concentration ([a-i]) differences of glucose and lactate were 0.43 +/- 0.16 (P < 0.05) and -0.13 +/- 0.05 mmol/l, respectively, in normal subjects. In NIDDM subjects, [a-i] differences for glucose and lactate were nonsignificant. Muscle blood flow was similar in controls and NIDDM subjects. During the glucose clamp, the glucose [a-i] differences increased and the lactate [a-i] differences decreased significantly in both groups. The glucose 170 infusion rate was 8.0 +/- 0.77 vs. 3.2 +/- 0.51 mg.kg-1.min-1 (P < 0.001), and blood flow was 9.9 +/- 1.6 vs. 6.7 +/- 0.9 ml.100 g-1.min-1 (P < 0.05) in controls and NIDDM subjects, respectively. These results show that 1) the capillary wall is rate limiting for muscle glucose uptake and lactate release in control subjects but not in postabsorptive hyperglycemic insulin-resistant subjects, 2) vasodilation during insulin infusion does not prevent the increase in [a-i] difference of glucose in normal subjects, and 3) in severely insulin-resistant muscle, the [a-i] difference of glucose is not extended despite lack of vasodilation.

The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan.

This multicentre study compared the antihypertensive effect and tolerability of the novel angiotensin II antagonist candesartan cilexetil with those of losartan and placebo. Men and women aged 20-80 years, with primary hypertension and sitting diastolic blood pressure (DBP) 95-114 mm Hg after a 4-week placebo run-in period, were randomized to once daily double-blind treatment with candesartan cilexetil 8 mg (n=82), candesartan cilexetil 16 mg (n=84), losartan 50 mg (n=83) or placebo (n=85) for 8 weeks. Blood pressure was measured 6 and 24 h after dose, i.e. at peak and trough. Differences between treatments were analysed by analysis of covariance, and the primary effect variable was reduction in trough sitting DBP. Compared with placebo treatment, trough DBP was significantly reduced by a mean (95% CI) of 8.9 (6.0; 11.8) mm Hg with 8 mg and 10.3 (7.4; 13.2) mm Hg with 16 mg candesartan cilexetil. The 8 mg dose was as effective as losartan 50 mg, while 16 mg candesartan cilexetil was significantly more effective, with a difference between treatments of 3.7 (0.8; 6.7) mm Hg (p=0.013). The placebo corrected trough/peak ratio was 0.9-1.1 with candesartan cilexetil and 0.7 with losartan. Candesartan cilexetil was similarly well tolerated as placebo. In conclusion, candesartan cilexetil 8 mg or 16 mg once daily is an effective and well tolerated antihypertensive treatment. Candesartan cilexetil 16 mg is significantly more effective than losartan 50 mg once daily.

Vasoconstriction during acute hypervolemic hemodilution in hypertensive patients is not prevented by calcium blockade.

The reduction of blood viscosity by moderate acute hypervolemic hemodilution in untreated hypertensives can be associated with a secondary vasoconstriction. The aim of this study was to examine whether a vasodilating therapy prevents this hemodynamic reaction. Twelve hypertensive patients (WHO stage II) were treated with the vasoselective calcium channel blocker isradipine in a placebo-controlled, double-blind, crossover study. Acute hypervolemic hemodilution was performed twice: at the end of the placebo period and after two months of treatment. Hemodilution was achieved by the intravenous infusion of 1000 mL saline over a 10- to 15-minute period. Arterial blood pressure, heart rate, cardiac output (dye dilution), renal blood flow, glomerular filtration, natriuresis, hematocrit, whole blood, and plasma viscosity were assessed before and after infusion. Flow resistance and vascular hindrance in the central and renal circulation were calculated. Acute hemodilution associated with a significant reduction of blood (P<0.01) and plasma (P<0.01) viscosity did not influence the mean arterial pressure and cardiac output. Consequently, the total flow resistance remained unchanged. However, as a result of hemodilution, the calculated vascular hindrance index in the systemic circulation increased, indicating a vasoconstrictive reaction, both with placebo (from 5.22 to 6.07 U x mPa(-1) x s(-1), P < 0.05) and during chronic treatment with calcium blockade (from 3.75 to 4.22 U x mPa(-1) x s(-1), P<0.02). Vasoconstriction was not observed in the renal circulation, either during the placebo or active treatments. The results of this study indicate that the systemic vasoconstriction evoked by the acute moderate hypervolemic hemodilution in hypertensive patients was not prevented by a calcium channel blockade.

Measurement of interstitial muscle glucose and lactate concentrations during an oral glucose tolerance test.

To study the relationship between blood flow rate and muscle metabolism, muscle microdialysis was performed in nine human subjects (5 females and 4 males) after an oral glucose load (75 g). Two microdialysis probes were inserted into the medial femoral muscle for estimation of glucose and lactate concentrations in the interstitial fluid, and the muscle blood flow was measured concomitantly with strain-gauge plethysmography. After subjects fasted overnight, their glucose concentration in arterial plasma and interstitial fluid was 4.6 +/- 0.13 vs. 3.8 +/- 0.23 mmol/l (P < 0.05), and the corresponding lactate concentrations were 0.60 +/- 0.07 vs. 0.83 +/- 0.07 mmol/l (P < 0.05). Muscle blood flow was 5.2 +/- 0.7 and 7.5 +/- 1.4 ml.100 g-1.min-1 (P < 0.05) at 0 and 90 min after oral glucose, respectively. The arterial-interstitial concentration differences of glucose increased after oral glucose [at 0 min 0.73 +/- 0.24 vs. 2.19 +/- 0.60 mmol/l at 90 min (P < 0.001)]. The corresponding values for lactate were -0.23 +/- 0.10 at 0 min vs.-0.26 +/- 0.18 mmol/l at 90 min (not significant). The data show that 1) the capillary wall is partly rate limiting for glucose uptake, and 2) after oral glucose, the glucose concentration gradient over the capillary wall increases despite a limited increase in blood flow rate, which then mediates approximately 10-20% of total enhancement of glucose uptake in muscle.

Hemorheologic effects of vasodilation in essential hypertension.

Arterial hypertension is often associated with plasma volume contraction and hemoconcentration, which negatively affect the vascular flow resistance and microcirculation. Since some antihypertensive drugs can affect blood rheology, the purpose of this study was to evaluate whether acute and long-term arterial vasodilation with cadralazine influences rheologic parameters in essential hypertension. Twelve patients with unsatisfactorily controlled essential hypertension were studied. In the acute double-blind phase of the study the patients were allocated to treatment with either cadralazine or placebo. Intraarterial blood pressure, cardiac output (dye dilution), and blood rheology (viscosity, hematocrit) were registered before and after the first dose of cadralazine. Then 9 patients (3 dropouts) were treated with cadralazine and placebo during two four-week crossover periods and continued with cadralazine medication during the eight-week open phase of the study. Blood pressure and blood hemoglobin were followed during long-term treatment. A single oral dose of cadralazine caused vasodilation (total peripheral resistance index decreased from 45 to 33 U x m2, P < 0.05), which was accompanied by hemodilution (hematocrit declined from 46.9% to 42.5%, P < 0.05) and a blood viscosity reduction of more than 10%. Viscosity of 45% suspension of erythrocytes in plasma was also reduced, suggesting a possible modification of the microrheologic factors. The changes in total peripheral resistance correlated negatively with the changes in hematocrit. An antihypertensive effect of cadralazine was still observed during the chronic phase of the study, which was not accompanied by hemodilution. It is concluded that arterial vasodilation with cadralazine reduces flow resistance in the circulatory system in hypertension and has acute rheologic effects that disappear during chronic medication.

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.

A felodipine-metoprolol extended-release tablet: its properties and clinical development.

The current failure of antihypertensive therapy to control BP in many hypertensive patients highlights the need for new treatment strategies. Ideally, these new strategies should provide reliable, effective 24 h BP control in all types of patients with a convenient, well-tolerated regimen. Logimax, an extended-release tablet containing felodipine and metoprolol, has been developed, which provides more effective control of BP in a wider range of patients than either component as monotherapy, without compromising tolerability. This combination increases the likelihood of achieving target BP and is therefore likely to provide further reductions in cardiovascular risk.

Body weight and fat cell size in young men with mild blood pressure elevation.

The aim of the study was to assess the relationship between body fat distribution and blood pressure. Forty-four men, aged 19-22 years, with mild blood pressure elevation (MBPE) and 29 normotensive controls (NC) were investigated. Body fat distribution was assessed by calculating fat cell size in biopsy samples of adipose tissue from different subcutaneous depots. The subjects in MBPE group were heavier than those in NC group (79.7 +/- 2.7 and 71.5 +/- 1.6 kg, p < 0.05). Total body fat was also significantly higher in the MBPE group (12.5 +/- 1.6 and 8.1 +/- 1.3 kg, p < 0.05) but not the lean body cell mass (36.8 +/- 1.1 and 34.7 +/- 0.9 kg, n.s.). Fat cell size (microgram/cell) in the lower abdominal area were significantly bigger in MBPE than in NC (respectively 40.9 +/- 4.4 and 28.0 +/- 3.1, p < 0.05). The same differences applied for fat cell size in the upper abdominal (respectively 43.1 +/- 3.0 and 26.8 +/- 3.0, p < 0.001) and averaged abdominal areas (respectively 40.1 +/- 3.4 and 26.8 +/- 2.8; p < 0.05). Fat cell size in gluteal, femoral and averaged gluteofemoral areas did not differ between MBPE and NC. Therefore, the abdominal/gluteofemoral ratio was significantly higher in MBPE than in NC (respectively 1.1 +/- 0.1 and 0.7 +/- 0.1; p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)