Catecholamines and the renin-angiotensin-aldosterone system during treatment with felodipine ER or hydrochlorothiazide in essential hypertension.

The neurohumoral responses after 10 mg of felodipine extended release (ER), a new dihydropyridine calcium antagonist, and 25 mg of hydrochlorothiazide (HCTZ) were compared in a randomized, double-blind, crossover trial in 28 mild to moderate hypertensives. Antihypertensive drugs were gradually discontinued. Felodipine ER, 10 mg was given once daily for 2 weeks; after another washout period of 1 week, patients were switched to 25 mg of HCTZ once daily and vice versa. Blood pressure (BP) was measured at baseline, 2.5 h after medication, and after 2 weeks of treatment (24 h postdosing) using an oscillometric device. Felodipine ER and HCTZ both lowered BP effectively. However, felodipine ER was superior in reducing systolic and diastolic BP during the short term and medium term. Treatment with felodipine ER over 2 weeks increased sympathetic outflow as indicated by elevated plasma norepinephrine levels, whereas plasma epinephrine was mainly unaffected, as were plasma renin and aldosterone levels. On the other hand, 25 mg of HCTZ increased plasma renin and aldosterone, but left catecholamines unchanged. Despite persistent increased sympathetic activity, the reduction in BP in this study was more pronounced after felodipine ER as compared to HCTZ. The lack of a difference between heart rates under both medications after 2 weeks of treatment suggests a resetting of the baroreflex by felodipine ER and furthermore that the increased norepinephrine levels may not be clinically relevant, but demonstrate the maintained baroreflex activity. HCTZ, in doses as low as 25 mg, is still capable of stimulating the renin-angiotensin-aldosterone system.     

Renal and endocrine effects of long-term converting enzyme inhibition as compared with calcium antagonism in essential hypertension.

In a double-blind, double-dummy, placebo-controlled crossover design, the renal hemodynamic and tubular effects of 2-month specific vasodilation with a converting enzyme inhibitor (enalapril, 40 mg once daily) was compared with that of a calcium antagonist (verapamil slow release, 240 mg twice daily) in 15 patients with established essential hypertension. Enalapril and verapamil treatment induced a 9% reduction in mean blood pressure (BP). Heart rate (HR) was similar after placebo (66 beats/min), enalapril (63 beats/min), and verapamil (63 beats/min). Plasma norepinephrine (P-NE) was unaltered after enalapril and verapamil as compared with placebo (0.92, 0.88, and 1.33 nM, respectively). Plasma angiotensin II and aldosterone decreased and plasma renin activity (PRA) increased after enalapril but were unaltered after verapamil. Glomerular filtration rate (51Cr-EDTA) was not altered by either enalapril or verapamil, whereas renal blood flow (125I-hippurate) was reduced 9% by verapamil. Renal vascular resistance (RVR) was unchanged after enalapril as well as verapamil. Fractional excretion of electrolytes and diuresis were unaltered and body weight was similar after enalapril, verapamil, and placebo (81.0, 82.5, and 80.2 kg, respectively). Long-term treatment with enalapril and verapamil had a comparable antihypertensive effect. Neither enalapril nor verapamil appeared to induce reflex activation of the sympathetic nervous system. Renal hemodynamic and tubular function was well preserved with both drugs without signs of sodium and water retention.     

Cytosolic calcium and lymphoproliferative response during calcium antagonism in men

Objective: A double-blind, placebo-controlled parallel study was conducted on the effect of mibefradil, both an L- and T-type Ca²⁺-channel blocker with a more selective blockade of T-type channels, administered once daily for 1 week to normal male subjects, on blood pressure, intracellular cationic concentrations, sodium-proton exchange rate and ³ H-thymidine incorporation in peripheral blood mononuclear cells (PBMC). Methods: After a 1-week run-in period on placebo, the subjects (n = 40) were allocated to a placebo or a mibefradil group. Placebo or 50 mg mibefradil was administered once daily in the morning for 1 week. All subjects were investigated at baseline and after 1 week of placebo or mibefradil administration. Standing or recumbent blood pressure and heart rate of subjects in the mibefradil group was decreased (P < 0.05 or less) compared with that of subjects in the placebo group. Results: Decreased (P < 0.001) intracellular free Ca²⁺ concentration and reduced (P < 0.001) ³ H-thymidine incorporation in the PBMC were observed in the mibefradil-treated subjects. The intracellular sodium, potassium or magnesium concentration as well as the sodium-proton exchange rate were not changed during mibefradil administration. Conclusion: The blood pressure lowering action of mibefradil in men is accompanied by a decrease in intracellular free Ca²⁺ concentration. Mibefradil also reduced the ³ H-thymidine incorporation or de novo DNA synthesis in PBMC by modulating the calcium homeostasis. Received: 24 June 1998 / Accepted in revised form: 3 October 1998     

Haemodynamic long-term effects of metoprolol at rest and during exercise in essential hypertension.

1 Twelve men with untreated essential hypertension in WHO stage I were studied on an outpatient basis to evaluate the haemodynamic long-term effect of a new beta-adrenoceptor blocker, metoprolol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial pressure were recorded at rest in a supine and sitting position and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with metoprolol (dose 50-250 mg/day) as the sole drug for 1 year and the haemodynamic study was repeated. 4 Mean arterial blood pressure was reduced about 12% at rest and 9% during exercise. The heart rate was decreased about 22% at rest and 20% during exercise. There was no significant compensatory increase in the stroke volume and consequently the cardiac index was reduced about 22% at rest sitting and about 17% during exercise. There was no decrease in total peripheral resistance. 5 No side-effects were seen. 6 The major haemodynamic long-term effects of metoprolol in mild and moderate essential hypertension resemble those seen by other beta-adrenoceptor blockers like alprenolol, atenolol and timolol. The study has not given support to the assumption that metoprolol should cause less depression in cardiac output than other beta-adrenoceptor blockers.     

Treatment of essential hypertension with felodipine in combination with a diuretic

Summary In a double-blind cross-over study, the effect on blood pressure (BP), heart rate (HR) and plasma noradrenaline concentration (pNA) of placebo or felodipine given in addition to hydrochlorothiazide was studied in 12 male patients with essential hypertension, not satisfactorily controlled with the diuretic alone. The first dose of felodipine decreased BP and increased HR for about 6 h. After 4 weeks of treatment with felodipine, BP was reduced for 24 h, whereas HR was only transiently increased. The elimination half-life of felodipine was about 23 h. The plasma noradrenaline concentration increased after felodipine and serum uric acid decreased. Side-effects were few and usually mild.     

Ketanserin in essential hypertension: Effects during rest and exercise

Ketanserin is a new, specific serotonin receptor blocking agent, which causes vasodilatation, presumably by an action on the vascular wall. The antihypertensive response to ketanserin 40 mg twice daily as monotherapy was assessed in 8 patients with essential hypertension. The investigation was an 8 week, double-blind, cross over study, which also included measurements during isometric (handgrip) and dynamic exercise (bicycle ergometry), as well as determination of plasma catecholamines and ketanserin. Ketanserin caused a reduction of supine and standing systolic and diastolic blood pressure (BP) during rest and a slight bradycardia. Although there was attenuation of the pressor response to handgrip, treatment with ketanserin did not really affect the changes in BP or heart rate during exercise, i.e. the base-line differences remained the same. There was no significant correlation between the effect on BP and the plasma level of ketanserin. The changes in BP produced by ketanserin showed little correlation with the initial levels of plasma catecholamines or with alterations in those levels. Although the results did not indicate direct interference by ketanserin with sympathetic tone, the lack of reflexogenic tachycardia, as well as the lack of increase in plasma noradrenaline during hand grip, indicates at least some modulation of autonomic function. It is concluded that ketanserin lowers BP in essential hypertension without interference with cardiovascular reflexes during standing or exercise, and that the compound may offer an alternative approach in the treatment of hypertension.     

Captopril and opiate antagonism in essential hypertension.

Six patients maintained on 50-100 mg captopril, for 2-25 months, were administered captopril 50 mg orally, together with either naloxone or 0.9% saline vehicle (placebo) given intravenously, in a double-blind crossover study. Naloxone did not appear to modify the circulatory effects of captopril in these patients, in contrast to earlier findings after acute captopril administration in normotensives. The results do not support an important endogenous opioid role in the chronic antihypertensive effect of captopril, but provide evidence that different mechanisms may contribute to the early short term falls in blood pressure, compared to the later long term effects.     

国产复方非洛地平缓释片治疗原发性高血压的疗效和安全性

目的 评价国产复方非洛地平缓释片治疗轻、中度原发性高血压的疗效和安全性.方法 采用多中心、随机、双盲双模拟、前瞻性平行对照方法,从321例高血压患者中筛选出经非洛地平(5mg)单药治疗4wk、血压不能满意控制者217例,随机分为试验组和对照组,继续治疗8wk,分别服用复方非洛地平缓释片(由马来酸依那普利和缓释非洛地平组成,5mg/5mg)1片和非洛地平缓释片(5mg)、马来酸依那普利片(5mg)各1片.双盲治疗4wk后DBP不低于90mm Hg(1mm Hg=0.133kPa)者剂量加倍.结果 前4wk非洛地平单药治疗的有效率32.4%,降压无效而人组者血压平均下降(5.4±3.3/2.7±1.9)mm Hg.后8wk联合用药降压的总有效率试验组和对照组分别为88.3%和92.2%,血压分别进一步下降16.2/10.5mm Hg和14.8/11.4mm Hg.单药的不良反应主要为头痛、头晕、头胀、面部潮红等(12.0%).双盲试验期不良反应总发生率试验组和对照组分别为19.4%和14.7%,其中干咳发生率分别占6.5%和8.3%.结论 国产复方非洛地平缓释片治疗轻、中度原发性高血压安全、有效.     

Prizidilol in essential hypertension: long-term effects on plasma volume, extracellular fluid volume, and central hemodynamics at rest and during exercise

We studied the long-term hemodynamic effect of prizidilol (a precapillary vasodilator and beta-adrenoceptor blocker) in 14 men aged 25-66 years with mild and moderate essential hypertension (EH). Cardiac output (by Cardiogreen) and intraarterial blood pressure (BP) were measured at rest and during exercise before and after 8 months of therapy. Changes in body fluid volumes were measured by isotope dilution techniques. After 8 months on prizidilol, eight of the 14 patients were normotensive, and the mean casual BP was lowered by 23/17 mm Hg to 140/91 mm Hg. The intraarterial systolic and diastolic pressures fell by 15-20% of the pretreatment levels at rest supine, sitting, and during 50, 100 and 150 W exercise. The fall in BP was due to a marked reduction in total peripheral resistance ranging from 17 to 23% at rest and during exercise. Cardiac output was unchanged at all work loads, whereas heart rate fell. The stroke volume increased in all settings; at maximum work load by 30%. Body weight and body fluid volumes did not change significantly. Except for some coldness in hands and feet in one patient, which disappeared after 2-3 months, no side effects were observed. We conclude that, in mild and moderate EH, prizidilol induces a substantial fall in BP with an excellent hemodynamic profile both at rest and during exercise.     

Effects of nisoldipine on sympathetic activity, the renin-angiotensin-aldosterone system, and water-sodium-calcium metabolism in patients with essential hypertension

The effects of nisoldipine (Bay k 5552), a long-acting Ca2+ antagonist, on sympathetic activity, the renin-angiotensin-aldosterone (RAA) system, the renal metabolism of water and electrolytes, and parathyroid hormone (PTH) were investigated following single dose and 4 weeks administration. The administration of nisoldipine led to the following results: 1. Mean arterial pressure (MAP) fell and heart rate slightly increased after the first dose, but did not show any appreciable change over 4 weeks treatment. 2. The urinary excretion of sodium, fractional excretion of sodium, plasma renin activity (PRA) and plasma noradrenaline concentration (pNA) were elevated initially, but the trend was to return to pretreatment levels after 4 weeks treatment. 3. A decrease in plasma aldosterone concentration was observed from the commencement of treatment. 4. Urinary excretion of calcium, fractional excretion of calcium and 24-h urine volume (UV) increased from the beginning, and maintained elevated levels after 4 weeks treatment. A decrease in body weight was also observed. 5. Plasma Ca2+ concentration did not change significantly throughout the treatment period, but PTH was decreased significantly both after 1 week and 4 weeks. 6. The percent changes in MAP (% delta MAP) after 4 weeks showed a significant negative correlation with pretreatment levels of MAP and the increment of UV (delta UV), as well as a positive correlation with pretreatment PRA or pNA levels. These findings suggest that in addition to its direct vasodilative effect, suppression of sympathetic activity and the renin-angiotensin-aldosterone system, reduction in body fluid and sodium, and a decrease in PTH and the related calciuresis may contribute to the hypotensive mechanism of nisoldipine.     

Plasma noradrenaline concentration in essential hypertension during long-term beta-adrenoceptor blockade with oxprenolol.

1. Chronic beta-adrenoceptor blockade with oxprenolol causes elevation of plasma noradrenaline levels, as compared with placebo, despite a significant fall in blood pressure and pulse rate. 2. The plasma noradrenaline concentration is not influenced by the frequency of administration or the formulation of the drug. 3. Plasma noradrenaline levels are not correlated with the plasma concentration of the drug. 4. The changes in plasma noradrenaline concentrations support a peripheral rather than central mechanism of action of beta-adrenoceptor blockers in man.     

Glucose tolerance in hypertensive patients during treatment with the calcium antagonist, felodipine.

1 Twelve non-diabetic hypertensive male patients insufficiently controlled by a diuretic were included in a double-blind, randomised study. In addition placebo or felodipine was given for 4 weeks followed by a 2 week wash-out period, after which the alternative treatment was given for another 4 weeks. At the end of each treatment period an oral glucose tolerance test (OGTT) was performed and blood pressure, plasma noradrenaline and felodipine levels were measured. 2 There was no change in either glucose, insulin or glucagon levels during the OGTT after felodipine compared with placebo. Blood pressure was significantly reduced during the dosage interval of felodipine (12 h). Plasma noradrenaline increased significantly after felodipine. Side effects were few. 3 In a separate open study 58 hypertensive patients were treated with felodipine in addition to a diuretic and a beta-adrenoceptor blocker for up to 1 year. There were no significant changes in fasting blood glucose levels during the study.     

Effects of acute and long-term beta-adrenoceptor blockade with propranolol on haemodynamics,plasma catecholamines and renin in essential hypertension

Summary The effect of an acute intravenous and repeated oral doses of propranolol on haemodynamics, plasma and urinary catecholamines and plasma renin activity was studied in patients with essential hypertension. Intravenous injection of propranolol 5 mg produced a fall in cardiac output but had no consistent effect on blood pressure. Treatment with oral propranolol for 24 weeks lowered cardiac output and blood pressure; total peripheral resistance did not differ from the pretreatment values. Neither acute intravenous nor chronic oral administration of the beta-blocker affected the resting plasma levels of noradrenaline and adrenaline. Long-term treatment with propranolol reduced urinary excretion of vanilmandelic acid without affecting urinary catecholamine excretion. Acute intravenous injection of propranolol decreased plasma renin activity less than did chronic oral treatment with the drug. The observed time course of plasma renin activity was compatible with the view that suppression of this enzyme contributed to the antihypertensive effect of propranolol.     

Blood pressure and catecholamines following exercise during selective beta-blockade in hypertension

Summary This study examines and compares the hemodynamic and sympathoadrenal response to bicycle exercise in hypertensive subjects during two weeks' treatment with a cardio-selective (metoprolol) and nonselective (propranolol) beta-blocker. The increase in plasma norepinephrine and epinephrine concentration following exercise was augmented to a similar degree with each beta-blocker. Pre-exercise blood pressure and heart rate were similar for the two drugs. However immediately after exercise and particularly after resting for 20 min post exercise, diastolic blood pressure was lower during metoprolol treatment. Systolic blood pressure was also lower 20 min post exercise during metoprolol treatment. These observations indicate that cardio-selective beta-blockers offer advantages in blood pressure control during exercise through intact vascular ₂-adrenoceptors opposing sympathetically mediated vasoconstriction.     

Long-term hemodynamic effects of penbutolol at rest and during exercise in essential hypertension

Summary Thirteen men with previously untreated essential hypertension (WHO Stage I) were studied as out-patients. Oxygen consumption, heart rate, cardiac index and brachial arterial pressure were recorded at rest supine and whilst sitting position, and during steady state exercise at 50, 100 and 150 W. The subjects were then treated with penbutolol 20–80 mg/day. In 12 responding patients hemodynamic study after 1 year demonstrated that systolic, diastolic and mean arterial pressure were reduced by approximately 20% at rest and 18% during exercise. Heart rate was reduced about 24% at rest and 26% during exercise. The stroke index did not show any significant change during rest, but during exercise the post-treatment values were 8%, 13% and 18% higher than the pre-treatment values at the 50, 100 and 150 W exercise levels, the last two changes being significant. Thus, the reduction in cardiac index during exercise was less than the reduction in heart rate — about 15%, but 24% when sitting at rest. The total peripheral resistance index did not show any significant change at rest or during exercise. Dizziness or muscular fatigue occurred in 6 patients during the first two weeks of treatment. From then on no side-effects were noted. It is concluded that the hemodynamic effects of longterm treatment with penbutolol in mild to moderate hypertension largely resemble those after the majority of other beta-blockers.     

Different aortic reflection wave responses following long-term angiotensin-converting enzyme inhibition and beta-blocker in essential hypertension

1. In arterial hypertension, aortic wave reflections contribute to determining central systolic and pulse pressures. The present study assessed the central pressure alterations at the level of the common carotid artery following 1 month treatment with perindopril or atenolol and investigated during the 8 h following drug intake. 2. Twenty patients suffering from permanent hypertension were included after a 4 week run-in placebo period in a double-blind, randomized cross-over study comparing the angiotensin-converting enzyme (ACE) inhibitor perindopril with the beta-blocker atenolol during a 4 week treatment period. 3. Before and during the 8 h after drug intake, serial measurements included brachial artery systolic and diastolic blood pressures (SBP and DBP, respectively; mercury sphygmomanometer), carotid artery SBP and pulse pressure (PP; applanation tonometry), aortic pulse wave velocity (Complior; Colson, Les Lilas, France) and arterial wave reflections from the aorta (applanation tonometry; Sphygmocor; PWV Medical, Sydney, NSW, Australia). 4. Both treatments decreased brachial and carotid artery SBP, DBP and PP. Heart rate and pulse wave velocity decreased following atenolol (P < 0.001). Pulse wave velocity was reduced slightly following perindopril (NS). Arterial wave reflections were significantly (P < 0.001) decreased with perindopril in comparison with atenolol, but this effect on wave reflections was not associated with a larger decrease in carotid artery PP. 5. Thus, during chronic treatment, ACE inhibition and selective beta1-adrenoceptor blockade resulted in a similar decrease in brachial and carotid artery PP, but only atenolol reduced heart rate. Aortic pulse wave velocity was reduced with both drugs, but atenolol appeared more effective in improving aortic stiffness. Arterial wave reflections were decreased only following perindopril. 6. Central pulse pressure was improved following 1 month treatment with an ACE inhibitor or beta-adrenoceptor blockade following a decrease in arterial wave reflections with perindopril and a higher decrease in regional aortic stiffness with atenolol.     

非洛地平加吲哒帕胺与加利尿药对高血压左室肥厚及心功能影响比较

目的 :比较非洛地平联用吲哒帕胺与非洛地平联用利尿药治疗老年中、重度高血压的疗效和对左室肥厚 (LVH )、左室舒张功能的影响。方法 :6 0例高血压伴左室肥厚病人随机分为 2组 ,停用降压药 1wk。一组非洛地平 5mg联用吲哒帕胺 2 .5mg ,po ,qd× 4 8wk ,另一组非洛地平 5mg联用氢氯噻嗪 2 5mg ,po ,qd× 4 8wk。结果 :非洛地平联用氢氯噻嗪组和联用吲哒帕胺组降压总有效率分别为90 % ,83% (P >0 .0 5)。 2组均可明显改善LVH及左室舒张功能 ,(P <0 .0 1)。但非洛地平联用吲哒帕胺组改善更显著 ,组间比较 ,P <0 .0 1。不良反应小 ,不影响糖、脂肪代谢。结论 :对老年中、重度高血压 ,非洛地平联用吲哒帕胺是一组适合长程治疗的满意组合     

Long-term haemodynamic effects of sustained-release trimazosin at rest and during exercise in essential hypertension

Summary The long-term haemodynamic effect of sustained-release trimazosin (mean daily dose 418 mg) at rest and during exercise has been examined in 14 male patients (age 30–61 y) with previously untreated mild or moderate essential hypertension. Cardiac output (dye dilution), heart rate and intra-arterial blood pressure were measured supine and sitting at rest, and during bicycle exercise.After 11 months of trimazosin treatment the mean casual blood pressure was reduced from 165/106 mm Hg to 147/92 mm Hg. The intra-arterial systolic and diastolic pressure was reduced by 3–7% at rest and during 50, 100 and 150 W exercise. Total peripheral resistance was reduced by 8–14% and cardiac output was slightly higher (2–8%) in all situations.Stroke volume and heart rate remained unchanged, as did body fluid volumes (isotope dilution) and body weight.Side effects were minor and transient.Thus, the haemodynamic responses to trimazosin are similar to but weaker than those of other alpha₁-adrenoceptor blockers. The efficacy of the sustained-release formulation of trimazosin was low and daily doses above 600 mg are likely to be needed by many patients.     

Beta-adrenergic receptors and reflex tachycardia after single and repeated felodipine administration in essential hypertension.

To verify the possible contribution of beta-adrenergic receptor down-regulation to the reversal of reflex tachycardia during chronic treatment with a dihydropyridine calcium antagonist, 11 hypertensive patients were studied with noninvasive blood pressure (BP) and heart rate (HR) monitoring after a placebo period, and on the first and seventh day of felodipine administration, 5 mg twice daily. Plasma catecholamines and neutrophil beta-adrenergic receptors were measured on the first and seventh day of treatment, immediately before and 2 h after drug administration. The first administration of felodipine was followed by a significant drop in BP (peak reduction in mean BP 24 +/- 7 mm Hg), lasting 6 h and mirrored by reflex tachycardia (peak increase in HR 14 +/- 9 beats/min). On the morning of the seventh day, 12 h after the previous felodipine administration, mean BP (MBP) was 16 mm Hg lower than on the last placebo day, while HR was unchanged. The next administration of felodipine was followed by a smaller drop in BP (MBP - 15 +/- 7 mm Hg; NS vs. placebo), while reflex tachycardia was the same as after acute felodipine (HR 13 +/- 8 beats/min; p less than 0.05 vs. placebo, NS vs. acute administration). Plasma noradrenaline concentration increased after both acute and chronic administration (p less than 0.0001), and preadministration values were highest on day 7 (p less than 0.05). Neutrophil beta-adrenergic receptor density and affinity did not change either acutely or chronically. This study gives both indirect and direct evidence that beta-adrenoceptor down-regulation does not occur during repeated felodipine administration in hypertension. Reflex tachycardia is not abolished, but is reset to lower BP levels.     

Angiotensin converting enzyme inhibition, parasympathetic activity and exercise in essential hypertension

Reduced parasympathetic activity has been reported in essential hypertension. Converting enzyme inhibition seems to increase parasympathetic tone. In order to evaluate the effects of enalapril on parasympathetic control of heart rate, the authors studied ten mild-to-moderate essential hypertensive patients (7 F, 3 M), treated for 2 weeks with placebo and for 1 month with enalapril. Compared to placebo, enalapril significantly reduced blood pressure (p less than 0.005 at least, both systolic and diastolic), without any change in heart rate. Enalapril enhanced parasympathetic activity as judged by the increased variation of heart period (VHP) during regular breathing. VHP was derived during continuous ECG recording by the difference between the mean of all maximum and minimum R-R intervals, taken as a measure of respiratory sinus arrhythmia: the higher the VHP, the higher the parasympathetic cardiac influence and vice versa. The response to exercise, used as an index of sympathetic stimulation, was not modified by enalapril: the heart rate peak reached during either static (hand grip) or dynamic (bicycle ergometer) exercise and the slope of the increase in blood pressure were unchanged. Therefore, enalapril appears to increase parasympathetic tone in essential hypertension, without any interference with sympathetic adaptation to stress.