Oxidation of Hantzsch 1,4-dihydropyridines of pharmacological significance by electrogenerated superoxide.

PURPOSE: To study the reaction of a series of Hantzsch dihydropyridines with pharmacological significance such as, nifedipine, nitrendipine, nisoldipine, nimodipine, isradipine and felodipine, with electrogenerated superoxide in order to identify products and postulate a mechanism. METHODS: The final pyridine derivatives were separated and identified by gas chromatography/mass spectrometry (GC-MS). The intermediates, anion dihydropyridine and the HO2*/HO2- species, were observed from voltammetric studies and controlled potential electrolysis was used to electrogenerate O2*-. RESULTS: The current work reveals that electrogenerated superoxide can quantitatively oxidize Hantzsch dihydropyridines to produce the corresponding aromatized pyridine derivatives. CONCLUSIONS: Our results indicate that the aromatization of Hantzsch dihydropyridines by superoxide is initiated by proton transfer from the N1-position on the 1,4-dihydropyridine ring to give the corresponding anion dihydropyridine, which readily undergoes further homogeneous oxidations to provide the final aromatized products. The oxidation of the anionic species of the dihydropyridine is more easily oxidized than the parent compound.

Analysis of phenomena involved in the apical growth of Phycomyces blakesleeanus.

The effects of the Ca(2+)/H(+) exchanger A23187 and the K(+)/H(+) exchanger nigericin, the electrogenic membrane-potential depleters valinomycin and CCCP, and the calcium channel blockers ruthenium red, nifedipine, and nitrendipine on the apical growth of Phycomyces blakesleeanus were analyzed. While all of the compounds inhibited the growth of germlings in liquid medium, the Ca(2+) channel blockers were the least effective. Chitin synthesis in vivo was also sensitive to the inhibitors; here again, the calcium channel blockers were less efficient, and their effect occurred after a lag phase, in contrast to the electroneutral ionophores whose effects were immediate. The ionophores rapidly inhibited protein secretion, and reduced the number of secretory vesicles and chitosomes in the hyphal apex of P. blakesleeanus. The results suggest that not only tip-to-base calcium gradients but also transmembrane ionic gradients and membrane potential have a role in the apical growth of P. blakesleeanus. They are probably involved in the formation, migration, and/or fusion with the plasmalemma of secretory vesicles and chitosomes.

Effect of amyotrophic lateral sclerosis serum on calcium channels related to spontaneous acetylcholine release.

OBJECTIVES: The aim of this work was to further investigate the effect of sera from sporadic amyotrophic lateral sclerosis (ALS) patients on miniature end-plate potentials (MEPP) frequency, by the mouse passive transfer model, and to study whether the transferred serum induces any change in the sensitivity of the L-type voltage-dependent calcium channels (VDCC) to its specific blocker Nitrendipine. METHODS: A total of 35 CF1 mice were divided into 3 groups: (a) ALS group receiving sera from 15 patients that had been clinically and electromyographycally diagnosed as having sporadic ALS; (b) normal group receiving sera from 13 healthy volunteers and from 3 disease control patients, and (c) control group, which was kept untreated. Animals in groups (a) and (b) received daily intraperitoneal injection of 0.5-1ml of serum for 3 days, and 24h later the left hemidiaphragm was excised for electrophysiological recordings. RESULTS: Analysis of MEPPs frequency recorded from ALS group showed that 3 of them induced an increase in spontaneous neurotransmitter release while in 4 a decrease was observed, suggesting that sera alter spontaneous secretion as result of an increased or decreased Ca(2+) influx through the normally involved N-type or L-type VDCC, respectively. When the effect of Nitrendipine, an L-type VDCC blocker, was studied on ALS sera-injected mice, we found variable responses to the drug: only two mice showed control sensitivity to Nitrendipine, while in 7 its action was lower and surprisingly in 4 was greater than that without the drug. CONCLUSIONS: These results suggest that ALS sera contain factor(s) that are able to modify spontaneous neurotransmitter release by altering calcium current through L-type and N-type VDCC, and even inducing changes in the sensitivity to the L-type VDCC blocker.

Hydrolytic degradation of nitrendipine and nisoldipine.

The development of a new HPLC-UV diode array procedure applied to follow the hydrolytic degradation of two well-known 4-nitrophenyl-1,4-dihydropyridine derivatives, nitrendipine and nisoldipine is reported. Hydrolysis of each drug were carried out in ethanol/Britton-Robinson buffer at different pHs, stored into amber vials at controlled temperatures of 40, 60 and 80 degrees C and periodically sampled and assayed by HPLC. Nitrendipine degradation in different parenteral solutions was also evaluated. The HPLC procedure exhibited an adequate selectivity, repeatability (<1%) and reproducibility (<2%). The recoveries were higher than 98% with CV of 1.13 and 1.54% for nitrendipine and nisoldipine, respectively. A significant degradation was observed at alkaline pH (>pH 8) with a first order kinetic for both drugs. At pH 12, 80 degrees C, k values of 3.56x10(-2) x h(-1) and 2.22x10(-2) for nitrendipine and nisoldipine, respectively were obtained. Also, activation energies of 16.8 and 14.7 kcal x mol(-1) for nitrendipine and nisoldipine, respectively, were calculated. Furthermore, from the results obtained from hydrolytic degradation in different solutions for parenteral use, we can affirm that solutions significantly increased the degradation of nitrendipine. In conclusion, the HPLC proposed procedure exhibited adequate analytical requirements to be applied to the hydrolytic degradation studies of nitrendipine and nisoldipine. Furthermore, all tested parenteral solutions significantly increased the hydrolytic degradation of nitrendipine, the composition of solution being a relevant factor.

The influence of chloroethylclonidine-induced contraction in isolated arteries of Wistar Kyoto rats: alpha1D- and alpha1A-adrenoceptors, protein kinase C, and calcium influx.

BACKGROUND: It has recently been reported that chloroethylclonidine (CEC) elicited contraction in tail arteries (alpha(1A)-adrenoceptors) and aorta (alpha(1D)-adrenoceptors) from normotensive and spontaneously hypertensive rats (SHR). This study investigated the relationship between CEC-induced contraction and the role of protein kinase C (PKC) and extracellular Ca(++) influx in tail arteries and aorta from Wistar Kyoto rats (WKY). METHODS: Time-course of CEC-induced contraction in endothelium-denuded arteries from Wistar, WKY, and SHR rats was evaluated. In WKY arteries, calphostin C (1 x 10(-6) M) and nitrendipine (1 x 10(-6) M) were used to determine the role of PKC and extracellular Ca(+1) in the contractile response to CEC, respectively. RESULTS: Chloroethylclonidine (1 x 10(-4) M) elicited contraction in tail arteries and aorta from normotensive and hypertensive rats. Maximal response to CEC was similar in tail arteries among strains (approximately 30% of norepinephrine effect), while in aorta CEC elicited a higher contraction in WKY and SHR than in Wistar (59, 86, and 18% of norepinephrine effect, respectively). CEC-elicited maximal contractile responses were reached in 5 min in tail arteries and in 30-45 min in aorta irrespective of the rat strain, suggesting that different intracellular signaling pathways are involved in the contractile response to CEC in these arteries. In WKY tail arteries, calphostin C and nitrendipine blocked CEC-induced contraction while in aorta nitrendipine, but not calphostin C, inhibited CEC action. CONCLUSIONS: This study confirms marked strain-dependent differences in rat aorta responsiveness to CEC and suggests a central role for PKC in response to CEC in tail arteries and for extracellular Ca(+1) influx in aorta.

Coupling of L-type calcium channels to neurotransmitter release at mouse motor nerve terminals.

Previously, we have presented evidence for the presence of L-type voltage-dependent Ca2+ channels (VDCC) in 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, (acetoxymethyl)ester (BAPTA-AM)-incubated motor nerve terminals (MNTs) of the levator auris muscle of mature mice. The aim of the present work was to study the coupling of these L-type VDCC to neurotransmitter release by inhibiting protein phosphatases. We thus studied the effects of the protein phosphatase inhibitors okadaic acid (OA) and pervanadate on quantal content (QC) of transmitter release with the P/Q-type channels fully blocked. The QC was not significantly different under the three experimental conditions tested: incubation with dimethylsulphoxide (DMSO), ethylene-glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid, (acetoxymethyl)ester (EGTA-AM) and BAPTA-AM. After preincubation with OA (1 microM), but not with pervanadate, QC increased substantially in the BAPTA-AM-incubated (up to 400%) MNT, but not in those incubated with DMSO or EGTA-AM. The OA-induced increment of QC was attenuated greatly (approximately 95% reduction) by preincubation with either nitrendipine (10 microM) or calciseptine (300 nM). The effect of OA (1 microM) and pervanadate (0.1 mM) on spontaneous neurotransmitter release was also studied. After preincubation with OA, but not per-vanadate, miniature end-plate potential (MEPP) frequency increased only in the BAPTA-AM-incubated MNT (up to 700% increment). This response was attenuated (by approximately 80%) by nitrendipine (10 microM) or calciseptine (300 nM). In contrast, neither omega-agatoxin IVA (120 nM) nor omega-conotoxin GVIA (1 microM) affected this OA-induced increment significantly. We also evaluated the relationship between QC and extracellular [Ca2+] ([Ca2+]o) in BAPTA-AM-incubated MNT. Under conditions in which only P/Q-type VDCC were available to participate in neurotransmitter release, QC increased as [Ca2+]o was raised from 0.5 to 2 mM. However, when only L-type VDCC were available, QC increased when [Ca2+]o increased from 0.5 to 1 mM, but decreased significantly at 2 mM. The mean latency for P/Q-type VDCC-mediated EPP was 1.7-1.9 ms; for L-type VDCC-mediated EPP, 1.9-2.5 ms. The rise time of the L-type VDCC mediated EPP was significantly slower than that mediated by P/Q-type VDCC. Preincubation with H-7 (100 microM), a potent inhibitor of protein kinase C (PKC) and adenosine 3',5'cyclic monophosphate (cAMP)-dependent protein kinase (PKA), attenuated the OA-induced increment of both QC and MEPP frequency (50% and 70% decrement, respectively), suggesting the participation of at least these two protein kinases in the coupling of L-type VDCC. In summary, our results show coupling of L-type VDCC to neurotransmitter release when protein phosphatases are inhibited and intracellular [Ca2+] is buffered by the fast chelator BAPTA.

Papel de los calcio-antagonistas en el control de ventos vaso-oculsivos y hemolíticos en drepanocitosis: estudio piloto con nitrendipina / Paper of the calcium-antagonists in the control of events occlusives and hemoliticos in sickle cell disease: study pilot with nitrendipin

Recientemente se inició el estudio de fármacos capaces de inhibir la pérdida de agua y K+ del glóbulo rojo dependiente de Ca++, mediante el bloqueo del canal de gardos, como medida terapéutica para evitar el fenómeno de falciformación. Nuestro estudio intenta establecer el rol de la nitrendipina en el control de las manifestaciones clínicas y paraclínicas en drepanocitosis. Se realizó un estudio clínico controlado con placebo, randomizado, bajo protocolo simple ciego, de grupo en paralelo, con dos niveles de dosis, de 10 semanas de duración. Se incluyeron 26 pacientes (16 mujeres y 10 hombres) aleatoreamente distribuidos en tres grupos para recibir placebo o nitrendipina a 20 mg/día o nitrendipina a 30 mg/día. En ambos grupos de tratamiento con nitrendipina se apreció una tendencia hacia una menor frecuencia de eventos vaso-oclusivos con una menor proporción de pacientes afectados, pero sin lograr una diferencia estadísticamente significativa en las medias de evento por paciente, ni de intensidad medida en cada grupo. La nitrendipina logró una reducción significativa en el porcentaje de reticulocitos y en los niveles de bilirrubina indirecta basales en ambos niveles de dosis con respecto al placebo (comparación intergrupo e intragrupo: p<0.005). El resto de los parámentros no se modificaron. La droga fue bien tolerada. La nitrendipina redujo algunos marcadores de hemólisis (porcentaje de reticulocitos y BI). El verdadero potencial terapéutico de este agente debe ser confirmado en nuevos protocolos clínicos controlados

The use of calcium blockers to study biochemical behaviour of Saccharomyces cerevisiae cells.

Calcium channel blockers, currently used in clinical medicine, from the dihydropyridine class (nifedipine and nimodipine) were used to study biochemical behaviour of Saccharomyces cerevisiae cells. At a concentration of 200 microM, both drugs partially blocked calcium uptake from an extracellular medium. On the other hand, nifedipine (300 microM) induced a collapse of the membrane potential (delta psi) of these cells, while nimodipine, at the same concentration, produced a similar but less intense effect. Probably, the small difference in the chemical structure between these drugs may explain the same effect with different intensity. With these experiments was possible to observe that these microorganisms have type 'L' calcium channels.

Amyotrophic lateral sclerosis IgG-treated neuromuscular junctions develop sensitivity to L-type calcium channel blocker.

In order to search for early changes induced by the application of human immunoglobulin G (IgG) on motor nerve terminals, IgG from patients with amyotrophic lateral sclerosis (ALS) and control subjects was injected subcutaneously into the levator auris muscle of mice. A week or a month after the last injection, endplate potentials were recorded. No changes in quantal content of transmitter release were observed. In control and ALS IgG-treated muscles, neurotransmitter release remained sensitive to P/Q-type and insensitive to N-type voltage-sensitive calcium channel (VSCC) blockers as in untreated muscles. In contrast, IgG from 5 of 8 different ALS patients induced a significant reduction in quantal content of the evoked response after incubation with nitrendipine, indicating that a novel sensitivity to this calcium channel blocker appears in these motor nerve terminals. These results indicate that ALS IgG induces plastic changes at nerve terminals. The expression of transmitter release coupled to L-type VSCC indicate that ALS IgGs are capable of inducing plastic changes at the nerve terminals that may participate in the process leading to neuronal death.

Damaging effects of the calcium paradox are reduced in isolated hearts from ethanol-dependent rats: paradoxic effects of dihydropyridine drugs.

Previous experiments showed that isolated hearts from ethanol-exposed rats show a marked increase in sensitivity to anoxic myocardial damage, and we suggested that this may be due to excess calcium entry through L-type voltage-operated calcium channels (L-VOCCs). To challenge this hypothesis, we investigated the effect of ethanol treatment ex vivo on a damaging stimulus, the "calcium paradox," which is associated with removal of calcium from the perfusate. Adult male Sprague-Dawley rats were exposed to intoxicating concentrations of ethanol for 6-10 days by inhalation. Isolated hearts from these animals were perfused with Krebs-Henseleit buffer by using a modified Langendorff technique, and the calcium paradox induced by a 10-min period of perfusion with calcium-free buffer, followed by reperfusion with calcium-containing buffer. Compared with controls, hearts from ethanol-exposed rats were significantly protected against myocardial damage, as shown by a marked reduction in release of intracellular proteins (lactate dehydrogenase, creatine phosphokinase, and myoglobin) during the reperfusion phase. These indices of myocardial damage were modified by the presence of the dihydropyridine (DHP) calcium channel antagonist nitrendipine (10(-6) M) and the DHP L-VOCC activator Bay K 8644 (10(-7) M) in the perfusate during the calcium paradox. Paradoxically, both drugs appeared to increase the damaging effects of calcium-free perfusion, with this effect being generally greater in the preparations from ethanol-exposed rats. As a result, the difference between these hearts and those from control rats was reduced, although a significant degree of protection against the calcium paradox remained. The results support the hypothesis that long-term exposure to ethanol in vivo produces marked alterations in the toxic effects of changes in myocardial calcium concentration. The increased sensitivity to DHP drugs of isolated hearts from ethanol-treated rats is consistent with previous experiments showing increased DHP radioligand-binding sites in these tissues.

Increased sensitivity to damaging effects of hypoxia and anoxia of isolated hearts from rats after prolonged exposure to ethanol: apparent protection by nitrendipine.

The studies described here investigate whether pathologic states that are thought to cause myocardial damage through excess calcium entry (i.e., hypoxia and anoxia) indeed cause greater damage in hearts from ethanol-exposed animals, and whether L-type voltage-operated calcium channels (L-VOCCs) are implicated. Adult male Sprague-Dawley rats were exposed to intoxicating concentrations of ethanol vapor for 6-10 days, and their isolated hearts compared with those of control animals in a Langendorff perfusion system. Hypoxia was induced by perfusion with Krebs-Henseleit buffer, which had not previously been bubbled with oxygen; anoxia was produced by perfusion with buffer bubbled with nitrogen. On reperfusion with oxygenated buffer, evidence of myocardial damage during the hypoxic/anoxic period was obtained by the release of intracellular proteins into the perfusate. After hypoxia, release of myoglobin (MYO) was significantly greater from hearts from ethanol-exposed rats than from controls; other indices of myocardial damage also were increased by hypoxia but did not differ significantly between treatment groups. After anoxic perfusion, release of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) as well as MYO were all markedly and significantly increased from ethanol-exposed hearts compared with those from control rats. The role of L-VOCCs in this damage was assessed with the calcium channel antagonist nitrendipine (10(-6) M) present in the perfusing buffer immediately before and during the anoxic stimulus. This completely reversed the situation so that preparations from ethanol-exposed rats now showed a reduced release of intracellular proteins compared with hearts from controls. Comparisons with absolute values from the previous experiments suggest that nitrendipine increased release of LDH and CPK from control hearts with little effect on these indices from ethanol-exposed hearts. However, in the case of anoxia-induced MYO release, nitrendipine markedly and significantly reduced this in hearts from ethanol-treated rats but had only a very small effect on the same parameter in controls. The results strongly suggest increased pathologic effects of hypoxia/anoxia in hearts from ethanol-exposed rats. This increased sensitivity may be at least partly a consequence of increased numbers of L-VOCCs in this tissue.

Effects of prolonged exposure to ethanol in vivo on functional parameters and sensitivity to nitrendipine in the isolated rat heart.

This study investigated the possibility that previously reported marked upregulation of binding sites for the dihydropyridine calcium channel antagonist nitrendipine in heart tissue during the development of ethanol dependence in the rat may represent functional L-type voltage-operated calcium channels (L-VOCCs). Isolated hearts obtained from adult Sprague-Dawley rats, which received intoxicating concentrations of ethanol for 6-10 days, by inhalation, were perfused with Krebs-Henseleit solution in the Langendorff mode. Basic measurements of cardiac function were compared with hearts from control rats not exposed to ethanol vapor. In another study, concentration-response curves were constructed for nitrendipine at concentrations in the range of 10(-10)-10(-6) M for hearts obtained from control and ethanol-exposed animals. Changes in measured cardiac parameters such as R-wave amplitude, heart rate, diastolic and systolic pressure, and (+)dP/dt(max) and coronary flow were recorded. All comparisons were made between preparations set to a similar left ventricular end-diastolic pressure. Under these conditions, there were no significant differences in R-wave amplitude, but isolated hearts from ethanol-dependent rats showed significantly greater indices of myocardial contraction than did controls. These included increased systolic and developed ventricular pressure and increased (+)dP/dt(max). Coronary flow also was significantly greater in hearts from ethanol-dependent rats compared with controls. Heart rate was higher in the alcohol-exposed group, but this difference did not achieve significance. When nitrendipine was added to the perfusate at concentrations between 10(-10) and 10(-6) M, hearts from ethanol-dependent animals showed a greater sensitivity to the effects of the drug on heart rate and systolic pressure. Effects on R-wave amplitude and (+)dP/dt(max) were less clear but also suggested a greater sensitivity to nitrendipine in hearts from ethanol-exposed rats. Effects on coronary flow were small and did not differ significantly between preparations from control and ethanol-dependent rats. The results suggest that the increase in Bmax of DHP binding previously observed in hearts from ethanol-dependent animals might represent an increase in L-VOCCs, which alters physiologic function, and pharmacologic responses in the isolated heart. These changes may represent the exposure of an adaptive mechanism designed to overcome the generally depressant effects of ethanol on cardiac function in vivo.

L-type calcium channels unmasked by cell-permeant Ca2+ buffer at mouse motor nerve terminals.

The involvement of the different types of voltage-dependent calcium channels (VDCC) in both DM-BAPTA-AM-incubated and EGTA-AM-incubated mature mice levator auris neuromuscular junctions (NMJ) was studied. We evaluated the effects of omega-agatoxin IVA (omega-Aga IVA), nitrendipine and omega-conotoxin GVIA (omega-CgTX) (P/Q-, L- and N-type VDCC blockers, respectively) on perineurial calcium currents (ICa) and nerve-evoked transmitter release. The application of omega-Aga IVA (100 nM) drastically reduced perineurial ICa (>90%) and nerve-evoked transmitter release (>90% of reduction in quantal content, m) at both DM-BAPTA-AM-incubated and EGTA-AM-incubated NMJ. The L-type VDCC antagonist nitrendipine (10 microM) caused a significant reduction (23+/-9%, n=5) of perineurial ICa at DM-BAPTA-AM-incubated NMJ. In addition, after the block of P/Q-type VDCC with omega-Aga IVA (100 nM), nitrendipine reduced (>90%, n=2) the remaining perineurial ICa. Such reduction was not observed at EGTA-AM-incubated NMJ, before or after the total block of P/Q-type VDCC. Moreover, nitrendipine did not significantly reduce the quantal content of DM-BAPTA-AM-incubated NMJ. Finally, the application of omega-CgTX (5 microM) did not significantly affect perineurial ICa or nerve-evoked transmitter release at either DM-BAPTA-AM-incubated or EGTA-AM-incubated NMJ. These results show the existence of a nitrendipine-sensitive, L-type component of perineurial ICa in DM-BAPTA-AM-incubated NMJ of mature mice.

Calcium channels coupled to neurotransmitter release at neonatal rat neuromuscular junctions.

1. The effects of different calcium channel blockers (omega-agatoxin IVA (omega-Aga IVA), omega-conotoxin GVIA (omega-CgTx GVIA) and dihydropyridines) were tested on spontaneous and evoked transmitter release at embryonic and newborn rat neuromuscular junctions (NMJs). 2. The nerve-evoked transmitter release quantal content (m) was strongly reduced by the P/Q-type voltage-dependent calcium channel (VDCC) blocker omega-Aga IVA (100 nM) at newly formed endplates of embryos and 0- to 11-day-old rats, in agreement with the effect of this blocker on transmitter release at mature and reinnervating muscles. 3. omega-CgTx GVIA (1-5 microM), the N-type VDCC blocker, also caused a significant reduction in m at newly formed NMJs early in development (embryos and 0- to 4-day-old rats), while it was ineffective in more mature animals (5- to 11-day-old rats). 4. L-type channel blockers, nitrendipine (1 microM) and nifedipine (1 microM), did not significantly affect neurally evoked release at developing NMJs. However, nifedipine (10 microM) was able to increase m significantly at 0- to 4-day-old rat NMJs. 5. At developing NMJs, K+-evoked transmitter release was dependent on Ca2+ entry through VDCCs of the P/Q-type family (100 nM omega-Aga IVA reduced 70 % of the K+-evoked miniature endplate potential frequency). N- and L-type VDCC blockers did not affect this type of release. 6. We conclude that at rat neuromuscular junctions the presynaptic calcium channel types involved in transmitter release undergo developmental changes during the early postnatal period.

Eficacia de la nitrendipina en pacientes obesos hipertensos / Nitrendipine in obese hipertensive patients

La obesidad puede producir resistencia a la terapia antihipertensiva. La nitrendipina es un bloqueador de los canales del calcio de la familia de las dihidropiridinas, es efectivo en el manejo de la hipertensión arterial y ha demostrado mejorar la sensibilidad a la insulina. Para evaluar la eficacia de la nitrendipina en el control de la presión arterial del paciente hipertenso obeso, 20 pacientes adultos no diabéticos, obesos hipertenso obeso, 20 pacientes adultos no diabéticos, obesos hipertensos que no controlaron su presión arterial con modificaciones al estilo de vida pero sin manejo farmacológico, recibieron tratamiento farmacológico con 10 mg de nitrendipina una vez al día durante cuatro semanas. En todos los pacientes se realizó una prueba de tolerancia a la glucosa antes y después del estudio. Todos los pacientes redujeron la presión arterial a las dos semanas, persistiendo el control hasta el final del estudio. (p< 0.0001). La nitrendipina también mejoró significativamente la tolerancia a la glucosa de esos pacientes, especialmente a los 30 (p< 0.0008), 60 (p< 0.009) y 90 (p< 0.09) minutos, aunque no se observó cambio significativo a los 120 minutos (p> 0.2). Estos resultados sugieren que la nitrendipina tiene eficacia terapéutica como monoterapia en sujetos hipertensos obesos, no diabéticos con resistencia a la insulina

Parathyroid hormone stimulates calcium influx and the cAMP messenger system in rat enterocytes.

Direct effects of parathyroid hormone (PTH) on calcium uptake by isolated rat duodenal cell preparations enriched in enterocytes were investigated. PTH significantly stimulated enterocyte 45Ca2+ influx in a time-dependent (1-10 min) manner and at all doses tested (2 x 10(-13) to 10(-7) M). The Ca2+ channel antagonists verapamil (10 microM) and nitrendipine (1 microM) completely blocked the stimulation of Ca2+ influx by the hormone (10(-8) M). PTH markedly increased cAMP levels in rat duodenal cells (88, 167, and 67%, after 1, 2, and 3 min, respectively). In agreement with these observations, forskolin (adenylate cyclase activator), dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), and Sp-cAMPS (cAMP analogs) mimicked, whereas Rp-cAMPS (cAMP antagonist) suppressed PTH and DBcAMP activation of enterocyte calcium uptake. Furthermore, the effects of DBcAMP were abolished by nitrendipine. These results show direct rapid effects of PTH on duodenal cells' Ca2+ influx, which involve the activation of a dihydropyridine-sensitive Ca2+ influx pathway and the cAMP second messenger system.

Hipertensión renovascular y soplo abdominal en un caso: ¿ha modificado la tecnología su interpretación? / Renovascular hipertension and abdominal bruit: diagnostic implications of modern technological assessments: report of one case

A lateral abdominal bruit is considered an important finding for the detection of renovascular hypertension. However, the precision and accuracy of new techniques such as angiography, Doppler ultrasound and studies with radioisotopes have changed its value and clinical interpretation. We report a 75 years old woman with a bilateral renal artery stenosis in whom a bruit was heard over the artery that did not contribute to the genesis of hypertension and the significant arterial stenosis causing hypertension was silent. This particular situation could lead to erroneous clinical decisions

Conversión de sandimmune a neoral en pacientes trasplantados renales que reciben ciclosporina-ketoconazol / Conversion of sandimmune to neoral in patients with renal transplantation treated with cyclosporine-ketoconazol

Patients and methods: Thirty four patients with more than one year after the transplantation, with stable renal function and receiving triple immunosuppression were studied. Conventional cyclosporine was changed to the microemulsion form maintaining the same daily dose. Drug serum levels, serum creatinine and blood pressure were measured within two to eight months after the conversion. Doses of microemulsion cyclosporine were adjusted to achieve serum levels of 150 ñ 40 ng/ml. Results: Microemulsion cyclosporine induced a slight initial increase in blood cyclosporine levels. Afterwards, levels were more stable than with conventional cyclosporine (165-185 and 145-210 ng/ml respectively) and the dispersion of values were lower (standard deviations of 70 and 100 ng/ml respectively). Twenty three patients did not require dose adjustments, in four it was reduced and in five it was increased. There were no changes in serum creatinine or blood pressure after the conversion. Conslusion: More stable serum levels without adverse reactions were obtained with microemulsion cyclosporine. Doses of cyclos porine need not to be changed during the conversion

Calcioantagonistas en gineco-obstetricia / Calcium antagonists in gynecobstetrics

Los calcioantagonistas tiene una serie de efectos sobre la musculatura lisa de los vasos y también sobre otra musculatura lisa como es la del útero. En el presente trabajo se revisa la farmacología de los diferentes agentes así como sus efectos sobre el útero y el feto. También se plantea los usos que pueden tener estos agentes y su rol en una patología importante de la gestación, como es la hipertensión.