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.     

Changes in renal function induced by endralazine,a new antihypertensive drug

Summary The effects of endralazine, a new antihypertensive hydrazinopyridazine derivative, on heart rate, mean blood pressure (mBP), glomerular filtration rate (GFR), effective renal plasma flow (C_PAH), urine volume (V), the clearance of Na, K, urea (U_r) and uric acid (U_A), plasma renin activity (PRA) and plasma aldosterone (PA) were studied in hypertensive patients after a single oral dose of 10–15 mg, and after 8–17 days of treatment with daily doses of 15–90 mg. In the acute experiments, heart rate increased by 27%, mBP decreased on average by 17% and GFR by 33% and C_PAH fell by only 5%. Urine volume and electrolyte clearance were also depressed. There was a significant increase in PRA and PA. The fall in GFR correlated directly with mBP, C_PAH and the product (mBP×C_PAH). The logarithms of the Na clearance and V were correlated with GFR and mBP. The logarithms of the fractional excretion of Na and water also correlated with mBP, suggesting that tubular reabsorption of sodium and water may be affected by change in mBP. The fractional potassium excretion correlated directly with C_PAH and ln PA. In contrast, on sustained daily treatment, mBP was less depressed (9%), but GFR increased strikingly by 27% and C_PAH by 46%. The body weight increased by 4.5% as a consequence of salt and water retention. GFR was correlated with C_PAH, the product (mBP×C_PAH) and the increase in body weight. Thus, the improvement in GFR and effective renal plasma flow observed under these conditions may be due, in part, to volume expansion. However, a direct renal vasodilating effect of the drug appears to be the more important determinant.     

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.     

Acute changes in renal function induced by bisoprolol,a new cardioselective beta-blocking agent

Summary The acute effects of bisoprolol 10 mg i.v., a new beta₁-selective adrenoceptor antagonist, on heart rate, mean blood pressure (mBP), glomerular filtration rate (GFR), para-aminohippuric acid clearance (C_PAH), sodium clearance, urine volume and plasma renin activity (PRA), were studied in 6 patients with essential hypertension. Heart rate decreased by 23%, mBP remained unchanged, and GFR decreased by 14% and C_PAH by 23%. PRA was depressed on average by 25%. Urine volume and sodium clearance also declined by 9 and 13%, respectively, but the changes were not statistically significant. The fall in heart rate was significantly correlated with that in GFR and C_PAH. Changes in GFR were correlated significantly with those in C_PAH. The acute changes in renal function induced by bisoprolol are considered to be due to a reduction in cardiac output and increased systemic vascular resistance.     

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.     

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.     

Effect of oral labetalol on plasma catecholamines,renin and aldosterone in patients with severe arterial hypertension

Summary Arterial blood pressure and plasma catecholamines, renin activity and aldosterone concentration in 12 patients with severe essential hypertension were studied before and after combined -and -adrenergic receptor blockade induced by oral labetalol treatment for 2 months. Furosemide in a fixed dose was employed as a basic antihypertensive agent throughout the study. Blood pressure was adequately controlled in only 6 patients. Mean body weight increased by 1.8 kg and there was a rise in body weight which was inversely correlated with the fall in standing mean blood pressure. The mean plasma noradrenaline concentration decreased from 0.30 to 0.20 ng/ml, whereas plasma adrenaline did not change significantly. Plasma renin activity and aldosterone concentration varied greatly, but the mean values did not change significantly. Change in body weight was correlated inversely with changes in plasma noradrenaline and renin. The results suggest that labetalol, through its combined - and -adrenergic receptor blocking action, induces a rise in body weight, probably due to sodium and fluid retention, which partly counterbalances the antihypertensive effect of labetalol, and partly modifies both renin and sympathetic nervous activity.     

Effects of a new long-acting beta-blocker bopindolol (LT 31-200) on blood pressure,plasma catecholamines,renin and cholesterol in patients with arterial hypertension

Summary Bopindolol (LT 31-200), a new, long-acting, non-selective beta-blocker, was given as monotherapy to 13 patients, 12 with essential hypertension and 1 with renovascular hypertension. After a placebo period of 4–6 weeks, bopindolol was given once daily, starting with 1 mg and subsequently increasing at two-weekly intervals to 2 and 4 mg once daily until a diastolic blood pressure⩽90 mmHg was achieved. The effective dose was continued for 12 weeks. In 10 patients plasma levels of renin, noradrenaline, adrenaline and cholesterol were measured during placebo and after 3 months of therapy. Blood pressure and heart rate were lowered significantly during bopindolol treatment. The mean effective dose was 2.2 mg per day. In 10/13 patients a diastolic blood pressure⩽90 mmHg was achieved. Side effects were minimal. Changes in plasma noradrenaline and adrenaline were small and not significant, but renin and cholesterol were significantly reduced. Thus, LT 31-200 is an effective and well tolerated beta-blocker when given in a once daily dosage.     

Antihypertensive assessment of two new angiotensin-converting enzyme (ACE) inhibitors: CGS 13945 and CGS 13934

CGS 13945 (1-(4-(ethoxycarbonyl)-2,4-dimethyl-2R,4R-butyryl)-2,3-dihydro-2S-indole-2-carboxylic acid) and CGS 13934 (its dicarboxylic acid derivative) are nonthiol angiotensin-converting enzyme (ACE) inhibitors which have antihypertensive properties. Acute administration of CGS 13945 lowers systolic pressure in spontaneously hypertensive rats (SHR) and sodium depletion enhances the blood pressure reduction; the acute antihypertensive effects of CGS 13934 are minimal. Acute administration of CGS 13945 or CGS 13934 also elevates plasma renin activity, especially in sodium-depleted SHR. CGS 13945 reduces systolic blood pressure of SHR in a dose-dependent manner following oral administration on each of 4 consecutive days, whereas the antihypertensive effect of CGS 13934 is not apparent until the third day of drug administration. After 3 consecutive daily doses, 30 mg/kg (PO) of CGS 13945, CGS 13934 or captopril produce equal antihypertensive effects. CGS 13945 also reduces systolic blood pressure of sodium-depleted normotensive rats. Daily oral administration of CGS 13945 to either sodium-replete or -deplete perinephritic hypertensive dogs does not appreciably affect mean arterial pressure. Results suggest that CGS 13945 must be endogenously de-esterified to the free acid form for endowment of optimal biological activity to inhibit the ACE. While the rat is apparently capable of such hydrolysis, the dog's capacity for endogenous hydrolysis appears to be quite limited.     

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.     

Postprandial changes in supine and erect heart rate,systemic blood pressure and plasma noradrenaline and renin activity in normal subjects

Summary The haemodynamic effects of a standard meal were assessed in a balanced cross-over study in eight normal fasting subjects, investigated under conditions applicable to many drug tests.Both the supine and erect diastolic blood pressure were reduced on average by 10 mmHg over the 4 h following the meal.The supine systolic pressure was increased on average by 2 mmHg, a difference of no biological relevance. Erect systolic blood pressure was not affected by eating.Supine heart rate was slightly but significantly increased, but the erect heart rate did not change.Postprandial plasma renin activity was increased. Venous plasma noradrenaline levels in the supine position were not affected by eating and after standing erect, and immobile for 5 min they were only slightly and not-significantly increased.A food-induced vasodepressor response combined with baroreceptor resetting is considered to have occurred in this population. The changes had a gradual onset, reaching their maximum about 2 h after eating and they were still evident after 3 h. Eating should be considered as an important potential source of bias in cardiovascular studies.     

Antihypertensive effect of labetalol, a new alpha- and beta-adrenergic blocking agent.

Labetalol (AH5158) a new alpha- and beta-adrenergic blocking agent was given to 12 hypertensive patients for an average of 7 months. Statistically significant and clinically relevant reductions of blood pressure both in the recumbent and standing positions were observed. Side effects were few and the absence of postural hypotension was noted.     

Failure of methyclothiazide to lower home blood pressure level in “essential” hypertensive and normotensive young men,despite significant plasma volume contraction

Summary Home blood pressure measurements were used to assess the effect of methyclothiazide in young essential hypertensive and normotensive males. Although plasma volume was reduced by approximately 10 percent, blood pressure was not reduced in either group. The lack of effect on blood pressure was probably not attributable to dosage employed, as doubling the dose (5 to 10 mg) in the normal subjects (who were equilibrated on constant diet) did not significantly increase changes in plasma volume, plasma renin activity, aldosterone excretion, urine sodium or blood pressure. The higher dose did result in greater changes in plasma potassium and uric acid. Homeostatic mechanisms which limit the volume mediated and other antihypertensive effects of methyclothiazide apparently achieved complete compensation in these young males. This suggests that thiazide diuretics may not be the drug of first choice in the treatment of hypertension in young adults. Further studies with other diuretics are clearly necessary before the significance of these findings can be fully assessed.     

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.     

Acute effects of a new vasodilator,Ro 12-4713, on blood pressure,plasma renin activity,aldosterone and catecholamine levels,and renal function in hypertensive and normal subjects

Summary Selected cardiovascular and endocrine effects of the new oral vasodilator Ro 12-4713 have been evaluated in an acute single dose study. In five patients with essential hypertension, Ro 12-4713 caused a dose-dependent decrease in supine and upright blood pressure and an increase in heart rate. Initial effects occurred one to 2 h after drug ingestion and maximal effects were noted after five hours and persisted for at least 8 h. Blood pressure was normalized, and the antihypertensive and chronotropic effects persisted for 24 h after a dose of about 300 mg/1.73 m². Plasma and urinary norepinephrine and plasma renin levels tended to be raised, whereas plasma and urinary epinephrine and plasma aldosterone did not change. Changes in supine heart rate were inversely correlated with changes in mean blood pressure (r=–0.60; P<0.02), and positively with those in plasma norepinephrine (r=0.55; P<0.05) and renin (r=0.62, P<0.01); changes in supine plasma renin level were also inversely correlated with those in mean blood pressure (r=–0.65; P<0.01), and positively with those in plasma norepinephrine (r=0.58; P<0.05). 24 h-urinary sodium excretion was significantly (P<0.001) decreased; it was positively correlated with mean blood pressure (r=0.51; P<0.05) and inversely with supine plasma renin activity (r=–0.63; P<0.01). In six normal subjects and six patients with essential hypertension, effective renal plasma flow and the renal clearance of sodium, potassium, calcium and uric acid were not significantly altered five hours after a dose of Ro 12-4713 of about 250 mg/1.73 m²; glomerular filtration rate tended to be slightly decreased, and filtration fraction was significantly (P<0.05) reduced in the hypertensive patients. At the same time blood pressure was decreased and plasma norepinephrine (P<0.01) and renin (ns) were slightly increased in both groups. Ro 12-4713 in a single oral dose of about 300 mg appeared to be a potent, long acting, hypotensive vasodilator.     

Time course of blood pressure,pulse rate,plasma renin and metoprolol during treatment of hypertensive patients

Summary Eleven patients were treated for essential hypertension with metoprolol (Selokén^®) for more than three months. The time course of changes in blood pressure, pulse rate and plasma renin activity was studied during treatment with an oral maintenance dose of 100 mg twice daily. Significant decreases in pulse rate, diastolic blood pressure and plasma renin activity were observed even after the first dose. The plasma concentration of metoprolol reached equilibrium after the second dose. After the third dose there was no further significant change in blood pressure. There was a significant correlation (p<0.001) between the initial (after three doses) and final (after >90days) effect of metoprolol on blood pressure (r=0.86 and 0.91 for systolic and diastolic blood pressure change, respectively).     

Prizidilol,a combined vasodilatory and β-adrenoceptor blocking drug,in primary hypertension

Summary After an initial placebo period of four weeks 24 patients with primary hypertension were treated with prizidilol, a hydrazinopyridazine derivative with combined vasodilator and non-selective beta-adrenoceptor blocking actions, for a dose titration period of 14 weeks. Prizidilol 200 to 800 mg was given once daily to achieve a target supine diastolic blood pressure (BP)<90 mmHg. Supine and standing BP recorded 24–27 h after drug intake decreased from 172±17/106±6 mmHg (mean±SD) and 167±18/111±8 mmHg, respectively, after placebo to 159±16/99±8 and 154±18/101±9 mmHg after active treatment for six weeks (mean dose 447 mg), and to 154±16/97±7 and 148±14/97±7 mmHg after treatment for 14 weeks (mean dose 687 mg/day). A slight reduction in HR was seen after treatment for six weeks and in plasma renin activity and urinary methoxycatecholamine excretion after treatment for 14 weeks. A sustained decrease in BP was observed for 10 h after prizidilol 800 mg (n=9), with a maximum antihypertensive effect (mean reduction in supine BP 33/18 mmHg) 2.5 h after dosing, which coincided with the mean peak plasma concentration. The plasma elimination half-life of the drug was 3.9 h (range 2.0–8.9 h). Changing to a twice daily regimen in 17 patients (mean daily dose 748 mg at six months) did not produce any further reduction in the BP (recorded 12–15 h after dosing) as compared to the once daily regimen at 14 weeks. During treatment for up to 24 months, 16 patients did not achieve satisfactory BP control. Eight of them were withdrawn and eight received additional treatment with bendroflumethiazide (2.5–5 mg/day). In 7 of the latter satisfactory BP control was achieved. Side effects were few. Dizziness and tiredness occurred in four patients 2–5 h after prizidilol 600–800 mg once daily. These symptoms partly subsided when the subjects changed to a twice daily regimen. No ocular side-effects were found. Before treatment 13 out of 24 patients had a low titre of IgM antinuclear antibodies (ANA) and one patient also a low titre of IgG ANA. During treatment the frequency of patients with positive ANA-titres became higher, and after treatment for 12 months (n=17) 15 patients had positive IgM and seven patients positive IgG ANA-titres. However, the titres were low and no patient showed a clinical lupus erythematosus syndrome. There was no relation between acetylator phenotype of the patient and acute or longterm effecton BP, pharmacokinetics of the drug or the development of a raised ANA-titre. Part of this work was presented at the VIII Scientific Meeting of the International Society of Hypertension, Milan 31 May–3 June 1981     

Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor

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Mechanism of the interaction of propranolol and a potent vasodilator antihypertensive agent — Minoxidil

Summary A study, using non-invasive techniques, was carried out in ten patients with essential hypertension to examine the mechanism of the hypotensive effect of propranolol when used in combination with a potent vasodilator antihypertensive — minoxidil. The hypotensive effect of minoxidil, a mean (± SEM) decrease of 42.4±4.3 mm Hg, was accompanied by a marked increase in heart rate, cardiac index and plasma renin activity and a significant decrease in total peripheral resistance, limb vascular resistance and pre-ejection period. Addition of propranolol further reduced mean arterial pressure by an average of 12.9±2.0 mm Hg. Propranolol returned cardiac index to control values and total peripheral resistance index rose but not to control levels. Plasma renin activity was significantly reduced by propranolol. By multiple regression analysis no correlation was found between propranolol-induced decrease in mean arterial pressure and changes in cardiac index, total peripheral resistance index or plasma renin activity. Quantitatively, the reduction in cardiac index observed probably accounted for the hypotensive effect of propranolol. The role of plasma renin activity reduction in the hypotensive effect of propranolol in this situation remains to be clarified. The findings in the present study were consonant with the known actions of vasodilator antihypertensive agents and propranolol and indicate the applicability of non-invasive methodology to the investigation of cardiovascular drugs in man.     

The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man

Summary L-dopa 7 µg·kg^–1·min^–1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate.Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study.These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.