A double-blind comparison of felodipine and hydrochlorothiazide added to metoprolol to control hypertension

Summary Seventy-six uncomplicated hypertensive patients treated in General Practice, whose seated diastolic blood pressure (Phase V) (dBP) remained 95 mmHg after a minimum of 4 weeks treatment with metoprolol 50 mg b.i.d. as antihypertensive monotherapy, were randomized to receive the selective calcium antagonist felodipine 5 mg b.i.d. or hydrochlorothiazide 12.5 mg b.i.d. in addition to metroprolol 50 mg b.i.d. The trial duration was 8 weeks, the dose of the felodipine or hydrochlorothiazide being doubled after 4 weeks if control of BP (dBP <90 mmHg) was not achieved on the initial doses.Over the trial period of 8 weeks, felodipine reduced dBP from 102 to 85 mmHg and hydrochlorothiazide from 101 to 91 mmHg; the dBP reduction in the felodipine group was greater than that in the hydrochlorothiazide group (17 vs 9 mmHg) and the attained dBP lower in the felodipine group. About half of the patients in each group required the higher dose.Both regimes were effective and well tolerated. In the dosages used, felodipine was a slightly more effective antihypertensive drug than hydrochlorothiazide when added to metoprolol. There was no apparent difference in the tolerability of the two regimes.     

Acute haemodynamic effects of felodipine in congestive heart failure

Summary The haemodynamic effects of felodipine 0.1 mg/kg p.o., a new arteriolar dilator, were studied in 7 patients with severe congestive heart failure of NYHA Class IV (Group A) and in 3 patients in Class II–III (Group B). In Group A, measurements were made before and 1 and 4 h after felodipine administration. There was a substantial fall in systemic arterial pressure, which was not associated with a compensatory tachycardia. In fact, there was a fall in heart rate from 92 to 82 beats/min 1 h after drug administration. The pulmonary capillary wedge pressure was reduced from 22 to 14 mm Hg and the cardiac index and stroke volume index rose significantly. Consequently, there was a marked reduction in systemic vascular resistance. In Group B measurements were performed at rest and during exercise before and 1 h after felodipine. The pulmonary wedge capillary pressure during exercise was lower than in the control situation. Coronary sinus flow was increased and there was a pronounced fall in coronary vascular resistance. The results would suggest that felodipine, by virtue of its ventricular unloading potency, might be a valuable drug in the treatment of congestive heart failure.     

Acute and long-term haemodynamic effects of propranolol and indenolol in hypertension

Summary The haemodynamic effect of indenolol, a -adrenoceptor blocker with intrinsic sympathomimetic activity (ISA) in animals, has been evaluated in a double-blind cross-over randomized trial after acute (3 days) and long-term treatment (28 days), in 12 hypertensive patients in comparison with that of propranolol. Patients were evaluated at rest and during isometric exercise (hand grip). The overall acute effect of both -adrenoceptor blocking drugs was to decrease mean blood pressure, heart rate and cardiac output, while total peripheral resistance increased. In the long-term studies the haemodynamic effect of propranolol was still characterized by cardiodepression and unchanged peripheral resistance. Patients on the long-term treatment with indenolol showed normal cardiac output and reduced total peripheral resistance.The data are compatible with a relatively strong ISA of indenolol, which would be responsible for the haemodynamic pattern observed during chronic treatment.     

Contribution of baroreflex sensitivity and vascular reactivity to variable haemodynamic responses to cocaine in conscious rats

1. Baroreflex function is critical for short-term arterial pressure regulation and decreased baroreflex responsivity may predict a predisposition to hypertension and sudden cardiac death. In the present study, we assessed whether baroreflex sensitivity (BRS) and/or vascular reactivity covary with haemodynamic responsiveness to cocaine in vascular and mixed responders. 2. We assessed the heart rate index of BRS in resting animals. We examined dose-response relationships to pressor and depressor agents to determine cardiovascular reactivity. Subsequently, rats were given cocaine (5 mg/kg, i.v.) to classify them as vascular or mixed responders. Vascular responders (n=16) were defined as those rats with a substantial (>8%) decrease in cardiac output in response to cocaine owing to a larger increase in systemic vascular resistance. The remaining rats (n=8) were mixed responders because they had smaller increases in vascular resistance and little change or an increase in cardiac output. 3. The BRS determined with angiotensin (Ang) II, but not with phenylephrine, was impaired in mixed responders compared with vascular responders. At equipressor doses, there were significantly greater reductions in cardiac output in vascular responders compared with mixed responders in response to phenylephrine or AngII. Methacholine produced greater decreases in heart rate in vascular responders, suggesting greater muscarinic responsivity. 4. We conclude that differences in vascular reactivity to AngII may contribute to differences in haemodynamic response profiles to cocaine in individual rats. More importantly, the differences in vascular responsivity and BRS do not appear to be primary determinants of haemodynamic response variability.     

EFFECTS OF 1-SAR-8-ALA-ANGIOTENSIN II ON SYSTEMIC AND PULMONARY HAEMODYNAMICS IN HYPERTENSIVE PATIENTS

1.The angiotensin II antagonist, 1-Sar-8-Ala-angiotensin II (saralasin), was infused intravenously at a rate of 10 μg/kg per min in thirty-three hypertensive patients, on a normal sodium diet (130 mmol per day) and/or during sodium depletion by low sodium diet (20 mmol per day) and chlorthalidone. 2. In both series, saralasin induced a transient rise in intra-arterial pressure (P < 0.01), accompanied by a slight decrease in heart rate (P < 0.01). The elevation of systolic arterial pressure reached its maximum after 4 min and was more pronounced in sodium-replete patients. Plasma noradrenaline was significantly elevated by 29.7% (P<0.01), but the rise in pressure was not related to concomitant changes in plasma noradrenaline. 3. After the initial pressor effect, arterial pressure, heart rate, cardiac output and total peripheral resistance remained unchanged in the sodium-replete patients, while in the sodium-depleted conditions mean arterial pressure and peripheral resistance were reduced, by 17.8% and 18.6% (P< 0.001) respectively, within 60min. Reflex increases in heart rate (+3.8%) and cardiac output (+ 11.1%) occurred after 10 min (P<0.05), but were not sustained thereafter. 4. Pulmonary vascular resistance was not affected by saralasin. In sodium-depleted patients, pulmonary capillary wedge pressure decreased by 1.2mmHg (P<0.01), with parallel changes of pulmonary artery pressure (P< 0.01).     

Haemodynamic effects and pharmacokinetics of felodipine at rest and during exercise in hypertensive patients treated with metoprolol or atenolol

Summary A study has been performed in thirteen patients with essential hypertension, WHO Class I–II, and a diastolic blood pressure 95 mm Hg, on beta-blocker (metoprolol or atenolol) monotherapy, who were also given felodipine 10 mg b.d. for 28 days. The acute and steady state blood pressure response at rest and during exercise, and the pharmacokinetics of felodipine and metoprolol, were examined.Felodipine in combination with the beta-blocker reduced the systolic and diastolic blood pressures acutely and at steady-state. The duration of the effect was longer at steady-state. There was a significant correlation between the plasma concentration of felodipine and the change in blood pressure. The increase in systolic blood pressure during exercise was of the same magnitude before and after felodipine administration. No change in resting supine heart rate was found after the administration of felodipine.There were no significant differences in the pharmacokinetics of felodipine during long-term treatment, except for the trough plasma concentration, which was increased at steady-state, even though cumulation of felodipine and its metabolite did not occur. There was a significant decrease in the maximal plasma concentration and AUC of metoprolol after 28 days of treatment with felodipine, but its elimination half-life was not changed.The adverse reactions reported during this study were those generally seen after dihydropyridines and, except for two patients who were withdrawn after the first study day, the effects were well tolerated.     

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.     

Central and peripheral haemodynamic responses to felodipine in congestive heart failure

Summary Using non-invasive radionuclide techniques, we studied the arterial and venous effects of 0.1 mg/kg oral felodipine in 12 men with heart failure due to ischaemic heart disease aged 37–72 y. All were in New York Heart Association Class II or III, required frusemide 40–120 mg daily and were clinically stable.Felodipine produced significant falls in blood pressure (–19%) and systemic vascular resistance (–39%) with increases in cardiac index (+34%), heart rate (+12%) and left ventricular ejection fraction (from 0.25 to 0.32). Peripheral venous volume fell by 10.6% after felodipine indicating venoconstriction rather than venodilatation and may be caused by an acute sympathetic reflex associated with the increase in heart rate.Our results confirm that felodipine is an arterial vasodilator. The previously observed changes in cardiac filling pressures may simply represent improved ventricular function as a consequence of reduced afterload, not venodilatation.     

Combination therapy in hypertension

Summary The acute hypotensive effect of captopril 25 mg was investigated in 26 hypertensive patients (11 with essential and 15 with renal arterial disease). Intra-arterial blood pressure was recorded continuously and arterial blood was sampled for renin, angiotensin I and II, aldosterone, kininase II, catecholamines and prostaglandins. Captopril led to an increase in plasma renin activity, active and total plasma renin concentration and angiotensin I, a decrease in plasma kininase II activity, angiotensin II, aldosterone, prostaglandins E₂ and F_2* and no change in plasma (nor)adrenaline, dopamine and inactive renin concentration. The hypotensive effect of captopril was related to the changes in plasma angiotensin II level and inversely to the change in prostaglandin E₂; the correlation coefficients were low, respectively 0.61 and −0.44. It is likely that the acute hypotensive effect of captopril to some extent is related to changes in plasma angiotensin II and in prostaglandins E₂ and F_2*. There is no evidence for a role of the adrenergic systems in the hypotensive response.     

Acute calcium entry blockade inhibits the blood pressure but not the hormonal responses to angiotensin II

Summary The effects of acute calcium entry blockade by isradipine (IS) and placebo (P) on the haemodynamic and humoral responses to angiotensin II (A II) have been compared in two groups of 9 patients with essential hypertension. During 4 sequential periods each of 20 min, an i.v. infusion of A II 0, 2, 4 and 8 ng · kg^–1 · min^–1 was given before (control) and 30 min after the oral administration either of IS or P.After IS, both the blood pressure and the angiotensin II-induced pressor effect were significantly reduced. Isradipine increased the heart rate and this cardio-acceleration was potentiated by A II. In contrast, when A II was infused in the absence of IS, heart rate tended to decrease. IS stimulated plasma renin activity and reduced plasma aldosterone. However, it did not affect either the inhibition of plasma renin activity or the rise in plasma aldosterone in response to A II.In conclusion, acute calcium entry blockade in patients with essential hypertension reduces the pressor response to A II, but not the A II-induced inhibition of renin and increase in plasma aldosterone.     

Comparative evaluation of the new vasodilator carprazidil and minoxidil in the treatment of moderate to severe hypertension

Summary The efficacy and side effects of the new vasodilator carprazidil and the established vasodilator minoxidil were compared in 18 hypertensive patients inadequately controlled by 2 to 4 conventional drugs; the latter included diuretics, beta-blockers and/or sympatholytics and, in half the cases, vasodilators, such as hydralazine, diazoxide or the postsynaptic alpha-blocker prazosin. The vasodilators were withdrawn and, using a crossover design all patients received carprazidil (mean final dose 88 mg) and minoxidil (20 mg) for an average period of 5 to 6 months. The effects of the 2 agents appeared to be qualitatively and quantitatively similar. Both tended to cause sodium retention and an increase in heart rate, which required an increased dose of diuretic in one third of the cases or of a beta-blocker in a quarter. With this approach mean body weight and blood volume were not altered in the established phase of carprazidil or minoxidil treatment; heart rate and plasma norepinephrine tended to be only minimally increased, plasma renin was slightly increased, and plasma aldosterone and epinephrine were largely unchanged. Supine and upright blood pressure were reduced from initial values of 189/113 and 167/113 mm Hg, to 149/95 and 138/95 mm Hg (–18 and –17%), respectively, during carprazidil, and to 154/95 and 141/96 mm Hg (–17 and –15%) during minoxidil therapy. Hypertrichosis occurred with both agents in almost all patients, and limits their more prolonged use in females. No adverse side effects on haematological parameters, liver or renal function were observed, nor was antinuclear antibody detected. It is concluded that carprazidil and minoxidil are equivalent vasodilator agents in the treatment of severe hypertension, particularly in males.     

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.     

Acute haemodynamic and neurohumoral effects of intravenous nisoldipine in patients with severe congestive heart failure

Summary Twenty patients (5 females, 15 males) with severe heart failure (NYHA IV), due to coronary artery disease in 14, and congestive cardiomyopathy in 6, received an intravenous bolus of the calcium blocker nisoldipine 0.2 mg followed by a continous infusion of 0.2 g · kg^–1 · min^–1. Haemodynamic measurements were performed at baseline and after 30 min.The mean arterial pressure fell from 91 to 73 mm Hg, pulmonary capillary wedge pressure from 31 to 26 mm Hg and systemic vascular resistance from 1695 to 1040 dyn · s · cm^–5.The cardiac index (2.2 to 2.71 · min^–1 · m^–2, and stroke volume index (25 to 33 ml · m^–2) were markedly increased. There was no reflex tachycardia as the heart rate dropped from 92 to 85 beats · min^–1. Plasma renin activity and norepinephrine concentration did not change significantly.The findings indicate that nisoldipine acts as a strong vasodilator and that it has a beneficial acute haemodynamic effect in patients with severe left heart failure irrespective of its aetiology.     

Effects of treatment with nifedipine and metoprolol in essential hypertension

Summary In a double-blind trial 26 patients with essential hypertension were treated with nifedipine or placebo for 8 weeks, following a 4-week run-in place-bo period in all patients. The daily dosage of nifedipine during this phase was 10mg 3 times daily. Metoprolol was then added to the therapeutic regimen of both groups for a further 12 weeks. Both nifedipine and metoprolol used as mono-therapy caused statistically significant reductions of arterial pressure. The addition of metoprolol to nifedipine tended to reduce blood pressure further, but blood pressures were not significantly lower than during nifedipine mono-therapy. Side-effects were few and only two patients had to be withdrawn during active therapy, one for headaches during nifedipine therapy, and another for asthma during metoprolol treatment. Combined therapy with a beta-adrenoceptor blocking agent, such as metoprolol, and a calcium antagonist with vasodilating properties, such as nifedipine, offers a theoretically interesting approach in the treatment of hypertension, even though the practical outcome in the present study probably suffered from an inadequate dose of nifedipine during the period of combined therapy.     

非洛地平/美托洛尔复方贴剂体外透皮特性及皮肤刺激性考察

目的 制备非洛地平/美托洛尔复方透皮贴剂,考察其对离体兔皮的经皮渗透性及对家兔皮肤的刺激性.方法 采用改良的Franz透皮扩散装置,以离体兔皮为渗透屏障,NS-乙醇(6040)为接受液,用HPLC法同时测定经皮渗透液中两药浓度并计算其渗透动力学参数.通过皮肤刺激性试验法考察该贴剂对家兔皮肤的刺激性.结果 非洛地平/美托洛尔复方透皮贴剂中非洛地平和美托洛尔48h内均以零级动力学经兔皮转运,并具一定同步性;该贴剂对家兔皮肤无刺激性.结论 非洛地平/美托洛尔复方透皮贴剂缓释长效特征明显,药物体外经皮渗透性较好且稳定,符合经皮给药系统应对皮肤无刺激性的设计要求.     

A comparison of felodipine and propranolol as additions to hydrochlorothiazide in the treatment of hypertension

Summary Eighty one patients with uncomplicated hypertension who required additional antihypertensive medication (diastolic Phase V [dBP]95 mm Hg) after 4 weeks treatment with hydrochlorothiazide (HCTZ) 25 mg o.m. were randomized to receive felodipine 5 mg b.i.d. (n=40) or propranolol (n=41) 80 mg b.i.d. in addition to HCTZ 25 mg o.m. If the dBP measured about 12 h post-dose was not 90 mm Hg after 4 weeks, the dose of felodipine or propranolol was doubled. The double blind trial period was 8 weeks for all patients.Over the 8 week period, felodipine reduced the seated dBP from 100 to 83 mm Hg and propranolol from 101 to 86 mm Hg. The attained seated dBPs were significantly different in the two groups. About one third of patients in each group received the high dose of second-line therapy. After 8 weeks 91% of patients receiving HCTZ+felodipine and 84% receiving HCTZ+propranolol had a dBP 90 mm Hg. Both regimens were well-tolerated with an equal incidence but different pattern of adverse events (felodipine: flushing, headache and peripheral oedema; propranolol: dyspepsia, fatigue and vasospasm).In this 8-week study, felodipine and propranolol were safe and effective second-line antihypertensive drugs when added to hydrochlorothiazide. At the doses selected, felodipine was at least as effective as propranolol.     

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.     

Acute effects of felodipine and nifedipine on hepatic and forearm blood flow in healthy men

Summary The acute effects of oral administration of felodipine 10 mg and nifedipine 10 mg on heart rate, blood pressure, forearm blood flow and hepatic blood flow were studied in nine healthy men.Both drugs caused an increase in heart rate of 16 and 7 beats · min^–1, respectively. Hepatic blood flow was significantly increased by 1.2 and 0.41 · min^–1 after felodipine and nifedipine. There was also a decrease in diastolic blood pressure, 10 and 5 mm Hg, respectively, after felodipine and nifedipine. The forearm blood flow was increased by about 30 ml · 100 ml^–1 · min^–1 after felodipine, but nifedipine had no effect.The haemodynamic effects were most pronounced 50 min after drug administration.     

Effect of nifedipine on plasma renin,aldosterone and catecholamines in arterial hypertension

Summary Acute sublingual administration of nifedipine 10–20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r=0.92, p<0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r=0.80, p<0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30–60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p<0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r=0.74, p<0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.     

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.