Cardiovascular effects of alinidine and propranolol alone and in combination with hydralazine in normal man

1 The effect of single oral doses of alinidine 80 mg, propranolol 40 mg, hydralazine 50 mg, alinidine 80 mg combined with hydralazine 50 mg, propranolol 40 mg combined with hydralazine 50 mg, and placebo on arterial pressure and heart rate was studied in five normal volunteers in the supine and standing positions and during exercise. Observations were made before and at 1, 2, 3, 4 and 6 h after drug administration.

2 Alinidine 80 mg and propranolol 40 mg significantly reduced heart rate in the supine position, and on exercise. The reductions in supine heart rate produced by alinidine and propranolol were not significantly different, but the maximum effect of alinidine on exercise heart rate was observed later than that of propranolol. Propranolol reduced heart rate in the standing position at all time intervals after drug administration, but alinidine reduced standing heart rate only at 6 h (P < 0.01 when compared to placebo).

3 Hydralazine 50 mg increased supine heart rate by 8-10 beats min^-1 when compared to the pre-treatment value. These increases were significant (P < 0.05) when compared to the pre-treatment value, but not when compared to placebo. Hydralazine increased standing heart rate from 71.4 ± 6.5 to 90.0 ± 7.0 beats min^-1 (P < 0.05 when compared to placebo), but had no effect on exercise heart rate. The small increase in supine heart rate following hydralazine therapy was reduced by alinidine and propranolol, but only propranolol reduced the significant increase in standing heart rate produced by hydralazine.

4 Hydralazine reduced diastolic arterial pressure in the supine position at 2 and 4 h after drug administration (P < 0.05 when compared to placebo), but had no effect on systolic or diastolic arterial pressure in the standing position or on exercise.

5 Propranolol produced small reductions in systolic arterial pressure in the standing position, which were not significant when compared to placebo; diastolic pressure was unchanged. Propranolol reduced systolic pressure during exercise at 2, 4 and 6 h after drug administration (P < 0.05 when compared to placebo); diastolic pressure was unchanged. The effects of hydralazine and propranolol combined on arterial pressure in the standing position were similar to those observed after propranolol alone, but combined therapy produced a greater reduction in exercise systolic pressure, although these differences were not significant.

6 Alinidine reduced systolic arterial pressure in the supine position at 3, 4 and 6 h after drug administration (P < 0.01) and diastolic pressure at 2 and 4 h (P < 0.05 when compared to placebo). Alinidine reduced systolic arterial pressure in the standing position at 3, 4 and 6 h after drug administration (P < 0.05) and diastolic pressure at 2 h (P < 0.01) and 6 h (P < 0.05 when compared to placebo). During exercise, alinidine produced a small reduction in systolic arterial pressure which was not significant, and a reduction in diastolic pressure at 1 h (P < 0.05 when compared to placebo). The effects of hydralazine and alinidine combined on arterial pressure were similar to those observed after alinidine alone.

7 Hydralazine and alinidine combined produced a greater fall in systolic arterial pressure in the standing position than the changes observed after hydralazine alone; these differences were significant (P < 0.05) at 2, 3, 4 and 6 h after drug administration. However, the increase in heart rate after combined therapy was less than that observed after hydralazine alone, but these differences were not significant. This would suggest that alinidine may reduce the tachycardia produced by hydralazine.

8 Combined therapy with hydralazine and alinidine was associated with a high incidence of side effects. Alinidine alone produced dry mouth and tiredness in some subjects and syncope in one.

9 A linidine reduced heart rate and arterial pressure in normal man, and may therefore have a role in the treatment of hypertension, when used alone or in combination with vasodilator therapy.

     

Indomethacin and cognitive function in healthy elderly volunteers.

1. The aim of this randomised, double-blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post-dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/- 3/3 mmHg; 142/89 +/- 5/3 mmHg; and 154/98 +/- 5/3 mmHg respectively; P < 0.001). Co-administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/- 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/- 1 beats min-1 and 74 +/- 2 beats min-1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/- 1 beats min-1 and 86 +/- 1 beats min-1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co-dosing (120/82 +/- 10/2 mmHg) compared with lacidipine (140/92 +/- 5/3 mmHg) and atenolol (146/90 +/- 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/- 8 beats min-1; 65 +/- 4 beats min-1 and 75 +/- 7 beats min-1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co-administration of both lacidipine and atenolol.     

Interaction between nifedipine and atenolol: pharmacokinetics and pharmacodynamics in normotensive volunteers

The cardiovascular effects of single oral doses of nifedipine (20 mg), atenolol (50 mg), or of their combination were compared with placebo in a double-blind randomized cross-over study in 10 normotensive volunteers. After subjects rested for 2 h, before drug administration, heart rate, blood pressure, stroke volume index, and cardiac index were measured noninvasively. These cardiovascular parameters were then determined prior to and after exercise periods (160 W, 10 min, bicycle ergometry) which were performed 40, 70, 130, 190, 310 min, and 22 h after drug intake. Nifedipine decreased resting diastolic blood pressure (p less than or equal to 0.05) after 2 h, whereas systolic blood pressure remained unchanged and heart rate significantly increased at rest and after exercise. Stroke volume index and cardiac index were unaffected. Atenolol significantly decreased systolic and diastolic blood pressure as well as heart rate; stroke volume index following exercise increased significantly, and cardiac index was unchanged. Administration of the combination caused a significantly more pronounced fall of systolic and diastolic blood pressure as compared with either drug alone, whereas the negative chronotropic effect was not different from that of atenolol. As did atenolol, the combination increased stroke volume index after exercise with no change in cardiac index. Maximum plasma concentrations of nifedipine (37.1 +/- 16.7 ng/ml) and atenolol (276.3 +/- 107.2 ng/ml) and terminal half-life of atenolol (9.9 +/- 2.6 h) were not altered by combined administration of the drugs.     

The assessment in man of the beta-adrenoceptor blocking activity and cardioselectivity of H-I 42 BS, a long acting beta-adrenoceptor blocking drug.

The pharmacokinetic and pharmacodynamic effects of the beta-adrenoceptor antagonist H-I 42 BS were examined in healthy subjects. In an open dose ranging study, H-I 42 BS 50, 100, 200 and 400 mg were given as single oral doses to four subjects. H-I 42 BS 400 mg caused maximum reduction in exercise heart rate (20.4 +/- 1.0%--mean +/- s.d.) at 4 h and still reduced exercise heart rate at 96 h (18.4 +/- 7.2%). Seven subjects received in double-blind, randomised order, single oral doses of H-I 42 BS 50, 100 and 200 mg, atenolol 50 and 100 mg and placebo. H-I 42 BS 400 mg was given in a single blind manner as the last dose of the study. Both H-I 42 BS and atenolol reduced supine and standing heart rate and systolic blood pressure (P less than 0.05) although atenolol had the more marked effect. The maximum percent reduction of exercise heart rate after H-I 42 BS 50 mg was 10.9 +/- 7.1%, after 100 mg was 18.7 +/- 5.8%, after 200 mg was 20.6 +/- 6.4% and after 400 mg was 21.9 +/- 8.2%. H-I 42 BS 400 mg still caused 11.0 +/- 3.5% reduction at 168 h. Atenolol 50 mg caused maximum percent reduction of exercise heart rate of 26.0 +/- 6.0% but did not reduce exercise heart rate after 24 h. The mean peak plasma concentrations for all doses of H-I 42 BS occurred at 5.1 +/- 1.5 h. The plasma elimination half-life was 47.6 +/- 8.1 h. There was a linear correlation between the dose and AUC0-infinity (r = 0.97). The cardioselectivity of H-I 42 BS and atenolol was compared. Six subjects received in double-blind random order H-I 42 BS 100 and 400 mg, atenolol 50 mg and placebo. After each dose, graded infusions of isoprenaline were given until the heart rate increased by 50 beats min-1. Dose-response curves for heart rate, diastolic blood pressure, forearm blood flow and finger tremor were constructed. There was no difference in the dose-response curves for forearm blood flow or finger tremor after H-I 42 BS 400 mg or atenolol 50 mg. Atenolol 50 mg caused more attenuation (P less than 0.01) of the diastolic blood pressure response. These results indicate that H-I 42 BS is a cardioselective beta-adrenoceptor antagonist with a long duration of action in man.     

Effects of ICI 141,292 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.     

An assessment of the contribution of clonidine metabolised from alinidine to the cardiovascular effects of alinidine.

Five healthy volunteers (mean age 20.6 years, mean weight 71 kg) received in random order on day 1 and day 8 a single dose of alinidine 40 mg, clonidine 0.1 mg or placebo and on days 2-7 alinidine 40 mg, clonidine 0.1 mg or placebo given three times a day with 1 week between treatment periods. Blood samples were taken for measurement of concentrations of alinidine and clonidine during alinidine administration and of clonidine during clonidine dosing. Heart rate and blood pressure were recorded in supine and standing positions and heart rate after 3 min exercise. Plasma concentrations of alinidine reached a maximum of 163.6 +/- 10.0 ng/ml 2 h after alinidine administration on day 1 and during chronic administration similar concentrations were achieved. Clonidine plasma concentrations reached 0.3 +/- 0.11 ng/ml 6 h after alinidine 40 mg on day 1, and during chronic administration of alinidine, increased to a steady state on day 5 with trough and 2 h values of 0.73 +/- 0.15 and 0.86 +/- 0.14 ng/ml respectively. After the first dose of clonidine on day 1, the maximum plasma concentration of clonidine was 0.32 +/- 0.1 ng/ml at 4 h, during chronic administration clonidine plasma concentration rose to 1.04 +/- 0.14 ng/ml 2 h after a dose on day 5. Alinidine produced a greater reduction in the exercise tachycardia than clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of once and twice daily administration of acebutolol in hypertension.

1 Thirteen hypertensive patients completed a double-blind comparison of placebo, acebutolol 200 mg twice daily and acebutolol 400 mg once daily, administered for 4 weeks in random order. 2 Blood pressure and heart rate were significantly reduced by both acebutolol treatments. The mean reduction of resting pressure 12 h after 200 mg twice daily (12/7 mmHg) was similar to that 24 hr after 400 mg once daily (13/9 mmHg). 3 Compared to placebo, reductions in exercise heart rate and systolic pressure at 12 h after 200 mg twice daily and 24 h after 400 mg once daily were significant and similar. 4 Beta-adrenoceptor antagonism was also assessed by inhibition of the heart rate response to sublingual glyceryl trinitrate taken in the standing position. Both acebutolol treatments reduced the response; the reduction after twice daily treatment (mean 25 beats/min) was significantly greater than after once daily treatment (mean 19 beats/min). 5 There was no difference in blood pressure control between acebutolol administered once and twice daily in a total daily dose of 400 mg.     

Effect of levamisole and azathioprine on the human mixed lymphocyte reaction (MLR)

The effects of sublingual nifedipine (10 mg) and of glyceryl trinitrate (500 micrograms), which produce arterial and venous vasodilatation respectively, on indocyanine green estimated apparent liver blood flow (LBF) were studied in six healthy volunteers. Nifedipine significantly increased (33 +/- 12%; mean +/- s.e. mean) and glyceryl trinitrate significantly reduced (18 +/- 3%) LBF. There was a positive relationship (r = 0.92, P less than 0.05) between the reduction in mean arterial pressure produced by nifedipine and the percentage increase in LBF. These results show that single doses of nifedipine and glyceryl trinitrate significantly alter LBF.     

Effects of dilevalol (R,R-labetalol) compared with nifedipine on heart rate, blood pressure and muscle blood flow at rest and on exercise in hypertensive patients.

1. Dilevalol (R,R-labetalol) is a non-selective beta-adrenoceptor antagonist with beta 2-adrenoceptor agonist activity. Its effects after 1 month's administration on heart rate, blood pressure and muscle blood flow were studied in a double-blind crossover comparison with nifedipine in 16 hypertensive patients. 2. Dilevalol and nifedipine were similarly effective in lowering systolic and diastolic blood pressure at rest, but dilevalol limited the rise in systolic blood pressure induced by exercise more than nifedipine (rise of 27 vs 53 mm Hg respectively, P < 0.01). 3. Dilevalol decreased resting heart rate compared with nifedipine (73 vs 92 beats min-1 respectively, P < 0.01). Dilevalol limited the exercise induced rise in heart rate more than nifedipine (36 vs 48 beats min-1 respectively, P < 0.01). 4. Muscle blood flow (measured by strain gauge plethysmography) was not affected by either dilevalol or nifedipine at rest. After exercise, dilevalol caused an increase in excess blood flow compared with placebo (10.8 vs 5.1 ml min-1 dl-1 respectively, P < 0.01). The difference between dilevalol and nifedipine did not reach statistical significance (10.8 vs 6.5 ml min-1 dl-1 respectively, P > 0.05). 5. On blood pressure and heart rate, dilevalol demonstrated beta-adrenoceptor blocker activity at rest and on exercise. On muscle blood flow, dilevalol appeared to have no effect at rest, but may have acted as a beta-adrenoceptor blocker rather than as a beta 2-adrenoceptor agonist during exercise.     

A mechanism of D-(+)-sotalol effects on heart rate not related to beta-adrenoceptor antagonism.

1. In order to determine whether the effects of d- or (+)-sotalol on heart rate are mediated by beta-adrenoceptor antagonism or might be due to other actions, we administered (+)-sotalol (400 mg every 12 h), atenolol (50 mg every 12 h) and placebo to eight healthy volunteers in a randomized, double-blind, crossover study. We also studied the affinity of human lymphocyte beta 2-adrenoceptor for (+)-sotalol, (-)-sotalol, and (+/-)-propranolol. 2. Compared with placebo, atenolol significantly reduced resting, standing and peak exercise heart rate whereas (+)-sotalol significantly reduced standing and peak exercise heart rate, but not resting heart rate. Atenolol significantly reduced resting, standing and peak exercise blood pressure while (+)-sotalol had no effect. 3. (+)-sotalol and atenolol both shifted the relationship between isoprenaline dose and heart rate to the right by similar degrees at the dosages tested. 4. (+)-sotalol but not atenolol significantly prolonged QTc interval. The degree of QTc prolongation due to (+)-sotalol, which has been shown to parallel action potential prolongation in the sinus node, correlated significantly with the reduction in peak exercise. heart rate it produced (r = 0.71, n = 8, P less than 0.05). 5. The affinity of the human lymphocyte beta 2-adrenoceptor was approximately 60-fold greater for (-)-sotalol (Ki, 108 +/- 12 nM) than for (+)-sotalol (Ki, 6,410 +/- 1,020 nM), and approximately 20,000-fold greater for (+/-)-propranolol (Ki, 0.33 +/- 0.08 nM) than for (+)-sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of alinidine on experimental cardiac arrhythmias

Alinidine (2.9 +/- 0.7 mg/kg) prevented an adrenaline-induced ventricular arrhythmia in dogs respired with halothane. In ouabain-induced ventricular tachycardia, a cumulative dose of alinidine (15.5 mg/kg) reduced the number of ventricular beats by 91.6 +/- 1.9%. The drug was much less effective in abolishing the ventricular tachycardia 24 h after ligation of a coronary artery, with only a 36 +/- 15% reduction in ventricular ectopic beats after 15.5 mg/kg. The administration of alinidine (0.5-1.0 mg/kg) to anaesthetized dogs with no cardiac arrhythmia reduced sinus node rate with little effect on the response of the node to vagal stimulation.     

Safety and efficacy of alinidine in symptom-free asthmatics

Summary Alinidine is a new bradycardic agent which has been shown to be beneficial in the treatment of coronary heart disease. Patients with both coronary heart disease and obstructive lung disease are difficult to treat, because the use of beta-blockers in them is greatly limited by their potential to provoke bronchospasm. Alinidine has no beta-blocking, muscarinic or quinidine-like properties. In a randomized double-blind cross-over study the heart rate reducing effect and safety of alinidine 40 mg p.o. has been examined in 12 symptom-free asthmatics. Alinidine significantly reduced mean heart rate from 81±10.5 beats/min to 65±9.7 beats/min two hours after administration. Forced expiratory volume in one second (FEV₁), vital capacity (CV), airway resistance (R_aw), functional residual capacity (FRC), and specific airway conductance (SG_aw) were not affected. It is concluded that alinidine did not influence respiratory function in patients with bronchial hypersensitivity.     

A comparison of the effects of human alpha calcitonin gene-related peptide and glyceryl trinitrate on regional blood velocity in man.

1. Human alpha calcitonin gene-related peptide (h alpha CGRP) is a potent vasodilator which in doses up to 1.5 micrograms min-1 i.v. produces little or no fall in blood pressure in normal volunteers, but does cause a substantial tachycardia. 2. We have explored the underlying mechanism of this effect by comparing h alpha CGRP infused so as to maintain heart rate 25-30% above baseline with glyceryl trinitrate (GTN) in a dose sufficient to maintain a throbbing headache. 3. Ten normal volunteers were studied. In addition to blood pressure and heart rate, blood velocity and pulsatility index (PI) were determined from Doppler signals recorded from the internal and external carotid, renal and femoral arteries. 4. Following h alpha CGRP blood pressure (mean +/- s.d., mm Hg) did not significantly change: 120 +/- 10/70 +/- 7 before compared with 121 +/- 12/67 +/- 7 during h alpha CGRP infusion. Heart rate (mean +/- s.d., beats min-1) increased from 62 +/- 8 to 86 +/- 10 (P less than 0.0001). In contrast the blood pressure fell following GTN: 124 +/- 12/74 +/- 8 before compared with 111 +/- 13/62 +/- 6 following treatment (P less than 0.02). Heart rate did not change following GTN: 64 +/- 9 compared with 69 +/- 10. 5. GTN significantly increased PI (mean +/- s.d.) in the common carotid artery from 2.8 +/- 0.5 to 3.4 +/- 0.5 (P less than 0.003) while h alpha CGRP increased PI in the internal carotid from 1.3 +/- 0.2 to 2.1 +/- 0.4 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of temazepam on blood pressure regulation in healthy elderly subjects.

1. Blood pressure regulation was studied in 12 healthy elderly subjects after double-blind randomised administration of placebo, 15 mg and 30 mg temazepam at 10.00 h and 22.00 h. 2. Supine and standing heart rate and blood pressure were measured after daytime administration and supine measurements were obtained during sleep. 3. Temazepam caused a fall in systolic blood pressure and an increase in heart rate after morning administration. These changes were greater in the standing position and were dose-dependent; for standing blood pressure and heart rate 1 h after administration there was a 7 mm Hg fall and 6 beats min-1 increase after 15 mg temazepam and a 10 mm Hg fall and 8 beats min-1 increase after 30 mg temazepam. Temazepam magnified the fall in systolic blood pressure and increase in heart rate that occurred with standing. Temazepam enhanced the fall in systolic blood pressure that occurred during sleep (mean +/- s.d.; placebo: -23 +/- 10 mm Hg, 15 mg temazepam: -31 +/- 13 mm Hg, 30 mg temazepam: -36 +/- 14 mm Hg). 4. These changes in blood pressure regulation caused by temazepam may have clinical importance in some elderly individuals.     

Acute and chronic effects of rilmenidine on baroreflex function in conscious dogs

The effects of acute and chronic administration of rilmenidine on blood pressure, heart rate and baroreflex function were assessed in two groups of six conscious dogs. Baroreflex function was evaluated using increasing doses of glyceryl trinitrate and phenylephrine to decrease and increase blood pressure respectfully. Acute administration of rilmenidine (1 mg/kg p.o.) reduced (P less than 0.05) blood pressure and heart rate, and enhanced (P less than 0.05) baroreflex function to increases in blood pressure with phenylephrine, but not to decreases in blood pressure by glyceryl trinitrate. Following chronic administration of rilmenidine, blood pressure remained lowered while heart rate and baroreflex function returned to control values.     

Effect of indoramin, labetalol and alinidine on sympathetic function in normal man.

The effects of single oral doses of indoramin (mean dose 58 mg), abetalol (mean dose 150 mg), alinidine 80 mg and placebo on arterial pressure and heart rate in the supine and standing positions were studied in six normal volunteers. Doses were chosen to give equivalent reductions of arterial pressure in the standing position. Observations were made before and at 2 and 4 h after drug administration. Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. In the supine position, alinidine produced a significant reduction of systolic arterial pressure from 124.0 +/- 3.0 mm Hg to 104.3 +/- 4.1 mm Hg at 2 h (P less than 0.01) and to 101.7 +/- 2.2 mm Hg at 4 h (P less than 0.01). Diastolic pressure was reduced from 74.7 +/- 2.6 mm Hg to 57.0 +/- 4.6 mm Hg at 4 h (P less than 0.01). Arterial pressure was unchanged after indoramin or labetalol administration. In the supine position, heart rate was unchanged after indoramin, and small reductions were observed after labetalol and alinidine. Indoramin produced a significant increase in plasma NA. A small increase of plasma NA was observed after labetalol, and a small decrease after alinidine. In the standing position, the three active drugs reduced systolic arterial pressure to a similar extent (indoramin, -26.7 mm Hg at 4 h after drug administration; labetalol, -21.3 mm Hg at 2 h; alinidine, -21.7 mm Hg at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.     

Slow release nifedipine plus atenolol in chronic stable angina pectoris.

1. The effects of adding slow release nifedipine in doses of 20 mg and 40 mg twice daily to atenolol therapy (50 mg twice daily) were assessed in 18 patients with chronic stable angina. 2. The addition of the lower dose of nifedipine to atenolol did not significantly alter the weekly consumption of glyceryl trinitrate or the mean number of anginal attacks as assessed by diary cards. However, 2 h after dosing there was a significant prolongation during stress testing in the time to onset of both 1 mm ST depression on the ECG (by 28%) and to angina (by 37%) compared with atenolol alone, but no benefit was apparent by 12 h after dosing. 3. At a dose of 40 mg twice daily, nifedipine significantly reduced glyceryl trinitrate consumption by 25% and the number of anginal attacks by 36%. The times to onset of ST depression and angina were increased by 37% and 55% respectively at 2 h and by 24% and 26% respectively 12 h after dosing. 4. Analysis of the frequency distribution of anginal attacks showed decreasing efficacy with time after administration of nifedipine. The overall results also suggest a relationship between efficacy and the plasma nifedipine concentration, with a mean 20% improvement in time to development of angina occurring at a nifedipine plasma concentration of approximately 30-40 ng ml-1. 5. In conclusion, the reduction of effort-related angina by nifedipine is related to its plasma concentration and the effective duration of action of the 20 mg slow release formulation is less than 12 h.     

Investigation of the effects of physiological and vasodilation-induced autonomic activation on the QTc Interval in healthy male subjects

AIMS: Drug-induced prolongation of the QTc interval is an important marker for potential proarrhythmic action. Prolongation of the QTc interval results from alteration of the ionic currents that regulate cardiac repolarisation. Such effects may result from direct drug action or alternatively they could also occur indirectly by drug-induced modulation of autonomic tone, which is known to regulate cardiac repolarization. This study examined the effects of physiological and drug-induced autonomic activation on heart rate, QT and QTc intervals. METHODS: We studied 29 healthy male subjects aged 18-30 years. Electrocardiographs were recorded before and during autonomic activation induced by mental activation, standing, exercise and glyceryl trinitrate (GTN) (0.5 mg sublingual)-induced vasodilation in the presence and absence of beta-blockade (atenolol 100 mg daily for 4 days). QT intervals were measured manually by electronic callipers and corrected using the Fridericia formula. RESULTS: Heart rates were significantly increased during mental arithmetic, standing, exercise and GTN and this effect was significantly attenuated by atenolol, except for mental activation. QTc intervals were significantly reduced on standing and exercise and this was significantly attenuated by atenolol during exercise. In contrast, GTN increased QTc intervals (Delta = 5.7 ms, confidence interval +/- 3.2 ms, P < 0.005) and this was not attenuated by atenolol. CONCLUSIONS: Alteration in QTc intervals may result from physiological manoeuvres and vasodilation, interventions known to induce autonomic activation. We suggest that QTc prolongation due to GTN is indirectly mediated and unlikely to carry any proarrhythmic effect. Understanding whether drug-induced QTc prolongation is directly or indirectly mediated may be important to determine any potential proarrhythmic risk.     

Relationships between heart rate and PR interval during physiological and pharmacological interventions.

The relationships between heart rates (HR) and corresponding PR intervals (PR) were studied in 12 healthy young subjects during rest, standing and graduated treadmill exercise to heart rates of 160 to 170 beats min-1 and during the infusion of isoprenaline to heart rates of 100 to 110 beats min-1. During exercise, PR diminished with increasing HR. Over the range of HR from 60 to 160 beats min-1 all 12 individual subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = -0.351 HR (beats min-1) + 176.7 for composite data. During isoprenaline infusion the PR interval also diminished with increasing heart rate. Over the range of HR from 60 to 110 beats min-1, 11 of the 12 subjects exhibited negative linear correlations between HR and PR described by the equation: PR (ms) = -0.582 HR (beats min-1) + 186.5 for composite data. The exercise model was used to study the indirect (or rate-dependent) effects and the direct actions on atrioventricular conduction of beta-adrenoceptor blocking drugs and calcium channel antagonists, alone and in combination, in three groups of healthy subjects. Control and placebo observations on HR and PR at rest, standing and during exercise in these additional subjects also exhibited individual inverse linear relationships between HR and PR. Following the administration of beta-adrenoceptor blockers, PR were prolonged more than expected at the HR observed. Rate-adjusted PR prolongation during exercise exceeded standing which exceeded resting, indicating greater beta-adrenoceptor blockade in atrioventricular nodal tissue than in sinoatrial nodal tissue at each level of activity.(ABSTRACT TRUNCATED AT 250 WORDS)