Circadian variation of alpha 1-adrenoceptor-mediated pressor response to phenylephrine in man.

The variability in the pressor effects of the alpha 1-adrenoceptor agonist phenylephrine was observed under placebo conditions in ten healthy subjects in a double blind randomized study. Phenylephrine infusions were administered before administration of placebo (baseline) and 2, 4, 8, 12, 24 and 48 h later. The doses of phenylephrine required to increase systolic blood pressure by 20 mmHg after 8 and 12 h (5.30 and 9.30 pm, 81.4 +/- 15.3 and 71.1 +/- 16.0 micrograms min-1, respectively) were significantly (P < 0.01) less than the baseline values (8.30 am, 108.0 +/- 27.6 g min-1). These results might indicate a circadian variation in the phenylephrine-induced alpha-adrenoceptor-mediated vascular response in healthy subjects. These observations lend further insight into circadian variations of vascular tone that might contribute to circadian rhythms in cardiovascular disease.

The dose dependency of the alpha- and beta-adrenoceptor antagonist activity of carvedilol in man.

1. The alpha- and beta-adrenoceptor antagonist activity of carvedilol, a beta-adrenoceptor antagonist with vasodilating properties, and labetalol were investigated in 10 healthy male subjects. They received infusions with serially increasing concentrations of isoprenaline and phenylephrine before and after single oral doses of carvedilol 6.25, 12.5 and 25 mg, labetalol 400 mg and placebo at weekly intervals in a double-blind randomised manner. An exercise step test was performed at the end of the infusions. 2. The dose of isoprenaline required to increase heart rate by 25 beats min-1 (I25) and the dose of phenylephrine required to increase systolic and diastolic blood pressure by 20 mm Hg (PS20 and PD20) were calculated using a quadratic fit to individual dose-response curves. Comparisons were made with placebo and P < 0.05 was considered significant. 3. The I25 was increased by carvedilol 25 mg and labetalol 400 mg (P < 0.05). The dose ratios at I25 were: carvedilol 6.25 mg 2.1 +/- 1.6, carvedilol 12.5 mg 3.1 +/- 1.9, carvedilol 25 mg 6.4 +/- 4.9 and labetalol 400 mg 8.8 +/- 4.4. 4. The PS20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PS20 were: carvedilol 6.25 mg 1.0 +/- 0.2; 12.5 mg, 1.2 +/- 0.2; 25 mg, 1.3 +/- 0.4 and labetalol 400 mg 2.2 +/- 0.8. 5. The PD20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PD20 were: carvedilol 6.25 mg 1.1 +/- 0.3; 12.5 mg, 1.3 +/- 0.3; carvedilol 25 mg 1.3 +/- 0.4 and labetalol 400 mg 2.1 +/- 0.8.(ABSTRACT TRUNCATED AT 250 WORDS)

The dose dependency of the alpha-adrenoceptor antagonist and beta-adrenoceptor partial agonist activity of dilevalol and labetalol in man.

1. The alpha-adrenoceptor antagonist, beta 1-adrenoceptor antagonist and beta 2-partial agonist activity of dilevalol, a beta-adrenoceptor antagonist with vasodilating properties and labetalol were investigated in two studies. 2. In the first study, six healthy male subjects received serially increasing concentrations phenylephrine after single oral doses of dilevalol 200 mg, labetalol 400 mg and placebo at weekly intervals in a randomised double-blind manner. An exercise step test was performed at the end of the infusions. 3. The doses of phenylephrine required to increase systolic and diastolic blood pressures by 20 mmHg (PS20 and PD20 respectively) were increased by labetalol 400 mg (P < 0.05) but unchanged by dilevalol 200 mg. The dose ratios for PS20 (means +/- s.d.) were: dilevalol 200 mg 1.1 +/- 0.1, labetalol 400 mg 2.2 +/- 0.1. There was no difference in the percentage reduction in exercise tachycardia between dilevalol and labetalol. 4. In the second study, 10 healthy male subjects received infusions with serially increasing concentrations of phenylephrine and angiotensin II before and after single oral doses of dilevalol 200, 400 and 800 mg, labetalol 200 mg and placebo at weekly intervals in a double-blind randomised manner. Finger tremor was measured (piezoelectric accelerometer) with each infusion. An exercise step test was performed at the end of the infusions. 5. The PS20 and PD20 of phenylephrine were increased by labetalol 200 mg and unchanged by dilevalol. The dose ratios for PS20 were: dilevalol 200 mg 1.1 +/- 0.2. dilevalol 400 mg 1.1 +/- 0.4, dilevalol 800 mg 1.4 +/- 0.4 and labetalol 200 mg 2.5 +/- 0.7. The dose ratios for PD20 were: dilevalol 200 mg 1.1 +/- 0.4, dilevalol 400 mg 0.9 +/- 0.3. dilevalol 800 mg 1.3 +/- 0.4 and labetalol 200 mg 2.3 +/- 0.9. 6. The PS20 and PD20 of angiotensin II were unchanged by any of the drugs. 7. Exercise heart rate was reduced by dilevalol 200 mg (130 +/- 13 beats min-1), 400 mg (123 +/- 12 beats min-1), 800 mg (125 +/- 9 beats min) and labetalol 200 mg (143 +/- 12 beats min-1) vs placebo (161 +/- 17 beats min-1). 8. Finger tremor was significantly increased by dilevalol 800 mg (13.17 +/- 10.51 vs 6.62 +/- 4.51 centivolts for placebo: P < 0.01). Neither phenylephrine nor angiotensin II had an effect on finger tremor. 9. In conclusion, dilevalol 200, 400 and 800 mg demonstrated beta 1-adrenoceptor antagonist activity with no evidence of alpha 1-adrenoceptor antagonist activity. Labetalol 200 and 400 mg showed both beta 1- and alpha 1-antagonist activity. Dilevalol 800 mg demonstrated significant partial beta 2-adrenoceptor agonist activity by increasing finger tremor.

Time and frequency domain assessment of heart rate variability: a theoretical and clinical appreciation.

Non-invasive techniques for assessing heart rate variability can be used either diagnostically, as in identification of autonomic neuropathy associated with diabetes mellitus or tissue rejection following cardiac transplantation, or as a prognostic indicator in coronary artery disease. The methodology is based upon calculation of successive R-R intervals from an electrocardiogram, which can then be plotted as a frequency histogram (time domain analysis), undergo power spectral analysis to yield information in the frequency domain or be applied to chaos theory. In this review, several parameters are discussed which can be derived to quantify heart rate variability in the time and frequency domains; the latter providing information on autonomic balance. In the frequency domain up to three peaks may be observed, with the peak below 0.15 Hz being mediated by sympathetic and parasympathetic activity and peaks above 0.15 Hz being of vagal origin. The effects of different physiological and pathophysiological conditions on various indices of heart rate variability, and the use of heart rate variability analysis as a pharmacological method to assess the impact of drug therapy on sympathovagal balance are discussed.

Dose-dependent alpha 1-adrenoceptor antagonist activity of the anti-arrhythmic drug, abanoquil (UK-52,046), without reduction in blood pressure in man.

1. The dose-dependency of the alpha 1-adrenoceptor antagonist activity of the anti-arrhythmic abanoquil (UK-52,046) was investigated in 10 healthy male subjects who received serially increasing infusions of phenylephrine before and 2, 4, 8, 12, 24 and 48 h after single oral doses of abanoquil 0.25, 0.5 and 1 mg and placebo in a double-blind randomised manner. 2. The doses of phenylephrine required to increase systolic BP by 20 mm Hg (PS20) were calculated using a quadratic fit to the individual dose-response curves. 3. Abanoquil 0.25, 0.5 and 1 mg increased the PS20 in a dose-dependent manner with effects which were maximal at 2 to 8 h and lasted for 24 to 48 h (P less than 0.05). Maximal dose ratios were: abanoquil 0.25 mg 2.0 +/- 0.9, 0.5 mg 2.4 +/- 1.3, 1 mg 3.4 +/- 1.1. 4. No change occurred in supine BP but a small increase (P less than 0.01) occurred in supine HR 8 h post-dosing (64 +/- 9, 58 +/- 6 beats min-1 for abanoquil 1 mg and placebo respectively). 5. Therefore abanoquil 0.25, 0.5 and 1 mg showed dose-dependent alpha 1-adrenoceptor antagonist activity with no effect on supine BP.

Educational supervision of pre-registration house officers.

An annual survey of the educational supervision of pre-registration house officers has been carried out since 1987 by the Northern Ireland Council for Postgraduate Medical Education and the Queen's University of Belfast. Educational supervision was considered by house officers to be unsatisfactory in 27% of medical posts and 52% of surgical posts. Regular teaching was provided at least weekly in 77% of the posts, but 50% of house officers wanted mor experience of managing common medical emergencies. Over one-third felt administrative duties were excessive. There is a strong argument that hospitals should designate within clinical units a consultant with responsibility for educational supervision of the pre-registration house officers. Creation of the hospital counterpart of the General Practitioner trainer--the educational supervisor--would enhance the educational value of the pre-registration year. This might avoid withdrawal of approval for training purposes from some pre-registration posts.

Cardiovascular effects of cromakalim (BRL 34915) in healthy volunteers.

1. The effect of oral doses of cromakalim 0.5, 1.0, 1.5 and 2.0 mg on several cardiovascular parameters was studied in healthy male volunteers. 2. In the first study, no dose of cromakalim reduced systolic or diastolic blood pressure in the supine or standing position. Reductions of diastolic blood pressure after exercise (P less than 0.01) were observed 4 h after administration of 2.0 mg. 3. There was a trend towards increased heart rate after 2.0 mg at all time intervals, and significant changes were observed in supine and standing heart rate at 2 and 4 h (P less than 0.01). No significant change was observed in exercise heart rate. 4. In the second study small increases in forearm blood flow were observed from 3 h to 5 h after oral administration of 1.0 and 2.0 mg of cromakalim. Forearm vascular resistance was significantly reduced after 2.0 mg (P less than 0.025) when compared with placebo. No change was observed in forearm venous capacitance after either dose of cromakalim, or placebo. Supine heart rate was significantly increased 4 h after 2.0 mg of cromakalim (P less than 0.025). 5. These results show that oral administration of cromakalim decreases diastolic blood pressure and forearm vascular resistance. A hypotensive effect is probably attenuated by reflex tachycardia.

Clinical pharmacology of vasodilatory beta-blocking drugs.

The clinical pharmacology of beta-adrenoceptor blockers is summarized. They have a variety of pharmacological actions on the beta-adrenoceptors. For example, propranolol is a nonselective beta-blocker with antagonist effects on both beta 1 and beta 2 receptors, atenolol is a selective beta 1-antagonist, and celiprolol is a selective beta 1-antagonist, partial beta 2-agonist. beta 1-Receptor blockade tends to reduce heart rate, cardiac output, and arterial pressure while increasing peripheral vascular resistance, whereas beta 2-receptor blockade tends to be disadvantageous in causing bronchoconstriction and peripheral vasoconstriction. Selective beta 1-antagonist, beta 2-agonist activity would, therefore, appear to be particularly beneficial in offering the advantages of beta 1 blockade plus peripheral vasodilation. The beta 1- and beta 2-receptor actions of drugs are not always clearly identifiable, as in the demonstration of celiprolol's partial beta 2-agonist activity in human beings. This is because, in vivo, cardiovascular reflexes are intact and it has not, so far, been possible to remove endogenous catecholamines. This review summarizes various studies to investigate partial agonist activity, with particular emphasis on celiprolol.

Selectivity of xamoterol, prenalterol and salbutamol as assessed by their effects in the presence and absence of ICI 118 551.

Selectivity for beta 1- and beta 2-receptors to xamoterol, prenalterol and salbutamol were tested using ICI 118 551, a specific beta 2-receptor antagonist. Measurements were made of heart rate at rest and exercise, blood pressure, forearm blood flow and finger tremor. The actions of xamoterol were similar to those previously demonstrated, and were unaffected by beta 2-blockade, indicating selectivity for the beta 1-receptor. Salbutamol was selective for the beta 2-receptor and prenalterol was active at both.

The pharmacokinetics of xamoterol in liver disease.

The pharmacokinetics of xamoterol, a beta 1-adrenoceptor partial agonist, have been studied in patients with liver disease and a group of age- and sex-matched normal controls. No significant differences were observed after the oral administration of xamoterol 200 mg. The low bioavailability of xamoterol was confirmed (6.1% in patients, 6.9% in controls). After i.v. xamoterol 0.2 mg kg-1, no significant differences between the groups were observed. A small increase in the terminal plasma elimination half-life (t1/2) was observed in patients when compared with controls (15.3 +/- 6.4 vs 8.4 +/- 2.8 h, mean +/- s.d., P = 0.08). Renal clearance accounted for about 50% of total clearance in patients and about 30% in controls. It is suggested that in patients with heart failure, hepatic dysfunction would probably not influence xamoterol disposition.

Haemodynamic and pharmacokinetic evaluation of alfuzosin in man. A dose ranging study and comparison with prazosin.

In an open dose ranging study with random inclusion of placebo, alfuzosin (alpha 1-adrenoceptor antagonist) 1, 2.5 and 5 mg was administered to 6 healthy volunteers, 3 of the volunteers received 10 mg alfuzosin. Supine systolic blood (SBP) pressure was not reduced by alfuzosin although significant increases occurred in supine heart rate (HR) after 2.5 and 5 mg. In the standing position, SBP was reduced at 2 and 4 h with 5 mg alfuzosin; significant increases in HR occurred following 1, 2.5 and 5 mg at 2, 4, 6 and 8 h after administration. Exercise SBP was not reduced; diastolic blood pressure was significantly reduced at 4 and 6 h with 5 mg alfuzosin. More marked effects were seen in the 3 subjects who received 10 mg alfuzosin. After 1 and 5 mg, tmax ranged from 1-2 h; Cmax (4.1 to 20.8 ng.ml-1; AUC (0-24) 20 to 132 ng.ml-1.h (1 and 5 mg respectively) increased progressively with dose indicating dose dependent kinetics; no significant changes occurred in the visual analogue scale for sedation. A comparison of alfuzosin 5 mg, prazosin 1 mg and placebo each administered for 4 days, indicated that alfuzosin did not significantly reduce standing SBP on either Day 1 or Day 4; prazosin reduced SBP at 2 and 4 h on Day 1 and 6 h on Day 4 compared to placebo. Standing HR was increased by alfuzosin at 2 h on Day 1 and Day 4; increases occurred with prazosin at 2, 4, 6 and 8 h on Day 1 and 6 h on Day 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the combination of alinidine and other anti-anginal drugs on heart rate and blood pressure in healthy volunteers.

1. Heart rate and blood pressure changes following the administration of alinidine 30 mg alone and in combination with atenolol 25 mg, nifedipine retard 20 mg and glyceryl trinitrate 500 micrograms were investigated in three groups of six healthy male volunteers. 2. Concomitant administration of alinidine and atenolol reduced (P less than 0.05) supine, standing and exercise heart rate when compared with alinidine alone. The maximum reduction in exercise heart rate was 116 +/- 2.4 beats min-1 for the combination vs 129.0 +/- 3.1 beats min-1 for alinidine alone. 3. Supine (3, 4, 8 h) and standing (2 h) systolic BP were also reduced (P less than 0.05) with the alinidine and atenolol combination compared with alinidine alone. Little change occurred in diastolic blood pressure. 4. Alinidine and nifedipine in combination reduced (P less than 0.05) the nifedipine induced increase in heart rate in the supine (2, 4 h) and standing (4 h) position and following exercise (2, 4 h). No further decreases in systolic and diastolic blood pressure occurred with the combination. 5. Alinidine administered 2 h before a glyceryl trinitrate challenge reduced (P less than 0.05) the glyceryl trinitrate induced increase in standing heart rate at all time intervals (1 to 6 min); the maximum reduction occurred at 3 min (105.0 +/- 4.3 (glyceryl trinitrate) vs 86.8 +/- 6.7 beats min-1 (combination]. Systolic blood pressure was further reduced at all time intervals with glyceryl trinitrate taken in the presence of alinidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the myocardial-selective alpha 1-adrenoceptor antagonist UK-52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs.

1. Adrenaline-induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK-52046, 3.8 +/- 1.4 micrograms kg-1 (mean +/- s.e.mean), atenolol 14.6 +/- 2.1 micrograms kg-1, or a combination containing equal amounts of the two drugs of 0.36 +/- 0.1 microgram kg-1. The pressor response to adrenaline was reduced (P less than 0.01) by UK-52046 but not by atenolol or the combination of both drugs. 2. In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK-52046, 32 micrograms kg-1, increased the number of sinus beats in each 5 min period from 137 +/- 47 to 662 +/- 99 (P less than 0.01); this was associated with a significant (P less than 0.01) fall in blood pressure. Atenolol in doses of up to 800 micrograms kg-1 had no effect. 3. UK-52046, 3.7 +/- 1.4 micrograms kg-1, prevented adrenaline-induced arrhythmias 3-4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100 micrograms kg-1 produced an 84.4 +/- 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 +/- 1.1 micrograms kg-1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P less than 0.05) by UK-52046, but resting blood pressure was unaffected by the different treatments. An increase (P less than 0.01) in heart rate was associated with both UK-52046 and the combination. 4. Neither UK-52046 (doses up to 64 micrograms kg-1) nor atenolol (up to 800 micrograms kg-1) had any effect upon ouabain-induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5. In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30 min of CAL was not reduced by 4 micrograms kg-1 UK-52046 but fell (P less than 0.01 compared with placebo) after 8 micrograms kg-1 [median values with ranges for placebo, 4 micrograms kg-1 and 8 micrograms kg-1 respectively 190 (4-674), 246 (9-1204) and 12 (1-154)]. Both doses of UK-52046 were associated with significant falls in blood pressure. 6. The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7-30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK-52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29). Compared with placebo, blood pressure fell with doses greater than 4jg kg- '. 7. These results indicate antiarrhythmic effects of UK-52046 in a number of experimental models and suggest an enhanced role of alpha-receptors in the genesis of ischaemia-related arrhythmias. In several of the models used, UK-52046 produced haemodynamic changes in keeping with peripheral alpha-adrenoceptor antagonism.

The selectivity of xamoterol, prenalterol, and salbutamol as assessed by their effects in the presence and absence of ICI 118,551.

The selectivity of single oral doses of xamoterol, 200 mg, prenalterol, 50 mg, and salbutamol, 8 mg, was compared in eight healthy male volunteers by measuring their effects on sleeping heart rate, supine heart rate, blood pressure, forearm blood flow, finger tremor, and exercise heart rate in the presence and absence of the specific beta 2-adrenoceptor antagonist ICI 118,551, 25 mg. Xamoterol, 200 mg, increased sleeping heart rate and systolic blood pressure, decreased exercise heart rate, and had no effect on diastolic blood pressure, forearm blood flow, or finger tremor. The concurrent administration of ICI 118,551, 25 mg, did not alter these results. Supine heart rate was increased by xamoterol and did not differ from that for xamoterol with ICI 118,551. Prenalterol, 50 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, and finger tremor, decreased diastolic blood pressure, and had no effect on exercise tachycardia. The concurrent administration of ICI 118,551 with prenalterol reduced the increase in sleeping heart rate, supine heart rate, and forearm blood flow, and reduced the fall in diastolic blood pressure caused by prenalterol alone. The increase in finger tremor following prenalterol with ICI 118,551 tended to be less than that following prenalterol. Salbutamol, 8 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, finger tremor, and exercise heart rate, and caused a fall in diastolic blood pressure. When salbutamol, 8 mg, was administered with ICI 118,551, 25 mg, the only changes detected were a small initial increase in finger tremor and a small rise in diastolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute and chronic oral administration of alfuzosin on baroreflex function and tremor in man.

1. The effects of the acute and chronic administration of the alpha 1-adrenoceptor antagonist alfuzosin (5 mg twice daily for 7 days) on baroreflex function, physiological tremor and sedation (visual analogue scale) were investigated in six healthy volunteers. 2. Phenylephrine-systolic pressure dose-response curves were shifted (P less than 0.05) to the right by alfuzosin compared with placebo on day 1, and on day 8 prior to the administration of alfuzosin indicating significant alpha-adrenoceptor blockade over 24 h with 5 mg twice daily administration. 3. Baroreflex sensitivity (delta R-R ms mmHg-1 systolic arterial pressure) was reduced (P less than 0.05) by alfuzosin compared with placebo on day 1 (13.8 +/- 2.6 vs 20.6 +/- 3.6 ms mmHg-1) and on day 8 (13.4 +/- 1.7 vs 21.1 +/- 2.7 ms mmHg-1). 4. Maximum power (microV2) or frequency (Hz) of physiological tremor did not change 2 h after alfuzosin administration on day 1 (13.7 +/- 4.4 microV2, 9.2 +/- 0.3 Hz) or day 8 (11.5 +/- 4.3 microV2, 10.0 +/- 0.4 Hz) compared with placebo on day 1 (16.9 +/- 7.5 microV2, 10.0 +/- 0.4 Hz) and day 8 (17.3 +/- 5.7 microV2, 10.2 +/- 0.8 Hz). 5. Alfuzosin 5 mg twice daily did not cause sedation on day 1 or day 8. 6. In conclusion the reduction in baroreflex sensitivity with the alpha-adrenoceptor antagonist alfuzosin may contribute to its antihypertensive activity in reducing the reflex tachycardia associated with its hypotensive action.

Effect of acute and chronic indoramin administration on baroreflex function and tremor in humans.

Several mechanisms have been suggested for the absence of reflex tachycardia in response to the hypotensive effect of the selective alpha 1-adrenoceptor antagonist indoramin, including, in animals, membrane-stabilising activity, prolongation of repolarisation time, and reduction in baroreflex sensitivity. The present study investigated the effect of acute and chronic oral administration of indoramin (50 mg daily for 8 days) on baroreflex sensitivity in six healthy male volunteers. Baroreflex function was measured by determining the relationship between systolic blood pressure (SBP) and R-R interval following intravenous administration of phenylephrine. Indoramin shifted (p less than 0.05) the phenylephrine dose-response curve to the right on days 1 and 8 compared with placebo. Baroreflex sensitivity [R-R (ms)/SBP (mm Hg)] was reduced (p less than 0.05) by indoramin on day 1 compared with placebo (18.3 +/- 1.3 vs. 11.2 +/- 2.2 ms/mm Hg), and on day 8 compared with pretreatment values (18.3 +/- 2.8 vs. 10.8 +/- 1.8 ms/mm Hg). Acute but not chronic administration of indoramin caused (p less than 0.05) sedation; tremor tended to increase with chronic administration. It is suggested that depression of baroreflex sensitivity by indoramin may explain, in part, the lack of reflex tachycardia associated with its antihypertensive effect.