Pharmacodynamic effects of the oral glucokinase activator AZD6370 after single doses in healthy volunteers assessed with euglycaemic clamp.

AIMS: This study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamic effects of the glucokinase activator (GKA) AZD6370 in non-diabetic subjects, using the euglycaemic clamp to avoid the risk of hypoglycaemia. METHODS: Oral single ascending doses of AZD6370 10-650 mg or subcutaneous short-acting insulin 4 or 12 U were given to healthy fasting subjects. AZD6370 safety, tolerability and pharmacokinetics were assessed. Pharmacodynamic effects on serum (S)-insulin and glucose infusion rate (GIR) were investigated with euglycaemic clamp. AZD6370 10-20 mg was also assessed when taken with food without euglycaemic clamp. RESULTS: AZD6370 was well tolerated and no safety concerns were raised. AZD6370 was rapidly absorbed and eliminated, and plasma concentration was proportional to dose. Both S-insulin and GIR increased following AZD6370 administration. The observed increase in GIR correlated with increasing AZD6370 area under the plasma concentration vs. time curve, demonstrating a dose-concentration-dependent pharmacodynamic effect. AZD6370 at doses of 50 and 80 mg had similar effects to short-acting insulin 4 U on peripheral S-insulin levels but greater effects on GIR, suggesting an effect beyond the increase of peripheral S-insulin levels at lower doses. In the food interaction part of the study, performed without euglycaemic clamp, dose escalation was stopped at a low dose (20 mg) because of hypoglycaemia. CONCLUSION: The euglycaemic clamp was successfully used to avoid hypoglycaemia and to demonstrate pharmacodynamic effects, that is, markedly increased insulin secretion and glucose utilisation, following administration of AZD6370 in healthy fasting subjects. In addition to the effect on pancreatic insulin secretion, the data support an extra-pancreatic (hepatic) component of GKA action.

Serum homocysteine concentration as an indicator of survival in patients with acute coronary syndromes.

BACKGROUND: Circulating homocysteine levels are predictive of survival in patients with stable coronary artery disease. The prognostic value of serum homocysteine levels, obtained in the acute phase in patients with myocardial infarction or unstable angina, is unknown. OBJECTIVES: To test the hypothesis that circulating homocysteine levels, obtained during the first 24 hours following hospital admission in patients with acute coronary syndromes, are predictive of long-term mortality. METHODS: To test this hypothesis we performed a prospective inception cohort study at a teaching hospital in Gothenburg, Sweden. A total of 579 patients (179 women and 400 men; median age, 67 years) were included (Q-wave myocardial infarction in 163 patients, non-Q-wave myocardial infarction in 210 patients, unstable angina pectoris in 206 patients). MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: During a median follow-up of 628 days, 65 patients died. The serum homocysteine level (mean [SD]) was significantly lower in long-term survivors (n = 514) than in nonsurvivors (n=65) (12.3 [7.0] vs 14.3 [5.9] pmol/L; P=.003). The relative risk (all-cause mortality) for patients with homocysteine levels in the upper quartile was 2.4 (95% confidence interval, 1.5-4.0) compared with that of patients in the 3 lower quartiles. After adjustment for relevant confounders, the relative risk estimate remained significant (relative risk= 1.69; 95% confidence interval, 1.02-2.80). In a stepwise model the homocysteine level provided prognostic information additional to that of patient age, diabetes mellitus, and diuretic usage prior to hospital admission (P=.03). CONCLUSION: The serum homocysteine level on hospital admission is an independent predictor of long-term survival in patients with acute coronary syndromes.

Physical activity, dyspnea, and chest pain before and after coronary artery bypass grafting in relation to a history of diabetes.

OBJECTIVE: To describe the limitation of physical activity and symptoms of chest pain and dyspnea before and after coronary artery bypass grafting (CABG) in relation to a history of diabetes. RESEARCH DESIGN AND METHODS: All patients in western Sweden in whom CABG was performed between 1988 and 1991 were asked to complete a questionnaire before 3 months and 2 years after the operation. The questionnaire evaluated limitation of physical activity and symptoms of chest pain and dyspnea. RESULTS: In all, 2,121 patients participated in the evaluation, of whom 13% had a history of diabetes. The overall 2-year mortality was 14% among patients with a history of diabetes and 6% among patients without such a history (P < 0.001). The proportion of patients with a limitation of physical activity caused by chest pain decreased from 76% before CABG to 19% 2 years after in diabetic patients (P < 0.001) and from 79 to 17% in nondiabetic patients (P < 0.001). The proportion of diabetic patients without dyspnea increased from 13% before to 31% 2 years after CABG (P < 0.001). The corresponding figures for nondiabetic patients were 12 and 43% (P < 0.001). Symptoms of angina pectoris were reported in 94% of diabetic patients before CABG versus 35% after 2 years (P < 0.001). Corresponding figures for nondiabetic patients were 93 and 29% (P < 0.001). Aggregate data confirmed differences between diabetic and nondiabetic patients, with more symptoms in the diabetic patients, particularly with regard to dyspnea. CONCLUSIONS: Mortality during 2 years of follow up was more than twice as high in diabetic than in nondiabetic patients. Limitation of physical activity, dyspnea, and angina pectoris improved markedly and similarly in diabetic and nondiabetic patients after CABG. Whereas limitation of physical activity and dyspnea was more frequent in diabetic than in nondiabetic patients, the occurrence of angina pectoris was more similar in the two groups.

Type of obesity and blood pressure.

To explore the relationship between blood pressure on the one hand and body composition variables and fat cell size and number on the other, these factors were determined in a population sample (n = 120) of 49-year-old men with blood pressure (BP) ranging from very low to very high. BP increased linearly with body weight throughout the entire BP range, while body fat and fat cell size increased with increasing BP in the nonhypertensive but not in the hypertensive BP range. Body cell mass and fat cell number were unrelated to BP. Fat cell size (but not fat cell number) was positively correlated with most variables of glucose metabolism. It can be concluded that in normal men: the previously well-established relationship between body weight and BP is explained by an association between body fat and BP; BP is positively correlated with increased fat cell size, indicating hypertrophic obesity, while BP is unrelated to fat cell number; and increased fat cell size is associated with impaired glucose tolerance and hyperinsulinemia. The results point to the possibility that hypertrophic obesity and essential hypertension may be related to each other via common pathogenetic mechanisms.

Effects of subpressor doses of angiotensin II on renal hemodynamics in relation to blood pressure.

The renal hemodynamic response to subpressor doses of angiotensin II (AII; 0.1 and 0.5 ng/min/kg) was investigated in untreated 49-year-old men (n = 50) representing a wide blood pressure range. Renal blood flow, renal vascular resistance (RVR), glomerular filtration rate (GFR), filtration fraction (FF), plasma renin activity (PRA), plasma AII, plasma aldosterone, and the urinary excretion of sodium and norepinephrine were studied. The higher the initial blood pressure the greater was the increase in RVR in response to AII infusion (p less than 0.002), indicating an increased renal vascular reactivity with increase in initial blood pressure. The AII infusion gave a significant rise in RVR in both the borderline and hypertensive group, but gave no increase in RVR in the normotensive group, implying an enhanced sensitivity of the renal vasculature in the borderline and hypertensive group. The increase in RVR was greater in the hypertensive than in the borderline group, i.e., the hypertensives had a steeper dose-response curve than the borderline group, which points to the presence of structural vascular changes in the renal vessels in the hypertensives. The increase in RVR in response to AII was positively correlated to sodium intake and plasma aldosterone concentration, indicating that these two factors might modulate the renal vascular reactivity. These factors could, however, only partly explain that RVR increased more the higher the initial blood pressure. Thus, the results indicate that there is an increased reactivity of the renal vascular bed to AII in essential hypertension. The increased reactivity seems to be mediated through an increased sensitivity of the renal vasculature to AII in mild essential hypertension and also through the presence of structural vascular changes in established hypertension. These factors may lead to a reduced excretion of sodium and water and may therefore be of importance in the development and progression of essential hypertension.

Left ventricular wall stress and systolic function in untreated primary hypertension.

A noninvasive investigation was undertaken in four blood pressure (BP) groups of untreated 49-year-old men derived by screening a random population sample: normotensive men (n = 20) and subjects with borderline (n = 30), mild (n = 45), or moderate BP elevation (n = 24). We here report the findings regarding left ventricular (LV) wall stress, LV wall thickness, and LV systolic function. Although there was an increase in LV wall thickness with hypertension, the raised BP was not compensated for by a sufficient degree of LV wall thickening to keep wall stress within normal limits in the hypertensive groups. Among a subset of individuals with pronounced increase in wall thickness peak systolic wall stress approached the normal range, but end-systolic wall stress was still high. In spite of high wall stress LV systolic function was normal or supranormal in the hypertensive men. The LV ejection phase indices showed a close inverse correlation with end-systolic wall stress (r = -0.67 to -0.84) in all four BP groups, but no correlation or only a weak correlation with peak systolic wall stress (r = 0.18 to -0.40). As judged from the relationship between end-systolic wall stress and ejection phase indices of LV function in the normotensive controls, all hypertensive groups had higher than expected values for LV ejection phase indices, which indicates an increased myocardial contractility secondary to adrenergic stimulation or to a more efficient contractile machinery in the myocardial cells.

Diastolic function of the heart in untreated primary hypertension.

To study left ventricular (LV) diastolic function of the heart in relation to blood pressure (BP) and other signs of hypertensive cardiac and peripheral vascular changes, isovolumic relaxation time and early diastolic filling were determined in four BP groups of untreated 49-year-old men: normotensive subjects (n = 20), men with borderline hypertension (n = 30), mild hypertension (n = 45), and moderate to severe hypertension (n = 24). Isovolumic relaxation time, measured as the distance between aortic closure (A2, phonocardiography) and mitral valve opening (echocardiography), and early diastolic filling, measured as the distance between mitral valve opening and the O point of the apexcardiogram, tended to increase with BP level, and the total interval from aortic closure to the O point (A2O interval) was significantly prolonged in the two groups with mild and moderate to severe hypertension. A prolonged A2O interval (greater than or equal to 117% of expected value at observed heart rate) was seen in several hypertensives, who had no obvious increase in LV wall thickness on M mode echocardiography. This suggests that a prolonged LV relaxation time may be an early sign of cardiac involvement in primary hypertension. In the group with moderate to severe hypertension, an increase in LV wall thickness was seen together with an increase in resistance at maximal dilation in the calf. This supports the theory that when changes in cardiac structure develop they occur in parallel with structural changes also in the periphery.

Monitoring 24-hour blood pressure in a drug trial. Evaluation of a noninvasive device.

To test the usefulness of noninvasive ambulatory 24-hour blood pressure recording, the Del Mar Avionics system was used in a double-blind clinical trial in which 31 hypertensive patients were randomly allocated to receive placebo or pafenolol (25 mg or 50 mg), a novel, long-acting, highly selective beta-blocker, once daily. The results of 24-hour blood pressure and heart rate recording after 4 weeks of treatment were compared with a previous 24-hour recording performed after a 4-week placebo run-in period using the 3-hour mean of recordings performed every 7.5 minutes both day and night. Furthermore, 24-hour means were analyzed in each patient before and after 4 weeks. The system was easy to use and, judging from two placebo periods in the same patients, the reproducibility was good. The 24-hour blood pressure and heart rate recordings showed a clear dose-response relationship for pafenolol that could not be detected by ordinary casual readings. A daily dose of 25 mg of pafenolol significantly reduced blood pressure during the 9 hours after tablet intake (p less than 0.01), while 50 mg per day of pafenolol resulted in a significant reduction throughout the 24-hour period (p less than 0.01). The same pattern was seen for heart rate, which indicates a greater degree of beta-blockade during treatment with the higher dose. These results indicate that the tested noninvasive equipment is a useful tool for monitoring ambulatory 24-hour blood pressure. It gives important information impossible to obtain from single casual readings. This noninvasive method should be further evaluated to define its place in clinical work and as a research tool.

Withdrawal of antihypertensive drug treatment: time-course for redevelopment of hypertension and effects upon left ventricular mass.

OBJECTIVES: To examine: (1) in how many treated hypertensive patients it was possible to discontinue drug treatment; (2) the time-course for redevelopment of hypertension after discontinuation of therapy; and (3) whether drug withdrawal was associated with an increase in left ventricular mass (LVM). DESIGN: Fifty-four men with primary hypertension treated for a mean period of 6 years (primarily beta 1-selective beta-blockade) were evaluated for withdrawal of treatment. Exclusion criteria were signs of organ damage, severe hypertension, other serious disease and unwillingness. Treatment was reinstituted if blood pressure increased above a safety level or if symptoms occurred. Echocardiographic estimations of LVM were obtained before withdrawal and 1, 4 and 8 weeks after withdrawal or before return to treatment. SETTING: Outpatient clinic in a city hospital. PATIENTS: A random sample of 56-year-old hypertensive men. INTERVENTION: Gradual discontinuation of treatment with close follow-up of blood pressure. MAIN OUTCOME MEASURES: Number of patients who could withdraw from treatment and who had to return to pharmacological therapy; time-courses for development of hypertension; absolute changes in LVM. RESULTS: Thirty-two patients withdrew from treatment for 1-1000 days. Therapy was reinstituted in all owing to hypertension or symptoms. Serial echocardiograms were obtained in 22 patients. During the drug-free period, relative wall thickness increased, but LVM did not. Patients with rapid redevelopment of hypertension had larger prewithdrawal LVM than patients whose blood pressure increased more slowly. CONCLUSION: It was possible to withdraw treatment and obtain readable echocardiograms in a minority of the patients. After drug-withdrawal, relative wall thickness increased, but not LVM. We suggest that previously treated patients should be avoided in studies examining reversal of left ventricular hypertrophy.

Improvement in various estimates of quality of life after coronary artery bypass grafting in patients with and without a history of hypertension.

OBJECTIVE: To describe various estimates of the quality of life (QOL) prior to and for 2 years after coronary artery bypass grafting (CABG) for patients with a history of hypertension compared with nonhypertensives. METHODS: Patients in western Sweden in whom CABG had been performed between 1988 and 1991 participated. Their QOL was estimated from the Physical Activity Score, the Nottingham Health Profile, and the Psychological General Well-being Index. RESULTS: All three questionnaires detected a significant improvement in QOL already at 3 months, which persisted at 1 and 2 years both for hypertensive and for nonhypertensive patients. With the Physical Activity Score and the Psychological General Well-being Index the improvement in QOL of hypertension patients was less marked 3 months after the operation compared with that of nonhypertensives (P < 0.05). Two years after the CABG improvement was less marked for hypertensive patients than it was for nonhypertensive patients in terms of the Physical Activity Score (P < 0.01). With the Nottingham Health Profile the improvement was similar for hypertensive and nonhypertensive patients at each evaluation after the operation. With all three measures the results indicated that hypertensive patients had a worse QOL that did nonhypertensive patients. However, in a multivariate analysis considering other risk indicators simultaneously, a history of hypertension did not appear as an independent risk indicator for an adverse QOL 2 years after CABG. CONCLUSION: There was a significant improvement in various QOL estimates after CABG both for hypertensive and for nonhypertensive patients. The degree of improvement tended to be less marked for hypertensive patients than it was for nonhypertensive patients, especially 3 months after the operation and concerning physical activities. Hypertensives had a worse QOL than did nonhypertensives. However, the differences were small and could mainly be explained in terms of factors other than hypertension.

Mortality and morbidity during a period of 2 years after coronary artery bypass surgery in patients with and without a history of hypertension.

OBJECTIVE: To describe mortality and morbidity during a period of 2 years after coronary artery bypass grafting (CABG) in relation to a history of hypertension. PATIENTS: All patients in western Sweden in whom CABG was undertaken between June 1988 and June 1991 and in whom simultaneous valve surgery was not performed were included in the study. DESIGN: A prospective 2-year follow-up study. RESULTS: Patients with a history of hypertension (n = 777) differed from patients without such a history (n = 1348) in that the proportion of women was higher, they were older and more frequently had a history of congestive heart failure, diabetes mellitus, renal dysfunction, cerebro-vascular disease, intermittent claudication and obesity, and the number of smokers and patients with previous CABG was lower. They were also more likely to develop post-operative cerebrovascular complications and signs of myocardia damage. Patients with hypertension tended to have increased mortality during the first 30 days after CABG and the late mortality (between day 30 and 2 years) was significantly higher than in non-hypertensive participants. Whereas the development of myocardial infarction was similar in both groups, the hypertensive study participants more frequently developed stroke during 2 years of follow-up. In a multivariate analysis including age, sex, history of different cardiovascular diseases, smoking, ejection fraction, and the occurrence of three-vessel disease, hypertension did not emerge as an independent predictor of death in the early or late phase or during a total of 2 years of follow-up. CONCLUSION: Among CABG patients, those with a history of hypertension have a different pattern of risk factors. They have a higher mean age, include a higher proportion of women and have a higher prevalence of congestive heart failure, diabetes mellitus, renal dysfunction, cerebro-vascular disease, intermittent claudication, and obesity. They also have an increased frequency of immediate post-operative complications and an increased 2-year mortality, even if a history of hypertension was not an independent predictor of death during 2 years of follow-up.

Effects of early rehabilitation on consumption of medical care during the first year after acute myocardial infarction in patients > or = 65 years of age.

A rehabilitation program that relied totally upon the primary health care system was created in Göteborg, Sweden, for patients > or = 65 years old with acute myocardial infarction. Patients from one primary health care district were assigned to a rehabilitation program (n = 91), while patients from a neighboring district constituted a control group (n = 99). The rehabilitation measures were initiated very early after the infarction with individual counseling in the home of the patient and later in the local health center, where 21% of the patients also joined a low-intensity exercise group. The control group was somewhat older and contained a greater number of women compared with the rehabilitation group, but size and course of infarction, complications, and previous morbidity were similar. To control for differences in age, a matching procedure was performed and 71 pairs of the same sex and age were found. During the first 3 months there was a significantly lower incidence of rehospitalization in the intervention group, regarding both percentage of patients (p < 0.04) and days of rehospitalization (p = 0.05). Visits to the emergency department without rehospitalization were also significantly lower in the intervention group (p = 0.005). After 12 months the differences still remained, with the exception of days of rehospitalization. In the matched groups the same result was seen. While readmissions and emergency department visits generally were well justified in the intervention group, vague symptoms dominated among the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Occurrence of hypotension during streptokinase infusion in suspected acute myocardial infarction, and its relation to prognosis and metoprolol therapy.

In all patients who received streptokinase infusion for strongly suspected acute myocardial infarction in 1 hospital during 1989 to 1990, the occurrence of hypotension during infusion is described and related to prognosis. In 54% of patients, the beta blocker metoprolol was simultaneously administered intravenously. The median systolic blood pressure (BP) before infusion was 135 mm Hg, and the median value for the lowest systolic BP recorded during infusion was 100 mm Hg (p < 0.001). A positive correlation between systolic BP before streptokinase and the lowest systolic BP during infusion was found (r = 0.53; p < 0.001). Among patients administered streptokinase and metoprolol, 23% had systolic BP < 90 mm Hg, and 12% had < 80 mm Hg at any time during infusion; corresponding values for patients administered streptokinase only were 47 and 30%, respectively. Patients with the lowest systolic BP < 80 mm Hg during infusion had a mortality during the first 2 weeks of 22 vs 11% for those with between 80 and 100 mm Hg, and 8% for those with > 100 mm Hg (p < 0.001). However, in a multivariate analysis the systolic BP before infusion rather than the lowest systolic BP during infusion was independently associated with death. It is concluded that although patients with low systolic BP during streptokinase infusion have a high mortality, the level of systolic BP before infusion is more strongly associated with the outcome. Simultaneous use of intravenous beta blockade does not increase the occurrence of hypotension during streptokinase infusion.

Göteborg Metoprolol Trial: clinical observations.

Heart rate, systolic blood pressure and rate-pressure product were analyzed during the first 18 hours and 4 days after intravenous metoprolol or placebo. On injection of metoprolol there was an immediate decrease in mean heart rate from 72.9 +/- 0.6 to 62.7 +/- 0.4 beats/min, but no change was found in the placebo group. The difference in heart rate remained during the first 4 days. Systolic blood pressure was reduced from 144.1 +/- 0.9 to 134.6 +/- 0.9 mm Hg after intravenous metoprolol and was lower than that in the placebo group during 4 days of follow-up. Indirect signs of congestive heart failure tended to be less severe in patients given metoprolol within 12 hours of the onset of symptoms than in those given placebo. The duration of hospitalization also tended to be shorter in patients given early metoprolol treatment than in those given placebo early.

Renal function before and after withdrawal of long term antihypertensive treatment in primary hypertension.

Glomerular filtration rate (GFR) and renal plasma flow (inulin and para-aminohippurate clearance) were measured in a random sample of 17 normotensive and 20 untreated patients with primary hypertension. At the 7-year follow-up, 19 patients were on metoprolol (as the sole drug or in combination with either hydrochlorothiazide or hydralazine) and 1 patient was on hydrochlorothiazide. They were re-examined after withdrawal of treatment and return of hypertension. At the 7-year follow-up GFR was more reduced in the hypertensive (-17%) than in the normotensive group (-9%). The percentage decrease in renal blood flow was the same in both groups. No significant renal function changes appeared after withdrawal of treatment. In conclusion, there was a slightly greater deterioration in GFR in the hypertensive patients after long term treatment with metoprolol than can be explained by normal ageing.

Urinary albumin excretion--a predictor of risk of cardiovascular disease. A prospective 10-year follow-up of middle-aged nondiabetic normal and hypertensive men.

To study how the risk of cardiovascular disease changes with increasing levels of urinary albumin excretion (UAE), we prospectively studied a random sample of 120 49-year-old men with a wide range of blood pressures. Based on diastolic blood pressure (DBP), the subjects were divided into normotensives (DBP < 90 mm Hg; n = 21), borderline hypertensives (DBP 90 to 94 mm Hg; n = 30), mild hypertensives (DBP 95 to 104 mm Hg; n = 45) and moderate to severe hypertensives (DBP > 105 mm Hg; n = 24). None had been previously treated for hypertension or had secondary hypertension, diabetes mellitus, or other cardiovascular diseases at baseline. Heart and kidney function and metabolic and hormonal variables were with beta-blockade, diuretics, or hydralazine. The cardiovascular morbidity during 10 years of follow-up was studied. The hypertensives were treated with beta-blockade, diuretics, or hydralazine. The cardiovascular morbidity during 10 years of follow-up was studied. The 19 subjects who developed cardiovascular disease had significantly higher baseline UAE than the group that did not (median value 16.6 mg/24 h; range 3.5 to 73, and 9.7 mg/24 h, range 0 to 308, respectively). UAE correlated to systolic blood pressure (P = .0115) and DBP (P = .031), but not to smoking behavior or serum cholesterol. The risk of cardiovascular disease was associated with UAE and smoking independently of blood pressure (P = .001 and P = .015, respectively), and the risk increased continuously with increasing UAE. The initial UAE thus emerged as an efficient and independent predictor of cardiovascular disease in middle-aged hypertensive and normotensive men. UAE appeared to be a stronger predictor than blood pressure and serum cholesterol.

Effect of 14 years of antihypertensive treatment on renal function and urinary albumin excretion in primary hypertension.

The effects on blood pressure (BP), renal function, and urinary albumin excretion (UAE) of 14 years of antihypertensive treatment were studied and compared to the changes seen with normal aging. The studied groups included randomly selected men with newly diagnosed primary hypertension at baseline (n = 23) and normotensive (NT) men of the same age (n = 11). The hypertensives (HT) were treated with beta-blockers either as monotherapy or combined with diuretics or hydralazine. Glomerular filtration rate (GFR; inulin clearance), renal blood flow (RBF, para-aminohippurate clearance), renal vascular resistance (RVR), and 24-h UAE were determined. The two groups were investigated at baseline (before treatment) and after 7 and 14 years. At baseline, BP and RVR were significantly increased and RBF was significantly decreased in the HT over that in the NT. The BP in the HT was significantly reduced after 7 years of treatment and a further but nonsignificant reduction to 139 +/- 14/88 +/- 6 mm Hg (mean +/- SD) was seen after 14 years. GFR in the HT was significantly reduced from 103 +/- 15 mL/min to 84 +/- 19 mL/min (mean +/- SD) after 7 years, but no further reduction was seen after 14 years. During the 14 years RBF decreased and RVR increased in the HT but these changes were of the same magnitude as in the NT. The UAE did not change significantly during the study. In conclusion, good blood pressure control with conventional antihypertensive treatment in mild to moderate primary hypertension seems to protect the kidney from progressive decline in GFR and increase in UAE. The increase in RVR and the decrease in RBF seen during 14 years of antihypertensive treatment was of the same magnitude as that seen with normal aging.

Effects of intensified blood-pressure reduction on renal function and albumin excretion in primary hypertension. Addition of felodipine or ramipril to long-term treatment with beta-blockade.

The effect of intensified blood pressure (BP) control with a reduction of the diastolic BP to < or = 85 mm Hg on renal function and urinary albumin excretion (UAE) was studied in 28 men with primary hypertension (aged 62 to 72 years) treated for 13 +/- 5 years with beta-blockade, diuretics, or hydralazine. They were compared with 25 normotensive (NT) men of similar age. At baseline (BL), glomerular filtration rate (GFR), renal plasma flow (RPF) (clearance of inulin and para-aminohippurate), and the UAE were studied. Thereafter, all antihypertensive drugs except beta-blockers were withdrawn and either felodipine (5 to 20 mg; n = 13) or ramipril (2.5 to 10 mg; n = 15) was added in a double blind, randomized fashion. Hydrochlorothiazide was added if necessary. The investigations were repeated after 6 weeks and 1 year of double-blind treatment. At BL, the BP and the renal vascular resistance (RVR) were significantly higher and GFR and RPF were significantly lower in both hypertensive groups than in NT. After 1 year, the BP treatment goal was reached by all patients in the felodipine group but only by two-thirds in the ramipril group in spite of addition of diuretics to 60% of the latter group. In the felodipine group, the BP, GFR, and RVR after 1 year no longer differed significantly from normal. The UAE and the fractional albumin clearance increased significantly after 1 year's treatment in the felodipine group but did not change in the ramipril group. The fractional albumin clearance, however, did not differ significantly from normal either at BL or after 1 year's treatment in any of the hypertensive groups. It is therefore possible to reduce BP and improve renal function in primary hypertension to levels not significantly different from normal after treatment with felodipine in combination with beta-blockade. Although this regimen increased the low UAE slightly, the fractional albumin clearance changed less and did not differ significantly from normal. The ramipril/beta-blocker combination reduced BP less and did not change the slightly reduced renal function or the UAE.

Effects of long-term antihypertensive treatment and aging on renal function and albumin excretion in primary hypertension.

The effects on renal function and urinary albumin excretion of 7 years of antihypertensive treatment compared to the effects of normal aging were studied in a random sample of 40 men with newly diagnosed primary hypertension and in 17 normotensive men of the same age, respectively. The hypertensives were treated with metoprolol either as monotherapy (n = 21) or combined with hydrochlorothiazide or hydralazine. Glomerular filtration rate (GFR; inulin clearance), renal blood flow (RBF; para-aminohippurate clearance), renal vascular resistance (RVR), and the 24 h urinary albumin excretion were determined. GFR was significantly reduced from 104 +/- 15 mL/min (mean +/- SD) to 86 +/- 20 mL/min (P < .001) in the hypertensive group, but the reduction was not significantly greater than in the normotensive group. As judged from the study of a subgroup of the hypertensives, most of the decrease in GFR occurred early as an immediate drug-induced, functionally explained decrease. The changes in RBF and RVR after 7 years of treatment did not differ significantly from those due to normal aging. RVR remained higher and RBF remained lower in the hypertensives than in the normotensives. The urinary albumin excretion in the hypertensives was significantly reduced after 7 years but remained higher than in the normotensives. In conclusion, the changes in renal function and hemodynamics seen after long-term treatment with metoprolol in primary hypertension were not significantly different from the changes caused by normal aging in normotensives.

An evaluation of the results of media and educational campaigns designed to shorten the time taken by patients with acute myocardial infarction to decide to go to hospital.

OBJECTIVE: To describe the benefits and pitfalls of educational campaigns designed to reduce the delay between the onset of acute myocardial infarction (AMI) and its treatment. METHODS: All seven educational campaigns reported between 1982 and 1994 were evaluated. RESULTS: The impact on delay time ranged from a reduction of patient decision time by 35% to no reduction. One study reported a sustained reduction that resulted in the delay time being halved during the three years after the campaign. The use of ambulances did not increase. Only one study reported that survival was unaffected. There was a temporary increase in the numbers of patients admitted to the emergency department with non-cardiac chest pain in the initial phase of educational campaigns. CONCLUSION: The challenge of shortening the delay between the onset of infarction and the start of treatment remains. The campaigns so far have not been proved to be worthwhile and it is not certain that further campaigns will do better. New media campaigns should be run to establish whether a different type of message is more likely to change the behaviour of people in this life-threatening situation.