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Biomedical subjects

J G Riddell

Publications and source records attributed to J G Riddell.

At least 37 records · Page 2Linked to original sources
PubMed1988

Characterization of the beta-adrenoreceptors which mediate the isoprenaline-induced changes in finger tremor and cardiovascular function in man.

We have studied the contribution of beta 1- and beta 2-adrenoceptors to the isoprenaline-induced changes in heart rate, blood pressure, forearm blood flow, peripheral vascular resistance, and finger tremor. This was achieved by a comparison of the effects of atenolol 50 mg, ICI 118551 25 mg, propranolol 80 mg, atenolol 50 mg combined with ICI 118551 25 mg, propranolol 80 mg combined with ICI 118551 25 mg, and placebo. Atenolol 50 mg and ICI 118551 25 mg caused similar attenuations in the isoprenaline-induced changes in heart rate and diastolic blood pressure, but the responses after the combination of atenolol and ICI 118551 were similar to those after propranolol 80 mg. There was no difference in the forearm blood flow responses to isoprenaline after atenolol 50 mg and ICI 118551, but atenolol 50 mg did not reduce peripheral vascular resistance compared with placebo. Both responses after treatment with atenolol combined with ICI 118551 were similar to those after propranolol 80 mg. Finger tremor responses to isoprenaline were antagonized by ICI 118551 alone and in combination with propranolol and atenolol but not by atenolol alone, suggesting that the response is beta 2-adrenoceptor-mediated. We conclude that the cardiovascular responses to isoprenaline are mediated by both beta 1- and beta 2-adrenoceptors, whereas the finger tremor response is mediated by beta 2-adrenoceptors.

Adult↗
PubMed1988

Studies of the agonist and antagonist activity of cicloprolol in man.

To assess the partial agonist activity of cicloprolol in man, four studies were carried out in normal male volunteers. I and II. Open dose escalating studies of the effects of oral doses of the drug on exercise tachycardia and sleeping heart rate. III and IV. Double-blind randomized studies of the effects of placebo, cicloprolol 25 mg, cicloprolol 50 mg, cicloprolol 100 mg, atenolol 50 mg, pindolol 10 mg, salbutamol 8 mg and prenalterol 50 mg on sleeping heart rate, resting supine heart rate, blood pressure, forearm blood flow, finger tremor and exercise tachycardia. All doses of cicloprolol above 2.5 mg reduced an exercise tachycardia but there was no increase in effect above a dose of 50 mg. Cicloprolol caused a dose dependent increase in sleeping heart rate up to 200 mg. Cicloprolol increased resting supine heart rate, systolic blood pressure, forearm blood flow and finger tremor. None of the drugs affected quality of sleep. Cicloprolol has significant partial agonist activity at the beta 1-adrenoceptor as indicated by increases in heart rate and systolic blood pressure. The increases in finger tremor and forearm blood flow suggest that cicloprolol has some partial agonist activity at the beta 2-adrenoceptor.

Adult↗
PubMed1988

Effect of acute administration of propranolol and atenolol on baroreflex function in normal man.

The acute administration of the beta-adrenoceptor antagonists propranolol (80 mg) and atenolol (50 mg) on baroreflex function were investigated in healthy volunteers. Two h after administration both propranolol and atenolol significantly prolonged the supine R-R interval (1126, 1128 ms respectively) compared to placebo (1012 ms); systolic arterial pressure also fell (102.9, 102.0 mm Hg respectively) compared to placebo (112.6 mm Hg). Baroreflex function, assessed using glyceryl trinitrate to deactivate the baroreceptors was unchanged by these drugs compared to placebo. Baroreflex sensitivity (slope of the linear regression line relating R-R interval to systolic blood pressure) using phenylephrine to activate the baroreceptors, was also unchanged (17.2, 17.9 ms/mm Hg respectively) compared to placebo (19.9 ms/mm Hg). However both regression lines were shifted (p less than 0.05) to the left compared to placebo.

Administration, Oral↗
PubMed1988

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.

Adult↗
PubMed1988

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)

Adrenergic beta-Antagonists↗
PubMed1988

The effect of acute and chronic captopril therapy on baroreflex function in man.

1. The effect of captopril 12.5 mg three times daily for 14 days on baroreflex sensitivity was investigated in six normotensive salt-replete male subjects. 2. Baroreflex sensitivity [delta R-R interval ms/mmHg systolic blood pressure (SBP)] was assessed following decreases and increases in SBP with glyceryl trinitrate and phenylephrine respectively and during Valsalva's manoeuvre. 3. Captopril had no effect on supine intra-arterial SBP or R-R interval on days 1 and 15 compared with placebo. However decreases (P less than 0.05) which occurred in plasma angiotensin II on day 1 (12.3 +/- 0.8 to 7.6 +/- 1.5 pg ml-1) and on day 15 (14.5 +/- 1.5 to 6.3 +/- 0.5 pg ml-1) and increases (P less than 0.02) in plasma renin activity on day 1 (1.2 +/- 0.7 to 4.8 +/- 0.8 ng A I ml-1 h-1) and on day 15 (1.1 +/- 0.2 to 5.4 +/- 0.9 ng A I ml-1 h-1) compared with placebo, indicated angiotensin-converting enzyme inhibition. 4. Baroreflex sensitivity was unchanged by captopril on day 1 and day 15 compared with placebo following the use of glyceryl trinitrate and phenylephrine to deactivate and activate respectively the baroreceptors, and during the strain and release phases of Valsalva's manoeuvre.

Adult↗
PubMed1988

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.

Adult↗
PubMed1987

Baroreceptor function in man following peripheral alpha 1- and alpha 2-adrenoceptor stimulation.

Methoxamine and alpha-methyl-noradrenaline were administered to six healthy male subjects on separate days as rapid bolus injections until blood pressure increased by approximately 30 mmHg; Valsalva's Manoeuvre was carried out on each occasion. Propranolol (80 mg) or placebo was administered (random order, double-blind, weekly intervals) and the observations were repeated after 2 h. Baroreceptor sensitivity (delta R-R interval ms/mmHg systolic BP) was less (p less than 0.05) with alpha-methyl-noradrenaline than methoxamine. Propranolol abolished the differences in baroreceptor-mediated bradycardia following alpha-methyl-noradrenaline and methoxamine, and shifted the baroreceptor sensitivity regression lines (p less than 0.05) to the left. During the release phase of Valsalva's Manoeuvre baroreceptor sensitivity was increased following propranolol. The smaller baroreceptor-mediated bradycardia response observed with alpha-methyl-noradrenaline does not support the hypothesis that pre-synaptic alpha-adrenoreceptors have a physiological role in the modulation of baroreceptor function in man, and may be due to alpha-methyl-noradrenaline having beta 1-agonist activity.

Adrenergic alpha-Agonists↗
PubMed1987

A comparison of the cardioselectivity of five beta-adrenoceptor blocking drugs.

The cardioselectivities of five beta-adrenoceptor antagonists were compared. Six normal subjects received, in a double-blind random order, 200 mg acebutolol, 50 mg atenolol, 10 mg betaxolol, 100 mg metoprolol, 80 mg propranolol, and placebo. All beta-adrenoceptor antagonists produced a similar reduction in exercise tachycardia. Isoprenaline infusions in incremental doses were given. Dose-response curves were constructed and the doses of isoprenaline required to increase heart rate by 25 beats/min (I25), forearm blood flow by 3 ml/100 ml/min (IF3), and finger tremor by 200% (IT200), and decrease diastolic blood pressure by 25 mm Hg (ID25), after each treatment were compared. After propranolol, I25, ID25, IF3, and IT200 were greater (p less than 0.02) than after atenolol, betaxolol, and metoprolol; I25, ID25, and IT200 were greater than after acebutolol. After acebutolol I25, ID25, and IF3 were greater than after atenolol and betaxolol; IT200 was greater than after betaxolol. Atenolol and betaxolol caused less reduction in the isoprenaline-induced changes in blood glucose, plasma potassium, lactate, renin activity, and serum insulin than propranolol. Acebutolol caused less attenuation of blood glucose and plasma lactate, and metoprolol less attenuation of plasma renin activity, than propranolol. It is concluded that acebutolol, atenolol, betaxolol, and metoprolol cause less blockade of beta 2-adrenoceptors than propranolol, and atenolol and betaxolol are more cardioselective than acebutolol.

Adrenergic beta-Antagonists↗
PubMed1987

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man.

1. The effects of single oral doses of three beta-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two beta-adrenoceptor antagonists (propranolol and atenolol), two beta-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta-adrenoceptor antagonists. 10. While Ro 31-1118 and flusoxolol are antagonists mainly at the beta 1-adrenoceptor they have agonist activity at both beta 1- and beta 2 adrenoceptors. 11. While pindolol is a non-selective antagonist its agonist activity is mainly at the beta 2-adrenoceptor.

Adrenergic beta-Agonists↗
PubMed1987

The assessment of the beta-adrenoceptor blocking activity and cardioselectivity of Koe 3290 in normal subjects.

1. The beta-adrenoceptor antagonist activity, cardioselectivity and antilipolytic properties of Koe 3290 were investigated in healthy subjects. 2. Koe 3290 12.5, 25, 50 and 100 mg, atenolol 25, 50 and 100 mg and placebo were given in double-blind randomised order to eight subjects. All doses of both Koe 3290 and atenolol reduced supine, standing and exercise heart rate (P less than 0.02). From 2 to 8 h after administration the exercise heart rate after Koe 3290 100 mg was similar to that for atenolol 50 mg. 3. The cardioselectivity of Koe 3290 and atenolol was compared. Koe 3290 50, 100 and 150 mg, atenolol 50 and 100 mg and placebo were given to six subjects in a double-blind random order. Isoprenaline dose-response curves were constructed for cardiovascular parameters and finger tremor. 4. For doses which were equipotent at the beta 1-adrenoceptor (Koe 3290 100 mg and atenolol 50 mg) atenolol caused less attenuation of heart rate, diastolic blood pressure, forearm blood flow and finger tremor (P less than 0.02). 5. There was no difference in the isoprenaline-induced changes in serum free fatty acids, blood glucose, plasma lactate or potassium after Koe 3290 and atenolol. Koe 3290 attenuated the rise in serum insulin more than atenolol (P less than 0.02). 6. Koe 3290 is an effective beta-adrenoceptor blocking drug in man. It is not as cardioselective as atenolol and does not possess specific antilipolytic properties.

Adrenergic beta-Antagonists↗
PubMed1987

Clinical pharmacokinetics of beta-adrenoceptor antagonists. An update.

The beta-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction. All the beta-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of beta-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug. Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma beta-adrenoceptor antagonist concentration measurement is usually unnecessary. The investigation of the clinical pharmacokinetics of the beta-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.

Adrenergic beta-Antagonists↗
PubMed1987

Celiprolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties and its therapeutic use in hypertension and angina pectoris.

Celiprolol is a new 'cardioselective' beta-adrenoceptor blocking drug with intrinsic sympathomimetic (partial agonist) activity and a weak vasodilating effect. Celiprolol appears not to cause bronchoconstriction or inhibit the effect of bronchodilating drugs in asthmatic patients and there is some evidence that it may have mild bronchodilating activity in such patients. Some studies suggest that celiprolol, because of vasodilation, may be less likely to reduce blood flow to the peripheries than other beta-adrenoceptor blocking drugs and hence cause fewer peripheral vascular side effects. Significant inhibition of exercise tachycardia occurs 24 hours after a single oral dose of celiprolol. In preliminary therapeutic trials celiprolol 200 to 600mg once daily was similar in efficacy to propranolol 40mg to 80mg twice daily or atenolol 100mg once daily in patients with mild to moderate hypertension or angina pectoris. If the apparent pharmacodynamic advantages of celiprolol are confirmed in well designed therapeutic trials then celiprolol should represent a definite advance in beta-adrenoceptor blocking therapy.

Adrenergic beta-Antagonists↗
PubMed1986

A method for producing constant plasma concentrations of drugs. Application to methohexitone.

A delivery system in which a dilute infusion of methohexitone is continuously added to a smaller volume of more concentrated solution has been used to infuse exponentially decreasing drug concentrations at a constant rate of infusion. The constants for calculation of concentrations and infusion rate are described. It was possible to achieve and maintain the target plasma concentration required to produce anaesthesia in conjunction with nitrous oxide in oxygen. Methohexitone is the only available drug suitable for this technique, but it requires frequent opioid supplementation and is not the ideal drug for such a technique.

Anesthesia, General↗
PubMed1986

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.

Adrenergic beta-Antagonists↗
PubMed1985

Effects of betaxolol, propranolol, and atenolol on isoproterenol-induced beta-adrenoceptor responses.

Five healthy young men received, in a double-blind fashion, single oral doses of 10 mg betaxolol, 40 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and placebo. After the dose each received serial 12-minute infusions of isoproterenol sulfate through the dose range 0.5 to 32 micrograms/min until the heart rate rose by 40 bpm or the subject could not tolerate the effects of the infusion. Heart rate, finger tremor, blood pressure, and forearm blood flow were measured after each infusion. Dose-response curves were constructed for the changes in these parameters with increasing doses of isoproterenol. The ascending order of potency of the drugs in preventing the changes in heart rate, finger tremor, diastolic blood pressure, forearm blood flow, and forearm vascular resistance induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg betaxolol, and 40 mg propranolol. The ascending order of potency of the drugs in preventing the change in systolic blood pressure induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and 40 mg betaxolol. Betaxolol, 10 mg, is equally cardioselective to 50 mg atenolol and at a dose of 40 mg betaxolol also exhibits cardioselectivity.

Adrenergic beta-Antagonists↗
PubMed1985

Comparative effects of adimolol, labetalol and propranolol on heart rate and blood pressure in man.

The cardiovascular effects of adimolol, a new, potent, long acting beta-adrenoceptor blocking drug were investigated in three studies. In the first study blood pressure and heart rate were measured in five male volunteers before and at 2, 4, 6, 8, 24, 32, 48, 72 and 96 h after single oral doses of adimolol. All doses of adimolol reduced supine, standing and exercise heart rates in a dose dependent manner. The maximum effect ranged from 18% following 25 mg to 29% following 600 mg and all doses showed an effect at 96 h (range 3.5-17.2%). In the second study the effects of adimolol, 25 and 400 mg, labetalol, 200 and 800 mg, propranolol 40 mg and placebo were compared on supine and standing heart rate and blood pressure and on exercise heart rate before and at 2, 4, 6 and 8 h after single oral doses. The exercise heart rate was significantly reduced at all times following adimolol 25 and 400 mg, labetalol 800 mg and propranolol 40 mg. At 2 h all the drugs significantly reduced standing systolic blood pressure. In the third study, 4 h after single oral doses of adimolol 400 mg, labetalol 400 mg and propranolol 40 mg six subjects received serial 4 min infusions of phenylephrine. The blood pressure was measured after each infusion. Labetalol 400 mg significantly shifted the blood pressure dose-response curve to the right. There was no difference between propranolol 40 mg and adimolol 400 mg. These studies show that adimolol is a potent, long acting beta-adrenoceptor blocking drug without evidence of alpha-adrenoceptor blockade in man.

Adrenergic beta-Antagonists↗