Effect of evening versus morning benazepril on 24-hour blood pressure: a comparative study with continuous intraarterial monitoring

In a single-blind, in-patient, crossover study, the influence on the circadian blood pressure (BP) profile of the 9:00 a.m. versus the 9:00 p.m. acute administration of a single dose of benazepril 10 mg, a new angiotensin-converting-enzyme inhibitor, was assessed in 10 hypertensive patients by means of 24-hour intraarterial ambulatory BP monitoring. Mean 24-hour BP for the three treatments (placebo, benazepril a.m., benazepril p.m.) were 155/93, 131/83 and 138/86 mmHg, respectively. No significant differences between the two benazepril schedules were found in terms of either 24-hour or day-time and night-time mean BP values. However, hourly averages showed that benazepril a.m. had a more sustained antihypertensive effect than benazepril p.m., where a loss of efficacy was observed 19 hours after the administration. BP responses to static and dynamic exercise and to cold pressor test were unchanged after both benazepril schedules, as were BP peaks. These results demonstrate that acute benazepril administration markedly reduces systolic and diastolic BP. The morning administration is preferable because it more effectively covers the whole 24 hours than an evening dose.     

Platelet alpha 2-adrenoceptors and diurnal changes of platelet aggregability in hypertensive patients

OBJECTIVE: To analyse whether platelets from hypertensive patients have an increased responsiveness to aggregating agents during morning hours and whether these changes might be related to concurrent changes in platelet membrane alpha 2-adrenoceptor characteristics, plasma catecholamine and cortisol levels, and blood pressure values. DESIGN AND METHODS: Blood samples from 14 mild-to-moderate essential hypertensive males were collected in the morning (0700-0900 h) and the evening (1900-2100 h) to determine platelet aggregability responses to adrenaline and ADP, platelet alpha 2-adrenoceptor number and binding affinity to [3H]-yohimbine, plasma catecholamines and cortisol. During the same day patients underwent 24-h ambulatory blood pressure monitoring. RESULTS: The lowest concentration of adrenaline required to induce biphasic aggregation was significantly lower in the morning than in the evening, indicating an increased morning platelet aggregability to adrenaline; the minimum ADP concentration inducing aggregation was similar in morning and evening samples. There were no significant differences between morning and evening samples in platelet alpha 2-adrenoceptor number and binding affinity. Plasma adrenaline, noradrenaline and cortisol levels were higher in the morning than in the evening, but no correlation was observed between hormonal changes and the morning increase in platelet sensitivity to adrenaline. Ambulatory blood pressure recording showed abrupt morning elevations in systolic and diastolic blood pressures over sleeping values. However, morning blood pressure readings were not significantly different from those recorded during the rest of the day and in the evening. The morning rise in mean arterial pressure displayed a significant inverse correlation with the increased platelet sensitivity to adrenaline that was observed during the same hours. CONCLUSIONS: The results indicate that the increased morning responsiveness to adrenaline that was observed in platelets obtained from hypertensive patients does not appear to be mediated by changes in the characteristics of platelet membrane alpha 2-adrenoceptors, but morning blood pressure elevations might play some role in inducing this platelet hyper-reactivity.     

Divergent effects of ACE-inhibition and calcium channel blockade on NO-activity in systemic and renal circulation in essential hypertension

OBJECTIVE: Nitric oxide is a vasodilating and blood pressure lowering substance. To investigate whether calcium antagonists or angiotensin-converting enzyme (ACE) inhibitors increase vascular nitric oxide activity, we assessed systemic and renal vascular sensitivity to nitric oxide synthase inhibition in hypertensives on and off medication. METHODS: Ten essential hypertensive patients, aged 22-51 years, were studied 3 times: > or = 4 weeks off medication, after 3 weeks treatment with enalapril 20 mg twice a day and after 3 weeks nifedipine 60 mg/day. Each time, 24-h blood pressure registration was performed, followed by a clearance study to obtain a 3-h dose-response curve for intravenously infused NG-monomethyl-L-arginine (L-NMMA, respectively 0.75, 1.5 and 3.0 mg/kg/h). RESULTS: L-NMMA dose-dependently increased mean arterial pressure with 5 +/- 2 mmHg and systemic vascular resistance with 24 +/- 5% at maximum dose, whereas cardiac output decreased (all P < 0.001). Enalapril and nifedipine treatment decreased blood pressure, while the L-NMMA-induced increase in systemic vascular resistance was potentiated (enalapril: 45 +/- 7% and nifedipine: 46 +/- 8%; both P < 0.01). L-NMMA also dose-dependently decreased renal blood flow by 58 +/- 8% at maximum dose (P < 0.001), but neither drug potentiated these effects. CONCLUSION: These results indicate that, in essential hypertensives, antihypertensive therapy with enalapril or nifedipine increases nitric oxide dependency of systemic vascular tone, which may play a role in the blood pressure lowering effect of these drugs. However, this phenomenon cannot be observed in the renal circulation, suggesting a different regulation of endothelium-dependent vasomotion in the hypertensive kidney.     

Comparison of blood pressure and angiotensin responses to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme inhibitor enalapril in essential hypertension

OBJECTIVE: To compare the responses of angiotensin II (Ang II) and blood pressure to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme (ACE) inhibitor enalapril. SUBJECTS: Eight non-sodium-restricted patients with mild-to-moderate essential hypertension. DESIGN: A single-blind crossover study. Ro 42-5892 (600 mg orally, once a day) and enalapril (20 mg orally, once a day) were given for 8 days before detailed investigations were carried out. METHODS: Ambulatory blood pressure was measured directly for 24 h by the Oxford technique on three occasions. Off-treatment and on day 8 of treatment with Ro 42-5892 and with enalapril. Ang II was measured by radioimmunoassay after separation by high-performance liquid chromatography. RESULTS: Plasma renin activity and Ang II were lowered by 83% [95% confidence interval (CI) 61-105] and 68% (95% CI 49-87), respectively, 0.5-1 h after Ro 42-5892, but after only 3 h values had returned to baseline. Unlike this rapid and short-term suppression of Ang II, the maximal antihypertensive response to Ro 42-5892 (fall in blood pressure 12.9/9.0 mmHg) occurred only after 6 h. Blood pressure returned to baseline after 8 h. In response to enalapril, Ang II was maximally suppressed by 63% (95% CI 32-94) after 2 h and by 83% (95% CI 76-90) after 8 h. Despite early maximal Ang II suppression, the maximal antihypertensive response to enalapril occurred only after 12 h (fall in blood pressure 25.3/16.3 mmHg). With this compound a significant antihypertensive effect was still present 24 h after dosing. CONCLUSIONS: Compared with enalapril at 20 mg once a day, repeated oral administration of a single dose of Ro 42-5892 at 600 mg caused only short-term suppression of Ang II and blood pressure. Suppression of Ang II and reduction in blood pressure were temporally dissociated, both with the ACE inhibitor and the renin inhibitor. This implies that the blood pressure lowering effect of these inhibitors is caused partly by Ang II suppression outside the circulation.     

Renal effects of guanabenz: a new antihypertensive

In order to determine the effects of guanabenz upon renal function, clearance studies were performed on hypertensive volunteers during sustained steady-state water diuresis. The data reveal an acute fall in renal hemodynamics and a marked reduction in sodium excretion during the 3rd and 4th hour after administration. Tha antinatriuresis was due to decreased filtration and enhanced distal nephron reabsorption of sodium, principally in association with secretion of potassium. Chronic administration of guanabenz for one week produced a sustained reduction in blood pressure, but there was no change in either body weight or 24-hour urinary sodium excretion. Repeat clearance studies revealed no change with either renal hemodynamics or sodium clearance. The data suggest that the acute antinatriuresis is a transient hemodynamic event and chronic therapy with guanabenz will not be complicated by sodium retention, a feature characteristic of other antihypertensive agents.     

Antihypertensive activity and pharmacokinetics of KD3-671, a nonpeptide AT1-receptor antagonist, in renal hypertensive dogs

The antihypertensive activity and pharmacokinetics of KD3-671 (previously named KT3-671), a nonpeptide AT1-receptor antagonist, were investigated in renal hypertensive dogs with normal or high plasma renin activity (PRA). A single administration of KD3-671 at 3 and 10 mg/kg, p.o., to the hypertensive dogs with high PRA dose-dependently reduced mean blood pressure (MBP), which was not correlated with plasma KD3-671 concentration. Significant increases in PRA and plasma angiotensin (Ang) II occurred 2 h after KD3-671 dosing. Enalapril at 3 mg/kg, p.o., also reduced MBP. Neither KD3-671 nor enalapril affected heart rate. When given orally once a day for 29 days to the hypertensive dogs with normal PRA, KD3-671 at 3 and 10 mg/kg/day dose-dependently reduced MBP, which was smaller than that in the dogs with high PRA. This was the case for enalapril. The hypotension induced by the first dose of KD3-671 or enalapril was consistently observed after doses 8, 15, 22, and 29. After cessation of repeated dosing, no rebound phenomenon in MBP was observed. Pharmacokinetic parameters of KD3-671 were not influenced by repeated dosing. KD3-671 markedly increased both PRA and plasma Ang II concentration at 2 h after dosing. These results suggest that KD3-671 may be useful for the treatment of hypertension.     

Effect of chronic treatment with ME3221 on blood pressure and mortality in aged stroke-prone spontaneously hypertensive rats

1. The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke-prone spontaneously hypertensive rats (SHRSP) was studied following long-term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril. 2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure. The reference drugs showed similar activity, but the antihypertensive effect of ME3221 was more potent. 3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age. 4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N-acetyl-beta-D-glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion). 5. These results indicate that ME3221 has a stable anti-hypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.     

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.     

Role of kinins in the acute antihypertensive effect of enalapril in hypertensive rats

1. We used the kinin antagonist HOE 140 to investigate the role of endogenous kinins in the acute antihypertensive effect of the angiotensin converting enzyme inhibitor enalapril in chronic and acute renal hypertensive rats. 2. In normotensive rats, treatment with HOE 140 (33 micrograms/kg, sc) caused a complete blockade of the depressor effect of bradykinin (100 ng, ia) without affecting the depressor effect of sodium nitroprusside (1 microgram, i.v.) or the basal blood pressure. 3. HOE 140 treatment (33 micrograms/kg, sc, plus 330 ng/min, i.v.) did not affect basal blood pressure of chronic (6-7 weeks) one-kidney, one clip and two-kidney, one clip hypertensive rats and in rats with acute hypertension, elicited by unclamping the renal pedicle that had been occluded for 5 h, but HOE 140 completely blocked the hypotensive response to bradykinin (100 ng, ia) during the 60-min period after enalapril administration (2 mg/kg, i.v.). 4. Acutely hypertensive rats treated or not with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) presented a similar fall in blood pressure after enalapril (165 +/- 5 to 137 +/- 6 mmHg and 166 +/- 5 to 136 +/- 6 mmHg, respectively). 5. Untreated two-kidney, one clip hypertensive rats presented a rapid and sustained fall in blood pressure after enalapril (177 +/- 4 to 148 +/- 4 mmHg) that did not differ from the HOE 140-treated (33 micrograms/kg, sc, plus 330 ng/min, i.v.) group (177 +/- 6 to 154 +/- 4 mmHg). 6. One-kidney, one clip hypertensive rats treated with HOE 140 (33 micrograms/kg, sc, plus 330 ng/min, i.v.) showed a significantly smaller fall in blood pressure after enalapril (204 +/- 7 to 179 +/- 9 mmHg) compared to the untreated rats (197 +/- 7 to 149 +/- 2 mmHg). 7. These results indicate that kinin potentiation plays an important role in the antihypertensive effect of acutely administered angiotensin converting enzyme inhibitor in the one-kidney, one clip model of hypertension.     

Incidence of fatal pulmonary embolism after 1,390 knee arthroplasties without routine prophylactic anticoagulation, except in high-risk cases

OBJECTIVE: To determine whether the time of administration (morning vs. evening) of pantoprazole influences the effect of a 40 mg dose upon intragastric pH in healthy subjects. DESIGN: Randomized, double-blind, two-period crossover study to compare intragastric pH following treatment with pantoprazole, 40 mg once daily for 7 days, the drug being given as either a morning or an evening dose before meals. METHODS: Intragastric pH was measured for 24 h on three occasions. The baseline recording was made 2 days prior to the first treatment period and subsequent measurements were made on days 6 to 7 of each period. Adverse events were recorded and fasting laboratory variables measured. RESULTS: Twelve subjects were evaluable for efficacy. Increases in median pH over 24 h were observed in all subjects with both dosage regimens. There was a greater increase from baseline in 24-h median pH values following morning than evening administration of pantoprazole (P < 0.05). This difference was due to a greater effect on median daytime pH (07.00-19.00 h, P < 0.01) compared with that after evening administration. No adverse events were reported and there were no clinically significant changes in laboratory variables. CONCLUSION: The study supports the recommendation of a once-daily morning dosage regimen of pantoprazole 40 mg in the treatment of acid-related diseases.     

Circadian variation of haemodynamics in patients with essential hypertension: comparison between early morning and evening

OBJECTIVE: An increased incidence of cardiovascular accidents in the morning has been reported, but the reason why is not clear. We measured 24-h haemodynamics and focused on its change in the morning. DESIGN: To study the circadian variation of haemodynamics, we recorded 24-h direct blood pressure and electrocardiogram using a telemetry method, in 21 untreated inpatients with essential hypertension, and measured cardiac output using the dye-dilution method in the morning, in the evening and during sleep. We also determined the beat-to-beat cardiac output (using the pulse-contour method), the total peripheral resistance and the ratio of low- to high-frequency components (using power spectral analysis of the R-R interval during 24 h), and made comparisons between morning and evening values. RESULTS: Both systolic and diastolic blood pressure increased rapidly in the early morning. Although the comparison of blood pressure between morning and evening showed no difference, total peripheral resistance and low- to high-frequency ratio were significantly higher in the morning than in the evening, but cardiac output was lower in the morning. CONCLUSIONS: Sympathetic nervous activity and vascular resistance seem to be higher in the morning than in the evening, and these haemodynamic changes may stress the cardiovascular system.     

Circadian blood pressure changes in untreated children with kidney disease and conserved renal function

Ambulatory blood pressure monitoring over 24 h was applied in 31 children with kidney disease, aged 3-19 (median 11) years, in the absence of renal insufficiency and without antihypertensive therapy. Median creatinine clearance was 112 ml/min/1.73m2. Ambulatory blood pressure monitoring revealed that eight patients (26%) were hypertensive during the daytime, compared to 62% through casual recordings obtained in the office and 38% when blood pressure was taken at home. Nocturnal hypertension was detected by ambulatory monitoring in six patients, two of whom had normal blood pressure in the daytime. Median nocturnal dipping was 13% for systolic and 21% for diastolic blood pressure, i.e. similar to healthy children. Rhythm analysis recognized a distorted circadian pattern for systolic and/or diastolic blood pressure in eight patients. In conclusion, ambulatory blood pressure monitoring allows the evaluation of hypertension more reliably than casual recordings in the office. Nocturnal hypertension, as a major risk factor for renal deterioration, is detected in a similar proportion as daytime hypertension in almost 20% of untreated children with kidney disease and normal renal function.     

Circadian variation of tacrolimus disposition in liver allograft recipients

The aim of this study was to characterize the circadian variation of oral tacrolimus disposition in 8 stable liver allograft recipients. In the steady state, a total of 23 blood samples was taken before and after tacrolimus administration during a 24-hr period and the pharmacokinetic parameters were compared. The area under the curve (AUC) of tacrolimus after the morning dose was significantly larger than after the evening dose (211+/-43 ng x hr/ml [morning] vs. 179+/-45 ng x hr/ml [evening], P=0.02). The time to peak (Tmax) was significantly shorter after the morning dose than after the evening dose (1.6+/-0.7 hr [morning] vs. 2.9+/-0.6 hr [evening], P=0.002). The peak (Cmax) was significantly higher after the morning dose than after the evening dose (32.2+/-10.2 ng/ml [morning] vs. 19.1+/-4.3 ng/ml [evening], P=0.003). However, the trough (Cmin) was not significantly different between the morning dose and the evening dose (13.1+/-3.9 ng/ml [morning] vs. 13.3+/-4.4 ng/ml [evening], P=0.4). This study demonstrated that tacrolimus disposition in liver transplant patients was determined by administration time.     

Clinical relevance blood pressure variability

Blood pressure fluctuates continuously over time, either spontaneously or in response to a variety of external stimulations. The occurrence of these continuous and often marked blood pressure variations is not only of pathophysiologic interest, but it may also have a clinical relevance. Indeed, it has been shown that the occurrence of pronounced blood pressure changes at the time of the physician's visit may introduce errors in the diagnosis of hypertension and in the assessment of the efficacy of antihypertensive treatment. Moreover, several studies have reported that the end-organ damage of hypertension is significantly and independently related to the degree of blood pressure variability during the day and night. This was shown by reports that assessed blood pressure variability by a variety of different methods, i.e. by computing the 24 h or daytime blood pressure standard deviation, the degree of morning blood pressure rise or that of night-time blood pressure fall, the frequency of blood pressure peaks over the 24 h, and the blood pressure increases under stressful conditions or during physical exercise. Results from a recent follow-up study have provided evidence that the degree of blood pressure variability may also have prognostic relevance in hypertensive patients. Thus, optimal antihypertensive treatment might also need to reduce the degree of blood pressure fluctuations together with the 24 h average blood pressure levels. Until recently, however, available antihypertensive drugs have been ineffective in buffering blood pressure variability or have even been responsible for an increase in the degree of blood pressure fluctuations. Further studies are needed to assess whether recently developed antihypertensive agents, and in particular those able to induce a smooth reduction in blood pressure over the 24 h or to modulate the sympathetic influences exerted on the cardiovascular system, may represent better tools to reduce the magnitude of an enhanced blood pressure variability in hypertensive patients over the 24 h. Recent progress in technology has offered us more powerful tools to address this issue. They include devices for continuous noninvasive ambulatory blood pressure monitoring (Portapres, TNO), and techniques for a more comprehensive analysis of all components which contribute to overall blood pressure variability (broad-band spectral analysis).     

Right ventricular diastolic filling: evaluation with velocity-encoded cine MRI

BACKGROUND AND PURPOSE: It has been reported that some angiotensin converting enzyme inhibitors can prevent stroke-prone spontaneously hypertensive rats from stroke at much higher doses than clinical doses used for hypertension therapy. This study was performed to investigate the prophylactic effectiveness of imidapril against stroke in comparison with enalapril. METHODS: Salt-loaded stroke-prone spontaneously hypertensive rats were orally given imidapril (0.5, 1, 2, and 5 mg/kg per day), enalapril (2 and 5 mg/kg per day), or hydralazine (5 mg/kg per day). Stroke signs were scored, and blood pressure, protein concentration, and N-acetyl-beta-D-glucosaminidase activity in urine were measured. After 2 weeks of medication, angiotensin converting enzyme activities in the aorta were measured 24 hours after dosing. RESULTS: In the control group, severe hypertension developed, and all rats died within 12 weeks because of stroke. Imidapril and enalapril dose-dependently decreased the stroke-related mortality, and both agents at 5 mg/kg per day showed excellent prophylaxis, although they did not inhibit hypertensive development. Imidapril at 0.5 mg/kg per day significantly prevented stroke to almost the same extent as enalapril at 2 mg/kg per day or hydralazine at 5 mg/kg per day. Imidapril dose-dependently suppressed the elevation of the two urinary indexes, which was followed by stroke. Imidapril inhibited enzyme activity in the aorta more strongly than did enalapril at the same dose. CONCLUSIONS: Imidapril prevented the incidence of stroke in stroke-prone spontaneously hypertensive rats at a dose of 0.5 mg/kg per day or more by amelioration of kidney dysfunction. Reduction of blood pressure is not necessary, although enzyme inhibition in the vasculature may partly relate to the effect.     

Twenty-four-hour ambulatory blood pressure evaluation of antihypertensive agents

EVALUATION OF A SMOOTH BLOOD PRESSURE RESPONSE TO TREATMENT: Smooth or uniform blood pressure control is an obvious goal of antihypertensive therapy, but it is difficult to assess by the traditional clinic blood pressure measurements. Ambulatory blood pressure monitoring is therefore increasingly being used to evaluate new antihypertensive drugs and to assess the adequacy of treatment. The use of ambulatory blood pressure monitoring is based on two assumptions: that treatment must be continuously optimal, and that more frequent blood pressure measurements during treatment, particularly at different times and during various types of activity and mental states, may lead to a more accurate assessment than infrequent measurements in the clinic. When ambulatory blood pressure monitoring is used, the effect of a given antihypertensive agent or of a given antihypertensive regimen can be tested on the average blood pressure values over 24 h, or on day- or night-time values. The actual verification of the achievement of a uniform reduction of blood pressure throughout the 24-h time span can be achieved by comparing 24-h blood pressure profiles before treatment and during treatment. The so-called trough: peak ratio is generally used in an attempt at a more quantitative assessment of smooth control. Recently, we have developed the Smoothness Index, defined as the ratio between the mean hourly change in blood pressure (calculated over the 24-h period), divided by the standard deviation of these hourly changes. We have some indication that this may be a more accurate measurement of smooth blood pressure control under therapy than trough: peak ratios. TWENTY-FOUR-HOUR BLOOD PRESSURE CONTROL BY IRBESARTAN: Ambulatory blood pressure assessments are important during the clinical testing of new antihypertensive agents. Our group recently performed a multicenter study to compare the anti-hypertensive effect of three irbesartan dose regimens (75 mg once a day, 150 mg once a day, 75 mg twice a day) and placebo as measured by 24-h ambulatory blood pressure monitoring and confirmed by office blood pressure measurements. All irbesartan regimens were significantly more effective than placebo. Irbesartan at 150 mg once a day provided clinically significant and sustained blood pressure reductions over a full 24 h and had the highest trough: peak ratio and Smoothness Index. No additional benefit was observed with twice-daily dosing using irbesartan at 75 mg compared with a single daily at 150 mg. Therefore irbesartan at a single daily dose of 150 mg offers real efficacy with the potential for greater ease of administration compared with twice-daily antihypertensive therapy.     

Effects of enalapril and nitrendipine on the excretion of epidermal growth factor and albumin in hypertensive NIDDM patients

OBJECTIVE: To compare the effect of the antihypertensive drugs nitrendipine and enalapril on the excretion of epidermal growth factor (EGF) and albumin in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) subjects. RESEARCH DESIGN AND METHODS: After a 4-week washout period, mildly hypertensive (systolic blood pressure [sBP] > or = 140 mmHg and/or diastolic blood pressure [dBP] > or = 90 mmHg) NIDDM patients with albuminuria (15-200 micrograms/min) were randomized into an 8-month-long therapy with either nitrendipine (n = 11) or enalapril (n = 10). Blood pressure, EGF, and microalbumin excretion were measured at baseline and throughout the treatment period. RESULTS: A significant fall in sBP was noticed in the enalapril group and in dBP in the nitrendipine group. In the enalapril group, EGF excretion progressively increased from 188 to 214 nmol/mmol creatinine after 6 weeks and to 274 after 8 months of therapy (P = 0.03). There was a significant fall in albumin excretion while patients were on enalapril, but in the nitrendipine group, neither albuminuria nor EGF excretion changed significantly. There was no correlation of improved EGF excretion with a decrease in albuminuria or BP. CONCLUSIONS: The angiotensin-converting enzyme inhibitor enalapril has been effective in decreasing albumin and increasing EGF excretion. Measurement of urinary EGF may provide a new valuable index of renal function.     

Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension

OBJECTIVE: To evaluate the blood pressure lowering efficacy as well as tolerability and safety of the angiotensin II antagonist losartan compared with that of the angiotensin converting enzyme inhibitor enalapril in patients with mild-to-moderate essential hypertension. DESIGN AND METHODS: The study was a multicentre, double-blind, double-dummy, randomized, parallel study. Patients (n = 407) with diastolic blood pressure > or = 95 and < or = 120 mmHg at the end of a 2-week baseline placebo period were randomly allocated to receive either 50 mg losartan once a day or 20 mg enalapril once a day for 12 weeks. Blood pressure, clinical and laboratory safety, specific symptoms including coughing determined using a symptoms questionnaire and metabolic variables were examined at baseline and at weeks 6 and 12. RESULTS: Both losartan and enalapril decreased systolic and diastolic blood pressure from baseline at weeks 6 and 12. Blood pressure changes from baseline at trough (22-26 h after the dose) did not differ between the two groups in the per-protocol analysis. Response to treatment at trough was excellent or good (diastolic blood pressure < 90 mmHg or reduction in diastolic blood pressure of 10 mmHg) in 51 and 53% of the patients in the losartan and enalapril groups, respectively. Enalapril administration increased dry coughing symptoms whereas losartan did not. The incidence of dry coughing was 1.0 and 12.2% as a spontaneously reported discomfort at week 12 and 3.0 and 15.1% as a clinical adverse experience in the losartan and enalapril groups, respectively. The difference from baseline at week 12 in the incidence of dry coughing between the two groups was 14.9% as a specific symptom in the symptoms questionnaire. Losartan reduced serum uric acid concentration, whereas effects on other metabolic parameters did not differ between the groups. CONCLUSIONS: Losartan is an effective and well-tolerated antihypertensive drug showing similar blood-pressure-lowering efficacy to that of enalapril at trough. However, in contrast to enalapril, losartan does not increase the incidence of dry coughing. Thus, the angiotensin II antagonist losartan provides a promising new approach to treatment of hypertension.     

Comparative antihypertensive effects of propranolol and metoprolol in DOC-treated rats

The effects of chronic twice daily s.c. injections of dlpropranolol, metoprolol and d-propranolol on systolic blood pressure and heart rate were assessed in conscious DOC-saline hypertensive rats. Measurements were taken (tail-cuff) 4 hr after the morning injection and 16-18 hr after the afternoon injection during 11 of 19 consecutive treatment days. Only dl-propranolol and metoprolol at 5 mg/kg lowered blood pressure and heart rate significantly relative to the changes occurring in control saline-injected animals. At the lower dose of 0.2 mg/kg, both agents tended to decrease heart rate while having little or no effect on blood pressure. The overall blood pressure and heart rate changes produced by propranolol at 5 mg/kg differed significantly from those of the control group at both the 4 and 16-18 hr post-dosing intervals. Metoprolol at 5 mg/kg produced significant overall changes in blood pressure and heart rate only at the 4 hr post-doing interval. D-propranolol had no effect on either blood pressure or heart rate. The results indicate tha s.c. propranolol and metoprolol lower systolic blood pressure in conscious DOC-saline hypertensive rats only at the higher dose of 5 mg/kg and that cardioselectivity does not afford increased antihypertensive activity in this model.     

Assessing hypertension management: the role of 24-hour blood pressure monitoring

BACKGROUND: The first fully automatic portable invasive blood pressure recorder was developed 30 years ago. Today, portable noninvasive ambulatory blood pressure devices are capable of measuring blood pressure intermittently for periods of 24 to 48 hours. OBJECTIVE: To discuss the utility of automatic ambulatory blood pressure recording in assessing antihypertensive therapy. SUMMARY: Ambulatory blood pressure monitoring is helpful in assessing the pharmacodynamics and the clinical efficacy of antihypertensive drugs. It is superior to office blood pressure measurement in predicting hypertensive end-organ disease. In clinical trials, ambulatory blood pressure monitoring permits a more varied population to enter a study, the number of subjects required is often reduced, and a placebo control group may be unnecessary. CONCLUSIONS: The various methods of analyzing ambulatory blood pressure data should be used in a complementary fashion to evaluate antihypertensive drug therapy. We believe that this technique will soon become much more commonly used for hypertension management.