Infusion Of Felodipine Research Articles

The application of glucose biosensor in studying the effects of insulin and anti-hypertensive drugs towards glucose level in brain striatum

The mechanisms involving insulin and anti-hypertensive drugs regulation for in vivo cerebral glucose metabolism are not well-understood. This might be due to lack of direct means of measuring cerebral glucose. It is known that the continuous delivery of glucose to the brain is critical for its normal metabolic function. In this study, we report the effect of insulin and anti-hypertensive drugs on glucose level in the striatum of rats. The rats were divided into two groups, i.e. hyperglycemia (14.8 ± 0.3 mM plasma glucose) and diabetic (10.8 ± 0.2 mM plasma glucose). A custom-built glucose microsensor was implanted at coordinates A/P 1.0 from bregma, M/L +2.5 and D/V −5.0 (from dura) in the striatum. The amperometric response obtained at +0.23 V vs. Ag|AgCl corresponded to the glucose level in striatum. By varying the concentrations of protaminc zinc insulin infused into the rats, striatum glucose level was found to remain constant throughout, i.e. 9.8 ± 0.1 and 4.7 ± 0.1 mM for hyperglycemic rats and for diabetic rats, respectively. However, infusion of valsartan and felodipine has lowered the striatum glucose level significantly. These findings agreed with the hypothesis that suggested striatum glucose uptake do not depend on insulin but is clearly dependant on anti-hypertensive drugs administration.

Calcium channel blockade with felodipine does not affect metabolic coronary vasodilation in patients with coronary artery disease.

The effect of calcium channel blockers may affect the feedback mechanism between myocardial metabolic activity and coronary blood flow. To test this hypothesis the effect of calcium channel blockade on metabolic coronary flow regulation was studied. In 10 patients with stable coronary artery disease, coronary sinus blood flow and myocardial oxygen supply and consumption (MVO2) were measured both at sinus rhythm and during atrial pacing (30 beats/min above sinus rate), at control and during infusion of felodipine, a vasoselective dihydropyridine. The myocardial oxygen supply-consumption ratio at control (i.e., the slope of the regression line characterizing normal metabolic flow regulation) was 1.58 (95% CI, 1.38-1.80). Following infusion of felodipine, systemic and coronary vascular resistance during sinus rhythm decreased by 20 +/- 11% and 23 +/- 15%, respectively, and coronary venous oxygen saturation increased from 36 +/- 6% at control to 42 +/- 7% (p = 0.047) during infusion of felodipine. The myocardial oxygen supply-consumption ratio, characterizing metabolic flow regulation during felodipine, was 1.52 (95% CI, 1.26-1.78) and thus not different from control. Metabolic coronary flow regulation was not affected by administration of felodipine, although the setpoint of this regulation mechanism might have been offset by the initial drug-induced coronary vasodilation, which persisted during pacing.

Vasodilation with felodipine in chronic asymptomatic aortic regurgitation

Background Afterload reduction decreases volume overload on the left ventricle and may thereby delay the need for valve replacement in chronic asymptomatic aortic regurgitation. The aims of this randomized double-blind, placebo-controlled trial to were examine short- and long-term hemodynamic effects of felodipine in chronic asymptomatic aortic regurgitation. Methods Sixteen patients were randomly assigned to an intravenous infusion of either felodipine 0.3 mg or placebo followed by 3 months' treatment with felodipine 10 mg or placebo orally once daily. Magnetic resonance imaging was performed at baseline, immediately after intravenous treatment, and after 3 months of oral treatment. Results Intravenous felodipine caused a statistically significant reduction in the systemic vascular resistance from (mean ± SD) 1160 ± 400 to 970 ± 320 dynes · s · cm −5 ( P < .05), in the regurgitant volume index from 1.5 ± 0.8 to 1.3 ± 0.8 L · min −1. m −2 ( P < .05) and in the regurgitant fraction from 0.31 ± 0.15 to 0.26 ± 0.14 ( P < .05). The forward cardiac output index increased significant from 3.2 ± 0.9 to 3.5 ± 0.7 L · min −1 ·m −2 ( P < .05). Three months of oral treatment with felodipine caused a corresponding but more pronounced decrease in systemic vascular resistance of 880 ± 330 dynes · s · cm −5 ( P < .05), regurgitant volume index of 1.2 ± 0.7 L · min −1 · m −2 ( P < .05), and regurgitant fraction 0.25 ± 0.11 ( P < .05), whereas the forward cardiac output index increased to 3.6 ± 0.7 l · min −1 · m −2 ( P < .05). No significant changes were found in the placebo group. Left ventricular volumes and ejection fraction remained unaffected by treatment, but compared with the placebo group left ventricular myocardial mass decreased significantly from 137 ± 24 to 132 ± 21 g · m −2 ( P < .01). Conclusion In chronic asymptomatic aortic regurgitation, felodipine causes beneficial hemodynamic effects that may postpone the need for valve replacement.

Renal hypoxanthine balance in cardiac surgery: Effects of felodipine

Objective: To test the hypothesis that felodipine, a renal vasodilator, can prevent a release of hypoxanthine during rewarming after moderate hypothermic cardiopulmonary bypass and that this is related to improved renal oxygen supply. Design: A prospective, randomized, and controlled study. Setting: Operating room in the cardiothoracic surgery department of a university hospital. Participants: Twenty-two patients submitted to elective first-time coronary bypass surgery. Interventions: A catheter was placed in the left renal vein for thermodilution renal blood flow (RBF) measurement and blood sampling. In 11 patients, felodipine was infused during the hypothermic period of cardiopulmonary bypass. Measurements and Main Results: Renal uptake (renal arteriovenous concentration difference × RBF) of hypoxanthine was maintained during rewarming in felodipine-treated patients but not in control patients (55 ± 28 v −39 ± 1 nmol/ min, p < 0.05). Oxygen consumption was higher after felodipine infusion despite unchanged total RBF. A positive correlation between renal oxygen consumption and hypoxanthine uptake and release ( r = 0.74, p < 0.01) was observed. Conclusions: Felodipine maintained renal uptake of hypoxanthine during rewarming after hypothermic cardiopulmonary bypass. This maintenance is the effect of improved renal oxygen supply secondary to improved nutritive blood flow at the expense of nonnutritive renal blood flow.

HEMODYNAMIC CHANGES DO NOT MEDIATE THE CARDIOPROTECTION INDUCED BY THE A1, ADENOSINE RECEPTOR AGONIST CCPA IN THE RABBIT

Stimulation of adenosine A1receptors is known to reduce infarct size in the rabbit heart. The aim of the present study was to verify whether a protective activity similar to that of the selective A1receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), could also be obtained by inducing comparable hemodynamic effects with drugs having different mechanisms of action. The effects of theβ-adrenoceptor blocker atenolol, the calcium channel blocker felodipine, the A2A-selective adenosine receptor agonist 2-hexynyl-5′-N-ethyl-carboxamidoadenosine (2HE-NECA), and the non-selective adenosine receptor agonist 5′-N-ethyl-carboxamidoadenosine (NECA) were tested.Groups of 12–15 anesthetized open-chest rabbits received a 5-min infusion of CCPA (50gmgkg−1min−1), atenolol (1mgkg−1min−1), felodipine (50gmgkg−1min−1), 2HE-NECA (1gmgkg−1min−1), and NECA (1gmgkg−1min−1). Myocardial infarction was induced by a 30-min occlusion of a branch of the left coronary artery, followed by 3-h reperfusion. Infarct size was measured by tetrazolium staining.In controls, infarct size was about 40% of the zone at risk. Pretreatment with CCPA induced a marked decrease in heart rate (−40%) and blood pressure (−48%), and showed antiischemic activity (28% of the zone at risk). The other drugs tested produced similar effects on either heart rate (atenolol, −25%), or blood pressure (felodipine, 2HE-NECA and NECA, about −45%), but did not affect infarct size.In this model, the reduction in infarct size by CCPA is most likely mediated by A1receptors,since comparable hemodynamic effects, induced by other means, are not effective. A2Areceptor stimulation does not appear to exert a protective effect.

Effects of felodipine on the ischemic heart: insight into the mechanism of cytoprotection.

To assess whether the administration of felodipine protects the myocardium in a dose-dependent manner against ischemia and reperfusion, isolated rabbit hearts were infused with three different concentrations of felodipine: 10(-10), 10(-9), and 10(-8) M. Diastolic and developed pressures were monitored; coronary effluent was collected and assayed for CPK activity and for noradrenaline concentration; mitochondria were harvested and assayed for respiratory activity; and ATP production and calcium content and tissue concentration of ATP, creatine phosphate (CP), and calcium were determined. The occurrence of oxidative stress during ischemia and reperfusion was also monitored in terms of tissue content and release of reduced (GSH) and oxidized (GSSG) glutathione. Treatment with felodipine at 10(-10) and 10(-9) M had no effect on the hearts when perfused under aerobic conditions, whilst the higher dose reduced developed pressure from 57.7 +/- 2.6 to 30.0 +/- 2.6 mmHg (p < 0.01). On reperfusion treated hearts recovered better than the untreated hearts with respect to left ventricular performance, replenishment of ATP and CP stores, and mitochondrial function. Recovery of developed pressure was 100% at 10(-8) M, 55% at 10(-9) M, and 46% at 10(-10) M. The reperfusion-induced tissue and mitochondrial calcium overload, release of CPK and noradrenaline, and oxidative stress were also significantly reduced. The effects of felodipine were dose dependent. Felodipine inhibited the initial rate of ATP-driven calcium uptake but failed to affect the initial rate of mitochondrial calcium transport. It is concluded that felodipine infusion provides dose-dependent protection of the heart against ischemia and reperfusion. Because this protection also occurred at 10(-9) M and 10(-10) M in the absence of a negative inotropic effect during normoxia and of a coronary dilatory effect during ischaemia, it cannot be attributed to an energy-sparing effect or to improvement in oxygen delivery. From our data we can envisage two other major mechanisms-(1) membrane protection and (2) reduction in oxygen toxicity. The ATP-sparing effect occurring at 10(-8) M is likely to be responsible for the further protection.

Felodipine inhibits intimal lesion formation in the hypercholesterolemic rabbit: differential effects on endothelial and monocyte determinants of atherogenesis.

The purpose of this study was to determine if the calcium entry antagonist felodipine inhibited intimal lesion formation in hypercholesterolemic rabbits, and to determine if this was due to an effect upon monocyte and/or endothelial determinants of this interaction. Twenty-three male New Zealand White rabbits received the following treatment regimen for 10 weeks: normal chow (NP, n = 3); normal chow with felodipine infusion (NF, n = 6); 0.5% cholesterol chow (CP, n = 7); or 0.5% cholesterol chow and felodipine infusion (CF, n = 7). After 10 weeks blood was collected for biochemical measurements and mononuclear cell binding assays, and thoracic aortae were harvested for vascular reactivity studies and histomorphometry. In the animals receiving normal chow, felodipine did not significantly affect blood pressure, plasma cholesterol levels, binding studies, vascular reactivity, or structure; therefore these animals were analyzed as one group (N). Plasma cholesterol levels were significantly elevated in groups receiving the 0.5% cholesterol diet (N, 29 +/- 3 mg/dl; CP, 1221 +/- 73 mg/dl; CF, 979 +/- 108 mg/dl). High-density lipoprotein cholesterol was not different between the groups (25 +/- 4 vs 23 +/- 4 vs 27 +/- 4 mg/dl; N vs CF vs CP respectively; p = NS). Cholesterol feeding markedly augmented the adhesiveness of mononuclear cells, as demonstrated by a 250% increase in cell binding. Felodipine did not alter the adhesiveness of mononuclear cells in hypercholesterolemic animals. Cholesterol feeding significantly impaired endothelium-dependent relaxations. Endothelium-dependent relaxations were restored by felodipine treatment as reflected by the maximal responses to acetylcholine (40 +/- 7% vs 58 +/- 4% vs 67 +/- 5%; CP vs CF vs N respectively). The improvement in endothelium-dependent relaxation in the felodipine-treated animals was associated with a 2.2-fold reduction in lesion surface area of the thoracic aorta (8.2 +/- 6.3% vs 18.2 +/- 9.5%; CF vs CP; p < 0.01). Moreover, the intima/media ratio reflecting lesion thickness was substantially reduced by felodipine treatment (0.05 +/- 0.02 vs 0.20 +/- 0.07; CF vs CP; p = 0.006). Ex vivo studies revealed that felodipine inhibited the adhesiveness of vascular endothelium, but not mononuclear cells, derived from hypercholesterolemic animals. Low-dose felodipine appears to inhibit monocyte-endothelial interaction, as indicated by a reduction in the formation of lesions in hypercholesterolemic animals. This effect is not due to an alteration in adhesiveness of mononuclear cells. The salutary effect of felodipine is associated with an increase in vascular nitric oxide activity which may reduce endothelial adhesiveness.

Renal Function During Cardiopulmonary Bypass

Glomerular filtration and tubular activity are decreased during hypothermic cardiopulmonary bypass (CPB). The role of vasoconstriction to explain these changes is not known. The calcium entry blocking drug felodipine dilates constricted arterioles and reduces renal vascular resistance during noncardiac surgery. The present study was initiated to evaluate the effects of felodipine on renal perfusion and function during hypothermic, low pressure CPB. Twenty-two male patients (aged 61.7 +/- 2.3 y) were included in a prospective, randomized, controlled study. Renal blood flow was measured with thermodilution technique; renal extraction of 51Cr-EDTA and p-aminohippurate (PAH) were used to evaluate glomerular and tubular function. Systemic blood flow during hypothermic CPB was varied experimentally between 1.45 and 2.2 L.min-1.m-2. Felodipine reduced systemic vascular resistance but did not reduce the total renal vascular resistance during CPB. On the contrary, renal vascular resistance was increased at low CPB flow rates. The extraction of PAH (signifying tubular activity) was higher during felodipine infusion (0.74 +/- 0.04 vs 0.64 +/- 0.03 during low CPB flow, and 0.64 +/- 0.03 vs 0.57 +/- 0.05 during high CPB flow), whereas 51Cr-EDTA extraction was not influenced. The mechanism of enhanced PAH extraction may involve reduced regional vasoconstriction in PAH-extracting areas.

Renal Function During Cardiopulmonary Bypass

Glomerular filtration and tubular activity are decreased during hypothermic cardiopulmonary bypass (CPB).The role of vasoconstriction to explain these changes is not known. The calcium entry blocking drug felodipine dilates constricted arterioles and reduces renal vascular resistance during noncardiac surgery. The present study was initiated to evaluate the effects of felodipine on renal perfusion and function during hypothermic, low pressure CPB. Twenty-two male patients (aged 61.7 +/- 2.3 y) were included in a prospective, randomized, controlled study. Renal blood flow was measured with thermodilution technique; renal extraction of51 Cr-EDTA and p-aminohippurate (PAH) were used to evaluate glomerular and tubular function. Systemic blood flow during hypothermic CPB was varied experimentally between 1.45 and 2.2 L centered dot min-1 centered dot m-2. Felodipine reduced systemic vascular resistance but did not reduce the total renal vascular resistance during CPB. On the contrary, renal vascular resistance was increased at low CPB flow rates. The extraction of PAH (signifying tubular activity) was higher during felodipine infusion (0.74 +/- 0.04 vs 0.64 +/- 0.03 during low CPB flow, and 0.64 +/- 0.03 vs 0.57 +/- 0.05 during high CPB flow), whereas51 Cr-EDTA extraction was not influenced. The mechanism of enhanced PAH extraction may involve reduced regional vasoconstriction in PAH-extracting areas. (Anesth Analg 1996;83:34-40)

Metoclopramide stimulates kaliuresis during felodipine without affecting its natriuresis.

Calcium entry blockers such as felodipine induce natriuresis without a parallel rise of potassium excretion. Previous studies with exogenous aldosterone and felodipine have suggested that the absence of kaliuresis might be explained by a felodipine-induced inhibition of aldosterone release. The natriuresis with calcium entry blockers could not be attributed to a similar mechanism but might be due to the stimulation of intrarenal natriuretic systems such as the dopaminergic system. We studied whether the aselective dopamine antagonist metoclopramide prevents the natriuresis with low and therapeutic felodipine doses and whether metoclopramide-induced aldosterone release promotes kaliuresis with felodipine. Twelve healthy male volunteers participated in a randomized, placebo-controlled, crossover study comparing felodipine infusion during metoclopramide with felodipine alone. Metoclopramide had no significant influence on the pronounced and dose-dependent increases of renal plasma flow and urinary sodium excretion with felodipine. Metoclopramide increased plasma aldosterone concentration from 0.17 +/- 0.03 to 0.60 +/- 0.14 nmol/L, and subsequent felodipine infusion clearly increased urinary potassium excretion by 23 +/- 6 and 35 +/- 8 mumol/min (low and therapeutic doses, respectively). In contrast, potassium excretion remained stable with felodipine alone (+5 +/- 4 and +7 +/- 5 mumol/min, respectively). In conclusion, the natriuretic action of calcium entry blockers cannot be blocked by the aselective dopamine antagonist metoclopramide. This natriuresis is accompanied by kaliuresis only in the presence of elevated endogenous aldosterone concentrations. The ability of calcium entry blockers to prevent a rise of plasma aldosterone thus seems essential for the prevention of urinary potassium losses.

Acute and chronic calcium antagonist treatment elevates sympathetic activity in primary hypertension.

Eleven men with mild to moderate primary hypertension were studied at rest and during mental stress before and during intravenous infusion of the calcium antagonist felodipine. Eight of them were restudied during long-term treatment (extended-release felodipine, 10 mg daily). For comparison, 10 normotensive control subjects were studied with the short-term protocol. Heart rate, cardiac output, central cardiovascular pressures, and forearm blood flow were registered. Arterial and venous sampling was performed. Norepinephrine spillovers to arterial plasma and from the forearm were assessed with the use of radiotracer methodology. In the hypertensive patients, felodipine lowered mean arterial blood pressure acutely by 8% (P < .01). Systemic vascular resistance decreased by 22% (P < .001), cardiac output increased by 20% (P < .01), and norepinephrine spillover to arterial plasma increased by 61% (P < .001). Forearm vascular resistance fell by 30% (P < .001), but norepinephrine overflow from the forearm increased by 115% (P < .001). These forearm responses were not seen in normotensive subjects despite similar systemic responses to felodipine infusion. After 8 weeks of treatment, mean arterial pressure decreased to 15% below baseline (P < .001), cardiac output returned toward pretreatment levels, and systemic vascular resistance remained low. Forearm blood flow returned toward basal levels, but forearm vascular resistance remained lowered. Total body and forearm norepinephrine spillover values were as elevated as in the acute situation. The hemodynamic "defense reaction" and the sympathoadrenal response to mental stress were essentially unaffected by felodipine. Stress-induced small elevations of neuropeptide Y-like immunoreactivity persisted during felodipine. Thus, the vasodilatation induced by felodipine elicits sympathetic counterregulation, which persists in the long term with respect to peripheral and total sympathetic activities, despite resetting of the baroreflex control of heart rate.

Cerebral blood flow in patients with severe hypertension, and acute and chronic effects of felodipine.

To evaluate whether a spontaneous increase in cerebral blood flow (CBF) could be observed in subjects with severe hypertension and to study the effect of a calcium antagonist, felodipine, on blood pressure and CBF after acute and chronic administration. Patients with severe hypertension were recruited at the emergency ward. Patients with previous treatment with calcium antagonists, women of child-bearing potential, severe uraemia, nephrotic syndrome, heart failure, manifest cerebrovascular lesions and pathological liver function tests were excluded. CBF was measured by single-photon emission computed tomography after intravenous administration of xenon-133 before (CBF1) and after intravenous infusion of felodipine, 0.01 mg/min during 40-60 min (CBF2) in 12 patients aged 25-67 years with no antihypertensive treatment except for beta-blockers in four patients and beta-blockers plus a diuretic in one patient. CBF was repeated after 3 weeks of oral therapy with felodipine, 5-10 mg twice a day with the addition of beta-blockers in 10/12 patients (CBF3). During the felodipine infusion blood pressure decreased. There were no neurological symptoms or signs before or during the felodipine administration. CBF1 was within normal limits with no significant differences between previously treated and untreated patients. There was a non-significant tendency to increase in global CBF after felodipine administration, associated with a significant reduction in the physiological side differences in blood flow. In spite of the initially very high blood pressure, no general or focal hyperaemia was observed, and thus no evidence for a 'breakthrough' of the cerebral autoregulation. Felodipine gives a smooth blood pressure reduction with a maintained CBF.

Effects of felodipine on the dog kidney: A lithium clearance study

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorp-ion rate increased significantly from 2.1±0.3 to 2.7±0.4 mmol min−1. Sodium clearance (C-Na) increased from 0.22±0.08 to 0.40±0.07 ml min−1. The α-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After α-adrenergic blockade felodipine caused an increase in C-Na from 0.28±0.06 ml min−1 to 0.63±0.04 ml min−1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after a-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local a-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.

Effects of Felodipine on the dog kidney: a lithium clearance study.

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorption rate increased significantly from 2.1 +/- 0.3 to 2.7 +/- 0.4 mmol min-1. Sodium clearance (C-Na) increased from 0.22 +/- 0.08 to 0.40 +/- 0.07 ml min-1. The alpha-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After alpha-adrenergic blockade felodipine caused an increase in C-Na from 0.28 +/- 0.06 ml min-1 to 0.63 +/- 0.04 ml min-1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after alpha-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local alpha-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.

Hemodynamic Effects of Calcium Antagonists with High or Low Vascular Selectivity

Infusion of felodipine and verapamil in increasing doses to anesthetized spontaneously hypertensive rats induced a progressive fall in arterial blood pressure (BP). To estimate the cardiac action of the different drugs, we also measured changes in cardiac output (CO) and velocity of flow (dF/dT) by a Doppler flow probe placed on the ascending aorta. Infusion of verapamil induced a parallel decrease in mean arterial BP, CO, and cardiac inotropy (as estimated by max. dF/dT). In contrast, upon felodipine administration, the decrease in arterial BP was accompanied by an initial small rise in dF/dT. A decrease in dF/dT was observed only after high doses of felodipine, which caused pronounced levels of hypotension.

Felodipine in severe chronic congestive heart failure: Acute effects on central hemodynamics and regional blood flow distribution

In order to assess the effect of felodipine, a new calcium antagonist with vascular selectivity, on regional blood flow distribution at rest in chronic congestive heart failure, ten patients were studied during an acute test. Right heart catheterization allowed the evaluation of hemodynamic parameters; renal blood flow was calculated using paraamino-hippuric acid clearance; hepatic blood flow measurement was based on indocyanine green clearance; and limb blood flow was assessed with venous occlusion plethysmography. Blood samples were collected for the analysis of plasma catecholamines, renin, and aldosterone. All parameters were recorded in duplicate under basal conditions and after felodipine infusion. The infusion of felodipine induced a significant increase in cardiac index, stroke work index, and limb blood flow. Systemic and pulmonary arterial blood pressure, pulmonary wedge pressure, and systemic resistance underwent a significant decrease. The heart rate, pulmonary resistance, renal blood flow, and hepatic blood flow were not changed. In conclusion, felodipine was of benefit in congestive heart failure at rest in an acute test, acting through a marked decrease in vascular resistance and a consequent improvement in cardiac output and limb blood flow. No changes in renal and hepatic blood flow were observed.

Effects of Felodipine on Local and Neurogenic Control of Vascular Resistance

Arterial vascular resistance is established by myogenic mechanisms and is modulated both by local factors such as vasodilator metabolites and by remote controls of neurogenic and hormonal origin. This paper reports on the effects of felodipine and hydralazine on the myogenic tone and the neurogenic control of the vascular resistance of skeletal muscle. The vascular bed of the calf muscle of anesthetized cats was isolated and autoperfused at a constant flow. The sympathetic vasomotor nerves were activated by efferent stimulation of the lumbar sympathetic chain. Intraarterial infusion of felodipine and hydralazine reduced, in a dose-dependent manner, basal vascular resistance determined by myogenic factors and the vasoconstriction induced by nerve stimulation. After the infusion of felodipine, the vasoconstrictor responses to low, physiological rates of stimulation (0.5-4 Hz) were depressed to the same relative extent as resistance determined by myogenic factors, whereas the vasoconstrictor responses to supramaximal stimulation rates (16-32 Hz) were relatively more resistant. Felodipine had no effect on noradrenaline (NA) release during vasomotor nerve stimulation as determined by the NA venoarterial concentration difference. Hydralazine also reduced basal vascular resistance in a dose-dependent manner, but in contrast to felodipine, supramaximal doses of hydralazine totally abolished vasoconstrictor responses to supramaximal stimulation rates (32 Hz). It is concluded that felodipine reduces vascular resistance by a direct action on the contraction of vascular smooth muscle in the resistance vessels, as myogenic activity and physiological levels of neurogenic vasoconstriction are equally suppressed by felodipine. During supramaximal stimulation of vasomotor nerves, a separate activation pathway or more proximal vascular segments are likely to be engaged that are less sensitive to felodipine.

Baroreflex Control of Heart Rate and Renin Release in SHR Following Administration of Felodipine, an Antihypertensive Ca2+ Antagonist

Baroreflex control of renin release following acute and prolonged blood pressure reduction by felodipine administration was investigated in conscious spontaneously hypertensive rats (SHR) fitted with arterial and venous catheters. Basal values of mean arterial pressure (MAP), heart rate (HR), and plasma renin activity (PRA) were obtained in SHR and in SHR given felodipine for 2 weeks (SHRF). In SHRFMAP was reduced by 12% (p less than 0.01) versus SHR, but PRA and HR were similar. Acute i.v. infusion of felodipine, during 5 h, maintained MAP reduction by 40%. Initially, HR increased 29 +/- 3% but returned to predrug levels after 3 h. PRA increased from 1.4 +/- 0.5 to 6.5 +/- 1.0 ng/ml/h. After 5 h PRA had reached low levels equal to those in SHR given placebo instead of felodipine. In SHR pretreated with metoprolol neither HR nor PRA increased following felodipine, an indication that the observed changes were neurogenically determined. This suggests that baroreflex control of cardiac and renal function resets within 3-5 h following blood pressure reduction by felodipine.

Effect of felodipine on renal hemodynamics and excretion in the dog.

The effects of felodipine on renal hemodynamics and excretion were evaluated in the anesthetized dog. Unilateral renal arterial infusion of felodipine produced ipsilateral increases in the absolute and fractional excretion of sodium and water which were greater than those of potassium; these effects occurred in the absence of changes in mean arterial pressure, renal blood flow, or glomerular filtration rate. There were no significant effects on renal hemodynamic or excretory function in the contralateral kidney. The unilateral renal arterial infusion of isotonic saline or vehicle produced no significant effects on renal hemodynamic or excretory function in either ipsilateral or contralateral kidney. Felodipine, a calcium antagonist with vasodilator antihypertensive properties, in doses which do not affect systemic or renal hemodynamics in the dog, increased urinary flow rate and sodium excretion by decreasing renal tubular water and sodium reabsorption. As a vasodilator antihypertensive agent, felodipine possesses potentially advantageous diuretic and natriuretic properties.

Effects of felodipine on renal function in animals.

The effects of felodipine on renal function were evaluated in dogs and rats using renal clearance, haemodynamic and micropuncture techniques. Unilateral renal arterial infusion of felodipine in anaesthetised dogs produced an ipsilateral diuresis and natriuresis without changing the mean arterial blood pressure, renal blood flow or glomerular filtration rate. In similar studies, the non-calcium antagonist vasodilator, hydralazine, produced antidiuresis and antinatriuresis. Continuous intravenous administration of felodipine in anaesthetised normotensive rats also produced a diuresis and natriuresis without changing mean arterial blood pressure, renal blood flow, whole kidney or single nephron glomerular filtration rate. Renal tubular reabsorption of water and sodium were inhibited in the distal tubule and collecting duct; neither potassium excretion nor reabsorption were affected. Bolus intravenous administration of felodipine to conscious spontaneously hypertensive rats produced dose-related decreases in mean arterial blood pressure and renal vascular resistance which were associated with increases in renal blood flow, glomerular filtration rate, urinary flow rate and sodium excretion; urinary potassium excretion was not affected. The non-calcium antagonist vasodilator minoxidil produced antidiuresis and antinatriuresis. Felodipine, a calcium-antagonist vasodilator used as an antihypertensive, possesses beneficial diuretic and natriuretic properties which are due to its direct effect on renal tubular water and sodium reabsorption.