Reduction of myocardial ischemia-reperfusion injury by KT-362, a new intracellular calcium antagonist in anesthetized dogs

The effects of a new intracellular calcium antagonist, KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]- 2,3,4,5,-tetrahydro-1,5-benzothiazepine fumarate) on myocardial infarct size following a 90-min occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD) were determined in anesthetized dogs. Regional myocardial blood flow was measured by radioactive microsphere technique, and infarct size was determined using triphenyltetrazolium chloride histochemical stain. Vehicle or KT-362 (300 micrograms/kg/min for 20 min followed by 150 micrograms/kg/min for 80 min) was administered intravenously (i.v.) 10 min prior to coronary occlusion and continued throughout the occlusion period in separate experimental groups. KT-362 produced a reduction in heart rate (HR) and the HR-systolic pressure product. Mean arterial pressure (MAP) was reduced during occlusion and early reperfusion in the KT-362-treated group, and segment function (% segment shortening) was improved during the first hour of reperfusion. There were no differences in collateral blood flow between the two groups. However, at 3 h postreperfusion, ischemic zone subendocardial blood flow in the KT-362-treated group was significantly greater than in the vehicle-treated group, resulting in an increase in endo/epi. There were no differences in ventricular mass, mass of the area at risk, or percentage of the left ventricle at risk. As compared with the control group, KT-362 produced a marked reduction in myocardial infarct size expressed as a percentage of the area at risk infarcted, percentage of the left ventricle infarcted, and absolute weight of infarcted tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog

We studied the hemodynamic effects of nicorandil (SG-75) and nitroglycerin in conscious dogs before and after beta-adrenergic receptor blockade. Nicorandil (25-300 micrograms/kg/min) and nitroglycerin (5-60 micrograms/kg/min) produced increases in heart rate and decreases in aortic and left ventricular pressures. In the doses studied, nicorandil caused greater decreases in aortic and left ventricular systolic pressure than nitroglycerin; however, nitroglycerin reduced left ventricular end-diastolic pressure to a greater degree. Nicorandil but not nitroglycerin produced an increase in cardiac output secondary to an increase in heart rate. Global contractility (peak positive dP/dt) was increased in a dose-related manner during nicorandil infusion before beta-blockade. In spite of marked hypotensive responses to higher doses, mean coronary blood flow and coronary conductance were increased by nicorandil. In contrast, both parameters were reduced during nitroglycerin infusion. The effects of nicorandil on coronary blood flow were unaltered by beta-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75-300 micrograms/kg/min) produced a dose-related increase in transmural myocardial blood flow with the greatest increases in perfusion occurring in the subepicardium and midmyocardium. The results of the present study demonstrate that despite structural similarities, nicorandil and nitroglycerin have varying hemodynamic spectra.     

Effects of KT-362, a new calcium release blocker, on vascular selectivity and hemodynamic actions in anesthetized dogs

Pharmacological properties of 5-(3-((2-(3,4-dimethoxyphenyl)ethyl)-amino)-1- oxopropyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine fumarate (KT-362), a newly synthesized calcium release blocker, were studied by comparing its vascular selectivity and cardiovascular actions with those of verapamil, a calcium entry blocker. The relaxing effect of KT-362 in rabbit femoral and basilar artery strips contracted with norepinephrine was greater than that in aortic and coronary artery strips. In anesthetized mongrel dogs, KT-362 (0.1-3.0 mg/kg, i.v.) decreased the mean blood pressure, heart rate and total peripheral resistance in a dose-dependent manner, while cardiac output increased slightly despite a decrease in left ventricular pressure. This is consistent with the data on verapamil. Both i.a. and i.v. injections of KT-362 produced a marked dose-dependent increase in vertebral and femoral blood flow. Pretreatment of atropine, propranolol or diphenhydramine exerted no significant effect on the KT-362-induced vasodilation. Verapamil caused a marked increase in the vertebral and coronary blood flows after the injections, but only a slight increase in femoral blood flow. KT-362 at the dose of 10 mg/kg, i.v., had no significant effect on the PQ interval on the electrocardiogram in anesthetized dogs, but 0.1 mg/kg of verapamil increased this interval significantly. These results suggest that KT-362 has properties similar to calcium entry blockers such as verapamil on systemic hemodynamic actions except for the reactivity of vasculatures.     

Effect of KT-362, a putative intracellular calcium antagonist, on norepinephrine-induced contractions and inositol monophosphate accumulation in canine femoral artery

The purpose of the present study was to determine if the intracellular calcium antagonist, KT-362, inhibits norepinephrine- (NE) induced contractions and inositol monophosphate (IP) accumulation in canine femoral arteries preincubated with [3H]inositol. Norepinephrine dose-dependently increased contractile tension and produced a parallel stimulation of inositol phospholipid hydrolysis as measured by IP accumulation. This stimulation was inhibited by the selective alpha 1 adrenoceptor antagonist, prazosin (0.1 microM), indicating that the NE-induced stimulation of inositol phospholipid hydrolysis is coupled to alpha 1 adrenoceptor activation in canine femoral artery. Pretreatment with nitroglycerin (100 microM), 8-Br cyclic guanosine monophosphate (cGMP) (1 microM), or diltiazem (40 microM) inhibited contractile responses produced by NE; however, these agents had no significant effect on NE-induced IP accumulation. In contrast, pretreatment with KT-362 (10-100 microM) greatly inhibited both the NE-induced contractions and IP accumulation. KT-362 also produced a marked inhibition of NE-induced contractions in normal as well as zero calcium buffer, whereas diltiazem (40 microM) had no effect in zero calcium buffer. These results indicate that the mechanism of action of KT-362 differs from diltiazem, nitroglycerin, and 8-Br cGMP, and these data suggest that one of the mechanisms by which KT-362 antagonizes NE-induced vasoconstrictor responses is by decreasing inositol phospholipid hydrolysis in canine femoral artery.     

Collateral blood flow following acute coronary artery occlusion: comparison of a new intracellular calcium antagonist (KT-362) and diltiazem

The effects of a new intracellular calcium antagonist, KT-362 (150 and 300 micrograms/kg per min), on hemodynamics and collateral function (retrograde pressure and flow, radioactive microspheres) distal to an acute coronary artery occlusion were studied in anesthetized dogs and compared with the effects of the structurally related classical calcium channel blocker, diltiazem (15 and 30 micrograms/kg per min), and a saline-treated control group. In the saline series, there were no changes in systemic hemodynamics or coronary collateral blood flow over the 90-min ischemic period. KT-362 reduced mean aortic pressure, heart rate, and dP/dt whereas diltiazem only decreased aortic blood pressure. When blood pressure was controlled by a distal aortic cuff, heart rate was significantly reduced in both groups and dP/dt was reduced in the KT-362 series and increased in diltiazem-treated dogs. In both drug-treated groups, retrograde pressure and flow were significantly increased only when aortic pressure was controlled. Regional myocardial tissue blood flow in the nonischemic or ischemic region did not change significantly after KT-362 treatment despite its hypotensive actions, and in the presence of a constant aortic pressure, transmural collateral blood flow and the ischemic/nonischemic blood flow ratio tended to increase. In contrast, diltiazem treatment resulted in a significant decrease in the ischemic/nonischemic blood flow ratio in the absence of blood pressure control. In the presence of constant aortic pressure, blood flow to the nonischemic area was markedly increased by diltiazem whereas subendocardial blood flow was significantly increased in the ischemic area.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular actions of the dihydropyridine calcium antagonist nimodipine in the dog

When injected i.v. into anaesthetized, open-chest dogs, isopropyl (2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (nimodipine, Bay e 9736) (0.3-10 micrograms/kg) produced an increase in coronary sinus outflow and decreases in mean arterial blood pressure, coronary resistance, arterio-venous oxygen difference and heart rate in a dose-dependent manner, but virtually no change in myocardial oxygen consumption. At 3 micrograms/kg i.v. of the drug coronary resistance fell nearly to half the pre-drug value, coronary sinus outflow nearly doubled and heart rate decreased by about 10 beats/min. Myocardial oxygen consumption was slightly reduced at 30 micrograms/kg i.v. and atrioventricular (AV) conduction time was slightly increased at 10 and 30 micrograms/kg i.v. of the drugs. When the coronary vascular and cardiac effects of nimodipine were assessed in isolated, blood-perfused dog heart preparations, i.e., sinoatrial node, AV node and papillary muscle preparations, by intra-arterial administration, the following was revealed. In nearly twice the dose doubling coronary arterial blood flow, nimodipine produced a 15% decrease in sinus rate and a 15% increase in AV conduction time. However, in reducing the force of contraction of the papillary muscle by half the pre-drug value was needed nearly 17 times the dose of nimodipine doubling coronary arterial blood flow. Suppression of AV conduction by large doses of nimodipine was evident only when it was injected into the artery supplying the AV node but not into the artery supplying the His-Purkinje-ventricular system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic, hormonal, and renal actions of adrenomedullin-5 in normal conscious sheep

Although blood pressure effects have been reported for adrenomedullin 5 (AM-5), a newly identified member of the calcitonin gene-related peptide superfamily, little is known about other biological actions. We report the integrated hemodynamic, hormonal, and renal actions of AM-5 (10 and 100 ng·kg·min each for 90 minutes) in normal conscious sheep. AM-5 reduced the mean arterial pressure by 12 mm Hg at the end of the high dose (P < 0.001) in association with dose-dependent increments in the heart rate (40 beats/min--high dose, P < 0.001) and cardiac output (50%-high dose, P < 0.001) and dose-dependent falls in calculated total peripheral resistance (P < 0.001). Plasma renin activity (4-fold increment, P < 0.001), aldosterone (2-fold increment, P = 0.014), and cyclic adenosine monophosphate (50% increment, P < 0.001) all rose in response to high dose AM-5. Urine volume and sodium excretion were unchanged. In conclusion, it is observed that intravenous infusions of AM-5 administered to normal conscious sheep induced significant hemodynamic actions including reduced mean arterial pressure and calculated total peripheral resistance and increased heart rate and cardiac output. Concurrently, AM-5 activated plasma cyclic adenosine monophosphate, plasma renin activity, and aldosterone. These actions are similar to those previously reported for AM and AM-2. Thus, AM-5 may be an another important regulator of volume and pressure homeostasis and may play a role in the pathophysiology of heart disease.     

Hemodynamic effects of a new calcium antagonist, bepridil, in patients with coronary artery disease

Hemodynamic Effects of the New Calcium Antagonist Bepridil in Patients with Coronary Artery Disease. For the evaluation of the hemodynamic effects of the new calcium antagonist bepridil 11 patients with coronary artery disease were studied. The following parameters were measured before, immediately after and 20 min after injection of 3 mg/kg bepridil i.v.: pulmonary capillary wedge pressure, pulmonary artery pressure, cardiac output, mean aortic pressure, peripheral vascular resistance, prolongation of the QT-interval in the ECG. Bepridil led acutely to a slight deterioration of the left ventricular function with a significant increase of the preload, but this negative effect was neutralized by the concomitant decrease of the afterload. These results indicate a favorable hemodynamic profile of this new agent.     

Stereoselective oxidation of nilvadipine, a new dihydropyridine calcium antagonist, in rat and dog liver

The stereoselective oxidation of nilvadipine (NV), a new 1,4-dihydropyridine calcium antagonist, to the corresponding pyridine analog was studied after incubation of (+)- and (-)-NV with rat and dog liver microsomes. The rates of formation of the pyridine analog and disappearance of NV were similar for each species, indicating that aromatization of NV is the primary metabolic step. Formation of the corresponding pyridine required the presence of an NADPH-generating system and was significantly inhibited by carbon monoxide and metyrapone, indicating the participation of cytochrome P-450. In male rat liver microsomes, the apparent Km values for the formation of the pyridine from (+)- and (-)-NV were 11.2 and 8.1 microM, and the Vmax values were 7.48 and 3.37 nmol/mg of protein/min, respectively. Therefore, the Vmax/Km value, which is equivalent to the intrinsic clearance of the drug, for the oxidation of (+)-NV was 1.59-fold greater than that for the oxidation of the (-)-enantiomer. In female rats, (-)-NV oxidation exhibited two distinct apparent Km values, whereas the that of the (+)-enantiomer did not. The (+)/(-) ratio of Vmax/Km was 1.23. On the other hand, in male dog microsomes the Km values for (+)- and (-)-NV were 21.9 and 12.2 microM, and Vmax values were 3.02 and 2.45 nmol/mg of protein/min, respectively; the (+)/(-) ratio of Vmax/Km was 0.69. These results indicate that the stereo-selective oxidation of NV is species dependent and is sex related in rat liver.     

Hemodynamic effects of labetalol in the dog. Comparative study in the anesthetized open-chest dog and in the conscious dog

Hemodynamic effects of labetalol, an alpha- and beta-adrenoceptor blocking drug, were investigated in the conscious dog and in the anesthetized open-chest dog. In the conscious dog, intravenous injection of labetalol, in a dose of 0.5 mg/kg, decreased the total peripheral resistance by approximately 20% (P less than 0.01) in association with falls in blood pressure and heart rate. The total peripheral resistance of the anesthetized open-chest dog was not affected by labetalol in the presence of the same extent of blood pressure fall as results of the conscious dog. In contrast, agents which have beta-adrenoceptor blocking effect alone provided substantial elevation of the total peripheral resistance in the anesthetized dog. These results indicate that the different responses of the resistance to labetalol probably result from the vascular alpha-adrenoceptor blocking action, and also show that in the conscious state alpha-adrenoceptor blocking action of labetalol is enhanced in comparison with the effect in the anesthetized open-chest dog.     

Comparative cardiac effects of KT-362 and verapamil in isolated heart--correlation to calcium channel current depression.

Direct cardiac effects of KT-362 (5-[3 [[-2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), a drug that may inhibit intracellular calcium mobilization as well as extracellular calcium influx was compared to verapamil. Guinea pig hearts (n = 19) were used to examine the changes in atrial rate, atrioventricular conduction time (AVCT), coronary flow, myocardial oxygen consumption (MVO2), and isovolumetric left ventricular pressure (LVP). Both drugs concentration-dependently and reversibly decreased atrial rate, contractility, and MVO2; AVCT increased during spontaneous rhythm. The increases in AVCT and the incidence of AV dissociation were accentuated during cardiac pacing. Verapamil significantly increased coronary flow, while KT-362 did not. Median effective concentration (EC50) was about 25 times lower for verapamil in depressing LVP and about three times lower in depressing atrial rate and AV conduction. The changes in calcium channel current in voltage-clamped single canine Purkinje cells (n = 6) were also examined. Verapamil (0.3 microM) and KT-362 (7 microM) decreased peak Ca2+ channel current at maximum activation (+10 mV) by 38.1 +/- 8% and 28.6 +/- 6%, respectively, without shifting the current-voltage relationship. This study indicates that verapamil is more potent than KT-362 in depressing contractile function, heart rate, and AV conduction in isolated hearts and calcium current in isolated cardiac Purkinje cells. Moreover, there was a much greater difference between the EC50 for verapamil and that for KT-362 for the depression of indices of contractility (23-30-fold) than for the depression of sinoatrial and atrioventricular nodal function (2.5-4-fold).     

Comparison of the characteristics of the negative inotropic actions of dinitrophenol, rotenone, antimycin A and the intracellular calcium antagonist, propyl-methylenedioxyindene

The characteristics of the reversal of the comparable negative inotropic actions of 10(-4) M propyl-methylenedioxyindene (an intracellular calcium antagonist), 3 X 10(-5) M dinitrophenol (an uncoupler of mitochondrial oxidative phosphorylation), 10(-6) M rotenone (a site I mitochondrial respiratory chain poison) and 3 X 10(-6) M antimycin A (a site II mitochondrial respiratory chain poison) were studied in the isolated, electrically-paced guinea-pig left atrium. The negative inotropic effect of propyl-methylenedioxyindene was more sensitive to reversal by 5 mM calcium and 10(-9)-10(-7) M isoproterenol than were the comparable negative inotropic effects of dinitrophenol, rotenone and antimycin A. These results indicate that the negative inotropic effect of propyl-methylenedioxyindene is not exerted through inhibition of mitochondrial electron transport nor through uncoupling of mitochondrial oxidative phosphorylation.     

Acute systemic and regional hemodynamic effects of felodipine, a new calcium antagonist, in conscious renal hypertensive rabbits

Using the radioactive microsphere technique, we studied the acute systemic and regional hemodynamic effects of felodipine (10, 30, and 100 nmol/kg, i.v.) in conscious renal hypertensive rabbits. A dose-dependent decrease in arterial blood pressure was observed after felodipine administration, accompanied by tachycardia. Cardiac output increased significantly after the third felodipine dose. Thus, the hypotensive effect of the drug resulted from a reduction in total peripheral resistance. An increase in blood flow to the heart was measured after felodipine. However, probably secondary to the reduction in diastolic perfusion time, a decrease in the endocardial/epicardial blood flow ratio was noticed in the left ventricular wall. The drug also enhanced the blood supply to the brain, the gastrointestinal tract, and, at higher doses, to the skeletal muscles while blood flow to the kidneys and the bones remained unchanged. After the highest dose of felodipine, a significant decrease in the blood flow to the skin was measured. With the exception of the cutaneous vascular bed, felodipine caused a rather generalized peripheral vasodilatation. In conclusion, felodipine appears to be a very effective antihypertensive agent. However, the stimulation of the heart and the unfavorable regional blood flow distribution in the left ventricular wall illustrate the negative aspects of single treatment with this arterial vasodilator.     

Effects of KT-362, a new Na and Ca influx and Ca release inhibitor, on canine ventricular arrhythmias

Antiarrhythmic effects of the new drug KT-362, which was reported to suppress Na and Ca currents of cardiac cells and also to suppress intracellular Ca release in isolated smooth muscle preparations, were examined using two-stage coronary ligation-, digitalis- and adrenaline-induced ventricular arrhythmias in the dog. Intravenous KT-362 at 10 mg/kg suppressed coronary ligation arrhythmia both at 24 and 48 hr after ligation, and the minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation and 48 hr coronary ligation were 6.1 +/- 1.7 and 8.6 +/- 2.7 micrograms/ml, respectively. Antiarrhythmic effects were accompanied by transient hypotension. Oral administration of 70-100 mg/kg was also effective on 24 hr coronary ligation arrhythmia. However, there was no prominent hypotension in these experiments. Intravenous KT-362 at 3 mg/kg suppressed digitalis arrhythmia; and the minimum effective plasma concentration was 3.3 +/- 1.2 micrograms/ml, which was lower than the effective plasma concentrations for coronary ligation arrhythmias. Intravenous KT-362 at 1 mg/kg also suppressed adrenaline arrhythmia; and the minimum effective plasma concentration was 1.0 +/- 0.1 microgram/ml, the lowest among the effective plasma concentrations. These pharmacological profiles of KT-362 are quite different from those of class 4 Ca antagonists, but similar to those of class 1 drugs such as propafenone. Though KT-362 has a hypotensive effect, it is effective on canine ventricular arrhythmias; thus its clinical usefulness for supraventricular and ventricular arrhythmias is expected.     

Antifibrillatory actions of bepridil and butyl-MDI, two intracellular calcium antagonists

The antifibrillatory and electrophysiologic actions of bepridil and butyl-methylenedioxyindene (BU-MDI), two intracellular calcium antagonists, were examined in anesthetized dogs. The administration of bepridil (1.0-10.0 mg/kg i.v.) significantly increased the electrical threshold for ventricular fibrillation determined during unobstructed coronary flow, and was associated with a significant decrease in ventricular excitability and a progressive depression in ventricular myocardial conduction. BU-MDI (3.0-30.0 mg/kg i.v.) did not significantly alter ventricular fibrillation thresholds during unobstructed coronary flow, nor did it significantly alter electrophysiologic properties such as ventricular excitability, conduction or refractoriness. The administration of either bepridil (10 mg/kg i.v.) or BU-MDI (30 mg/kg i.v.), however, resulted in significant increases in the ventricular fibrillation thresholds determined during transient myocardial ischemia, restoring the threshold values to corresponding non-ischemic levels. These results suggest that an inhibition of the action and/or availability of intracellular calcium may play a role in the antifibrillatory actions of BU-MDI and bepridil during transient ischemia.     

Effects of a new calcium antagonist, Rec 15/2375, on cardiac contractility of conscious rabbits

The new calcium antagonist Rec 15/2375, supposed to be selective for the vascular tissue, was compared to nifedipine, a non-selective agent that reduces blood pressure and impairs cardiac inotropism as well. Six rabbits, chronically catheterized and continuously monitored for systemic blood pressure, heart rate and the isovolumic contractility index dP/Tmax, were alternatively treated with Rec 15/2375 and nifedipine, according to a randomized cross-over design. Both drugs were given under either autonomically intact (AI) or suppressed (AS) heart function control, induced by cholinergic and beta-adrenoceptor blockade. The two agents reduced mean arterial blood pressure comparably and dose-dependently (P less than 0.01) under both experimental conditions (from 10 to 40%), thus causing heart rate to increase reflexly (P less than 0.01), similarly between drugs in AI rabbits, whereas the AS manoeuvre totally abolished such a response. Cardiac contractility, on the other hand, displayed opposing behaviour between the two drugs. Rec 15/2375 caused mild but significant (P less than 0.01) increases, which were similar at all doses (+10, +15%) and insensitive to the AS intervention, whereas nifedipine caused dose-dependent reductions (from -10 to -60%; P less than 0.01) of comparable intensity as mean blood pressure decrease in both protocols. We conclude that Rec 15/2375 effectively lowers blood pressure with no impairment, unlike nifedipine, of cardiac inotropism and we discuss the possibility that dP/dTmax may be increased as a result of the haemodynamic rearrangement following after-load reduction.     

Electrophysiological effects of KT-362, a new antiarrhythmic agent with vasodilating action, on isolated guinea pig ventricular muscle

The effects of KT-362, a newly synthesized vasodilating and antiarrhythmic agent, on transmembrane action potentials were examined in isolated papillary muscles of guinea pig. KT-362 (3 x 10(-6) to 3 x 10(-5) M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential without affecting the resting potential. In the presence of KT-362, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block was 2.8-2.9 s. The curves relating membrane potential and Vmax were shifted by KT-362 (10(-5) M) in the direction of more negative potentials (8.6 mV). In papillary muscles treated with KT-362 (10(-5) M), the Vmax of test action potential preceded by conditioning clamp pulses to 0 mV was progressively decreased with increasing number of pulses, while it was little affected by the duration of each clamp pulse within the range from 10 to 700 ms. These findings suggest that KT-362 has quinidine-like use-dependent inhibitory action on the fast sodium channel of cardiac muscles by the binding to the channel mainly during its activated state. At high concentrations (greater than or equal to 3 x 10(-5) M), KT-362 also suppressed the slow action potential in K+ depolarized papillary muscles.     

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.