Margareta Nordlander

Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing

Neuropeptide Y (NPY), a 36-aa peptide, is widely distributed in the brain and peripheral tissues. Whereas physiological roles of NPY as a hormone/neurotransmitter have been well studied, little is known about its other peripheral functions. Here, we report that NPY acts as a potent angiogenic factor in vivo using the mouse corneal micropocket and the chick chorioallantoic membrane (CAM) assays. Unlike vascular endothelial growth factor (VEGF), microvessels induced by NPY had distinct vascular tree-like structures showing vasodilation. This angiogenic pattern was similar to that induced by fibroblast growth factor-2, and the angiogenic response was dose-dependent. In the developing chick embryo, NPY stimulated vascular sprouting from preexisting blood vessels. When [Leu31Pro34]NPY, a NPY-based analogue lacking high affinity for the NPY Y2 receptor but capable of stimulating both Y1 and Y5 receptors, was used in the corneal model, no angiogenic response could be detected. In addition, NPY failed to induce angiogenesis in Y2 receptor-null mice, suggesting that this NPY receptor subtype was mediating the angiogenic signal. In support of this finding, the Y2 receptor, but not Y1, Y4, or Y5 receptors, was found to be widely expressed in newly formed blood vessels. Further, a delay of skin wound healing with reduced neovascularization was found in Y2 receptor-null mice. These data demonstrate that NPY may play an important role in the regulation of angiogenesis and angiogenesis-dependent tissue repair.

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 (AUCMAP 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 (AUCMAP 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.

Clevidipine in adult cardiac surgical patients: A dose-finding study

Background Treatment of elevated blood pressure is frequently necessary after cardiac surgery to minimize postoperative bleeding and to attenuate afterload changes associated with hypertension. The purpose of this study was to investigate the pharmacodynamics and pharmacokinetics of a short-acting calcium channel antagonist, clevidipine, in the treatment of hypertension in postoperative cardiac surgical patients. Methods Postoperative cardiac surgical patients were randomized to receive placebo or one of six doses of clevidipine. Hemodynamic parameters were recorded and blood samples were drawn for determination of clevidipine plasma concentrations during infusion and after discontinuation of clevidipine. The concentration–response relation was analyzed using logistic regression, and pharmacokinetic models were applied to the data using population analysis. Results There were significant decreases in mean arterial blood pressure and systemic vascular resistance at doses greater than or equal to 1.37 &mgr;g · kg−1 · min−1. There were no changes in heart rate, central venous pressure, pulmonary artery occlusion pressure, or cardiac index with increasing doses of clevidipine. The clevidipine C50 value for a 10% or greater decrease in mean arterial pressure was 9.7 &mgr;g/l and for a 20% or greater decrease in mean arterial pressure was 26.3 &mgr;g/l. The pharmacokinetics of clevidipine were best described with a three-compartment model with a volume of distribution of 32.4 l and clearance of 4.3 l/min. The early phase of drug disposition had a half-life of 0.6 min. The context-sensitive half-time is less than 2 min for up to 12 h of administration. Conclusion Clevidipine is a calcium channel antagonist with a very short duration of action that effectively decreases systemic vascular resistance and mean arterial pressure without changing heart rate, cardiac index, or cardiac filling pressures.

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

AbstractObjective: 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 · 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 · min−1 · kg−1 and a mean volume of distribution at steady state of 0.6 (0.1) l · 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.

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 0.069 l · 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.

Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR

Renal function and salt and water turnover were studied in SHR during acute and chronic administration of felodipine, which is an efficient antihypertensive vasodilating Ca2+ antagonist. In conscious SHR acute administration of felodipine in hypotensive doses increased renal sympathetic nerve activity but caused renal vasodilation, increases in GFR and a 2-3 fold increase in urinary flow rate and sodium excretion. The fraction of filtered sodium excreted (FENa) was approximately doubled. The diuretic and natriuretic effects of felodipine are therefore suggested to be due to a direct inhibitory action on the renal tubular cells, resulting in reduced sodium reabsorption. Nifedipine also induced diuresis and natriuresis in this system, while minoxidil reduced water and sodium excretion. Throughout 6 months of felodipine treatment, the mean arterial pressure (MAP), remained 25-20 per cent reduced. Felodipine in combination with metoprolol reduced MAP 25-30 per cent and also caused regression of left ventricular hypertrophy, while felodipine alone prevented its further progression. Also during chronic administration, felodipine induced diuresis but had no effect on plasma volume and on sodium or potassium excretion in SHR. It is concluded that in SHR felodipine induces diuresis; on acute treatment this is secondary to reduced tubular sodium reabsorption, although during chronic treatment the sodium loss is compensated for while the diuresis remains. Thus, the cardiovascular and renal effects of Ca2+ antagonists like felodipine differ substantially from those of other potent antihypertensive vasodilators e.g. minoxidil.

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.

Autonomic control of the diurnal variation in arterial blood pressure and heart rate in spontaneously hypertensive and Wistar???Kyoto rats

The relative influences of sympathetic and parasympathetic neural modulation on mean arterial pressure (MAP) and heart rate (HR), and their respective variabilities, were studied in young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and HR in unrestrained rats. In addition, the autonomic nervous control of MAP and HR was studied in ageing SHR and WKY. Both WKY and SHR showed diurnal rhythms with regard to MAP and HR. The MAP variability was higher in SHR than in WKY during both daytime (inactive) and night-time (active), and did not change in response to either beta 1-adrenoceptor- or cholinergic blockade. Structural vascular changes, with a resultant increase in reactivity, may explain the elevated MAP variability in SHR. HR variability was clearly reduced in SHR; this was not influenced by vagal blockade, whereas HR variability was significantly reduced in WKY. This pattern is suggested to be due to a reduced tonic vagal discharge in SHR, as part of a persistent, mild defence reaction. The initial reduction in vagal activity will in turn eliminate vagally mediated tachycardias. Furthermore, administration beta 1-blockade to SHR of different ages caused a greater fall in MAP and HR than in WKY, indicating an increased dependence upon the sympathetic nervous system in SHR with age.

Distribution of neuropeptide Y Y1 and Y2 receptors in the postmortem human heart

In the present study, we present for the first time the presence and distribution of neuropeptide Y (NPY) receptors Y1 and Y2 in the human postmortem heart using specific antibodies raised against extracellular parts of the receptors. A more intensive staining against the Y2 than against the Y1 receptors was detected on both atrial and ventricular cardiomyocytes. Immunoreactivity against both receptors was identified on both conducting fibers and cardiac nerves. More vessels stained positively for the Y2 than for the Y1 receptor, but the Y1 receptors were more abundant in subendocardial than subepicardial vessels of the left ventricular wall.

Sympathetic and parasympathetic influence on blood pressure and heart rate variability in Wistar—Kyoto and spontaneously hypertensive rats

The relative influence of sympathetic and parasympathetic nervous control of heart rate and heart rate variability, of mean arterial pressure (MAP) and MAP variability was investigated in young spontaneously hypertensive rats (SHR) and Wistar—Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and heart rate every 2.5 min in freely moving rats with indwelling arterial catheters. Variability was expressed as the standard deviation in each rat. Heart rate and MAP showed clear diurnal rhythms, both in WKY and SHR. Blood pressure variability was clearly higher in SHR than in WKY, both during dark, active hours and during light hours of relative sleep, and it did not change in response to either β-adrenoceptor or vagal blockade. Structural vascular changes with the consequent increase in vascular reactivity may be one explanation for the elevated blood pressure variability in SHR. Heart rate variability was clearly reduced in SHR compared with WKY. This may be due to a reduced tonic vagal discharge in SHR, whereby a vagally mediated tachycardia is eliminated. The vagal withdrawal is part of the defence reaction, which is more easily elicited in SHR than in WKY.