Kegg Pathway: Calcium channel-blocking drugs

Rev Prat. 2008 Apr 30; 58(8): 844-8
Bédry R

New antidotes appeared in the French pharmacopoeia (fomepizole, Viperfav), and old drugs, usually unused in toxicology, saw their indications enlarged in an antidotic activity (glucose and insulin, L-carnitine, octreotide). Fomepizole is an antidote for toxic alcohol and glycol intoxications, which is much easier to handle than ethylic alcohol and as efficient as the classical antidote of this kind of intoxication. Octreotide improves the result of hypertonic glucose infusion in sulfonylurea derivatives intoxications, by blocking insulin release. The glucose-insulin association allows the myocardium to use the main energy substrate necessary for its action in the setting of beta-blocking and Calcium channel blocking agents intoxications when they are associated to a cardiogenic shock. Viperfav is a polyvalent antivenom used in European adders envenomations, which showed its effectiveness and safety. Levocarnitine allows to correct the wrong metabolic pathway induced by a deficit in carnitine in valproïc acid intoxications.

Prescrire Int. 2008 Jun; 15(33): 115-8

(1) Reliable evidence supports the use of thiazide diuretics (chlortalidone or hydrochlorothiazide) as first-line treatment for uncomplicated arterial hypertension. (2) When patients fail to reach blood pressure targets with well-conducted treatment with thiazide diuretics, or this treatment is poorly tolerated, what are the best second-line options? To answer this question, we reviewed the available evidence, based on our standard in-house methodology. (3) We found no published trials specifically designed to evaluate second-line antihypertensive treatments in cardiovascular prevention. There were no available trials of dual- versus single-agent therapy after failure of a thiazide diuretic. (4) When the blood pressure target is not reached, inadequate drug efficacy is only one of several possible causes. Various other factors affecting blood pressure should also be investigated. (5) Dual-agent therapy carries an increased risk of adverse effects and drug interactions compared to monotherapy. (6) There is no consensus among clinical practice guidelines on second-line antihypertensive therapy. However, to minimise the risk of adverse effects, it is clearly better to select single-agent therapy with a drug that has been shown to prevent cardiovascular events in first-line treatment of otherwise healthy hypertensive patients. Possible options include: angiotensin-converting-enzyme inhibitors, angiotensin II antagonists, Calcium channel blockers or betablockers. In patients over the age of 60, betablockers seem less effective that the other drugs in preventing strokes. (7) There is too little evidence to choose a specific third-line combination rather than another. However, any adverse effects that the patient experienced during prior treatments should be taken into account.

Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2008 Mar; 43(3): 208-12
Guo CK, Li GQ, Kong WJ, Zhang S, Wu TT, Li JL, Li QT

OBJECTIVE: To explore the mechanisms of the influx of Calcium ions during the activation of ACh-sensitive BK channel (big conductance, Calcium-dependent potassium channel) in type II vestibular hair cells of guinea pigs. METHODS: Type II vestibular hair cells were isolated by collagenase type IA. Under the whole-cell patch mode, the sensitivity of ACh-sensitive BK current to the Calcium channels blockers was investigated, the pharmacological property of L-type Calcium channel activator-sensitive current and ACh-sensitive BK current was compared. RESULTS: Following application of ACh, type II vestibular hair cells displayed a sustained outward potassium current, with a reversal potential of (-70.5 +/- 10.6) mV (x +/- s, n = 10). At the holding potential of -50 mV, the current amplitude of ACh-sensitive potassium current activated by 100 micromol/L ACh was (267 +/- 106) pA (n = 11). ACh-sensitive potassium current was potently sensitive to the BK current blocker, IBTX (iberiotoxin, 200 nmol/L). Apamin, the well-known small conductance, Calcium-dependent potassium current blocker, failed to inhibit the amplitude of ACh-sensitive potassium current at a dose of 1 micromol/L. ACh-sensitive BK current was sensitive to NiCl2 and potently inhibited by CdCl2. NiCl2 and CdCl2 showed a dose-dependent blocking effect with a half inhibition-maximal response of (135.5 +/- 18.5) micromol/L (n = 7) and (23.4 +/- 2.6) micromol/L (n = 7). The L-type Calcium channel activator, (-) -Bay-K 8644 (10 micromol /L), mimicked the role of ACh and activated the IBTX-sensitive outward current. CONCLUSION: ACh-sensitive BK and L-type Calcium channels are co-located in type II vestibular hair cells of guinea pigs.

J Biol Chem. 2008 Jul 15;
Murakami M, Ohba T, Xu F, Satoh E, Miyoshi I, Suzuki T, Takahashi Y, Takahashi E, Watanabe H, Ono K, Sasano H, Kasai N, Ito H, Iijima T

N-type voltage-dependent Calcium channels (VDCCs) play determining roles in Calcium entry at sympathetic nerve terminals and trigger the release of the neurotransmitter norepinephrine. The accessory beta3 subunit of these channels preferentially forms N-type channels with a pore-forming CaV2.2 subunit. To examine its role in sympathetic nerve regulation, we established a beta3-over-expressing transgenic (beta3-Tg) mouse line. In these mice, we analyzed cardiovascular functions such as ECG, blood pressure, echocardiography, and isovolumic contraction of the left ventricle, with a Langendorff apparatus. Furthermore, we compared the cardiac function with that of beta3-null and CaV2.2 (alpha1B)-null mice. The beta3-Tg mice showed increased expression of the beta3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The beta3-Tg mice had increased heart rate and enhanced sensitivity to N-type channel specific blockers in ECG, blood pressure, and echocardiography. In contrast, cardiac atria of the beta3-Tg mice revealed normal contractility to isoproterenol. Furthermore, their cardiac myocytes showed normal Calcium channel currents, indicating unchanged Calcium influx through VDCCs. Langendorff heart perfusion analysis revealed enhanced sensitivity to electric field stimulation in the beta3-Tg mice, whereas beta3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the beta3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of beta3-Tg mice revealed increased Calcium channel currents, especially N- and L-type currents. These results identify a determining role for the beta3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.

Kardiol Pol. 2008 Jun; 66(6): 642-649
Banasiak W, Wilkins A, Pociupany R, Ponikowski P

Background: Comprehension of therapeutic methods in patients with stable coronary artery disease (CAD) is mandatory for the introduction of successful prevention. Aim:To gather information regarding individuals with stable coronary artery disease treated by specialists and general practitioners on an outpatient basis. Methods: A representative group of 215 general practitioners and 67 specialists participated in this study. The analysis contains data concerning pharmacotherapy in a group of 2,593 patients with stable CAD (mean age - 65.0+/-9.8 years, women - 44.6%). Results: The patients received the following treatment: acetylsalicylic acid - 75.3%, other antiplatelet drugs - 6.6% (antiplatelet drugs altogether - 81.9%), beta-blockers - 81.1%, ACE-I - 78.8%, statins - 71.9%, fibrates - 4.7%, long-acting nitrates - 53.0%, short--acting nitrates - 33.1%, molsidomine - 18.2%, Calcium channel blockers - 23.8%, metabolic drugs (trimetazidine) - 13.4%, diuretics - 43.5%, and angiotensin receptor antagonists - 1.7% of patients. drugs classified as non-cardiological were received by 36.2% of patients. The optimal pharmacotherapy including four medications, one from each therapeutic class used in order to improve the prognosis of the patient (an antiplatelet drug, a beta-blocker, an ACE-I, statin), was received by a total of 45.8% of the participants, three medications by 31.7%, two medications by 15.8%, and one medication by 5.5%; 1.2% of the participants did not receive any medication from the four groups of drugs improving prognosis. What is worth noting, however, is the use of relatively small doses of ACE-I and beta-blockers. 69.9% of patients also received at least one symptomatic drug (a long-acting nitrate, a Calcium channel blocker, a metabolic drug, molsidomine), including 39.7% - 1 drug, 22.7% - 2 drugs, 6.7% - 3 drugs, and 0.8% - 4 drugs from the classes mentioned above. Conclusions: The results of the RECENT study indicate that great progress has been made in the pharmacotherapy of CAD in Poland within the last few years. Currently, the majority of patients receive drugs that improve prognosis. The awareness of the benefits of the use of combined treatment with all the drug groups and their appropriate doses should be higher. The significant percentage of patients with persisting symptoms of angina pectoris indicates the necessity to improve the efficacy of intervention also in this respect.

Medicine (Baltimore). 2008 Jul; 87(4): 220-233
Montani D, Achouh L, Dorfmüller P, Le Pavec J, Sztrymf B, Tchérakian C, Rabiller A, Haque R, Sitbon O, Jaïs X, Dartevelle P, Maître S, Capron F, Musset D, Simonneau G, Humbert M

Pulmonary veno-occlusive disease (PVOD) is defined by specific pathologic changes of the pulmonary veins. A definite diagnosis of PVOD thus requires a lung biopsy or pathologic examination of pulmonary explants or postmortem lung samples. However, lung biopsy is hazardous in patients with severe pulmonary hypertension, and there is a need for noninvasive diagnostic tools in this patient population. Patients with PVOD may be refractory to pulmonary arterial hypertension (PAH)-specific therapy and may even deteriorate with it. It is important to identify such patients as soon as possible, because they should be treated cautiously and considered for lung transplantation if eligible. High-resolution computed tomography of the chest can suggest PVOD in the setting of pulmonary hypertension when it shows nodular ground-glass opacities, septal lines, lymph node enlargement, and pleural effusion. Similarly, occult alveolar hemorrhage found on bronchoalveolar lavage in patients with pulmonary hypertension is associated with PVOD. We conducted the current study to identify additional clinical, functional, and hemodynamic characteristics of PVOD.We retrospectively reviewed 48 cases of severe pulmonary hypertension: 24 patients with histologic evidence of PVOD and 24 randomly selected patients with idiopathic, familial, or anorexigen-associated PAH and no evidence of PVOD after meticulous lung pathologic evaluation. We compared clinical and radiologic findings, pulmonary function, and hemodynamics at presentation, as well as outcomes after the initiation of PAH therapy in both groups.Compared to PAH, PVOD was characterized by a higher male:female ratio and higher tobacco exposure (p < 0.01). Clinical presentation was similar except for a lower body mass index (p < 0.02) in patients with PVOD. At baseline, PVOD patients had significantly lower partial pressure of arterial oxygen (PaO2), diffusing lung capacity of carbon monoxide/alveolar volume (DLCO/VA), and oxygen saturation nadir during the 6-minute walk test (all p < 0.01). Hemodynamic parameters showed a lower mean systemic arterial pressure (p < 0.01) and right atrial pressure (p < 0.05), but no difference in pulmonary capillary wedge pressure. Four bone morphogenetic protein receptor II (BMPR2) mutations have been previously described in PVOD patients; in the current study we describe 2 additional cases of BMPR2 mutation in PVOD. Computed tomography of the chest revealed nodular and ground-glass opacities, septal lines, and lymph node enlargement more frequently in patients with PVOD compared with patients with PAH (all p < 0.05). Among the 16 PVOD patients who received PAH-specific therapy, 7 (43.8%) developed pulmonary edema (mostly with continuous intravenous epoprostenol, but also with oral bosentan and oral Calcium channel blockers) at a median of 9 days after treatment initiation. Acute vasodilator testing with nitric oxide and clinical, functional, or hemodynamic characteristics were not predictive of the subsequent occurrence of pulmonary edema on treatment. Clinical outcomes of PVOD patients were worse than those of PAH patients.

Bioorg Med Chem Lett. 2008 Jun 14;
Lee HK, Lee YS, Roh EJ, Rhim H, Lee JY, Shin KJ

We have synthesized and evaluated alpha,alpha'-disubstituted phenylacetate derivatives that were designed as T-type Calcium channel blockers. Among them, compound 10e (IC(50)=8.17+/-0.48nM) showed the most potent T-type Calcium current blocking activity and higher potency than Mibefradil (IC(50)=1.34+/-0.49muM). The PK profile and subtype selectivity over L-type Calcium channel were satisfied for further animal assay using disease model.

Curr Diab Rep. 2008 Jun; 8(3): 214-20
Deshmukh M, Lee HW, McFarlane SI, Whaley-Connell A

Hypertension and hyperlipidemia are interrelated and share common pathophysiologic mechanisms, such as insulin resistance and endothelial dysfunction. Accumulating evidence shows that it is important to regulate hypertension and hyperlipidemia to reduce cardiovascular risk. However, medications such as beta-blockers and thiazide diuretics, which are widely used for blood pressure regulation, are known to have several metabolic side effects. Despite deleterious effects on glucose metabolism and lipid metabolism, these medications have been proven to reduce cardiovascular risk. On the other hand, Calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers have either no effect or favorable effects on the lipid profile. This review outlines the need to control hypertension, options for several antihypertensive medications, their differing effects on lipid metabolism, and the clinical implications of their effects on lipid parameters.

J Cell Mol Med. 2008 Jun 28;
Dong Y, Wu Y, Wu M, Wang S, Zhang J, Xie Z, Xu J, Song P, Wilson K, Zhao Z, Lyons T, Zou MH

Background: Oxidation and glycation of low-density lipoprotein (LDL) promote vascular injury in diabetes; however, the mechanisms underlying this effect remain poorly defined. The present study was conducted to determine the effects of "heavily oxidized" glycated LDL (HOG-LDL) on endothelial nitric oxide synthase (eNOS) function. Methods and Results: Exposure of bovine aortic endothelial cells (BAECs) with HOG-LDL reduced eNOS protein levels in a concentration- and time-dependent manner, without altering eNOS mRNA levels. Reduced eNOS protein levels were accompanied by an increase in intracellular Ca(2+), augmented production of reactive oxygen species (ROS), and induction of Ca(2+)-dependent calpain activity. Neither eNOS reduction nor any of these other effects were observed in cells exposed to native LDL. Reduction of intracellular Ca(2+) levels abolished eNOS reduction by HOG-LDL, as did pharmacological or genetic through Calcium channel blockers or Calcium chelator BAPTA or inhibition of NAD(P)H oxidase (with apocynin) or inhibition of calpain (calpain 1-specific siRNA). Consistent with these results, HOG-LDL impaired acetylcholine-induced endothelium-dependent vasorelaxation of isolated mouse aortas, and pharmacological inhibition of calpain prevented this effect. Conclusions: HOG-LDL may impair endothelial function by inducing calpain[0]-mediated eNOS degradation in a ROS- and Ca(2+)-dependent manner.

Planta. 2008 Jul 8;
Gueta-Dahan Y, Avsian-Kretchmer O, Ben-Hayyim G

Detrimental effects of salinity on plants are known to be partially alleviated by external Ca(2+). Previously we demonstrated that in citrus cells, phospholipid hydroperoxide glutathione peroxidase (GPX1) is induced by salt and its activation can be monitored by pGPX1::GUS fusion in transformed tobacco cells. In this paper we further characterized the induction of GPX1 by additional treatments, which are known to affect Ca(2+) transport. Omission of Ca(2+) changed the pattern of the transient salt-induced expression of GPX1 and chelation of Ca(2+) by EGTA, or treatment with caffeine, abolished the salt-induced GPX1 transcript. On the other hand, La(3+) was found to be as potent as NaCl in inducing GPX1 transcription and the combined effect of La(3+) and NaCl seemed to be additive. Pharmacological perturbation of either external or internal Ca(2+) pools by La(3+), EGTA, caffeine, Ca(2+) channel blockers, or a Ca(2+)-ATPase inhibitor rendered the imposed salt stress more severe. Except for La(3+), all these Ca(2+) effectors had no effect on their own. In addition, the fluidizer benzyl alcohol dramatically increased the NaCl-induced GPX1 transcription. Taken together, our results show that: 1) the mode of action of La(3+) on GPX1 expression differs from its established role as a Ca(2+) channel blocker, 2) membrane integrity has an important role in the perception of salt stress, and 3) internal stores of Ca(2+) are involved in activating GPX1 expression in response to salt stress. We propose that the common basis for these effects lies in the membrane bound Ca(2+).

J Clin Hypertens (Greenwich). 2008 Jul; 10(7): 567-74
Singer GM, Setaro JF

The epidemic of obesity in the United States and around the world is intensifying in severity and scope and has been implicated as an underlying mechanism in systemic hypertension. Obese hypertensive individuals characteristically exhibit volume congestion, relative elevation in heart rate, and high cardiac output with concomitant activation of the renin-angiotensin-aldosterone system. When the metabolic syndrome is present, insulin resistance and hyperinsulinemia may contribute to hypertension through diverse mechanisms. Blood pressure can be lowered when weight control measures are successful, using, for example, caloric restriction, aerobic exercise, weight loss drugs, or bariatric surgery. A major clinical challenge resides in converting short-term weight reduction into a sustained benefit. Pharmacotherapy for the obese hypertensive patient may require multiple agents, with an optimal regimen consisting of inhibitors of the renin-angiotensin-aldosterone system, thiazide diuretics, beta-blockers, and Calcium channel blockers if needed to attain contemporary blood pressure treatment goals. J Clin Hypertens (Greenwich). 2008;10:567-574.

Pharmazie. 2008 Jun; 63(6): 475-9
Xu L, Huang C, Chen J, Jiang X, Li X, Bett GC, Rasmusson RL, Wang S

As the major component of I(to) (slow), Kv1.4 channel plays an important role in repolarization of cardiac myocytes. C-type inactivation is one of Kv1.4 inactivation and can be affected by open channel blockers. We used the two-electrode voltage clamp technique to observe the effect of amiodarone on Kv1.4 C-type inactivation and compare amiodarone's effects on Kv1.4 with propafenone and verapamil. Our data show that those three antiarrhythmic drugs blocked fKv1.4 delta N (N-terminal deleted Kv1.4 channel from ferret heart) in voltage- and frequent-dependent manners. The amiodarone's IC50 was 489.23 +/- 4.72 microM, higher than that of propafenone (98.97 +/- 1.13 microM) and verapamil (263.26 +/- 6.89 microM) for fKv1.4 delta N channel (+50 mV). After application of amiodarone, propafenone and verapamil, fKv1.4 delta N inactivation becomes bi-exponential: the faster portion of inactivation (drug-induced inactivation) and the slower portion of inactivation (C-type inactivation). Amiodarone and verapamil fastened C-type inactivation in fKv1.4 delta N, but propafenone did not. Unlike propafenone that had no effect on fKv1.4 delta N recovery, amiodarone and verapamil slowed recovery in fKv1.4 delta N.

Pharmazie. 2008 Jun; 63(6): 470-4
Wang RX, Jiang WP, Li XR, Lai LH

OBJECTIVE: Amlodipine (Aml) has R- and S-isomers with different pharmacological effects. However, no data are available on the influence of (S)-Aml and (R)-Aml on L-type Calcium channel current (I(Ca-L)) or cytosolic Calcium (Ca2+). This study is to investigate effects on I(Ca-L) and cytosolic Ca2+. METHODS: I(Ca-L), peak currents, I-V curves, steady state activation curves, steady state inactivation curves and recovery curves from inactivation with (S)-Aml and (R)-Aml were recorded by whole-cell patch clamp configuration. Cytosolic Ca2+ of smooth muscle cells was assayed by Fura-2/AM. RESULTS: At the concentrations of 0.1, 0.5, 1, 5, and 10 micromol/L, 1.5 +/- 0.2%, 25.4 +/- 5.3%, 65.2 +/- 7.3%, 78.4 +/- 8.1%, and 94.2 +/- 5.0% of I(Ca-L) were blocked by (S)-Aml. I-V curves were shifted upward. Half-activation voltages were -16.01 +/- 1.65 mV, -17.61 +/- 1.60 mV, -20.17 +/- 1.46 mV, -21.87 +/- 1.69 mV and -24.09 +/- 1.87 mV (P < 0.05). Half-inactivation voltages were -27.16 +/- 4.48 mV, -28.69 +/- 4.52 mV, -31.19 +/- 4.17 mV, -32.63 +/- 4.34 mV and -35.16 +/- 4.46 mV (P < 0.05). Recovery time were prolonged gradually (P < 0.05). 10.3 +/- 1.2%, 35.2 +/- 3.5%, 60.1 +/- 5.0%, 78.9 +/- 6.1%, and 91.2 +/- 7.6% of cytosolic Ca2+ were reduced at different concentrations (P < 0.05). However, (R)-Aml at different concentrations had no effect on I(Ca-L) and cytosolic Ca2+ (P > 0.05). CONCLUSION: Only (S)-Aml has Calcium channel blockade activity, while (R)-Aml has none of the pharmacologic actions associated with CCBs.

Kathmandu Univ Med J (KUMJ). 2007 Apr-Jun; 5(2): 199-203
Patowary S

Introduction Aspirin has been used as an analgesic from time immemorial. But the recent advances on various aspects of it in reducing risk of various fatal and non fatal diseases warrant a re-look. Objective: This study has been undertaken to assess the anti inflammatory and analgesic action of aspirin and Nifedipine alone as well as in combination and their individual and synergistic effect as anti-inflammatory and analgesic drug. Materials and methods: The anti - inflammatory and anti - nociceptive effect of aspirin and nifedipine was studied in a group of albino rats of Sprague Dowly strain. Anti - inflammatory action of the drugs were tested in experimentally produced inflammatory model by injecting turpentine oil in to the synovial cavity of knee joint of rats and anti - nociceptive effect was studied by hot plate method . Results From the study it was observed that nifedipine alone was a better anti - inflammatory drug causing 40.10 percent reduction of experimentally produced inflammation in the studied rats on the 12th day of observation compared to aspirin alone(33.80 %) and aspirin - nifedipine combination (39.82%) but as an analgesic nifedipine alone (51.20%) was not found to be as effective as aspirin(88.96%) at 90 minutes of observation. However, when nifedipine was combined with aspirin, it potentiated the anti - nociceptive action of aspirin (107.64 %) at 90 minutes of observation which was statistically significant (P<0.01). Conclusion: The above finding demonstrated that the dose of Non Steroidal Anti - inflammatory drugs (NSAIDs) probably could be reduced when it is combined with Calcium Channel Blockers (CCBs) and thus the adverse effect of NSAIDs could be reduced considerably. Student's t test was applied for statistical analysis. Key words: Anti inflammatory, anti - nociceptive, synergistic action.

Neurosci Res. 2008 Jun 17;
Kononenko NI, Honma S, Dudek FE, Honma KI

The master circadian clock of mammals in the suprachiasmatic nucleus (SCN) of the hypothalamus entrains to a 24-h daily light-dark cycle and regulates circadian rhythms. The SCN is composed of multiple neurons with cell autonomous clocks exhibiting robust firing rhythms with a high firing rate during the subjective day. The membrane target(s) of the cellular clock responsible for circadian modulation of the firing rate in SCN neurons still remain unclear. Previously, L-type Ca(2+) currents and fast delayed rectifier (FDR) K(+) currents have been suggested to contribute directly to circadian modulation of electrical activity. Using long-term continuous recording of activity from dispersed rat SCN neurons in multielectrode dish and ionic channel blockers, we tested these hypotheses. Neither an L-type Ca(2+) current blocker (20muM of nifedipine for 2 days) nor an FDR current blocker (500muM of 4-aminopyridine (4-AP) for 4 days) suppressed the circadian modulation of firing rate. A specific blocker of Na(+) persistent current (5muM of riluzole for 1 day followed by 10muM during the next day) reversibly suppressed firing activity in a dose-dependent manner. These data indicate that neither nifedipine-sensitive Ca(2+) current(s) nor 4-AP-sensitive K(+) current(s) are key membrane targets for circadian modulation of electrical firing rate in SCN neurons.

Am J Hypertens. 2008 Jul 3;
Hermida RC, Ayala DE, Mojón A, Fernández JR

BackgroundPrevious studies have shown that the circadian pattern of blood pressure (BP) remains unchanged after either morning or evening dosing of several Calcium-channel blockers (CCBs), including amlodipine, isradipine, verapamil, nitrendipine, and cilnidipine. This trial investigated the administration-time dependent antihypertensive efficacy of the slow-release, once-a-day nifedipine gastrointestinal-therapeutic-system (GITS) formulation.MethodsWe studied 180 untreated hypertensives (86 men and 94 women), 52.5 +/- 10.7 years of age, randomly assigned to receive nifedipine (30 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured for 48 h before and after 8 weeks of treatment.ResultsThe BP reduction after treatment was significantly larger with bedtime dosing mainly during night time sleep (P < 0.012). The number of patients with controlled ambulatory BP after treatment was greater with bedtime than morning treatment (P = 0.016). The baseline prevalence of nondipping was unaltered after ingestion of nifedipine on awakening, but reduced from 51 to 35% after bedtime dosing (P = 0.025). The morning surge of BP, a risk factor for stroke, was significantly reduced (P < 0.001) only after bedtime administration of nifedipine. Bedtime in comparison to awakening-time ingestion of nifedipine was also associated with a reduction in the incidence of edema from 13 to 1% (P < 0.001).ConclusionsThe increased efficacy on ambulatory BP as well as the significantly reduced prevalence of edema after bedtime as compared to morning ingestion of nifedipine should be taken into account when prescribing this medication to patients with essential hypertension.American Journal of Hypertension (2008). doi 10.1038/ajh.2008.216American Journal of Hypertension (2008). doi 10.1038/ajh.2008.216.

Minerva Endocrinol. 2008 Jul 3;
Mazza A, Armigliato M, Zamboni S, Rempelou P, Rubello D, Pessina AC, Casiglia E

This review describes the therapeutic approach of endocrine arterial hypertension in clinical practice. In mineralocorticoid-related hypertension, adrenalectomy is the treatment of choice for aldosterone-producing adenomas and monolateral primary aldosteronism, whereas pharmacologic blood pressure (BP) control is indicated for the other forms of primary aldosteronism such as bilateral adrenal hyperplasia. Spironolactone is the drug of choice, but intolerable side effects limit its use; amiloride or eplerenone are a valid alternative. If BP remains uncontrolled, angiotensin converting enzyme inhibitors (ACE-I), angiotensin II receptor antagonists (AII-RA) and Calcium channel blockers (CCB) may be added. Hypertension accompanying Cushing's syndrome can be approached with surgery, but antihypertensive treatment both pre- and postoperative is required as well. Eplerenone, AII-RA and ACE-I are indicated, while peroxisome proliferator activated receptor gamma-agonists may help for the insulin resistance syndrome. drugs that suppress steroidogenesis should be used with care because of their serious side effects. Subjects with catecholamine-dependent hypertension due to a neuroendocrine neoplasm need to undergo preoperative alpha-adrenergic blockade with phenoxybenzamine or doxazozine. When adequate alpha-adrenergic blockade is achieved, beta-adrenergic blockade with low dose propranolol may be added. If target BP is not achieved, CCB and/or metyrosine are indicated. Laparoscopic adrenalectomy is the procedure of choice for solitary intra-adrenal neoplasms <8 cm. Acute hypertensive crises that may occur before or during surgery should be treated intravenously with sodium nitroprusside, phentolamine, nicardipine or labetalol. For malignant neoplasms, chemo- and radiopharmaceutical therapy may be considered.

Yakugaku Zasshi. 2008 Jul; 128(7): 1023-9
Yano T

Radiocontrast nephropathy (RCN) is a major complication after radiographical examination with iodinated contrast media (CM). Although little is known about the mechanism of RCN, a direct toxic action on renal cells and/or decrease in renal blood flow are considered to be implicated in the pathogenesis of the disease/the condition, A large number of vasodilatory agents, including endothelin antagonists, adenosine antagonists, atrial natriuretic peptide, Calcium channel blockers, dopamine, dopamine D1 receptor agonist fenoldopam, and prostaglandin E1 have been tried clinically to prevent RCN, however, most of them have failed. Although prophylactic effects of antioxidant N-acetylcysteine have recently been reported by several investigators, only hydration is a universally accepted protocol to prevent it. In our recent in vitro and in vivo study, we have elucidated that CM induced apoptosis of renal tubular cells through the reduction in Bcl-2 expression and the subsequent activation of caspase-9 and caspase-3. Moreover, we found that CM caused an increase in ceramide content in renal tubular cells, which leads to apoptosis by inhibiting the phosphorylation of Akt and cAMP responsive element binding protein (CREB) and the subsequent reduction in Bcl-2 expression. The inhibitor of ceramide synthase, fumonisin B1, reversed both the elevation of ceramide content and renal cell injury induced by CM. On the other hand, a prostacyclin analog beraprost prevented RCN in mice by the increase of endogenous cAMP and subsequent CREB phosphorylation resulted in enhancement of Bcl-2 expression. These findings suggest that ceramide synthesis inhibitor or beraprost is potentially useful for the prophylaxis of RCN.