Chronopharmacokinetics and Cardiovascular Effects of Nifedipine

Orcadian phase dependency in pharmacokinetics and hemodynamic effects on blood pressure and heart rate of different galenic formulations of nifedipine (immediate-release, sustained-release, and i.v. solution) were studied in healthy subjects or in hypertensive patients. Pharmacokinetics of immediate-release but not sustained-release and i.v. nifedipine were dependent on time of day: immediate-release nifedipine had higher C_max (peak concentration) and shorter t_max (time-to-peak concentration) after morning than evening application, and bioavailibility in the evening was reduced by about 40%. Orcadian rhythm in estimated hepatic blood flow as determined by indocyanine green kinetics may contribute to these chronokinetics. A circadian time dependency was also found in nifedipine-induced effects on blood pressure and heart rate as monitored by 24-h ambulatory blood pressure measurements. In conclusion, the dose response relationship of oral nifedipine is influenced by the circadian organization of the cardiovascular system as well as by the galenic drug formulation.     

Chronopharmacology of Oral Nitrates in Healthy Subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5-monitrate (IS-5-MN, 60 mg) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (t_max of 0.9 h) than in the evening (t_max of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chrono-kinetics were observed after application of the slow-release formulation of IS-5-MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.     

Chronopharmacology of Oral Nitrates in Healthy Subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5- monitrate (IS-SMN, 60 rng) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (t_max of 0.9 h) than in the evening (t_max of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5- MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.     

硝苯地平联合缬沙坦治疗老年原发性高血压疗效分析

目的:探讨硝苯地平缓释片联合缬沙坦治疗老年原发性高血压的临床疗效。方法:将180例患者随机分入对照组与观察组,给予对照组86例患者硝苯地平缓释片口服降压;观察组94例患者接受硝苯地平缓释片联合缬沙坦治疗,比较两组患者治疗8周后血压、心率、脉压、肾功、尿酸、血钾及尿微量白蛋白的变化。结果:治疗后观察组患者收缩压、舒张压、脉压及心率均显著降低,治疗总有效率高于对照组,两组比较差异有统计学意义(P<0.01);观察组尿酸、尿微量白蛋白显著优于对照组(P<0.01),两组肾功、血钾比较差异无统计学意义(P>0.05)。结论:硝苯地平缓释片联合缬沙坦治疗老年原发性高血压,降压平稳,同时可显著降低尿酸及尿微量白蛋白,改善肾功能。     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure, Heart Rate, and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00-19:00 h, dark (D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Comparison between effects of dantrolene and nifedipine on lipopolysaccharide-induced endotoxemia in the anesthetized rats

Intracellular calcium is an important mediator for regulating the cellular response in endotoxemia. In this study, we investigated the effects of dantrolene and nifedipine, two agents of reducing intracellular calcium levels, on bacterial endotoxin (lipopolysaccharide, LPS; 10 mg/kg i.v.)-induced production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) as well as hemodynamic changes in the anesthetized rat. Injection of LPS (i) induced biphasic changes of blood glucose and rectal temperature: an initial increased phase (<180 min after injection of LPS) followed by a decreased phase (at 240 or 360 min), (ii) caused a significant fall in mean arterial blood pressure from 119+/-3 mmHg (at time 0) to 73+/-67 mmHg (at 360 min) with a concomitant increase of heart rate, (iii) resulted in a substantial hyporeactivity to norepinephrine (NE) (1 microg/kg i.v.), (iv) increased plasma nitrate (an indicator of NO formation) in a time-dependent manner, and (v) induced bell-shape changes in plasma TNF-alpha levels which reached a peak at 60 min. Pretreatment of animals with dantrolene (1 mg/kg i.v. at 20 min prior to LPS) or nifedipine (20 microg/kg i.v. infusion for 20 min at 20 min prior to LPS) not only attenuated the delayed circulatory failure (e.g. delayed hypotension and vascular hyporeactivity to NE), but also prevented the overproduction of NO caused by LPS in the rat. However, the prevention of NO overproduction by dantrolene, but not by nifedipine, was associated with an inhibition of TNF-alpha production elicited by LPS. Thus, both dantrolene and nifedipine have beneficial hemodynamic effects, although through different mechanisms, in animals with endotoxic shock.     

Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin

We aimed to investigate the effects of intracerebroventricularly (i.c.v.) injected glucagon-like peptide-1 (GLP-1) on blood pressure and heart rate, and whether central cholinergic system and vasopressinergic system play roles in these effects. Male Wistar albino rats were used throughout the experiments. Blood pressures and heart rates were observed before and for 30 min following drug injections. i.c.v. GLP-1 (100, 500 and 1000 ng/10 microl) caused a dose-dependent increase in both blood pressure and heart rate. Nicotinic receptor antagonist mecamylamine (25 microg/10 microl, i.c.v.) and muscarinic receptor antagonist atropine (5 microg/10 microl, i.c.v.) prevented the stimulating effect of GLP-1 on blood pressure. The effect of GLP-1 on heart rate was blocked only by mecamylamine. The V1 receptor antagonist of vasopressin (B-mercapto B, B-cyclopentamethylenepropionyl, O-Me-Tyr,Arg)-vasopressin (10 microg/kg), that was applied intraarterially, only prevented the effect of GLP-1 on blood pressure, but did not show any effect on heart rate. Our data indicate that i.c.v. GLP-1 increases blood pressure and heart rate, and stimulation of central nicotinic and partially muscarinic receptors and vasopressinergic system play a role in the effects of i.c.v. GLP-1 on blood pressure. The effect of GLP-1 on heart rate may be partially due to stimulation of central nicotinic receptors.     

EFFECTS OF AEROBIC EXERCISE ON THE CIRCADIAN RHYTHM OF HEART RATE AND BLOOD PRESSURE

Although the effects of aerobic exercise on resting heart rate, heart rate variability, and blood pressure have been investigated, there are scant data on the effects of aerobic exercise on the circadian rhythm of such cardiovascular parameters. In this study, we investigated the effects of aerobic exercise on the 24?h rhythm of heart rate and ambulatory blood pressure in the morning, when cardiovascular events are more common. Thirty-five healthy young subjects were randomized to control and aerobic exercise groups. Subjects in the latter group participated in their respective exercise program for two months, while those in the former group did not exercise. Twenty-four-hour electrocardiogram and ambulatory blood pressure monitoring data were obtained at baseline and at the end of the exercise intervention. The control group showed no changes, while the aerobic exercise group showed a significant decrease in heart rate (73.7?±?6.6?bpm to 69.5?±?5.1?bpm, p?<?0.005) and sympathetic activity such as LF/HF ratio (2.0?±?0.7 to 1.8?±?0.6, p?<?0.05) throughout the 24?h period, particularly in the daytime. The decrease in the heart rate was most prominent in the morning. However, heart rate and LF/HF ratio showed no statistical changes during the night. No significant changes were observed in blood pressure. These findings suggest aerobic exercise exerts beneficial effects on the circadian rhythm of heart rate, especially in the morning. (Author correspondence: hshio@kobe-u.ac.jp)     

Central benzodiazepine involvement in clonidine cardiovascular actions

It is well known that the GABAergic and noradrenergic systems play an important role in blood pressure and heart rate regulation. Benzodiazepines and beta-carbolines, respectively, increase or decrease the probability of chloride-channel opening induced by GABA. The aim of this study was to determine, in conscious rats, the interaction existing between the central alpha2-adrenoceptor stimulation induced by clonidine and the facilitation or impairment of benzodiazepine receptor activity through the administration of either diazepam, a benzodiazepine receptor agonist, or methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse benzodiazepine agonist. Clonidine (5-10 microg, intracerebroventricularly) reduced heart rate and increased mean blood pressure by activation of central alpha2-adrenoceptors. Diazepam (2 mg/kg, intravenously (i.v.)) induced an increase in heart rate, while DMCM (0.3 mg/kg, i.v.) elicited a bradycardic effect. The bradycardic effects induced by both clonidine and DMCM were antagonized by the prior administration of methylatropine (1.5 mg/kg, i.v.). DMCM (0.3 mg/kg, i.v.) prevented the clonidine effects on heart rate and mean blood pressure, while diazepam (2 mg/kg, i.v.) failed to modify these effects. Our results suggest that the bradycardic effects of clonidine are mediated by a vagal stimulation and are related to the activation of a GABAergic pathway.     

Cardiorespiratory effects of nifedipine in pregnant sheep

Four concentrations of nifedipine (AdalatR, Bayer) were infused into 25 pregnant sheep of 123-140 days of gestation (term, 147 days) and the effects on the ewe and the foetus have been studied. At all doses of nifedipine infused, maternal diastolic pressure fell by about 15% and maternal heart rate increased by 33%. There was no change in blood gases or pH. Uterine activity, as measured by uterine electromyographic recordings, was reduced due to an increase in the interval between periods of activity. The duration of a burst of activity remained unaffected. The effects of nifedipine on the foetus, were similar. Mean foetal arterial pressure fell by 4-5 mmHg and heart rate rose by 15 to 50%, both changes being maintained for the duration of the infusion and the increased heart rate for longer. The electrocorticogram of the foetal sheep was unaffected by nifedipine. The effects on foetal breathing movements were small. At the concentration of 5 micrograms/kg/min for either 2 or 4 hours the breathing pattern changed so that the episodes of breathing were shorter and more frequent. The total amount of breathing per hour was unaffected. Control infusion of ethanol had little effect on the ewe except for a significant increase in lactate production. In the foetus breathing was reduced at the highest concentration used.     

The effects of acebutolol alone and in combination with furosemide or hydralazine in experimentally induced hypertensive G-minipigs

Experimentally induced hypertensive G-minipigs were used for assessing the antihypertensive effects of acebutolol, a cardioselective beta-adrenergic blocking agent. In the acute experiment, six females were used. Acebutolol (3 mg/kg, i.v.) alone or in combination with furosemide (1 mg/kg, i.v.) or hydralazine (1 mg/kg, i.v.) was administered through an implanted catheter. In the chronic experiments, five females received oral acebutolol (100-200 mg/day). The blood pressure, heart rate, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were used as parameters. In the acute experiment, there were no marked changes in the blood pressure or heart rate during the nondosing period. Acebutolol alone caused a marked decrease in the blood pressure and heart rate. In the two combination tests, combined administration with acebutolol and furosemide had a greater effect on the blood pressure and heart rate than did acebutolol alone. A combined acebutolol and hydralazine regimen caused a slight reduction not only in the blood pressure, but also in the heart rate compared with acebutolol alone. PRA and PAC remained essentially constant, with minor fluctuations, throughout the nondosing period. Following the injection of acebutolol alone, PRA showed an elevation with a significant rise after three hours and PAC showed a tendency to increase. PRA and PAC generally tended to increase in the case of combined administration with furosemide or hydralazine, but these tendencies were less conspicuous than with acebutolol alone. On the other hand, chronic treatment with acebutolol produced a significant decrease in the heart rate from two weeks after the administration and in the blood pressure from four weeks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disturbance of cardiovascular circadian rhythms by pertussis vaccine in freely-moving rats

Vaccination of young children with diphtheria, tetanus, poliomyelitis and pertussis (DTPoP) vaccine is effective in preventing outbreaks of whooping cough but adverse events sometimes occur. This pilot study shows that in freely-moving rats, multiple treatment with DTPoP (at day 0 and day 5, 6 ml/kg i.v.) increased heart rate (HR) for 5 days after the first treatment and decreased diastolic blood pressure (DBP) for at least 26 days after the first treatment and inhibited the circadian rhythm of HR and DBP for at least 10 days. DTPo vaccine, containing no pertussis vaccine, was free of such effects. Thus, in rats, the pertussis component of DTPoP acts on the cardiovascular system and disturbs its circadian rhythm. The contribution of these findings to clinical adverse effects is as yet unknown and needs further research.     

Effects of Different Once-a-Day Medications on 24-Hour Blood Pressure Recordings in Hypertensives

Compliance with antihypertensive treatment can be increased by using medications that are taken only once daily. There is, however, concern as to whether the efficacy of such drugs is sufficient to cover 24 h. Ambulatory blood pressure monitoring (ABPM) is an ideal technique to assess the effect of this kind of drug and to determine over- or undertreatment. In this study three drugs were examined as once-a-day preparations. Thirty-six patients were treated with three different doses of bisoprolol, as an example of the β,-selective beta-blockers; 12 patients were treated with a combination of the AChE-inhibitor enalapril and hydrochlorothiazide; eight patients were treated with nifedipine once per day, a new galenic form of nifedipine, as an example of the calcium-channel blockers. In each group we saw a significant downward shift over the entire 24-h curve. Our results also show that using 24-h blood pressure monitoring devices can help establish an appropriate dose, avoid over- and undertreatment, and control the total burden of the patient.     

Blood pressure and heart rate in patients with ischaemic heart disease receiving nifedipine and propranolol.

A randomised controlled crossover trial was performed to assess the anti-anginal effects of nifedipine and propranolol separately and together. The effects of these treatments on blood pressure and heart rate were assessed at rest and after the cold pressor and mental arithmetic tests. Nifedipine and propranolol together produced the greatest reduction in supine and erect systolic and diastolic blood pressures. Propranolol (480 mg daily) lowered resting systolic/diastolic blood pressures by 7/6 mm Hg and nifedipine (60 mg daily) lowered it by 10/8 mm Hg, while in the erect position the hypotensive effect of these agents averaged 9/8 mm Hg. During the cold pressor test propranolol lowered the maximum pressure by an average of 11/6 mm Hg and nifedipine by 19/10 mm Hg. For the mental arithmetic test, the results were 7/2 mm Hg and 16/7 mm Hg respectively. Propranolol (480 mg daily)reduced supine and erect heart rate by 19 and 25 beats/minute respectively, while nifedipine did not alter heart rate significantly. The favourable haemodynamic responses to nifedipine suggest that it may be of value in the management of hypertension.     

Cardiovascular and parasympathetic effects of dexmedetomidine in healthy subjects

We evaluated the cardiovascular effects of intravenously (i.v.) and buccally administered dexmedetomidine, a selective alpha2-adrenoceptor agonist. Six healthy male subjects were studied unmedicated and after 2 micro g/kg i.v. or buccal doses of dexmedetomidine, using repeated recordings of ECG and blood pressure. Cardiac parasympathetic activity was estimated by measurements of high-frequency (HF) heart rate variability. Intravenous, but not buccal, dexmedetomidine raised systolic blood pressure by 11 +/- 5 mmHg (mean +/- SEM) and diastolic by 16 +/- 3 mmHg (maxima at 10 min). Later on, both i.v., and buccal dexmedetomidine produced a very similar hypotensive effect: on average, >or=10 mmHg reductions in systolic and diastolic pressure at 3 h. Intravenous dosing was followed by a decline in heart rate (-11 +/- 2 beats/min) accompanied by a trend toward enhanced HF variability (maximal effect at 10 min), which probably reflected baroreflex-mediated parasympathetic efferent neuronal activation. Buccal dexmedetomidine increased significantly the HF variability (maximum at 45 min) without influencing heart rate. We conclude that dexmedetomidine, when administered by a method that avoids concentration peaks, e.g., buccal dosing, can be used to produce a prolonged augmentation of cardiac parasympathetic efferent neuronal activity.     

Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.     

Dose- and administration time-dependent effects of nifedipine gits on ambulatory blood pressure in hypertensive subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow-release, once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest-activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1-2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up-titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non-responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose-dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

Dose‐ And Administration Time‐Dependent Effects Of Nifedipine Gits On Ambulatory Blood Pressure In Hypertensive Subjects

Previous chronotherapy studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several calcium channel blockers (CCB), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the antihypertensive efficacy and safety profile of the slow‐release, once‐a‐day nifedipine gastrointestinal therapeutic system (GITS) formulation administered at different times with reference to the rest‐activity cycle of each participant. We studied 80 diurnally active subjects (36 men and 44 women), 52.1±10.7 yrs of age, with grade 1–2 essential hypertension, who were randomly assigned to receive nifedipine GITS (30 mg/day) as a monotherapy for eight weeks, either upon awakening in the morning or at bedtime at night. Patients with uncontrolled BP were up‐titrated to a higher dose, 60 mg/day nifedipine GITS, for an additional eight weeks. BP was measured by ambulatory monitoring every 20 min during the day and every 30 min at night for 48 consecutive hours before and after therapy with either dose. The BP reduction after eight weeks of therapy with the lower dose of 30 mg/day was slightly, but not significantly, larger with bedtime dosing. The efficacy of 60 mg/day nifedipine GITS in non‐responders to the initial 30 mg/day dose was twice as great with bedtime as compared to morning dosing. Moreover, bedtime administration of nifedipine GITS reduced the incidence of edema as an adverse event by 91%, and the total number of all adverse events by 74% as compared to morning dosing (p=0.026). Independent of the time of day of administration, a single daily dose of 30 mg/day of nifedipine GITS provides full 24 h therapeutic coverage. The dose‐dependent increased efficacy and the markedly improved safety profile of bedtime as compared to morning administration of nifedipine GITS should be taken into account when prescribing this CCB in the treatment of essential hypertension.     

Chronotherapy in Coronary Heart Disease: Comparison of Two Nitrate Treatments

The purpose of this study was to assess the ischemic burden and the hemodynamic changes during daily activities in patients with coronary heart disease. Three exercise tests were performed during the day (10:00 a.m., 2:00 p.m., 6:00 p.m.), recording ST-segment depression, pulmonary artery pressure, pulmonary wedge pressure, and cardiac output as well as heart rate and systemic blood pressure during placebo and nitrate therapy. With placebo as well as nitrate therapy there was a gradual increase of ischemia and preload and a decrease of cardiac output during the day. High nitrate concentrations led to a significant reduction of both preload and ST depression with a marked circadian phase dependency of cardiovascular effects.