Comparison of clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery.

BACKGROUND AND OBJECTIVE: We set out to compare the efficacy of clevidipine and sodium nitroprusside infusions in the control of blood pressure and the haemodynamic changes they produce in hypertensive patients after operation for elective coronary bypass grafting. METHODS: Thirty patients were randomly allocated to receive either clevidipine or sodium nitroprusside after their mean arterial pressure (MAP) had reached > 90 mmHg for at least 10 min in the postoperative period. The MAP was continuously measured and related to time. Thus, the efficacy of the drugs in controlling arterial pressure could be inversely related to the total area under the MAP-time curve outside a target MAP range of 70-80 mmHg normalized per hour (AUC(MAP) mmHg min h(-1)). Haemodynamic variables and the number of dose-rate adjustments required to maintain MAP were also studied. RESULTS: There was no statistically significant difference in the efficacy (AUC(MAP) mmHg min h(-1)) of clevidipine (106 +/- 25 mmHg min h(-1)) compared with sodium nitroprusside (101 +/- 28 mmHg min h(-1)). Nor was any significant difference found in the total number of dose adjustments required to control MAP within the target range. The heart rate in patients receiving clevidipine increased less than in those given sodium nitroprusside. Stroke volume, central venous pressure and pulmonary artery pressure were significantly reduced upon administration of sodium nitroprusside but not of clevidipine. CONCLUSIONS: There was no significant difference between clevidipine and sodium nitroprusside in their efficacy in controlling MAP. The haemodynamic changes, including tachycardia, were less pronounced with clevidipine than with sodium nitroprusside.

The effect of a neuropeptide Y Y1 receptor antagonist in patients with angina pectoris.

AIMS: Neuropeptide Y (NPY) is a potent vasoconstrictor released during sympathetic activation that may be involved in myocardial ischaemia. We examined the effect of a Y1 receptor antagonist on haemodynamic and ischaemic responses to exercise in patients with coronary artery disease. METHODS AND RESULTS: Eighty-two evaluable male patients were included in a randomized, double blind, two-way crossover study with a low dose (6.7 microg/kg/min; n=59)and a high dose (13.3 microg/kg/min; n=23) of the Y1 receptor antagonist AR-H040922 given as infusions for 2h or placebo. Myocardial ischaemia during a symptom-limited exercise test was monitored by conventional ST-segment analysis and heart rate (HR)-adjusted ST changes including the ST/HR slope and ST/HR recovery. Administration of the high dose AR-H040922 attenuated systolic blood pressure by 6-11 mmHg (p<0.05) during and after exercise without affecting HR. None of the two doses of AR-H040922 influenced any of the ischaemic parameters or duration of exercise, however. The maximal increase in NPY was higher during AR-H040922 (p<0.05) compared with placebo. CONCLUSIONS: Selective NPY Y1 receptor blockade attenuates the increase in blood pressure during exercise indicating a role for endogenous NPY in blood pressure regulation. Despite this effect, the Y1 receptor antagonist did not influence exercise-induced ischaemic parameters in patients with coronary artery disease.

Pharmacology of H 394/84, a dihydropyridine neuropeptide Y Y(1) receptor antagonist, in vivo.

The object of the present paper was to investigate the in vivo pharmacological profile of the dihydropyridine neuropeptide Y Y(1) receptor antagonist 1,4-Dihydro-4-[3-[[[[3-[spiro(indene-4,1'-piperidin-1-yl)]propyl]amino]carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridine dicarboxylic acid, dimethylester (H 394/84). The renal vasoconstrictor response to neuropeptide Y in anaesthetized rats was dose-dependently antagonized by H 394/84 (ID(50) value=41+/-4 nmol/kg/min), whereas the renal vascular responses to noradrenaline and angiotensin II were only slightly affected by H 394/84 (500 nmol/kg/min). In pigs pretreated with reserpine and transection of sympathetic nerves (depleted of noradrenaline), H 394/84 dose-dependently antagonized renal and femoral vasoconstrictor responses evoked by sympathetic nerve activation (neuronally released neuropeptide Y) and exogenous neuropeptide Y. Significant inhibition was seen already at 1.0 nmol/kg/min, when plasma levels of the antagonist reached 29+/-4 nM. Around 70% of the antagonism remained 90 min after H 394/84 was given. The disposition of H 394/84 fits a biexponential model with initial and terminal half-lives of 2.6 and 48 min, respectively. H 394/84 (100 nmol/kg/min) did not inhibit vascular responses to neuropeptide Y Y(2) receptor-, alpha-adrenoceptor- or purinoceptor-activation in the pig in vivo. It is concluded that H 394/84 is a potent neuropeptide Y Y(1) receptor antagonist with rather long duration of action in vivo. The selectivity and specificity in vivo is more than 100-fold, and H 394/84 antagonizes vascular responses to exogenous and endogenous, neuronally released, neuropeptide Y with similar potency.

Pharmacokinetics and pulmonary extraction of clevidipine, a new vasodilating ultrashort-acting dihydropyridine, during cardiopulmonary bypass.

Clevidipine is a new vascular-selective, calcium channel antagonist of the dihydropyridine type with an ester side chain susceptible to esterase metabolism. In healthy volunteers, it has high clearance (0.069 litres min-1 kg-1) with a small volume of distribution at steady state (0.19 litres kg-1). The half-lives of the two initial rapid phases, accounting for approximately 95% of the area under the curve after an i.v. bolus, are 0.7 and 2.3 min, respectively. The aims of this study were to determine the pharmacokinetics and the pulmonary extraction ratio of clevidipine in patients undergoing cardiac surgery. Seventeen patients received clevidipine as an i.v. infusion before cardiopulmonary bypass (CPB), and eight of these patients were also given clevidipine during hypothermic CPB. Mixed venous and arterial blood samples were taken for pharmacokinetic analysis and calculation of pulmonary extraction ratio. A two-compartment pharmacokinetic model with zero-order input was used to describe the pharmacokinetics of clevidipine before and during CPB. Virtually identical concentrations in mixed venous and arterial blood suggest negligible pulmonary metabolism of clevidipine. The total blood clearance of clevidipine is extremely high (0.055 litres min-1 kg-1). During CPB, clearance of clevidipine was significantly reduced, to 0.03 litres min-1 kg-1 (P < 0.005), probably as a consequence of reduced body temperature.

Calcium antagonist protects the myocardium from reperfusion injury by interfering with mechanisms directly related to reperfusion: an experimental study with the ultrashort-acting calcium antagonist clevidipine.

To test the hypothesis that calcium antagonists protect the myocardium from reperfusion-induced damage by local myocardial mechanisms just at the time of reperfusion, the myocardioprotective effects of the dihydropyridine clevidipine were investigated, taking advantage of its ultrashort-acting effect. Pigs were subjected to 45 min of myocardial ischemia by occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Either clevidipine (0.3 nmol/kg/min, n = 6) or the corresponding amount of vehicle (n = 6) was administered to the ischemic myocardium by retrograde coronary venous infusion over a 30-min period starting 10 min before reperfusion. Hemodynamic variables (heart rate, left ventricular systolic and end-diastolic pressure, max dP/dt, and mean arterial blood pressure) as well as coronary blood flow were measured throughout the experiment. At the end of reperfusion, the area at risk (percentage of left ventricle) was determined by infusion of Evans blue into the left atrium, and the infarct size, by triphenyl tetrazolium chloride (TTC) staining. The plasma level of endothelin-like immunoreactivity (ET-LI) was analyzed in blood from the aorta and the anterior coronary vein before ischemia and at different times during reperfusion. The area at risk was similar in the vehicle and the clevidipine groups. The infarct size, expressed as a percentage of the area at risk, was 80 +/- 9.2 in the vehicle group, whereas it was significantly reduced to 51 +/- 9.2% in the clevidipine group (p < 0.01). Clevidipine did not influence any of the hemodynamic variables measured throughout the study. A nonsignificant trend toward decreased total ET-LI overflow during 4-h reperfusion was observed in the clevidipine-treated pigs compared with vehicle-treated ones (5.3 +/- 1.4 vs. 7.1 +/- 3.4 pmol). These results demonstrate that, in this model of ischemia/reperfusion-induced myocardial infarction, clevidipine reduced the damage to the myocardium when given in association with reperfusion. The local administration of the compound together with its short blood half-life shows that clevidipine reduces reperfusion-induced damage by local mechanisms within the ischemic tissue rather than by peripheral mechanisms.

Perioperative blood pressure control: a prospective survey of patient management in cardiac surgery.

OBJECTIVE: To conduct a survey of current cardiac anesthetic practice in Europe and the United States, as a first step toward establishing guidelines for the management of perioperative hypertension. DESIGN: Prospective, multicenter study. SETTING: University hospitals. PARTICIPANTS: Unselected patients (n = 1,930) requiring cardiac surgery. INTERVENTIONS: Data extending from the preoperative evaluation to 120 hours or more after surgery were collected from all patients. MEASUREMENTS AND MAIN RESULTS: Only the data from patients undergoing coronary artery bypass surgery, valve surgery, or combined procedures were analyzed, leaving a final total of 1,660 patients from the original 1,930. Of these, 88% were treated at least once perioperatively to lower arterial blood pressure. Deepening of anesthesia was the most commonly used antihypertensive measure (68%), regardless of the ongoing anesthetic regimen, and was usually combined with vasodilator therapy, most frequently nitroglycerin (53%) or sodium nitroprusside (28%). Reported perioperative mean arterial pressure (MAP) was 15 to 20 mmHg lower than MAP before anesthesia induction, regardless of the use of antihypertensive therapy. The MAP at which antihypertensive treatment was initiated varied markedly among the various phases of surgery and showed no clear correlation with preoperative MAP. CONCLUSIONS: The results of this survey show that current anesthetic practice tries to prevent perioperative hypertension wherever possible during cardiac surgery. Blood pressure measurements taken before surgery have little influence on the development of hypertension intraoperatively, and the main determinants of perioperative blood pressure control and the need for therapeutic intervention are factors arising from the surgical procedure itself, such as aortic cross-clamping and activation of adrenergic mechanisms.

Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgery.

BACKGROUND: The aim was to evaluate the use of clevidipine, a new vascular selective, ultra-short-acting calcium antagonist for blood pressure control after coronary artery bypass grafting (CABG). METHODS: The effects of clevidipine on central hemodynamics, myocardial blood flow and metabolism were studied at two different phases after CABG. In phase 1 (n=13), the hypertensive phase, the effects of clevidipine were compared to those of sodium nitroprusside (SNP) when used to control postoperative hypertension. In phase 2 (n=9), the normotensive phase, a clevidipine dose-response relationship was established. RESULTS: At a target mean arterial pressure (MAP) of 75 mmHg, systemic vascular resistance (SVR) and heart rate (HR) were lower, preload, stroke volume (SV) and pulmonary vascular resistance (PVR) were higher, while there were no differences in myocardial lactate metabolism or oxygen extraction with clevidipine compared to SNP. In the normotensive phase, clevidipine induced a dose-dependent decrease in MAP (-19%), SVR (-27%) and PVR (-15%), accompanied by an increase in SV (10%), but no reflex increase in HR or changes in cardiac preload. Clevidipine caused a direct coronary vasodilation, as indicated by a decrease in myocardial oxygen extraction from 54% to 45%. Myocardial lactate metabolism was unaffected by clevidipine. The blood clearance of clevidipine was 0.05 l x min(-1) x kg(-1), the volume of distribution at steady state was 0.08 l x kg(-1) and the initial and terminal half-lives were <1 min and 4 min, respectively. CONCLUSIONS: Clevidipine rapidly reduced MAP and induced a systemic, pulmonary and coronary vasodilation with no effect on venous capacitance vessels or HR. Clevidipine caused no adverse effects on myocardial lactate metabolism. Clevidipine thus appears suitable to control blood pressure after CABG.

Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers.

BACKGROUND: Clevidipine is an ultra-short-acting calcium antagonist developed for reduction and control of blood pressure during cardiac surgery. The objectives of the current study were to determine the pharmacokinetics of clevidipine after 20-min and 24-h intravenous infusions, and to determine the relation between the arterial and venous concentrations and the hemodynamic responses to clevidipine in healthy volunteers. METHODS: Four volunteers received clevidipine for 20 min, and eight subjects were administered clevidipine intravenously for 24 h at two different dose rates. Arterial and venous blood samples were drawn for pharmacokinetic evaluation, and blood pressure and heart rate were recorded. RESULTS: A triexponential disposition model described the pharmacokinetics of clevidipine. The mean arterial blood clearance of clevidipine was 0.069l/kg-1/min-1 and the mean volume of distribution at steady state was 0.19 l/kg. The duration of the infusion had negligible effect on the pharmacokinetic parameters, and the context-sensitive half-time for clevidipine, simulated from the mean pharmacokinetic parameters derived after 24 h infusion at the highest dose, was less than 1 min. The arterial blood levels reached steady state within 2 min of the start of infusion and were about twice as high as those in the venous blood at steady state. The peak response preceded the peak venous concentration and was slightly delayed from the peak arterial blood concentration. CONCLUSION: Clevidipine is a high clearance drug with a small volume of distribution, resulting in extremely short half-lives in healthy subjects. The initial rapid increase in the arterial blood concentrations and the short equilibrium time between the blood and the biophase suggest that clevidipine can be rapidly titrated to the desired effect.

Cardiac inotropic vs. chronotropic selectivity of isradipine, nifedipine and clevidipine, a new ultrashort-acting dihydropyridine.

Cardiac effects of clevidipine, a new ultrashort-acting dihydropyridine Ca2+ channel antagonist were investigated in Langendorff-perfused rat hearts and compared to those of nifedipine and isradipine. The aim was to determine and compare the negative inotropic vs. chronotropic potency of these drugs. The hearts were perfused with oxygenated Krebs-Henseleit buffer at a perfusion pressure of 90 cm H2O. After stabilization, one concentration of each drug was administered for 45 min followed by a higher concentration for an additional 45 min. The concentrations of each drug in this study were 10(-9), 3 x 10(-9), 10(-8), 10(-7), 10(-6.5) and 10(-6) M for clevidipine and nifedipine, and 10(-10), 3 x 10(-10), 10(-9), 10(-8), 10(-7.5) and 10(-7) M for isradipine. Each concentration of each drug was tested in six hearts. Coronary flow, left ventricular dP/dt max, left ventricular systolic pressure and heart rate were recorded when the hearts were beating spontaneously and during pacing at a constant rate for 1 min. Spontaneous heart rate and atrio-ventricular conduction were not affected by clevidipine at any of the concentrations studied, while nifedipine and isradipine caused a concentration-dependent decrease. These two drugs caused atrio-ventricular block at high concentrations. All three compounds reduced cardiac contractility in a concentration-dependent manner. When isradipine was administered, at a given concentration, heart rate and contractility decreased proportionately. When clevidipine or nifedipine was given, at a given concentration, the proportionate reduction in left ventricular dP/dt max was greater than that in heart rate, resulting in a high inotropic vs. chronotropic selectivity. It is concluded that in contrast to nifedipine and isradipine, clevidipine does not impair atrio-ventricular conduction. Like nifedipine, clevidipine is selective for inotropic vs. chronotropic cardiac effects.

Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers.

AIMS: To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug. METHODS: Twenty-five subjects were enrolled in the study and twenty-one of them were included twice, resulting in a total of forty-six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 0.12 to 48 nmol min-1 kg-1. Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were evaluated by non-compartmental and compartmental analysis. An Emax model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine. RESULTS: Clevidipine was administered up to a target dose rate of 48 nmol min-1 kg-1, where a pre-determined escape criterion was reached (HR>120 beats min-1 ) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non-compartmental analysis was 0.125 l min-1 kg-1. Applying the population approach to the sparse data on clevidipine concentrations, an open two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.121 l min-1 kg-1, and the volume of distribution at steady state was 0.56 l kg-1. The initial half-life, contributing by more than 80% to the total area under the blood concentration-time curve following i.v. bolus administration, was 1.8 min, and the terminal half-life was 9.5 min. At the highest dose rates, MAP was reduced by approximately 10%, and the HR reached the pre-determined escape criterion for this study (>120 beats min-1 ). CONCLUSIONS: Clevidipine is well tolerated and safe in healthy volunteers at dose rates up to at least 48 nmol min-1 kg-1. The pharmacokinetics are linear over a wide dose range. Clevidipine is a high clearance drug with extremely short half-lives. The effect of clevidipine on the blood pressure was marginal, probably due to a compensatory baroreflex activation in this population of healthy volunteers. A simple Emax model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blood concentrations of clevidipine.

Pharmacokinetics of new calcium channel antagonist clevidipine in the rat, rabbit, and dog and pharmacokinetic/pharmacodynamic relationship in anesthetized dogs.

Clevidipine is a new vascular selective calcium channel antagonist of the dihydropyridine type, structurally related to felodipine. Clinical trials have shown that the drug can be used to effectively control the blood pressure in connection with cardiac surgical procedures. The compound is tailored to be a short-acting drug and, due to incorporation of an ester linkage into the drug molecule, clevidipine is rapidly metabolized by ester hydrolysis. The pharmacokinetics of clevidipine and its primary metabolite, H 152/81, were studied in rats, rabbits, and dogs. In addition, the influence of the pharmacokinetics on the effect on mean arterial blood pressure was evaluated in anesthetized dogs. Compartmental nonlinear mixed effect regression analysis was used to calculate the population mean and individual pharmacokinetics of clevidipine, whereas nonlinear regression analysis of individual data was used to determine the pharmacokinetics of the primary metabolite. A linked Emax model was fitted to the individual pharmacodynamic/pharmacokinetic data in dogs. According to the results, clevidipine is a high-clearance drug with a relatively small volume of distribution, resulting in an extremely short half-life in all species studied. The median initial half-life of the individual value (Bayesian estimates) is 12, 20, and 22 s in the rabbit, rat, and dog, respectively. The primary metabolite is a high-clearance compound in the dog, whereas it is a low-clearance compound in the rat. A significant gender difference in the clearance of the metabolite was observed in the rat. The mean maximum reduction in arterial blood pressure is 38 +/- 12% (Emax) and is achieved at 85 +/- 46 nM (EC50). The half-life for reaching equilibrium between the central and the effect compartment (T1/2ke0) is 47 +/- 49 s.

Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy male volunteers following a constant rate infusion. METHODS: Eight healthy male volunteers received 1030 nmol x min(-1) of clevidipine together with a tracer dose of 3[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed for 7 days. RESULTS: A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) l x min(-1) x kg(-1) and a mean volume of distribution at steady state of 0.6 (0.1) l x kg(-1). The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min. CONCLUSION: Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The tmax value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination rather than distribution. The duration of action of clevidipine is short.

The vasodilator effects of clevidipine on human internal mammary artery.

UNLABELLED: Endothelial dysfunction and platelet activation with thromboxane release may contribute to spasm or alterations in internal mammary artery (IMA) graft flow during coronary artery surgery. Clevidipine, an ultrashort-acting dihydropyridine calcium channel blocker, is undergoing clinical development, but there are little data regarding its effects on human vasculature. We investigated the effects of clevidipine on human IMA obtained during surgery. After precontracting IMA segments with an analog of thromboxane (U46619, 10(-8) mol/L), acetylcholine and nitroglycerin were added cumulatively to examine endothelial function. Concentration-response curves to clevidipine were cumulatively obtained during submaximal contraction to the U46619 (10(-8) mol/L) in rings with and without endothelium. In the IMA samples with endothelium, acetylcholine did not completely reverse the U46619-mediated contraction, which implies impaired endothelial function (40% +/- 6% maximal response). Both clevidipine and nitroglycerin completely reversed U46619-induced contraction (clevidipine (50% effective concentration [EC50] = 3.88 +/- 0.84 x 10(-6) mol/L, nitroglycerin EC50 = 4.84 +/- 2.76 x 10(-8) mol/L). The responses to clevidipine were similar in preparations with or without intact endothelium. Clevidipine is an endothelium-independent arterial vasodilator that offers a potential therapeutic option in the treatment of perioperative arterial graft vasospasm and/or hypertension. IMPLICATIONS: Clevidipine is a new ultrashort-acting dihydropyridine calcium antagonist. In human internal mammary arteries precontracted with a thromboxane A2 analog, clevidipine was an effective vasodilator on vessel segments in the presence and in the absence of endothelium.

Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: focus on felodipine.

Calcium entry through L-type calcium channels is essential for contraction of both arterial smooth muscle and the myocardium, and is important in cardiac conduction. First-generation calcium entry blockers lack or have a modest degree of vascular selectivity and inhibit cardiac function at doses producing therapeutic arterial dilatation. Such agents may cause deterioration in patients with left ventricular dysfunction, and their combination with a beta-adrenergic blocker may adversely affect cardiac contractility and conduction. Development of newer agents has focused on obtaining a higher degree of vascular selectivity. Felodipine is a highly vascular selective calcium entry blocker, with a vascular selectivity ratio greater than 100, as shown experimentally. Isradipine and nicardipine are also vascularly selective calcium entry blockers. Hemodynamic studies in patients with hypertension, coronary artery disease, congestive heart failure, or in patients receiving beta-adrenergic blockade, show that felodipine can produce profound arteriolar dilatation without the negative effects of left ventricular systolic performance. Furthermore, felodipine alone or when added to a beta-adrenergic blocker does not interfere with cardiac conduction. The primary mechanism that accounts for the efficacy of dihydropyridine calcium entry blockers in hypertension and angina pectoris is arterial dilation, whereas nondihydropyridines may also derive part of their effect from inhibition of cardiac performance. As some of these patients, most commonly the elderly, have concomitant left ventricular dysfunction, it should be advantageous to avoid myocardial depression in the treatment of their primary disease. Preliminary studies in patients with heart failure indicate that felodipine and amlopidine may improve hemodynamics, reduce neurohormonal activation, and increase exercise tolerance, but final conclusions must await the randomized clinical trials now underway.

Vascular versus myocardial selectivity of dihydropyridine calcium antagonists as studied in vivo and in vitro.

The use of in vitro models for the study of cardiovascular effects of drugs may not be representative for the in vivo therapeutic effects. However, drug effects in vivo are often difficult to assess because of counteracting reflexes and auto-regulatory rearrangements. To solve this dilemma, the present study presents a two-step method using both in vivo and in vitro techniques to investigate vascular versus myocardial selectivity of three dihydropyridine calcium antagonists: amlodipine, felodipine and nifedipine. The ratio between intravenous drug doses causing 25% reduction in mean arterial blood pressure (vascular potency) and in heart rate (cardiac chronotropic potency) was determined in anaesthetised spontaneously hypertensive rats during autonomic cardiac blockade. In isolated hearts from spontaneously hypertensive rats, the inotropic versus chronotropic potency ratio was determined between the two drug concentrations producing a 25% reduction in cardiac contractility (dP/dt max) and in heart rate, respectively. The vascular versus chronotropic selectivity in vivo was higher for felodipine (121) than for nifedipine (47) and amlodipine (15). The inotropic versus chronotropic potency ratios obtained from the in vitro studies were: felodipine (1), amlodipine (2) and nifedipine (20). The in vitro results were used to extrapolate the vascular versus cardiac chronotropic selectivity obtained in vivo to a vascular versus myocardial selectivity drug ratio, being 20 and 60 times higher for felodipine than for amlodipine and nifedipine, respectively.

Relevance of plasma noradrenaline concentrations to estimate autonomic effects of antihypertensive drugs.

The sympathetic nervous system is important in regulating cardiovascular function. It is therefore of interest to study the influence of antihypertensive drugs on sympathetic nerve activity. For this purpose, measurements of noradrenaline concentrations in forearm venous plasma have often been used. For several reasons, this provides limited information: i) the sympathetic nervous system is highly differentiated, i.e. activity may be high in some organs and low in others; ii) noradrenaline in forearm venous plasma is largely derived from sympathetic activity to the forearm skeletal muscle; iii) plasma noradrenaline concentrations are determined not only by noradrenaline spillover from sympathetic nerve endings, which is related to sympathetic nerve activity, but also by noradrenaline clearance. Under most circumstances plasma noradrenaline concentrations are not high enough to produce hormonal effects. Many types of antihypertensive drugs may cause acute and long-term increases in forearm venous noradrenaline concentrations. The mechanisms underlying these increases are not fully understood but seem to differ between drug classes: Diuretics increase renal noradrenaline spillover; beta-blockers do not affect spillover but reduce total noradrenaline clearance; calcium antagonists and alpha-blockers probably increase noradrenaline spillover, but it is not known which organs are involved, particularly during long-term treatment. ACE inhibitors seem to have a sympatholytic action, which counteract reflex increases in sympathetic nerve activity during blood pressure reduction, and plasma noradrenaline concentrations are generally not affected. To be able to judge the possible clinical consequences of changes in plasma noradrenaline concentrations during chronic antihypertensive treatment, assessments of noradrenaline spillover from individual organs are needed.

Comparison of effects of dihydropyridine calcium antagonists on left ventricular systolic and diastolic performance.

We compared the effects of three dihydropyridine calcium antagonists (felodipine, nifedipine and amlodipine) on left ventricular (LV) contractile performance and diastolic filling dynamics in eight conscious animals. After administering metoprolol and atropine, felodipine (25 nmol/kg i.v.) produced significant decreases in LV end-systolic pressure (PES) (109 +/- 15 vs. 88 +/- 12 mmHg, P < .05) and arterial elastance (Ea) (12.6 +/- 4.5 vs. 8.5 +/- 3.4 mmHg/ml, P < .05), whereas the heart rate was unchanged. Felodipine increased the slopes of the end-systolic P-V relation (7.4 +/- 0.9 vs. 9.9 +/- 1.0 mmHg/ml, P < .05), the dP/dtmax-end diastolic volume (VED) relation (68.1 +/- 11.2 vs. 94.9 +/- 14.3 mmHg/sec/ml, P < .05), and the stroke work (SW)-VED relation (72.1 +/- 3.1 vs. 82.8 +/- 5.2 mmHg, P < .05), and shifted all three relations to the left, indicating enhanced contractile performance. In contrast, at doses that produced equivalent reductions of PES, nifedipine (375 nmol/kg i.v.) and amlodipine (780 nmol/kg i.v.), significantly decreased the slopes of the end-systolic P-V relation, the dP/dtmax-VED relation and the SW-VED relation and shifted all three relations to the right, indicating depressed LV contractile performance. Felodipine decreased the time constant (T) of LV relaxation (32.2 +/- 5.2 to 28.8 +/- 5.2 msec, P < .05) and increased the maximum rate of early diastolic LV filling (dV/dtmax) (167 +/- 22 to 207 +/- 26 ml/sec, P < .05). Amlodipine had the opposite effect, slowing T (31.0 +/- 4.9 to 33.9 +/- 5.4 msec, P < .05) and decreasing dV/dtmax (173 +/- 39 to 154 +/- 30 ml/sec, P < .05), whereas nifedipine had no significant effects on T, PGmax or dV/dtmax. Thus, we conclude that in conscious dogs after autonomic blockade, at dosages that produced equivalent arterial vasodilation, felodipine augmented, whereas amlodipine depressed, LV contractile performance, LV relaxation and early LV filling. Nifedipine decreased LV contractile performance but had no significant effect on LV relaxation and early LV filling.

Coronary venous retroinfusion of felodipine reducing infarct size without affecting regional myocardial blood flow.

Effects on the ischaemic and reperfused myocardium of felodipine, a vasoselective calcium blocker, retrogradely infused into the coronary vein was investigated in a porcine model. Sixteen open-chest pigs underwent 45 min of myocardial ischaemia by occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. Either felodipine (felo-retro group, 7 nmol.kg-1: n = 6) or the corresponding amount of vehicle (vehicle group: n = 5) was retroinfused over 30 min starting 5 min prior to reperfusion. In a third group, the same amount of felodipine was administered intravenously (felo-i.v. group n = 5). Myocardial regional blood flow was measured with radioactive microspheres prior to ischaemia and at different times of reperfusion. Infarction size, expressed as a percentage of the area at risk, was significantly reduced to 62 +/- 12% in the felo-retro group as compared to 86 +/- 12% (P < 0.05) and 94 +/- 5% (P < 0.05) in the vehicle and felo-i.v. group, respectively. Following an early hyperaemia, the regional blood flow decreased uniformly in the reperfused myocardium in all three groups and there were no significant differences between the groups at any period of reperfusion. In conclusion, felodipine retroinfused into the coronary vein could salvage ischaemic and reperfused myocardium without affecting the regional blood flow. The mechanism of this protective effect should be explained by factors other than an increased myocardial blood flow during reperfusion.

Coronary venous retroinfusion of felodipine reduces myocardial necrosis after coronary occlusion and reperfusion.

The effect of the vasoselective calcium antagonist felodipine on myocardial necrosis was studied in 14 anesthetized pigs subjected to 45-min occlusion of the left anterior descending coronary artery (LAD) followed by 24-h reperfusion. Felodipine (7 nmol/kg, n = 7), or the corresponding amount of vehicle diluted in 300 ml saline (n = 7) was infused in the great cardiac vein for 30 min beginning 5 min before onset of reperfusion. Regional myocardial function was measured as percentage of systolic segment shortening (%SS) by sonomicrometry. The recovery in ischemic myocardium was significantly already better among felodipine-treated animals after 30-min reperfusion (mean +/- SD = 9.1 +/- 6.1 vs. 0.1 +/- 3.2%, p < 0.05). The improved recovery in the felodipine group persisted throughout the observation period; %SS was 8.5 +/- 5.9% after 24-h reperfusion. No significant improvement was observed in the vehicle group after 24 h (%SS = 2.7 +/- 2.0%, p < 0.05). The area of the infarct was measured by triphenyl tetrazolium chloride staining. When expressed as percentage of the left ventricle, the infarct was smaller in the felodipine group (8.2 +/- 4.0%) than in the vehicle group (14.6 +/- 3.5%; p < 0.01). The corresponding values for infarct size expressed as percentage of the area at risk was 38.6 +/- 18.9% in the felodipine group and 69.8 +/- 6.7% in the vehicle group (p < 0.01). Peak plasma felodipine concentration was reached 30 min after onset of reperfusion (4.9 +/- 1.2 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of felodipine on the uptake and degradation of acetylated LDL in mouse peritoneal cells and on the distribution of acetylated LDL in macrophage-rich organs of the rat.

The effect of felodipine on lipoprotein metabolism ex vivo and in vivo was investigated. In the ex vivo studies mice were given felodipine (40-125 mumol/kg body weight) or vehicle for one week. Peritoneal macrophages from these animals and controls were isolated and used in binding and degradation studies with human iodinated acetylated LDL (Ac-LDL). Macrophages from felodipine-treated mice showed a significant decrease of binding and degradation of Ac-LDL compared to macrophages from control animals (P < 0.05). The in vivo studies were performed in rats pretreated with felodipine or vehicle. To determine the distribution and plasma turnover of LDL and Ac-LDL, 125I-tyramine cellobiose labelled LDL or Ac-LDL were given i.v. No differences in the removal rate of Ac-LDL or LDL were observed between felodipine-treated or untreated rats. However, an increased uptake of Ac-LDL could be seen in the liver of the felodipine-treated rats. This increased uptake could be ascribed to the parenchymal cells because no differences in uptake could be seen in the liver endothelial cells. However, a significant decreased uptake was seen in the Kupffer cells and in the spleen, a macrophage-rich organ, of the felodipine-treated rats. The present study suggests a possible mechanism behind the antiatherogenic effects of calcium antagonists, a decreased uptake of atherogenic modified lipoproteins by peripheral macrophages and an increased uptake by the liver.