IP3 and calcium signaling involved in the reorganization of the actin cytoskeleton and cell rounding induced by cigarette smoke extract in human endothelial cells.

Smoking increases the risk of cardiovascular disorders and leads to damage caused by inflammation and oxidative stress. The actin cytoskeleton is a key player in the response to inflammatory stimuli and is an early target of cellular oxidative stress. The purpose of this study was to investigate the changes in actin cytoskeleton dynamics in human endothelial EA.hy926 cells exposed to cigarette smoke extract (CSE). Immunostaining revealed that CSE exposure resulted in modification of the actin cytoskeleton and led to cell rounding in a dose- and time-dependent manner. In addition, the intracellular calcium concentration was increased by treatment with CSE. Pretreatment with antioxidants (lipoic acid, glutathione, N-acetyl cysteine, aminoguanidine, α-tocopherol, and vitamin C) significantly attenuated the CSE-induced actin cytoskeleton reorganization and cell rounding. Calcium ion chelators (EGTA, BAPTA-AM AM) and a potent store-operated calcium channel inhibitor (MRS 1845) also reduced CSE-induced intracellular calcium changes and attenuated actin cytoskeleton reorganization and cell morphology change. Moreover, the CSE-induced intracellular calcium increase was suppressed by pretreatment with the inositol trisphosphate receptor (IP3R) inhibitor xestospongin C, the phospholipase C (PLC) inhibitor U-73122, and the protein kinase C (PKC) inhibitor GF109203X. These results suggest that reactive oxygen species production and intracellular calcium increase play an essential role in CSE-induced actin disorganization and cell rounding through a PLC-IP3-PKC signaling pathway. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1293-1306, 2016.

Vasopressin-stimulated ORAI1 expression and store-operated Ca2+ entry in aortic smooth muscle cells.

Vascular calcification may result from stimulation of osteogenic signalling with upregulation of the transcription factors CBFA1, MSX2 and SOX9, as well as alkaline phosphatase (ALPL), which degrades and thus inactivates the calcification inhibitor pyrophosphate. Osteogenic signalling further involves upregulation of the Ca2+-channel ORAI1. The channel is activated by STIM1 and then accomplishes store-operated Ca2+ entry. ORAI1 and STIM1 are upregulated by the serum & glucocorticoid inducible kinase 1 (SGK1) which is critically important for osteogenic signalling. Stimulators of vascular calcification include vasopressin. The present study explored whether exposure of human aortic smooth muscle cells (HAoSMCs) to vasopressin upregulates ORAI1 and/or STIM1 expression, store-operated Ca2+ entry and osteogenic signalling. To this end, HAoSMCs were exposed to vasopressin (100 nM, 24 h) without or with additional exposure to ORAI1 blocker MRS1845 (10 µM) or SGK1 inhibitor GSK-650394 (1 µM). Transcript levels were measured using q-RT-PCR, cytosolic Ca2+-concentration ([Ca2+]i) by Fura-2-fluorescence, and store-operated Ca2+ entry from increase of [Ca2+]i following re-addition of extracellular Ca2+ after store depletion with thapsigargin (1 µM). As a result, vasopressin enhanced the transcript levels of ORAI1 and STIM1, store-operated Ca2+ entry, as well as the transcript levels of CBFA1, MSX2, SOX9 and ALPL. The effect of vasopressin on store-operated Ca2+ entry as well as on transcript levels of CBFA1, MSX2, SOX9 and ALPL was virtually abrogated by MRS1845 and GSK-650394. In conclusion, vasopressin stimulates expression of ORAI1/STIM1, thus augmenting store-operated Ca2+ entry and osteogenic signalling. In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394. KEY MESSAGES: • In HAoSMCs, vasopressin (VP) upregulates Ca2+ channel ORAI1 and its activator STIM1. • VP upregulates store-operated Ca2+ entry (SOCE) and osteogenic signalling (OS). • VP-induced SOCE, OS and Ca2+-deposition are disrupted by ORAI1 inhibitor MRS1845. • VP-induced SOCE, OS and Ca2+-deposition are disrupted by SGK1 blocker GSK-650394.

Calcium entry inhibition during resuscitation from shock attenuates inflammatory lung injury.

Trauma and hemorrhagic shock (T/HS) induce a systemic inflammatory response syndrome (SIRS). Neutrophils (polymorphonuclear leukocytes [PMN]) and other cells involved in acute lung injury (ALI) are activated by Ca2+ entry. Thus, inhibiting Ca2+ entry might attenuate post-traumatic lung injury. Inhibiting voltage-operated (L-type) Ca2+ channels during shock could cause cardiovascular collapse, but PMN are "nonexcitable" cells, lack L-type channels, and mobilize Ca2+ via nonspecific channels. We previously showed that PMN Ca2+ entry requires sphingosine 1-phosphate synthesis by sphingosine kinase and that both sphingosine kinase inhibition and blockade of nonspecific channels attenuate ALI when begun before shock. Pretreatment for clinical injuries, however, is impractical. Therefore, we now studied whether Ca2+ entry inhibition that begun during resuscitation from T/HS could attenuate SIRS and ALI without causing hemodynamic compromise. Male Sprague-Dawley rats underwent laparotomy and fixed-pressure shock (mean arterial pressure, 35 +/- 5 mmHg; 90 min). Sphingosine kinase inhibition or nonspecific Ca2+ channel inhibition was begun after resuscitation with 10% of shed blood. We then studied in vivo PMN activation and associated lung injury in the presence or absence of Ca2+ entry inhibition. Neither treatment worsened shock. Each treatment decreased CD11b expression, respiratory burst, PMN p38 MAP-kinase phosphorylation, PMN sequestration, and lung capillary leak in vivo. The similar results seen with two different forms of inhibition strengthen the conclusion that the biological effects seen were specific for calcium entry inhibition. Ca2+ entry inhibition is a candidate therapy for management of lung injury after shock.

Problem of measuring the positive inotropic property of a vasodilating drug: an illustration using felodipine.

A study was undertaken to determine the presence or absence in patients of positive inotropic activity in a vasodilator drug that improves cardiac output by virtue of that vasodilatation. Felodipine is a dihydropyridine calcium antagonist that has a positive inotropic effect at low concentration in the dog in vivo. In nine patients undergoing coronary angiography in whom heart rate was kept constant by atrial pacing the solvent for the intravenous administration of the drug was infused followed by the active solution. Haemodynamic variables were measured with the Mills combined left ventricular cathetertip manometer and aortic electromagnetic blood velocity transducer. Reflex positive inotropic effects were blocked with the beta adrenergic blocking drug atenolol. An index of contractility was used to assess inotropic effects--the maximum rate of rise of left ventricular pressure measured by cathetertip micromanometry; this was an isovolumic event and therefore not sensitive to arterial pressure change, and it was unaffected by changes in left ventricular end diastolic pressure. In all patients peripheral vasodilatation was observed in the plasma felodipine concentration range of 2-40 nmol.litre-1. In eight patients this was accompanied by an 11-36% increase in maximum rate of rise of left ventricular pressure, indicating a small positive inotropic effect. Felodipine appears to show both agonist and antagonist properties in man as well as in the dog.

An analytical method to separate inotropic and vasodilatory drug effects in patients with heart failure.

A recently proposed analytical technique to determine whether an inotropic agent improves cardiac pumping performance via its vasodilatory or its positive inotropic effects was adopted to evaluate the pharmacological properties of a positive inotropic agent, dobutamine, and a vasodilatory calcium antagonist, felodipine, in patients with severe heart failure. This technique used a new principle of pump-load interaction, which states that for a given change in vascular input impedance unaccompanied by any direct alteration in the pumping characteristics all possible values of pump power output due to the change in impedance per se are confined within two calculated limits. When dobutamine was infused at 10 micrograms.kg-1.min-1 seven out of 10 patients had power output values above the defined limits, implying that the technique can identify correctly in vivo the direct positive inotropic effects of dobutamine in the presence of its vasodilating activity. In contrast, when 5-10 mg of felodipine was given to 10 patients the consequent power outputs were all within the defined limits, implying that the effects can be explained by vasodilatation alone. In conclusion, this study showed that the analytical technique can be applied clinically to detect the presence of drug induced positive inotropic effects in the midst of vasodilatation and therefore may be useful in determining whether inotropic agents actually improve cardiac function via their positive inotropic effects.

Decreased dihydropyridine receptor number in hypertensive rat vascular muscle cells.

To further investigate the altered function of Ca2+ channels in vascular muscle cells in hypertension, a novel fluorescently labeled dihydropyridine was used with ultrahigh-sensitivity photometry to study dihydropyridine binding sites on the surface membrane of living vascular muscle cells from stroke-prone spontaneously hypertensive rats and their normotensive controls. Fluorescent nitrobenzoxadiazol-6-dihydropyridine in concentrations of 1 to 100 nmol/L bound specifically to vascular muscle cells' Ca2+ channels, and was displaced by the unlabeled dihydropyridine analogue or nisoldipine (10 mumol/L). Stroke-prone spontaneously hypertensive rat vascular muscle cells showed significantly decreased binding of nitrobenzoxadiazol-6-dihydropyridine compared with normotensive National Institutes of Health rats. Decreased binding of dihydropyridine by vascular muscle cells from stroke-prone spontaneously hypertensive rats (cells that in other studies show increased Ca2+ channel function) indicates a change in channel regulation that is possibly due to a deficiency in the inactivation mechanism, consistent with our earlier electrophysiological studies reporting deficiencies in Ca(2+)-dependent inactivation in genetic hypertension. These data demonstrate decreased numbers of localized sites of dihydropyridine binding on the sarcolemma of living vascular muscle cells, and support the hypothesis that Ca2+ channel alterations may significantly contribute to the molecular etiology of genetic hypertension.

Felodipine, blood pressure, and cardiovascular reflexes in hypertensive humans.

The influence of acute and chronic treatment with felodipine on ambulatory intra-arterial blood pressure, certain cardiac reflexes, and plasma renin activity was studied in nine patients with essential hypertension. Acute oral administration of the drug caused a significant reduction in blood pressure associated with an increase in heart rate mediated by the sinoaortic baroreceptor-heart rate reflex. After 1 week of treatment reflex resetting had occurred, returning heart rate to normal despite continuing blood pressure reduction. This effect was maintained throughout 6 weeks of treatment. Withdrawal of treatment was followed by return of the blood pressure to control levels associated with significant bradycardia caused by reflex reactivation at its reset level. No change was observed in response to tilting or Valsalva's maneuver or in plasma renin activity. Ambulatory intra-arterial data suggested that the clinically useful antihypertensive action of felodipine persists for 9 hours.

Effects of nifedipine and felodipine on adenosine and inosine release from the hypoxemic rat cerebral cortex.

The cerebral cortical cup technique has been used to study the effects of nifedipine and felodipine on adenosine and inosine release from the rat brain. After basal and hypoxia (8% 02)-evoked control levels of purine release had been established, these 1,4-dihydropyridine calcium antagonists were administered intraperitoneally (1 mg/kg). Both agents depressed basal levels of purine efflux and suppressed the hypoxia-evoked release of adenosine and inosine. An inhibition of the transporter that mediates purine efflux from brain cells is likely to account for the suppression of release from the cerebral cortex. A reduced release of adenosine into the interstitial space also explains the ability of both agents to block the increase in CBF evoked by hypoxic challenges.

The contribution of systemic hypertension to progression of chronic renal failure in the rat remnant kidney: effect of treatment with an angiotensin converting enzyme inhibitor or a calcium inhibitor.

In order to establish if pharmacological treatment of systemic hypertension modifies the course of progressive renal failure, we studied the effects of an angiotensin converting enzyme inhibitor and a calcium antagonist, on the renal structure and function in the remnant kidney model of chronic renal failure in the rat. Progressive renal failure was induced in adult female Sprague Dawley rats (SDR) by surgical removal of the right kidney, and segmental infarction of seven-eighths of the left kidney. Following subtotal nephrectomy, plasma creatinine rose from 65 +/- 16 mumol/l to 173 +/- 19 mumol/l (P less than 0.001) over a period of 6 weeks, systolic blood pressure (SBP) rose from 121 +/- 2 mmHg to 176 +/- 7 mmHg (P less than 0.001) and urinary protein excretion from 0.6 +/- 0.2 to 84 +/- 22 mg/24 h (P less than 0.001). Glomerular mesangial expansion was present after 2 weeks, then progressed, in association with the development of glomerular sclerosis, which became prominent after 6 weeks. Rats were treated with enalapril (5 mg/kg per day) or felodipine (30 mg/kg per day) from 1 week after subtotal nephrectomy, and their course compared with that of untreated rats. Systemic SBP decreased to a similar degree by both drug treatments. Six weeks after surgery, plasma creatinine concentration was lower in the enalapril-treated group (110 +/- 8 mumol/l, P less than 0.05) than in the felodipine-treated group (153 +/- 23 mumol/l). The latter group showed similar plasma creatinine concentrations to those of the untreated rats (173 +/- 19 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of acute and long-term treatment with felodipine in essential hypertension.

Enhanced renal vasoconstriction and renal tubular sodium reabsorption mediated by noradrenaline and angiotensin II (Ang II) have been implicated in the pathogenesis of essential hypertension. Since these effects seem to be calcium-dependent, renal haemodynamic and tubular function were studied following acute and long-term treatment with the calcium antagonist felodipine in 10 patients with essential hypertension. After acute felodipine administration mean blood pressure (MBP) decreased (from 111 to 95 mmHg; P less than 0.01), renal blood flow (RBF), estimated from hippurate clearance, increased (from 1030 to 1175 ml/min; P less than 0.01) and glomerular filtration rate (GFR) was unchanged (109 versus 112 ml/min). Fractional excretion (FE) of sodium, potassium, calcium, magnesium, chloride, bicarbonate and urate increased for 12 h. Following long-term felodipine treatment, mean blood pressure was reduced (97 mmHg; P less than 0.01) and RBF and GFR were unchanged (1032 and 114 ml/min, respectively). Fractional excretion of urate and calcium was increased for 24 h (from 5.9 to 6.9%; P less than 0.05 and from 1.1 to 1.3%; P less than 0.05, respectively). Serum urate decreased (from 377 to 347 mumol/l; P less than 0.01) whereas serum calcium was unchanged. Fractional excretion of sodium, potassium and chloride was increased between 3 and 6 h after felodipine. The renal haemodynamic findings after acute felodipine administration are indicative of a direct renal vasodilator action of felodipine which augments the autoregulatory renal vasodilation to produce an overall increase in RBF. Since GFR was unchanged, the increased renal excretion of electrolytes and urate reflects an action at the tubular level. Following long-term felodipine administration autoregulatory adjustment of RBF predominated.

Effect of felodipine on blood pressure and vascular reactivity in stroke-prone spontaneously hypertensive rats.

Isolated tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP), but not from normotensive Wistar-Kyoto rats (WKY), exhibit oscillatory contractions in response to norepinephrine. Previous studies indicate that the mechanism for these oscillations involves altered membrane calcium and/or potassium handling, and that this vascular change is a genetic defect associated with hypertension in SHRSP. The purpose of this experiment was to determine whether treatment of SHRSP with the calcium entry blocker felodipine would alter oscillatory activity. Adult SHRSP and WKY rats were treated orally with felodipine for 8 weeks. Felodipine treatment produced a significant decrease in blood pressure in SHRSP (control SHRSP: 240 +/- 7 mmHg, n = 6; felodipine-treated SHRSP: 164 +/- 8 mmHg, n = 5, P less than 0.05; tail-cuff method). Helically-cut tail artery strips from all rats were mounted in tissue baths for isometric force recording and exposed to norepinephrine (6 x 10(-9) to 6 x 10(-6) mol/l) for 20 min at each concentration. Oscillatory activity was defined as the sum of the magnitudes of all phasic contractions occurring during the final 10 min of norepinephrine incubation. Oscillatory activity was markedly reduced in tail arteries from felodipine-treated SHRSP when compared with control SHRSP. Felodipine also inhibited oscillatory activity when added directly to the tissue bath. It seems, therefore, that felodipine may lower blood pressure in SHRSP, at least in part, by correcting the genetic defect responsible for oscillatory activity.

The use of Doppler echocardiography to assess the acute haemodynamic response to felodipine and metoprolol in hypertensive patients.

In order to evaluate the use of Doppler echocardiography in the assessment of the haemodynamic effects of antihypertensive drugs, the acute haemodynamic response to felodipine and additional administration of metoprolol after 90 min was assessed in 10 hypertensive patients, by using both the Fick method and Doppler blood flow velocimetry in the ascending aorta. Intrabrachial artery pressure was significantly reduced by the treatment. Both the Fick and Doppler estimates of cardiac output (CO) rose significantly with felodipine and reached their highest values after 30 min, 45 +/- 8% (s.e.m.) and 58 +/- 7%, respectively. The felodipine-induced increase of heart rate (HR) persisted for 90 min, but the increase of stroke volume was only transient. Metoprolol brought CO and HR back to control levels. The felodipine- and metoprolol-induced changes of CO and stroke volume (SV) from control were on average not different between the observations with the Fick and the Doppler techniques throughout the study. As for the absolute values (control period), the Doppler measurement under-estimated SV (10 ml) and CO (1.1 l/min) in comparison with the Fick method, and the limits of agreement (mean difference +/- 2 s.d.) between both methods were 42 and -22 ml for stroke volume and 3.4 and -1.2 l/min for CO. In conclusion, despite the poor agreement in absolute results between the two methods, aortic Doppler velocimetry reflects the acute haemodynamic changes induced by felodipine and metoprolol in a group of hypertensive patients. The technique should facilitate the study of haemodynamic effects of drugs in man.

Effect of calcium antagonism on intracellular concentrations and transmembrane fluxes of cations in erythrocytes of men at rest and during exercise.

The effect of calcium (Ca2+) antagonism with felodipine on the intracellular concentrations and transmembrane fluxes of cations in erythrocytes, was studied in 10 normal volunteers at rest and during exercise. All subjects performed two uninterrupted incremental exercise tests on a bicycle ergometer in a randomized order either after placebo administration or after 3 days of pretreatment with felodipine 5 mg t.i.d. Felodipine did not affect the erythrocyte ouabain-sensitive 86rubidium uptake, furosemide-sensitive sodium (Na+)- and potassium (K+)-effluxes and the Na+,Li+-countertransport at rest and during exercise and recovery. Intra-erythrocyte and plasma Na+ and K+ concentrations were not different during felodipine whereas the plasma Ca2+ concentration was significantly increased. Plasma magnesium (Mg2+) concentration was reduced during felodipine treatment while the intra-erythrocyte Mg2+ concentration tended to be increased. The intra-erythrocyte to plasma concentration ratios for Na+ and K+ were not significantly affected by felodipine whereas the ratio for Mg2+ was increased. It is concluded that short-term Ca2+ antagonism with felodipine is not accompanied by major alterations in the intracellular concentrations and transmembrane fluxes of Na+ and K+ in red blood cells of normotensive subjects. The red cell transmembrane gradient for Mg2+ is however altered by felodipine.

Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients. A comparison with young healthy subjects.

The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intravenous dose of 3H-felodipine (0.04mg) was given together with the oral dose on the study day. Cmax (17 nmol/L), Cmin (5 nmol/L) and AUC (82 nmol/L.h) were 3 times higher in the elderly than in the young subjects. Systemic availability was about 15% in both groups. Plasma clearance (CL) was reduced from 56.1 L/h in the young to 25.4 L/h in the elderly. There was no effect of age on the volume of distribution at steady-state (Vss). Reduced hepatic blood flow and enzyme activity or increased gut wall metabolism are possible reasons for the altered pharmacokinetics in the elderly. Blood pressure was reduced in the elderly from 190/99 to 177/91 mm Hg 12 hours after 5mg felodipine during twice daily dosage. The effect on blood pressure correlated with plasma concentrations of felodipine.

Acute effects of felodipine in exertional angina pectoris.

To investigate the antianginal efficacy, duration of action and tolerability of 2 doses of the new calcium antagonist felodipine, 15 patients (14 men and 1 woman, mean age 62 years) with stable exertional angina pectoris and angiographically demonstrated coronary artery disease were randomly given felodipine, 5 and 10 mg, and placebo on 3 different days. A bicycle ergometer exercise test was performed 3 and 10 hours after dosing. In comparison with placebo, felodipine 5 and 10 mg significantly increased resting heart rate and decreased resting systolic and diastolic blood pressure 3 hours after administration (p less than 0.001). Ten hours after administration, only supine systolic blood pressure was still significantly lower (p less than 0.001). Anginal (time to mild chest pain) and ischemic (time to 1 mm ST depression) thresholds, as well as duration of exercise and total work at peak exercise, were higher in comparison with placebo at 3 and 10 hours (p less than 0.001). In comparison with the lower dose, 10 mg felodipine induced a decrease in supine (p less than 0.05) and sitting (p less than 0.01) systolic blood pressure at rest and an increase in total work to anginal threshold (p less than 0.01), as well as in total work and duration of exercise at peak exercise (p less than 0.05). These results suggest that a single administration of felodipine, 5 and 10 mg, may improve exercise capacity over a 10-hour period in patients with stable exercise-induced angina due to atherosclerotic heart disease.

Intervascular and stimulus selectivity of nitrendipine and related derivatives in KCl and prostaglandin F2 alpha precontracted porcine arteries.

1. Dihydropyridine-type calcium entry blockers exhibit a different vasodilator potency depending on the arterial tissue (intervascular selectivity) as well as on the precontracting stimulus used (stimulus selectivity). In addition, the structure of their ester side chains seems to influence their activity. 2. Vascular activity of nitrendipine and six related 3-ester side chain derivatives was investigated in isolated coronary, ulnar and basilar arteries of the pig following precontraction with KCl or prostaglandin F2 alpha (PGF2 alpha). 3. After depolarization, all dihydropyridines exhibited a weak preferential action on coronary arteries. Bay E 6927 produced the strongest effect in all vessel types. By contrast, precontraction with PGF2 alpha resulted in a marked preferential action in basilar arteries, although higher concentrations of the dihydropyridines were required for half maximal vasorelaxation. In each case, ulnar arteries were less sensitive. 4. Except with Bay O 5572, the most bulky substituted and least active derivative, only moderate differences were observed within the dihydropyridines studied. On the other hand, there was a pronounced increase in the ratios of the half maximal active concentrations required after precontraction of the vessels with PGF2 alpha compared to KCl (stimulus selectivity) following a limited prolongation of the 3-ester side chain up to an isopropyl-group. 5. It is suggested that the observed shift in the intervascular selectivity after precontraction with PGF2 alpha is a consequence of different contractile mechanisms in the three vessel types studied. The degree of the stimulus selectivity may also depend on the structure of the dihydropyridines.

Clinical pharmacokinetics of felodipine. A summary.

Felodipine is completely absorbed from the gastrointestinal tract. However, the amount reaching the systemic circulation is reduced to about 15% because of first-pass degradation. The bioavailability is constant within the dose interval of 5 to 40mg orally. The frequency histogram of the area under the plasma concentration-time curve (AUC) seems to be normally distributed. The disposition of felodipine is independent of the administered dose over the intravenous dose interval (1-3 mg). The plasma concentration-time curve declines in 3 distinct phases. The mean elimination half-life of felodipine is approximately 25h. Felodipine is extensively distributed to extravascular tissues. The volume of distribution of felodipine is about 10 L/kg, implying that less than 1% of the amount of drug in the body is localised in the blood. Felodipine is more than 99% bound to plasma proteins. Mean total clearance from the blood is 1 to 1.5 L/min and, therefore, felodipine is considered a high clearance drug. Felodipine is metabolised completely and no unchanged drug is eliminated in the urine. The first step in the metabolism involves oxidation to the corresponding pyridine derivative by the cytochrome P-450 system. Identified metabolites in plasma and urine are devoid of vasodilating activity. Long term treatment, and the presence of hypertension and impaired renal function do not affect the disposition of felodipine. Elderly people may have higher plasma levels than the young and middle-aged. Impaired liver function significantly decreases systemic clearance. Cimetidine and food affect felodipine kinetics, but with negligible clinical implications. Therapeutic concentrations of felodipine do not interact with highly protein-bound drugs and these drugs have no effect on the binding of felodipine to human plasma proteins in vitro. Plasma levels of digoxin and metoprolol tended to increase during felodipine treatment. There is a significant correlation between plasma concentrations of felodipine and haemodynamic effects in both healthy subjects and hypertensive patients during short term as well as during long term treatment.

Pharmacodynamic properties of felodipine.

This overview presents the pharmacodynamic properties of felodipine as studied in animal experiments with emphasis on results from our laboratory. Felodipine is 100-fold more potent in causing inhibition of spontaneously active vascular smooth muscle than myocardium in vitro. This vascular selectivity is significantly greater than that of nifedipine (potency ratio 15). Verapamil, D-600, La3+ and reduction of [Ca2+]o lack selectivity. The cellular mechanisms underlying this variable selectivity are not clear at present. In conscious spontaneously hypertensive rats (SHR), the plasma concentration required for 20% reduction of mean arterial pressure is approximately 10 nmol. Mean arterial pressure is lowered dose-dependently as a result of reduced peripheral vascular resistance accompanied by increased cardiac output due to transient tachycardia and increased stroke volume. There was rapid resetting of the baroreflex set point but unaltered sensitivity after felodipine and hydralazine in SHR. Therefore, the reflexogenic increase in heart rate and plasma renin activity subsided within 3 to 5 hours of continuous felodipine administration in SHR. In addition, there was a uniform dilatation of the peripheral vascular beds after felodipine administration. During long term treatment of SHR with felodipine, progression of left ventricular and vascular wall hypertrophy was prevented. Within the 'therapeutic dose range', the only primary effect observed in addition to arterial vasodilation is diuresis/natriuresis caused by a renal tubular action.

Felodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension.

Felodipine is a dihydropyridine calcium antagonist which selectively relaxes vascular smooth muscle. By acting at peripheral arterioles, it lowers systemic vascular resistance and thereby produces substantial decreases in blood pressure and increases in cardiac output. Felodipine is indicated for the management of hypertension, and in patients with mild to moderate disease felodipine monotherapy markedly lowers blood pressure. It proved as effective as atenolol, and equivalent to hydrochlorothiazide, either with or without amiloride, in terms of antihypertensive activity. Comparative studies also demonstrated that once daily administration with an extended-release formulation provides equivalent antihypertensive efficacy to the same amount of drug administered twice daily as the standard tablets. As a second- or third-line treatment for patients with moderate to severe hypertension refractory to standard drug combinations, felodipine produced considerable reductions in blood pressure when added to beta-blockers and diuretics, either alone or in combination, in studies lasting up to 48 weeks. In comparative studies of multiple-drug treatments felodipine was found to have superior efficacy to hydralazine and prazosin, and was at least as effective as nifedipine, minoxidil and propranolol, when used with diuretics and/or beta-blockers. As an alternative to hydrochlorothiazide, in combination with beta-blockers, felodipine consistently controlled blood pressure in a greater percentage of patients and usually provided greater decreases in blood pressure. The main side effects with felodipine are ankle oedema, headache and flushing. Although the overall incidence of effects is quite high, they are usually mild in nature. Nevertheless, withdrawal due to side effects has been necessary in about 7% of patients overall. Thus, the efficacy of felodipine has been demonstrated in mild, moderate and severe hypertension. At the present time it seems particularly suitable as a second- or third-line treatment in refractory hypertension, but it also can be used as monotherapy for mild to moderate disease.

Metabolism of [14C] felodipine, a new vasodilating drug, in healthy volunteers.

After oral administration of [14C] felodipine (27.5mg) to 4 healthy volunteers, 6 main urinary metabolites were identified by gas chromatography-mass spectrometry. The compounds were isolated by solvent extraction at pH 2.2 and silylated prior to analysis. They were formed by dehydrogenation of felodipine followed by ester hydrolysis, hydroxylation of the alkyl groups and conjugation. These metabolites were excreted both as free acids and as conjugates accounting on average for 37% of the excreted amount (23% of the dose). A specific liquid chromatographic assay with radioactive detection was developed to determine the acidic metabolites in all collected samples. The urinary excretion rate declined biphasically for the mono-acids III and IV, whereas the excretion rates of metabolites VI, VII and VIII, formed via aliphatic hydroxylation, were better fitted to equations of first-order processes.