Haemodynamic and hormonal changes during acute and chronic diuretic treatment in essential hypertension

Summary The short- and long-term effects of diuretic treatment with chlorthalidone 50 mg/day on haemodynamic and hormonal parameters in patients with essential hypertension (WHO grade I) were investigated. After three days of treatment, all patients showed a rise in plasma renin activity (PRA), plasma aldosterone (PA), urinary norepinephrine excretion (UNE) and heart rate (HR), and a decrease in body weight (BW) and extracellular volume (ECV) and blood volume (BV); the change in blood pressure (BP) was variable. The changes in BP were correlated with those in BV. After three months of therapy, the signs of volume depletion tended to fade, but the lower ECV persisted. In contrast to the 4-day study, after three months the change in BP correlated inversely with changes in ECV and renin dependency (saralasin response), and positively with PRA and changes in UNE. It is concluded that the BP response to diuretic treatment is determined by the adaptation with time of the haemodynamic reactions to the volume-depleted state. Whether this adaptation will take place cannot be predicted from the control values of the parameters studied, or from acute changes observed during the first days of treatment.     

Antihypertensive and hormonal effects of single oral doses of Captopril and Nifedipine in essential hypertension

Summary In a single-dose crossover study Captopril (SQ 14225), 1 mg/kg body weight, and Nifedipine (Bay a 1040) 20 mg were administered orally to 12 hospitalized patients with essential hypertension (Stage 1 or 2, W. H. O.). Both drugs significantly reduced blood pressure, but each dose acted differently: the mean maximum arterial pressure reduction was faster and greater with Nifedipine than with Captopril: –23±2% at 37±15 min and –17±1% at 86±25 min, respectively. Captopril inhibited angiotensin II and aldosterone production, but did not accelerate heart rate or stimulate vasopressin release. Nifedipine stimulated vasopressin release and increased heart rate, but the renin angiotensin aldosterone system was not significantly affected. The blood pressure reduction was related to the initial level of activation of the renin angiotensin system only for Captopril. The blood pressure reduction induced by one drug was not related to that produced by the other in the same patient.     

Aliskiren as a novel therapeutic agent for hypertension and cardio-renal diseases

Objectives High blood pressure (BP) is a major risk factor for cardiovascular and renal complications. A majority of treated hypertensive patients still complain of high BP. The renin‐angiotensin aldosterone system (RAAS) has been a centre‐stage target for all the cardiovascular and cardio‐renal complications. Aliskiren, is the first direct renin inhibitor (DRI) to be approved by the US FDA. Renin controls the rate‐limiting step in the RAAS cascade and hence is the most favorable target for RAAS suppression. Key findings This review article strives to summarize the pharmacokinetic, preclinical and clinical studies done so far pertaining to the efficacy of aliskiren. Further, the pharmacology of aliskiren has been comprehensively dealt with to enhance understanding so as to further research in this unfathomed area in the multitude of cardiovascular disorders and renal diseases. Summary Aliskiren has been shown to have comparable BP‐lowering effects to other RAAS inhibitors. Recent clinical trials have indicated that it might contribute significantly in combination with other agents for the protection of end‐organ diseases.     

Antihypertensive effect of fractionated sublingual administration of nifedipine in moderate essential hypertension

Summary The magnitude and duration of the antihypertensive effect of nifedipine were studied in 7 cases of moderate essential hypertension. In a double-blind crossover study, nifedipine 10 mg or a placebo were administered sublingually 4 times a day for 2 days, and the results were compared. Each dose of nifedipine reduced systolic and diastolic blood pressure by 14% both in the supine and upright positions. The antihypertensive action lasted for about 3 h and it was not cumulative. The reduction in blood pressure was associated with a temporary increase in heart rate. Administration of nifedipine 10 mg did not significantly raise plasma renin activity or plasma aldosterone. The drug was well tolerated and no side effects were detected.     

Blood pressure response to enalaprilic acid in essential hypertension: Dose-response and effect of pre-treatment with furosemide

Summary Enalaprilic acid (MK 422), the active metabolite of enalapril, has recently become available for intravenous administration. In order to establish the proper dose for rapid blood pressure reduction, 9 patients with moderate to severe essential hypertension on a constant sodium intake of 100 mmol/24 h were studied. They received four single doses of MK 422 according to an up-and-down titration schedule. Doses between 5 and 80 mg resulted in effective blood pressure reduction with an onset of action of about 10 minutes. Within this dose range the response was flat. No symptomatic hypotension was observed. The fall in blood pressure was less pronounced in patients with low initial plasma renin activity (PRA). Accordingly, a study was done to show whether the blood pressure response could be augmented by preceding stimulation of PRA by injection of 40 mg furosemide 15 minutes before the administration of MK 422. PRA increased after furosemide, but the blood pressure response to MK 422 was not augmented.     

Effects of dilevalol,an R,R-isomer of labetalol,on blood pressure and renal function in patients with mild-to-moderate essential hypertension

Summary The effects of oral dilevalol (an R, R-isomer of labetalol), a new -adrenoceptor blocker with ₂-receptor stimulating and -recepter blocking properties on blood pressure, renal function, plasma renin activity (PRA) and plasma aldosterone have been studied in 15 patients with mild-to-moderate essential hypertension treated with it for 6 weeks.Two patients with apparent treatment failure and one patient who developed muscle pain and cramps, and had an elevated creatine phosphokinase level, were excluded from the study.Dilevalol monotherapy 100 mg once daily for 6 weeks significantly lowered both the systolic and diastolic blood pressure compared to placebo. Total renal vascular resistance was significantly reduced, and RBF and GFR remained unchanged. Dilevalol significantly decreased PRA.The results suggest that prolonged daily treatment with dilevalol preserves renal function and produces a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. The ancillary pharmacological properties of dilevalol rather than PRA suppression may be relevant to its renal effects.     

比索洛尔与培哚普利治疗原发性高血压的疗效及心率变异性比较

目的观察比索洛尔与培哚普利治疗高血压的降压效果及对心率变异性的影响。方法选择原发性高血压患者60例随机分为比索洛尔（A）组30例和培哚普利（B）组30例,疗程为4周,治疗前后均作动态血压（ABPM）监测,并作心率变异性分析。结果降压疗效：A组显效9例（30．0％）,有效11例（36．7％）,无效10例（33．3％）,总有效20例（66．7％）;B组显效4例（13．3％）,有效8例（26．7％）,无效18例（60．0％）,总有效12例（40．0％）,两组总有效率差异有统计学意义（X2=3．95,19〈0．05）;两组治疗后极低频（VLF）、低频（LF）水平明显低于治疗前（P〈0．05或P〈0．01）;A组总不良反应总发生率（3．1％）低于B组（10．0％）（X2=3．85,P〈0．05）。结论比索洛尔能有效地降低血压,减慢心率,改善高血压患者的心率变异性,从而防止高血压患者心血管事件发生。     

Acute effects of prizidilol on blood pressure,heart rate,catecholamines, renin and aldosterone in essential hypertension

Summary Prizidilol is a new antihypertensive agent reported to possess combined precapillary vasodilator and betareceptor-blocking properties. To clarify the profile of the acute effects of prizidilol in man, a variable dose study was performed in 8 patients with benign essential hypertension. Blood pressure, heart rate, plasma renin activity, aldosterone, plasma and urinary catecholamines and electrolytes were determined at short intervals before and up to 23 h after oral administration of placebo and prizidilol 150, 300 and 600 mg. The 4 studies were performed at weekly intervals according to a Latin square design. Prizidilol produced dose-dependent decreases in supine and upright blood pressure, with an initial change after about 2 h and maximal effects from 4 to 8 h after drug ingestion. Following a high dose of prizidilol, supine mean blood pressure (average 128 mmHg prior to treatment) was normalised (<107 mmHg) from 3 to 7 h and was still below predose levels 23 h after ingestion. The only reported side effects were postural dizziness in 2 cases (corresponding to a fall in systolic upright blood pressure to <95 mmHg) and headache in one case. A biphasic variation in heart rate and plasma renin activity, with an early drop and a subsequent tendency to a slight rise, was observed after an intermediate or high dose of prizidilol. Plasma norepinephrine levels were increased by a high dose of prizidilol, while plasma epinephrine, aldosterone and plasma and urinary electrolytes were not consistently changed. Prizidilol in a single oral dose appeared to be a potent antihypertensive agent. The profile of heart rate and plasma renin point to early dominance of beta-blockade followed by appearance of the concomitant vasodilator properties of prizidilol.     

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension

Summary Mean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 — 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r=0.80, p<0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the -blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r=0.79, p<0.001).     

Influence of prostaglandin inhibition on dihydralazine induced acute effects in patients with essential hypertension

In order to determine whether vasodilator prostaglandins (PG) contribute to the acute vascular and endocrine responses to intravenously administered dihydralazine, we examined its effects on systolic and diastolic blood pressure (BP), heart rate (HR), plasma renin activity (PRA) and the plasma catecholamines (CA) noradrenaline (NA), adrenaline (A) and dopamine (DA) as well as on sodium, potassium and creatinine clearance (CNa, CK and CCr respectively), urinary flow rate, urinary catecholamines (NA, A, DA) and iPGE2 and i6-keto-PGF1 alpha excretion rate in six patients (three females, three males) with essential hypertension before and after PG synthesis inhibition by the nonsteroidal, anti-inflammatory agent diclofenac. Diclofenac, which reduced urinary iPGE2 and i6-keto-PGF1 alpha excretion by 62% (P = 0.026) and 45% (P = 0.037), respectively, antagonized dihydralazine induced diastolic BP reduction (P = 0.0009), HR increase (P = 0.01), noradrenaline and adrenaline increase in plasma (P = 0.02 and P = 0.05, respectively), increase in urine flow rate (P = 0.03), sodium clearance (P = 0.01) and tended to reduce PRA. We conclude that dihydralazine-mediated changes can be reduced by cyclo-oxygenase inhibition, most likely on the basis of a reduction of its effect on peripheral resistance, thereby leading to less reflex activation of the sympathetic nervous and renin-angiotensin systems.     

Hypotensive effects of diltiazem to normals and essential hypertensives

Summary The hypotensive effect of acute and long-term, intravenous and oral administration of the calcium antagonist, diltiazem, was investigated in 8 normotensive volunteers and 55 patients with essential hypertension. Diltiazem i.v. infusion of 45 mg/h (0.5 mg/min, then 1.0 mg/min, each for 30 min rapidly decreased both blood pressure (BP) from 164±22/98±8 to 144±15/86±9 mmHg (mean±SD) and total peripheral resistance from 32.6±8.4 to 25.3±5.4 mmHg/l/min (p<0.001), and increased stroke volume from 58.2±9.5 to 64.2±8.6 ml/beat (p<0.05). It altered neither heart rate nor cardiac output in the hypertensives (n=10). Oral diltiazem 60 mg rapidly decreased BP from 155±10/103±6 to 142±12/90±8 mmHg after 3 hours (p<0.01/p<0.001) in hypertensives (n=8), but not in normotensives (n=8). Diltiazem 90 mg p.o. decreased BP from 157±15/102±9 to 129±13/83±8 mmHg (p<0.01) in hypertensives (n=15), and reduced the heart rate from 71±8 to 65±8 beats/min (p<0.01). The drug did not change plasma renin activity either in normotensives or hypertensives. The fall in diastolic BP was correlated with the plasma diltiazem concentration (r=0.910, n=6, p<0.05). Long-term treatment with diltiazem 30mg t.d.s. decreased BP from 163±12/104±8 to 145±9/88±9 mmHg (p<0.001, n=13), and 60mg t.d.s. decreased BP from 169±15/102±6 to 148±13/87±8 mmHg (p<0.001, n=8), and significantly reduced the heart rate (p<0.01) in hypertensives. Thus, the hypotensive action of diltiazem, which is due to arterial dilatation, is effective, either on intravenous or oral administration, during acute and long-term treatment of essential hypertension.     

Plasma concentrations of propranolol in patients with essential hypertension

Summary Sixteen patients with essential hypertension were treated with propranolol 160 to 640 mg daily for three months. Significant decreases both in recumbent and standing blood pressure were observed after three days treatment and subsequently. Reduction of blood pressure was more pronounced when the dose of propranolol was increased. However, neither the mean dose nor the plasma concentration of propranolol could be correlated with the mean decrease in blood pressure. There was great interindividual variation in the plasma concentrations of propranolol produced by the same daily dose. The initial stimulation of plasma renin activity and the therapeutic response to propranolol could not be correlated.     

Effects of once daily indapamide and pindolol on blood pressure,plasma aldosterone concentration and plasma renin activity in a general practice setting

Summary Sixteen patients with essential hypertension completed a double blind factorial trial comparing the effects of indapamide (2.5 mg daily) and pindolol (10 mg daily) on blood pressure, heart rate, plasma renin activity and plasma aldosterone concentration. There were four randomised test phases of eight weeks each during which patients received indapamide alone, pindolol alone, indapamide plus pindolol and no active treatment (placebo). Blood pressure and heart rate were measured every two weeks. Supine mean arterial pressure fell from 117 mm Hg in the placebo phase to 111 mm Hg in the indapamide phase, 106 mm Hg in the pindolol phase and 103 mm Hg in the combined indapamide plus pindolol phase. Factorial analysis confirmed that the hypotensive effects of the two drugs were additive, without evidence of potentiation or antagonism. Indapamide caused significant reductions in plasma potassium and chloride, and increases in plasma bicarbonate and urate concentrations; it also caused increases in plasma renin activity and aldosterone concentration. These changes are similar to those observed with thiazide diuretics.     

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.     

Effects of the dopaminergic agonist cianergoline on blood pressure,the renin-angiotensin-aldosterone axis and the sympathetic nervous system in patients with essential hypertension

Summary Cianergoline is a new dopaminergic agonist with a predominant cardiovascular action. Its effects on blood pressure, the renin-angiotensin-aldosterone axis, the sympathetic nervous system and lipid metabolism were assessed in 20 patients with benign essential hypertension. Cianergoline given in increasing doses for 4 weeks (maximum daily dose 12±2 mg (SD)) and placebo both caused a slight decrease in arterial pressure, (from 159/104 to 152/98 mm Hg and from 154/104 to 149/103 mm, respectively; difference not significant). Supine and upright plasma renin activity, plasma aldosterone, norepinephrine, epinephrine and dopamine levels, urinary catecholamine excretion rates as well as serum prolactin, low and high density cholesterol and triglyceride concentrations were not changed after cianergoline or placebo. Total serum cholesterol and triglyceride levels decreased significantly after placebo, but were unchanged after cianergoline. 3 out of 10 patients in the cianergoline group complained of nausea. The findings indicate that the new dopaminergic agonist cianergoline exerts only a mild blood pressure lowering effect in patients with essential hypertension and does not modify the release of prolactin, lipid metabolism or the basal activity or postural responsiveness of the renin-angiotensin-aldosterone axis and of the sympathetic nervous system.     

应用动态血压监测评估氨氯地平、培哚普利治疗高血压效果分析

目的观察氨氯地平、培哚普利治疗高血压的效果扣安全性。方法选取42例高血压患者给予氨氟地平、培哚普利联合治疗,通过24h动态血压监测评估治疗4周后患者治疗效果。结果治疗4周后患者收缩压、舒张压均低于治疗前,差异均有统计学意义（P〈0．05）。治疗4周后患者24h、白昼、夜间的收缩压和舒张压均低于治疗前,差异均有统计学意义（P〈0．05）。结论氨氯地平、培哚普利可以有效地降低血压水平,减轻血压负荷。     

缬沙坦干预非杓型高血压者恢复杓型血压昼夜节律后对血醛固酮水平的影响

目的：了解非杓型高血压患者进行药物干预以恢复其杓型血压昼夜节律，并观察节律改变后对血浆醛固酮水平的影响。方法：对杓型和非杓型两组原发性高血压患者分别给予缬沙坦160mg／d，观察对血压昼夜节律的影响，并监测用药前后血浆醛固酮水平的变化。结果：对杓型和非杓型高血压患者应用缬沙坦治疗前后收缩压及舒张压均有不同程度的下降，非杓型组夜间收缩压及舒张厍的下降值与杓型相比有统计学差异，出现了明显的昼夜节律，血浆醛固酮水平出现了统计学差异。结论：缬沙坦对非杓型高血压患者有良好的降压作用，并能恢复非杓型高血压患者的昼夜节律，向杓型血压变化。     

Co-dergocrine mesylate inhibits the increase in plasma catecholamines caused by nifedipine in essential hypertension

Summary Co-dergocrine mesylate (Cod), which inhibits norepinephrine secretion by stimulating presynaptic dopamine receptors, and has no known metabolic side effect, has an additive antihypertensive effect to that of Nifedipine (Nif). Plasma norepinephrine, epinephrine, renin activity and aldosterone have been measured after acute administration of Nif and Cod alone and in combination to 18 patients with a diastolic blood pressure > 105 mm Hg in a cross-over, randomized, double-blind study. Every patient received 4 mg Cod then 20 mg Nif, placebo then 20 mg Nif and 4 mg Cod then placebo. The second treatment was always given 1 h after the first medication. Blood pressure was measured before and every 15 min during the study period. Blood for measurement of catecholamines, aldosterone and renin activity was collected before medication, 1 h after the first dose and 90 min after the second treatment.Blood pressure was significantly lower (P < 0.05) where Cod preceded Nif. Cod caused a significant decrease in plasma norepinephrine from 293 to 202 pg · ml^–1 and in epinephrine from 67 to 55 pg · ml^–1. The Nif-induced increase in norepinephrine from a pre-treatment value of 293 pg · ml^–1 with preceding Cod to 331 pg · ml^–1 was much less than the increase with placebo as premedication, from 284 to 440 pg · ml^–1. Nif caused an increase in renin activity but no increase in aldosterone.Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication. Due to the stabilizing action of Cod on catecholamines and on the side effects of Nif, Cod may be preferable to other antihypertensives in augmenting the antihypertensive action of Nif.     

Time-course of the anti-hypertensive action of atenolol: Comparison of response to first dose and to maintained oral administration

Summary To show whether repeated administration of atenolol for several days would influence its pharmacokinetic parameters and the extent and duration of the pharmacologic responses, the plasma level of atenolol and changes in heart rate, blood pressure and plasma renin activity were measured in 12 hypertensive patients at various times of day (9 a. m., 12 noon, 3 p. m. and 7 p. m.) after oral administration of the first dose of atenolol 100 mg, again during the 7th and 14th days of continued once-daily administration of the same dose, and finally during the three days following withdrawal of the drug. The peak plasma concentration of atenolol (about 600 ng/ml) was found 3 h after administration of the first dose, and measurable amounts (50–70 ng/ml) were found after 24 h. None of the pharmacokinetic characteristics were changed by administration of a single daily dose for two weeks. After withdrawal of the drug, detectable amounts of atenolol were found in plasma for at least 48 h. The first dose of atenolol caused prompt (3 h) and prolonged (up to 24 h) lowering of supine and standing systolic and diastolic blood pressures, slowing of supine and standing heart rate, reduction of the blood pressure and heart rate responses to dynamic exercise, and a decrease in plasma renin activity. The extent and time-course of all these responses were not influenced by repeated once-daily administration of the 100 mg dose for two weeks. Most of the effects continued during the withdrawal days, the lowering of blood pressure being somewhat more prolonged than the slowing of heart rate. It is concluded that a once-daily dose of atenolol 100 mg decreases blood pressure and heart rate throughout the following 24 h, without excessive daily fluctuation in its effects, and without signs of tolerance or accumulation.