Identification of novel pregnane X receptor (PXR) agonists by In silico and biological activity analyses and reversal of cigarette smoke-induced PXR downregulation.

Cigarette smoke (CS) contains many toxins that collectively harm nearly every organ in the body, and smoking is a key risk factor for many chronic diseases. Aside from its toxic actions, CS may alter expression of the drug- and steroid-binding pregnane X receptor (PXR), which when activated upregulates expression of cytochrome P450 (CYP) enzymes, glutathione transferases (GSTs), and multidrug resistance protein 1 (MDR1), an adaptive metabolic array that mediates clearance of CS component toxins. We sought to identify new PXR agonists that may be useful for restoring PXR activity in conditions wherein it is suppressed, and their mechanisms of PXR binding and activation. PXR has a uniquely larger, hydrophobic, and highly flexible ligand-binding domain (LBD) vs. other nuclear receptors, enabling it to interact with structurally diverse molecules. We tested certain calcium channel blockers (CCBs) as a pharmacological subset of potential PXR ligands, analyzing by molecular docking methods, and identified a putative active site in the PXR LBD, along with the relevant bonds and bonding energies. We analyzed felodipine binding and agonist activity in detail, as it showed the lowest binding energy among CCBs tested. We found felodipine was a potent PXR agonist as measured by luciferase reporter assay, whereas CCBs with higher binding energies were less potent (amlodipine) or nearly inactive (manidipine), and it induced CYP3A4 expression in HepG2 cells, a known target of PXR agonism. Felodipine also both induced PXR mRNA in HepG2 hepatocytes and reduced CS extract-induced diminution of PXR levels, indicating it modulates PXR expression. The results illuminate mechanisms of ligand-induced PXR activation and identify felodipine as a novel PXR agonist.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.

Drugs and Scaffold That Inhibit Cytochrome P450 27A1 In Vitro and In Vivo.

Cytochrome P450 27A1 (CYP27A1) is a ubiquitous enzyme that hydroxylates cholesterol and other sterols. Complete CYP27A1 deficiency owing to genetic mutations is detrimental to human health, whereas 50% of activity retention is not and does not affect the whole body cholesterol levels. CYP27A1 is considered a potential therapeutic target in breast cancer and age-related neurodegenerative diseases; however, CYP27A1 inhibition should be ≤50%. Herein, 131 pharmaceuticals were tested for their effect on CYP27A1-mediated cholesterol 27-hydroxylation by in vitro enzyme assay. Of them, 14 drugs inhibited CYP27A1 by ≥75% and were evaluated for in vitro binding to the enzyme active site and for inhibition constants. All drugs except one (dasatinib) elicited a spectral response in CYP27A1 and had Ki values for cholesterol 27-hydroxylation either in the submicromolar (clevidipine, delavirdine, etravirine, felodipine, nicardipine, nilotinib, and sorafenib) or low micromolar range (abiratone, candesartan, celecoxib, dasatinib, nilvadipine, nimodipine, and regorafenib). Clevidipine, felodipine, nicardipine, nilvadipine, and nimodipine have the same 1,4-dihydropyridine scaffold and are indicated for hypertension. We used two of these antihypertensives (felodipine and nilvadipine) for administration to mice at a 1-mg/kg of body weight dose, daily, for 7 days. Mouse 27-hydroxycholesterol levels in the plasma, brain, and liver were reduced, whereas tissue levels of total cholesterol were unchanged. Structure-activity relationships within the 1,4-dihydropyridine scaffold were investigated, and features important for CY27A1 inhibition were identified. We confirmed our previous finding that CYP27A1 is a druggable enzyme and found additional drugs as well as the scaffold with potential for partial CYP27A1 inhibition in humans.

[Effect of puerarin combined with felodipine on mRNA and protein expression of apelin and APJ in renovascular hypertensive rat].

OBJECTIVE: To explore the effect of puerarin combined with felodipine on the mRNA and protein expression of apelin and APJ in renal tissue of renovascular hypertensive rat. METHOD: Sixty-two Sprague-Dawley rats were used, of which 8 rats were randomly chosen as sham-operation group. The remaining rats were made for the rat model with renovascular hypertension. The renovascular hypertensive rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (0.8 mg x kg(-1) x d(-1)), puerarin (50 mg x kg(-1) x d(-1)), puerarin combined with felodipine (puerarin 25 mg x kg(-1) x d(-1) + felodipine 0.4 mg x kg(-1) x d(-1)) or captopril combined with felodipine (captopril 15 mg x kg(-1) x d(-1) x felodipine 0.4 mg x kg(-1) x d(-1)), and 1 group which was treated with distilled water. Drugs or distilled water were administered for 8 weeks. The expression of apelin and APJ mRNA and protein in ischemic and non-ischemic kidneys was assessed by RT-PCR or Western blot. RESULT: Compared with sham-operation group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys in model group was increased significantly (P < 0.01); the expression of APJ mRNA and protein in ischemic kidneys had no significance, while that in non-ischemic kidneys was decreased (P < 0. 01). Compared with model group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys was decreased significantly in all drug-treated groups (P < 0.01); while that of APJ mRNA and protein in non-ischemic kidneys was upregulated (P < 0.01). Compared with felodipine group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys was decreased (P < 0.01 or P < 0.05) in the group treated with both puerarin and felodipine; and the expression of APJ mRNA and protein in ischemic kidneys did not reach significant level, however, that was upregulated in non-ischemic kidneys (P < 0.01 or P < 0.05). CONCLUSION: Puerarin downregulates the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys, and upregulates that of APJ mRNA and protein in non-ischemic kidneys. Combination of puerarin and felodipine enhances the above-mentioned effects and shows no significant difference versus the combination of felodipine and captopril. The results suggest that puerarin regulates blood pressure and protects target organ through apelin/APJ pathway and that puerarin has synergetic effects with CCB.

Blockade of calcium channels and AT1 receptor prevents the hypertensive effect of calcilytic NPS 2143 in rats.

Calcilytics, antagonists of calcium receptor, decrease sensitivity of this receptor to plasma calcium concentration and increase parathyroid hormone (PTH) secretion. Moreover, it was recently indicated that calcilytic NPS 2143 induces hypertension in rats. This study tested whether the increase of mean arterial blood pressure (MAP) induced by NPS 2143 administration is mediated by calcium channel and angiotensin II type 1 (AT1) receptor activity. Wistar rats were anaesthesized with Thiopental i.p. and infused i.v. with saline supplemented with the anaesthetic. Blood pressure was monitored continuously in the carotid artery. Effects of NPS 2143 administered i.v. as bolus on MAP in the presence and absence of felodypine and losartan were investigated. Both, felodipine and losartan pretreatment provoked a persistent DMAP decrease by 18+/-3 and 14+/-3 mmHg, respectively. Infusion of NPS 2143 at 1 mg/kg b.w. confirmed hypertensive activity of calcilytic and increased blood pressure for 21+/-4 mmHg. In contrast, administration of NPS 2143 in felodipine as well as in losartan pretreated rats did not change DMAP as compared to felodipine/control and losartan/control groups, respectively. Our study indicated that both the blockade of calcium channels and the AT1 receptor activity prevented the hypertensive effect of calcilytic NPS 2143. This finding might be particularly important in understanding the mechanisms that mediated blood pressure changes related to the activity of calcium receptor.

Felodipine reduces cardiac expression of IL-18 and perivascular fibrosis in fructose-fed rats.

Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy, and elevated inflammatory status. To determine whether metabolic syndrome-associated elevation of the inflammatory cytokine interleukin-18 (IL-18) in serum and cardiac tissue, and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight, and blood insulin. Serum IL-18 levels in these rats were also elevated significantly. These changes were significantly different compared to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.

A small-molecule screen in C. elegans yields a new calcium channel antagonist.

Small-molecule inhibitors of protein function are powerful tools for biological analysis and can lead to the development of new drugs. However, a major bottleneck in generating useful small-molecule tools is target identification. Here we show that Caenorhabditis elegans can provide a platform for both the discovery of new bioactive compounds and target identification. We screened 14,100 small molecules for bioactivity in wild-type worms and identified 308 compounds that induce a variety of phenotypes. One compound that we named nemadipine-A induces marked defects in morphology and egg-laying. Nemadipine-A resembles a class of widely prescribed anti-hypertension drugs called the 1,4-dihydropyridines (DHPs) that antagonize the alpha1-subunit of L-type calcium channels. Through a genetic suppressor screen, we identified egl-19 as the sole candidate target of nemadipine-A, a conclusion that is supported by several additional lines of evidence. egl-19 encodes the only L-type calcium channel alpha1-subunit in the C. elegans genome. We show that nemadipine-A can also antagonize vertebrate L-type calcium channels, demonstrating that worms and vertebrates share the orthologous protein target. Conversely, FDA-approved DHPs fail to elicit robust phenotypes, making nemadipine-A a unique tool to screen for genetic interactions with this important class of drugs. Finally, we demonstrate the utility of nemadipine-A by using it to reveal redundancy among three calcium channels in the egg-laying circuit. Our study demonstrates that C. elegans enables rapid identification of new small-molecule tools and their targets.

Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo.

OBJECTIVES: Our study was designed to determine the effect of peppermint oil and ascorbyl palmitate on cytochrome P4503A4 (CYP3A4) activity in vitro and oral bioavailability of felodipine in humans. METHODS: Reversible and mechanism-based inhibitions of nifedipine oxidation were studied in human liver microsomes. The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined in 12 healthy volunteers after administration of felodipine, 10-mg extended-release tablet, with grapefruit juice (300 mL), peppermint oil (600 mg), ascorbyl palmitate (500 mg), or water in a randomized 4-way crossover study. RESULTS: Peppermint oil (inhibition constant [K(i)] = 35.9 +/- 3.3 microg/mL, mean +/- SEM) and 2 constituents, menthol (K(i) = 87.0 +/- 7.0 micromol/L), and menthyl acetate (K(i) = 124.0 +/- 7.0 micromol/L), produced reversible inhibition of nifedipine oxidation. Ascorbyl palmitate was more potent (K(i) = 12.3 +/- 0.5 micromol/L). None of these substances were mechanism-based inhibitors. Grapefruit juice and peppermint oil increased the area under the curve (AUC) values of felodipine to 173% (range, 94%-280%; P <.01) and 140% (range, 77%-262%; P <.05), respectively, of those with water. They augmented the peak plasma concentration (C(max)) of felodipine and the AUC and C(max) of dehydrofelodipine but did not alter the half-life (t(1/2)) of either substance. Grapefruit juice decreased the dehydrofelodipine/felodipine AUC ratio, but peppermint oil did not. Ascorbyl palmitate did not change the pharmacokinetics of felodipine or dehydrofelodipine compared with water. CONCLUSIONS: Peppermint oil, menthol, menthyl acetate, and ascorbyl palmitate were moderately potent reversible inhibitors of in vitro CYP3A4 activity. Grapefruit juice increased the oral bioavailability of felodipine by inhibition of CYP3A4-mediated presystemic drug metabolism. Peppermint oil may also have acted by this mechanism. However, this requires further investigation. Ascorbyl palmitate did not inhibit CYP3A4 activity in vivo.

Immunomodulating effects of second-generation calcium channel blockers on experimental heart transplantation.

The administration of second-generation calcium channel blockers (CCBs) to counteract the adverse effects of conventional immunosuppression gains more and more acceptance. Since these newly developed molecules differ in their chemical structure and possess specific pharmacokinetic profiles, we hypothesized that exposure to clinically relevant concentrations may have a significant immunomodulatory potential. The effects of various second-generation CCBs, felodipine, amlodipine, mibefradil and clentiazem, on cardiac allograft survival were therefore evaluated. Inbred male Lewis rats were used as recipients and Brown-Norway rats as donors. After abdominal implantation of the donor heart, allograft recipients were exposed to felodipine (31 microg/kg/day), amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). Other allograft recipients were treated with low-dose cyclosporine (CsA) alone (2 mg/kg/day) or with low-dose CsA combined with amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). All drugs were given daily by gavage. Median survival time of untreated cardiac allografts was 6.5 days. When given alone, not all the second-generation CCBs elicited a positive effect: the dihydropyridines felodipine and amlodipine were ineffective (median survival time was 6.5 and 7.0 days, respectively), the T- and L-type CCB mibefradil had a significant but minor impact (median survival time = 9.0 days, p <0.0015) while the benzothiazepine clentiazem produced the most significant result (median survival time = 16.0 days, p <0.0033). Neither amlodipine nor mibefradil modified the extent of survival provided by low-dose CsA (median survival time = 9.0 days), while clentiazem had a significant positive effect. These data indicate that second-generation CCBs differ in their immunomodulatory potential. These observations of pharmacodynamic specificity appear to be related to differences in their chemical structure as well as their interaction with other sites than the calcium channel.

Rational use of calcium-channel antagonists in Raynaud's phenomenon.

Raynaud's phenomenon (RP) is a peripheral circulatory disorder characterized by sudden episodes of digital artery spasm, often precipitated by cold temperature or emotional stress. Although the cause of RP is not fully known, it appears to involve inappropriate adrenergic response to cold stimuli. Treatment of RP is conservative in most patients, but in patients with severe disease includes the use of agents that promote digital vasodilation. The calcium-channel antagonists, particularly the dihydropyridine derivative nifedipine, are the most thoroughly studied drug class for the treatment of RP. Approximately two thirds of patients respond favorably, with significant reductions in the frequency and severity of vasospastic attacks. Nifedipine use is often limited by the appearance of adverse vasodilatory effects such as headache or peripheral edema. The newer second-generation dihydropyridines such as amlodipine, isradipine, nicardipine, and felodipine also appear to be effective in patients with RP and may be associated with fewer adverse effects.

Nuevos estudios multicéntricos en hipertensión arterial / New multicentric studies in arterial hypertension

Prospective, randomized and long term multicentric studies, published since 1988, on the effects of pharmacological or non pharmacological treatment of hypertension are analyzed. Former studies, performed between 1967 and 1987, are devoted, in chronological order, to special populations or to forms of hypertension not sufficiently studied previously (elders and isolated systolic hypertension), using classical pharmacological treatments such as diuretics and beta blockers. Their results confirm the reduction in mortality obtained using such therapies. Ensuing studies, focused on the analysis of new drugs such as calcium antagonists and angiotensin converting enzyme inhibitors, also demonstrated a reduction in cardiovascular risk, even in severely damaged populations. Thereafter, meta analysis of new pharmacological treatments and of non pharmacological therapies such as sodium restriction, weight reduction, avoidance of alcohol intake, calcium and potassium supplementation have appeared. These studies have emphasized the importance of prevention through changes in lifestyles. Their positive, although modest results, encourage the assessment of long term preventive and therapeutic measures in hypertension

Cardiovascular and renal effects of the combination of felodipine and metoprolol during a high-salt and a moderate-salt diet in spontaneously hypertensive rats.

In the present study the influence of dietary salt on the cardiovascular and renal effects of the calcium channel blocker felodipine (1.2 mg/kg sc) and the beta 1-adrenoceptor blocking drug metoprolol (250 mg/kg po), alone and in combination, was examined in the spontaneously hypertensive rats (SHRs) in a 4-week study. In addition, the influence of different diet and drug regimens on vascular functions was assessed by measuring the vascular relaxation and contractile responses of mesenteric arterial rings in vitro at the end of the experimental period. In SHRs, a high-salt diet caused a marked rise in blood pressure, impaired the endothelium-dependent vascular relaxation responses to acetylcholine and induced left ventricular hypertrophy (LVH) and renal hypertrophy. Metoprolol had little if any effect on salt-induced changes in blood pressure, endothelium-dependent vascular relaxation or renal hypertrophy, but it partially prevented the development of salt-induced LVH. Felodipine during the high-salt diet lowered blood pressure to normotensive level and completely prevented salt-induced left ventricular and renal hypertrophy as well as endothelial dysfunction. Felodipine produced tachycardia, especially at the beginning of drug treatment. The combination of felodipine and metoprolol abolished the effects of the individual drugs on heart rate. The drug combination also completely prevented the detrimental cardiovascular and renal effects induced by a high salt intake. Although salt restriction did not further enhance the profound antihypertensive effect of the combination of metoprolol and felodipine, it enhanced the effects of the drug combination on LVH and renal hypertrophy. Our findings indicate that felodipine treatment, alone and in combination with metoprolol, normalizes blood pressure and prevents the development of salt-induced LVH and renal hypertrophy. During the high-salt diet the beneficial vascular effects of felodipine as well as those of the combination of felodipine and metoprolol are mediated, at least in part, by prevention of salt-induced endothelial dysfunction. The only apparent benefit from the use of metoprolol in combination with a relatively high dose of felodipine was the prevention of tachycardia.

[Multicenter comparative study of felodipine-ER and nifedipine-OROS in the treatment of mild-to-moderate arterial hypertension]. / Estudo multicêntrico comparativo da felodipina-ER e nifedipina-OROS no tratamento da hipertensão arterial leve e moderada.

PURPOSE: To compare the efficacy and tolerance of felodipine-ER and nifedipine OROS, both once daily, in the treatment of mild-to-moderate uncomplicated arterial hypertension (AH). METHODS: This was a multicentric, opened, randomized, paralled trial, that selected 121 patients with uncomplicated, mild to moderate essential AH (diastolic blood pressure (DBP) > or = 95 and < or = 110 mmHg; not under anti-hypertensive medication. All patients received placebo for two weeks. After that period, they would take either 5mg/day of felodipine, or 30mg/day of nifedipine OROS, both once daily, in a randomized fashion. Patients underwent laboratory tests and electrocardiogram (ECG) at the begining and at the end of the study, and heart rate and blood pressure (BP) measurements, nearly 24 hours after the last active drug dose. RESULTS: Completed the study 111 patients, 60 in the felodipine group and 51 in the nifedipine group. Compared to baseline, the average of systolic BP and DBP decreased from 162.5 +/- 14.3mmHg and from 102.2 +/- 5.1mmHg to 143.3 +/- 14.6 and 87.9 +/- 7.2mmHg, respectively, at the end of the treatment in the felodipine group; and from 160.5 +/- 16.3mmHg and 102.5 +/- 6.2mmHg to 136.1 +/- 14.2 and 86.7 +/- 7.0mmHg, respectively in nifedipine group (p < 0.0001 for all diferences). Adequate BP response to the treatment (DBP normalization or reduction > 10mmHg from baseline) occured in 47/60 (78.3%) patients in the felodipine group and in 38/51 (74.5%) in the nifedipine group (NS). Side effects, occured in approximately 15% of the cases, and were similar in both groups. These were usually moderate and transient, but were responsible for the withdrawal from the study of two cases in the felodipine group and of three cases in the nifedipine group. CONCLUSION: Felodipine-ER and nifedipine OROS, are similarly effective and generally well tolerated in patients with mild-to-moderate essential hypertension.

Effects of felodipine on utero-placental blood flow in normotensive rabbits.

The utero-placental blood flow was investigated in anaesthetized normotensive pregnant rabbits after repeated administration of a high dose of the antihypertensive calcium antagonist felodipine and in untreated controls. By means of the microsphere technique blood flow was also determined in the lungs, skin, intestine, skeletal muscle and kidneys during chloralose anaesthesia. Felodipine reduced mean arterial blood pressure, which was associated with a marked reduction in vascular resistance in the skeletal muscle vascular bed, where blood flow was increased seven-fold. In contrast, blood flow to placentae and kidneys were reduced. The pronounced reduction in placental blood flow may limit foetal nutrition and hence explain reported foetal digital defects after administration of high doses of felodipine to pregnant normotensive rabbits.

The effect of felodipine on bile flow in pentobarbital anaesthetized rats and conscious rats receiving bile salt supplementation.

Felodipine, a vasoselective dihydropyridine calcium antagonist, has been given i.v. (0.2 mumol/kg) to anaesthetized and conscious male rats. There was no effect of pentobarbital anaesthesia on bile flow over a 6 h observation period. Felodipine increased the 6 h recovery of bile by approximately 25% in the conscious rat but in the anaesthetized rat there was a 20% decrease in bile flow following i.v. felodipine. A positive effect of Na-taurocholate infusion (1 mumol/min/100 g body weight) on bile flow in conscious rats was reinforced by concomitant felodipine dosing. Accumulated 6 h recoveries were 2.32 +/- 0.80 g/100 g body weight (control), 3.09 +/- 0.91 g/100 g body weight (taurocholate) and 5.00 +/- 0.80 g/100 g body weight. (taurocholate plus felodipine). The excretion of felodipine in the bile was significantly reduced during anaesthesia and during infusion of 2% bovine serum albumin (0.01 ml/min/100 g body weight) to conscious rats.

Evaluation of the efficacy of felodipine in two models of acute renal failure in dogs.

Acute renal failure was induced in pentobarbital anesthetized dogs either by withdrawal of the blood and/or by acute renal artery occlusion and efficacy of felodipine in preserving renal function was evaluated. In Wiggers' model of hemorrhagic shock, animals were allowed to bleed into a reservoir and after maintaining a hypotensive state (40-45 mm Hg) for 150 minutes, blood was reinfused and recovery in the renal function was evaluated. In a separate series, a renal artery was completely occluded for 45 minutes and after release of the occlusion recoveries in various markers of renal function were monitored. Felodipine 0.01 mumol/kg i.v. or the vehicle was administered ten minutes before hemorrhage or ten minutes prior to initiation of renal artery occlusion. Comparison of the data between the vehicle-treated dogs from the two models show that although renal blood flow (RBF) was restored to similar levels, recoveries in glomerular filtration rate (GFR), urine volume (UV), urinary excretion of sodium (UNa V) and potassium (UK V) were severely depressed in shock model (15 to 25% of the basal value) and consistently lower than the recoveries in the renal artery occlusion model (30-50%). These data could suggest that the extent of renal impairment is more severe in hemorrhagic shock. Nevertheless, felodipine pretreatment provided significant protection to renal function from ischemic damage in both the models; the drug-treated groups were characterized by significant recoveries in GFR, UNa V and UK V (60-100%) and by prompt and full restoration of RBF and UV.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute renal tubular and hemodynamic effects of the calcium antagonist felodipine in healthy volunteers.

To evaluate the renal tubular effects of felodipine in a low (1.25-mg) and a high (10-mg) dose, lithium clearance was measured and related to renal hemodynamics in 10 healthy volunteers. After felodipine (1.25 mg), mean blood pressure decreased 4 mm Hg and heart rate increased 4 beats per minute. GFR and renal hemodynamics were unaltered. Natriuresis and diuresis increased and lithium clearance and fractional excretion of lithium were unchanged as compared with placebo. Felodipine (10 mg) decreased mean blood pressure 8 mm Hg; heart rate increased 16 beats per minute, and plasma catecholamines were elevated. GFR was unaltered, whereas RBF increased and renal vascular resistance decreased. Natriuresis and diuresis were further increased, and lithium clearance and fractional excretion of lithium were elevated. In conclusion, felodipine in a low dose of 1.25 mg, which did not change renal hemodynamics, had natriuretic and diuretic effects at a predominantly postproximal tubular site, whereas a high dose of 10 mg, which increased RBF and decreased renal vascular resistance, had additional natriuretic and diuretic effects in the proximal tubule.

In vitro inhibition of dihydropyridine oxidation and aflatoxin B1 activation in human liver microsomes by naringenin and other flavonoids.

Recent in vivo studies in humans have shown a dramatic effect of grapefruit juice in blocking the oxidation of dihydropyridine calcium channel blockers. The flavonoid naringin is the most abundant natural product specific for grapefruit and related citrus--the aglycone naringenin, known to be readily formed from naringin in humans, was found to inhibit the oxidation of the dihydropyridines nifedipine and felodipine in human liver microsomal preparations. These observations were of interest in light of the knowledge that the same human liver cytochrome P450 (IIIA4) appears to be a major catalyst in both nifedipine oxidation and aflatoxin B1 activation. Several flavones inhibited the in vitro activation of aflatoxin B1 in a system employing umuC gene activation due to DNA damage in Salmonella typhimurium TA1535/pSK1002, with naringenin being as effective as any. The high concentration of derivatives of naringenin in certain citrus fruits may be of relevance to cancer chemoprevention involving those carcinogens that are activated by cytochrome P-450IIIA4.

The effects of Ca2+ antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice.

1. The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM. 6. Verapamil (25mgkg-', i.p.), nicardipine (25mgkg-1, i.p.) and nifedipine (20mgkg-1, i.p.) all markedly inhibited the 5-HT2 receptor-mediated head twitch response in mice produced by injection of 5- methoxy-N,N-dimethyl-tryptamine (5-MeODMT). Felodipine had the same effect with an ED50 of 2.6mgkg-'. Bay K 8644 did not reverse this effect. Both verapamil (IC50:2.5 microM) and nicardipine (IC50:8 microM) were 5-HT2 antagonists as indicated by inhibition of [3H]-ketanserin binding in mouse frontal cortex. However felodipine and nifedipine antagonized 5-HT2 receptor binding only in the millimolar range.7. Hydralazine (5mg kg 1, i.p.) induced the 5-HT behavioural syndrome in tranylcypromine pretreated rats, enhanced the tranylcypromine/L-tryptophan behavioural syndrome, inhibited 5-MeODMT-induced head twitch behaviour in mice and was not a 5-HT2 receptor antagonist. 8. These data indicate that at a high dose, Ca2+ antagonists produce complex changes in 5-HT function in rodents which are similar to those produced by lithium administration. The data with hydralazine suggest that the effects seen are not related to an action at Ca2 + channels.