Cardiovascular effects of eating, atenolol and their interaction: beta1-adrenergic modulation does not play a predominant role in the genesis of postprandial effects.

1. Eight healthy subjects were investigated on four occasions at least 1 week apart when they either ate a standard 3100 kJ cold meal or fasted. One hour earlier, either 50 mg atenolol or placebo was administered. 2. Eating was followed by prominent changes of systolic cardiovascular function: a rise of heart rate (+7, 95% CI: 4 to 9 beats min(-1)), systolic BP (+5, CI: 1 to 8 mmHg), a drop of diastolic BP (-6, CI:-9 to -3 mmHg), shortening of the pre-ejection period PEP (-11, CI: -13 to -9 ms) and electromechanical systole QS2c (-13, CI: -17 to -8 ms), a rise of the estimated cardiac output CO (+1.3, CI: 1.0 to 1.6 1 min(-1)) and a reduction of the calculated total peripheral resistance TPR (-306, CI: -389 to -222 dyn s cm(-5)). 3. Eating was also followed by an increase of the non-renal clearance of sorbitol (as a measure of hepatic blood flow) and this change was larger than proportional to the increase of CO. The plasma renin activity rose after the meal but the venous plasma noradrenaline and adrenaline concentrations were not affected. 4. The postprandial effects peaked over the first 1-2 h after the meal but remained well detectable up to 4 h after eating. 5. The administration of 50 mg atenolol before the meal reduced the postprandial effects to the same extent as the atenolol effects in the fasting state. This lack of interaction (or mere arithmetic additivity) indicates that the efferent beta1-adrenergic tone does not play a predominant role in the modulation of postprandial cardiovascular changes.

Disagreement between standard transthoracic impedance cardiography and the automated transthoracic electrical bioimpedance method in estimating the cardiovascular responses to phenylephrine and isoprenaline in healthy man.

1. Impedance cardiography is a well-established noninvasive method to assess within-subject changes of cardiovascular function. We compared the standard approach (ZCG) which requires tedious signal analysis with an automated approach (TEB: NCCOM 3) with its own specific equipment, algorithms and equations in order to assess agreement of the method-specific measurements and calculations. 2. Ten healthy men were studied on two occasions with either ZCG or TEB, at rest and at the end of 5 min i.v.-infusions with 1 microgram min-1 isoprenaline and 100 micrograms min-1 phenylephrine. 3. There was good agreement for the method-independent changes (HR, SBP/DBP), but there were large differences for method-specific measurements: dZ/dtmax [TEB-ZCG] = -0.68, CI: -0.83 to -0.53 ohm s-1, PEP [TEB-ZCG] = -22.1, CI: -35.0 to -9.2 ms and QS2c [TEB-ZCG] = -16.5, CI: -32.4 to -0.6 ms and for the calculated stroke volume SV [TEB-ZCG] = 30.3, CI: 15.5 to 45.2 ml. The responses of dZ/dtmax and SV to isoprenaline and phenylephrine, although qualitatively similar, reached no quantitative agreement either. A substantial disagreement was evident for the STI responses to isoprenaline where TEB failed to detect the expected reduction of VETc and thus grossly underestimated the shortening of QS2c. 4. It is concluded that TEB-measurements and -calculations did not agree with standard ZCG, that the methods, albeit related, cannot be considered as interchangeable and that suspicion is justified that TEB might yield erroneous results under specific circumstances.

Noninvasive estimates of the inodilatory effects of isoprenaline and their inhibition by transdermally delivered mepindolol in healthy men.

We analyzed the reproducibility and sensitivity of noninvasive estimates of cardiovascular performance (impedance cardiography and systolic time intervals) to detect and describe the inodilatory responses to isoprenaline (ISO) and their attenuation by transdermally applied mepindolol. The responses to 5-min intravenous (i.v.) infusions of 1 microgram/min ISO in 9 young male healthy volunteers were evaluated repeatedly before and at the end of chronic treatments with daily applied TSD skin patches for transdermal drug delivery with either mepindolol or placebo (double-blind randomized cross-over design). ISO caused a clear increase in mean heart rate (HR), systolic blood pressure (SBP), maximum velocity of impedance changes, estimated stroke volume (SV), and the Heather index, and a reduction in diastolic BP (DBP), estimated systemic vascular resistance (SVR), and a shortening of all systolic time intervals (STIs). These responses were effectively blunted at the end of 1-week treatment with mepindolol TSD patches. Despite overall good agreement of the mean baseline data (under placebo), their within-subject reproducibility nevertheless was too weak to guarantee adequate power to detect small changes under active treatment. Reproducibility of the ISO responses was quite poor, although in a method-independent way. The methods used allowed us to describe the cardiac and vascular components of the ISO responses with adequate detail. Transdermally delivered mepindolol was shown to block ISO responses effectively, but the overall variability of the responses was too large to detect slight changes in them, although the methods in themselves did not appear to be the main cause of this lack of sensitivity.

Interactions between domperidone and ropinirole, a novel dopamine D2-receptor agonist.

1. Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2-receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone-placebo, and those of a single dose of domperidone followed by ropinirole-placebo. 2. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. 3. Pretreatment with 20 mg domperidone 1 h before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. 4. Ropinirole did not alter supine or standing catecholamine concentrations. 5. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 h earlier.

Noninvasive assessment of the inodilator action of amrinone in healthy man.

The effects of a single dose of 2 mg/kg amrinone (60 min constant rate IV infusion) have been assessed in a double-blind, placebo-controlled, within-subject cross-over study in six healthy volunteers. Combined impedance cardiography, phonocardiography and electrocardiography revealed a protracted drop in mean ventricular ejection time and electromechanical systole together, with a protracted rise in the "contractility" indices dZ/dtmax and the Heather index HI. The profile is compatible with combined venous vasodilation and positive inotropic action. In spite of the methodological constraints, endpoints were reached that were both detectable and relevant. The profiling permitted a better distinction to be made between the possible levels of action than systolic time intervals alone could have done. Therefore, these methods may be of value in the early development of "inodilator" drugs.

Pressor tests in clinical pharmacology: response morphology heterogeneity.

Heart rate, blood pressure and venous plasma catecholamine responses to passive upright tilt, immobile erect standing, upright sitting, immersion of hand or foot in cold water, isometric handgrip and delayed auditory feedback were assessed in young healthy volunteers. Each of the tests was characterized by its own typical response morphology. Postural stress caused mainly a rise in heart rate and diastolic blood pressure with little change in systolic blood pressure. The cold pressor test caused a rapid rise in heart rate, systolic and diastolic blood pressure which then was attenuated on further exposure to cold. Isometric handgrip caused the largest pressor responses in linear fashion relative to time. Protracted isometric handgrip (i.e., 5 rather than 3 min) seemed to add psychological stress to the response profile. Delayed auditory feedback caused a less well structured rise in heart rate, systolic and diastolic blood pressure. The postural tests were the most powerful stimuli for venous plasma catecholamines. For all further tests, the catecholamine responses were in general quite small. Therefore, the tests should be considered as complementary and more than one test should be used in order to cover the spectrum of relevant pressor drives. All tests were affected by substantial variability. Sufficiently large samples should be used in order to assure appropriate statistical power and precision when the effects of investigational drugs on these test responses are studied.

Carvedilol increases the systemic bioavailability of oral digoxin.

The effects of a single oral dose of 25 mg carvedilol on the plasma and urinary kinetics of digoxin after an oral and intravenous 0.5 mg dose, were investigated in two separate double-blind, placebo-controlled, period-balanced cross-over studies in healthy male subjects. Carvedilol increased the mean maximum plasma concentration and the area under the plasma concentration time-curve of digoxin when administered orally. The effects were virtually confined to the first 4 h after dosing, and the apparent terminal disposition rate constant was not changed. Carvedilol did not alter the plasma and urinary kinetics of intravenously administered digoxin.

Effects of the novel D2-dopaminergic agonist ropinirol on supine resting and stimulated circulatory and neuroendocrine variables in healthy volunteers.

Ropinirol (SK&F 101468) is a novel drug characterized preclinically as a potent and selective D2-dopaminergic agonist. In the present study the effects of acute doses of 0.4, 0.8 and 1 mg were profiled in eight healthy male volunteers, using a placebo-controlled cross-over study design with incremental dosing. The drug was found to cause mild nausea and postural faintness at the highest dose in one subject. There were no further relevant clinical events, and the postural responses at 200 and 360 min after dosing remained in general well maintained, with the exception of a slight reduction of standing systolic blood pressure. The drug furthermore was found to reduce serum prolactin levels; the magnitude and duration of this effect were dose-related. The drug tended to reduce the noradrenaline responses to 5 min isometric handgrip testing (30% of maximal strength) at 165 min after dosing, and the noradrenaline responses to 3 min immobile standing at 200 min after dosing. The drug also tended to blunt the venous plasma dopamine responses to 3 min cold pressor test (90 min after dosing) and to standing at 200 min after dosing. These changes are concluded to be compatible with the assumed peripheral D2-dopaminergic actions of the drug.

Transdermal delivery of mepindolol and propranolol in normal man. 1st communication: study design, clinical and pharmacodynamic aspects.

In the present study the beta-adrenoreceptor blocking effects of acute and repeated transdermally delivered mepindolol (20 mg/9.8 cm2 patch) and propranolol (40 mg/9.8 cm2 patch) on supine and stimulated circulatory function (isoprenaline infusion, isometric hand grip, delayed auditory feed-back) in nine healthy male volunteers were assessed. The study was conducted in a placebo-controlled double-blind cross-over fashion, with three one-week treatment courses randomly allocated in a period-balanced fashion. Treatment phases were separated by a one-week wash-out phase. The placebo and mepindolol patch were well tolerated, whereas the propranolol patch caused skin irritation and itching in most subjects, and even vesicular lesions in 3/9 subjects. Acute and repeated 24 h application of the propranolol patch caused only small and clinically not relevant changes of heart rate and blood pressure. Acute application of the mepindolol patch induced only mild blunting of the diastolic blood pressure and heart rate responses to isoprenaline i.v. infusion at 8 h. However, the isoprenaline responses were nearly abolished after one week repeated 24 h application of the mepindolol patch, in a stable and protracted fashion. The circulatory responses to isometric handgrip and delayed auditory feedback tended to be reduced, but to a smaller extent than for the isoprenaline test. Repeated application of mepindolol via the investigational device for transdermal drug delivery (BIO TSD) thus resulted in stable and protracted beta-adrenoreceptor blockade.

Transdermal delivery of mepindolol and propranolol in normal man. 2nd communication: pharmacokinetic and neuro-endocrine aspects.

The plasma and urinary pharmacokinetics of mepindolol and propranolol were assessed in nine healthy volunteers after single and 1-week daily repeated application of the drugs by a novel transdermal delivery system (BIO TSD). Qualitatively, the time courses of the plasma concentrations for both compounds were similar and indicative of effective drug input. On the first day of the treatment courses plasma levels rose slowly, reaching their observed maximum after 24 h. The latter still was in the rising phase of the curve and further input on longer application is likely. After 1 week daily repeated application apparent steady state conditions were reached. The plasma concentrations were low in comparison to the levels reported for oral dosing. Only small amounts of unchanged drug were excreted via urine. The effects of the investigational treatments on supine-resting and stimulated neuroendocrine variables were assessed also. A blunting of the adrenaline response to delayed auditory feed-back mental stress testing (DAF) was consistently observed after propranolol, but not after mepindolol. Noradrenaline responses to DAF were not altered. No consistent effects were observed in terms of the adrenaline responses to 3 min isometric handgrip testing (IHG). Noradrenaline responses to IHG were slightly blunted, relative to placebo on the first day when propranolol and mepindolol were applied. This was probably related to the usually high responses to placebo as reference. At the end of 1 week repeated application of the patches mean supine resting plasma renin activity (PRA) was significantly reduced by propranolol but not by mepindolol, and the mean PRA responses to 5 min i.v. infusion of isoprenaline was reduced by both.

Pharmacokinetic and pharmacodynamic interactions between single oral doses of ibopamine and food in normal man.

The pharmacokinetic and pharmacodynamic interactions between single oral doses of 200 mg ibopamine and a standard cold 3100 kJ meal were assessed in 12 normal male subjects, who were studied on 4 occasions, receiving either ibopamine or matched placebo (double-blind) in fasting condition or at the end of a meal. Treatments were randomly allocated in a period-balanced within-subject cross-over study design. The plasma concentrations of epinine (N-methyldopamine) were extensively profiled up to 4 h after dosing. Food caused a profound reduction of both Cmax and AUC of unconjugated epinine with a prolongation of Tmax. The subjects were furthermore profiled in detail up to 4 h after dosing by transthoracic impedance cardiography. Food caused substantial and protracted effects that affected virtually all parameters profiled. Ibopamine had clear cardiac performance enhancing effects only over the first hour after dosing. These effects were furthermore subject to significant food interaction. It therefore appeared that food resulted in a profound blunting of both ibopamine's pharmacokinetic and pharmacodynamic characteristics.

Time course and nature of postprandial haemodynamic changes in normal man.

The present study describes the nature and time course of the cardiovascular and neuro-endocrine changes that followed a standard 3100 kJ cold meal in 12 supine and fasting normal men who were studied in a balanced cross-over design. Heart rate, blood pressure, systolic time intervals and estimates of cardiac performance by impedance cardiography were measured every 10 min up to 4 h after eating. Eating caused a rapid and short-lasting increase in systolic blood pressure, estimated stroke volume and maximum velocity of impedance changes. Eating also caused a rapid and more protracted decrease in diastolic and mean blood pressure, PEP-i, QS2-i and estimated systemic vascular resistance with an increase in heart rate and estimated cardiac output. In the later phase of the profiling a drop in LVET-i was also observed. The differences vs. fasting were statistically significant and judged to be biologically relevant. Venous plasma noradrenaline rose during eating as a consequence of the postural change, but eating itself did not alter venous plasma noradrenaline, and plasma adrenaline even tended to decrease. This reflects both the roughness of venous catecholamines in estimating adrenergic changes and the complexity of the underlying mechanisms and related reflexes.

SK&F 86466, a novel alpha-adrenolytic drug: effects on heart rate, blood pressure, and neuroendocrine function in supine resting position and in response to postural and cold stimulation in normal humans.

SK&F 86466 is a novel alpha-adrenoceptor blocking drug shown in preclinical profiling to have relative selectivity for the pre- and postjunctional alpha 2-adrenoreceptor. In the present clinical study, the effects of single oral doses of 10, 25, and 50 mg SK&F 86466 on supine and stimulated circulatory and neuroendocrine function were assessed in eight normal subjects studied in a placebo-controlled balanced cross-over design with the drugs administered in double-blind fashion. SK&F 86466 caused a dose-related increase in stimulated (postural and cold challenge) and supine plasma norepinephrine (NE) concentrations. This increase was associated with an increase in supine heart rate (HR) and plasma renin activity and orthostatically stimulated HR, with little increase in systolic blood pressure (SBP) and no increase in diastolic blood pressure (DBP). Assuming that no changes occurred in catecholamine clearance, SK&F 86466 thus appeared to have a prejunctional alpha 2-adrenoreceptor blocking effect, which was countered by a post-junctional alpha-adrenoreceptor blocking effect at the level of the resistance vessels, whereas this latter effect did not alter the pressor responses to cold and postural challenge.

Effects of low-dose atenolol on postural and postprandial changes in heart rate, blood pressure, venous plasma catecholamines, and plasma renin activity.

The administration of a single dose of atenolol 50 mg 1 h before a standard 3100 kJ cold meal in fasting healthy subjects reduced the supine preprandial heart rate and systolic blood pressure, and blunted the postural and postprandial rises in mean heart rate and systolic blood pressure relative to placebo. It did not affect the preprandial supine diastolic blood pressure, nor the postural rise and postprandial drop in diastolic blood pressure. Preprandial administration of atenolol blunted the postural and postprandial rises in mean plasma renin activity, and it enhanced the rise in plasma noradrenaline during eating in the sitting position, and the postprandial concentrations of noradrenaline. The findings do not permit the conclusion that beta 1-adrenergic stimulation was the predominant cause of these atenolol-responsive changes.

Postprandial haemodynamic changes: a source of bias in cardiovascular research affected by its own methodological bias.

The effects of heart rate and systolic and diastolic blood pressure of eating a 3100 kJ cold meal were assessed in eight young normal subjects studied in a randomised and balanced crossover study. Blood pressure was measured simultaneously and in the same arm by auscultation of the fossa cubitalis (Korotkoff I, IV, and V), by an automated device with a microphone over the brachial artery (equivalent to Korotkoff I and V), and by graphical analysis of these microphone signals (equivalent to Korotkoff I and IV). Eating caused a rise in mean heart rate, a small rise in systolic blood pressure, and a decrease in diastolic blood pressure, which was overestimated when Korotkoff V rather than Korotkoff IV endpoints were considered. Both the automated device and the graphical analysis yielded acceptable overall quantitative agreement with the auscultatory method. Both alternative methods allowed similar postprandial blood pressure trends to be detected, but the quantitative agreement in estimating the postprandial effects was far less optimal. Eating therefore was shown to cause changes that might distort and confuse the interpretation of cardiovascular data in studies in which subjects are allowed to eat. This source of bias itself appeared to be affected by its own methodological bias.

Variant responses impair the usefulness of passive upright tilt in drug research.

Thirty-five male normal subjects underwent gradual passive upright tilt (1 minute at 15 degree, 2 minutes at 45 degree and 7 minutes at 85 degree) on a total of 256 occasions, in drug-free condition or after administration of placebo. Although a cardio-acceleratory and vasopressor response prevailed, seven subjects experienced imminent syncope on 9 occasions, after 2 to 7 minutes erect standing. These reactions were hypotensive in nature, and preceded by (5 instances) or concurrent with (3 instances) a sudden drop of the initially adequately rising heart rate. These reactions are likely to be of vagal origin. All reactions occurred suddenly and unexpectedly and improved rapidly when the subject was tilted back to supine position. Imminent syncopes on passive upright tilt appeared to be incidental phenomena occurring in subjects who uneventfully underwent previous or subsequent tilting, either on the same day or on another day. The potential severity of these reactions, their unpredictability and their lack of reproducibility restrict the usefulness of passive upright tilt as a test procedure in drug research. In the event that such reactions would appear after exposure to an investigational drug, it cannot be proven beyond reasonable doubt that the reaction is caused by the drug, is a variant response intrinsic to the test procedure, or a drug-related enhancement of the onset and/or severity of such a variant response.

Noninvasive assessment of cardiac performance by impedance cardiography: disagreement between two equations to estimate stroke volume.

Impedance cardiography, phonocardiography, and ECG were registered prior to, during, and after 10 min of gradual passive upright tilt in 35 normal male subjects. Stroke volume (SV) was estimated according to both the standard equation of Kubicek et al. and a newly introduced equation by Sramek et al. Sramek's equation estimated larger SV values throughout. It furthermore estimated a larger SV response to upright tilt: a bias of -17 ml (95% Cl: -20 to -13) was identified for Sramek's minus Kubicek's approach. Corresponding disagreement was identified for cardiac output and systemic vascular resistance derived from SV. A far better agreement was identified when the data were expressed as percent of the supine base line prior to tilt. Under such transformation, Sramek's approach estimated slightly smaller SV responses to tilt: a bias of 4.2% (95% Cl: 3.6 to 4.7) was identified for the percent response of SV to upright tilt for Sramek's minus Kubicek's equation. Data generated by these two equations are, nevertheless, not readily interchangeable nor comparable. As Sramek's equation estimated consistently larger SV values than Kubicek's equation, it is unlikely that Sramek's equation could solve the issue of the quantitative inaccuracy which remains intrinsic to the usage of Kubicek's equation in impedance cardiography.

Pharmacokinetics and pharmacodynamics of single oral doses of ibopamine, quinidine and their combination in normal man.

The pharmacokinetics and haemodynamics (phono- and impedance cardiography) of single oral doses of 200 mg ibopamine (SK&F 100168), 400 mg quinidine sulphate, and their combination, have been assessed in 6 healthy male volunteers. No significant differences in the mean pharmacokinetic parameters of either drug were seen between the single and combined doses. Ibopamine caused an increase in mean estimated stroke volume (SV +29% for the maximum change from baseline and +15% cumulatively over the first h) with no change in mean heart rate (HR) or QTc. Quinidine administered concomitantly blunted the response of SV. A tendency to a lower mean concentration of epinine early after administration of the combination may have contributed to the difference. Quinidine alone hardly affected SV (-3% from baseline over the first h), but it did increase mean HR (+6 beats.min-1) and mean QTc (+30 ms). These changes were sustained up to 8 h after dosing, and were not affected by concurrent ibopamine.

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

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