Administration Of Minoxidil Research Articles

508 Hair follicle rejuvenation is induced by topical minoxidil administration in a humanized mouse model of androgenetic alopecia

508 Hair follicle rejuvenation is induced by topical minoxidil administration in a humanized mouse model of androgenetic alopecia

Split-scalp pilot study to evaluate effectiveness of Minoxidil 0,5% MMP® versus Topical Minoxidil 5% in the treatment of Female Pattern Hair Loss.

Female Pattern Hair Loss (FPHL) is a common form of non-scaring hair loss that occurs in adult women. Although several treatments have already been proposed for FPHL, only Topical Minoxidil accumulated an adequate level of evidence. This study aimed to evaluate the therapeutic response of MMP® (intradermal infiltration) of Minoxidil formulation in the frontal-parietal-vertex regions compared with the gold-standard home administration of Minoxidil 5% Capillary Solution. This self-controlled comparative study evaluated 16 FPHL patients, without treatment for at least 6months, confirmed by trichoscopy with TrichoLAB® software. They received 4 monthly sessions of MMP® with Minoxidil 0,5% on the right side of the scalp (frontal-parietal-vertex areas), followed by occlusion with plastic film for 12h and prescription of Minoxidil 5% Solution for home use once a day, on both scalp sides, starting 72h after the procedure. The reassessment trichoscopy was 6weeks after the last session and they answered a "self-assessment" questionnaire. Treated scalp areas were compared and showed both treatments, in general, were effective, with no difference between them. If they were analyzed separately by treated areas, there were signs of better response in the parietal-vertex regions with treatment by MMP® with Minoxidil, while clinical treatment indicated a better response in the other regions. When patients were divided into more and less advanced cases, a better response in parietal-vertex regions treated by MMP® with Minoxidil in less advanced patients was confirmed. MMP® with Minoxidil showed a better response in the parietal-vertex regions in less advanced FPHL patients. It represents yet another resource to improve quality of life of these suffering patients.

Application of validated UV spectrophotometric and colorimetric method to quantify minoxidil in the development of trilayer dissolving microneedle: Proof of concept in ex vivo and in vivo studies in rats

Alopecia areata (AA) is an autoimmune-induced hair loss condition, by utilizing MNX, a hair growth-promoting compound. However, minoxidil (MNX) administration's efficacy is hindered by low bioavailability and adverse effects. To enhance its delivery, Trilayer Dissolving Microneedles (TDMN) are introduced, enabling controlled drug release. The study's primary was to establish a validated UV-Vis Spectrophotometer method for Minoxidil analysis in rat skin affected by alopecia areata. This method adheres to International Conference Harmonization (ICH) and FDA guidelines, encompassing accuracy, precision, linearity, quantification limit (QL), and detection limit (DL). The validation method was conducted through two approaches, namely UV region validation using PBS and the colorimetric method in the visible region (Vis). The validated approach is then employed for assessing in vitro release, ex vivo permeation, and in vivo pharmacokinetics. Results indicate superior MNX extraction recovery using methanol compared to acetonitrile. Method C (5mL methanol) is optimal, offering high recovery with minimal solvent usage. Precision assessments demonstrate %RSD values within MNX guidelines (≤15%), affirming accuracy and reproducibility. UV-Vis spectroscopy quantifies MNX integration into TDMN, using PVA-PVP, with concentrations aligning with ICH standards (95% to 105%). In conclusion, TDMN holds promise for enhancing MNX delivery, mitigating bioavailability and side effect challenges. The validated UV-Vis Spectrophotometer method effectively analyzes MNX in skin tissues, providing insights into AA treatment and establishing a robust analytical foundation for future studies.

Increased plasma renin by vasodilators promotes the progression of abdominal aortic aneurysm.

Background: It is well-accepted that antihypertensive therapy is the cornerstone of treatment for abdominal aortic aneurysm (AAA) patients with hypertension. Direct-acting vasodilators were used in the treatment of hypertension by directly relaxing vascular smooth muscle but may have destructive effects on the aortic wall by activating the renin-angiotensin system axis. Their roles in AAA disease remain to be elucidated. In this study, we used hydralazine and minoxidil, two classical direct-acting vasodilators, to investigate their influence and potential mechanisms on AAA disease. Methods and results: In this study, we investigated the plasma renin level and plasma renin activity in AAA patients. Simultaneously, age and gender ratio-matched patients diagnosed with peripheral artery disease and varicose veins were selected as the control group using a ratio of 1:1:1. Our regression analysis suggested both the plasma renin level and plasma renin activity are positively associated with AAA development. In view of the well-established relationship between direct-acting vasodilators and increased plasma renin concentration, we established a porcine pancreatic elastase-infused AAA mouse model, followed by oral administration of hydralazine (250mg/L) and minoxidil (120mg/L) to investigate effects of direct-acting vasodilators on AAA disease. Our results suggested both hydralazine and minoxidil promoted the progression of AAA with increased aortic degeneration. Mechanistically, the vasodilators aggravated aortic inflammation by increased leukocyte infiltration and inflammatory cytokine secretion. Conclusion and relevance: The plasma renin level and plasma renin activity are positively associated with AAA development. Direct vasodilators aggravated experimental AAA progression, which raised cautionary concerns about their applications in AAA disease.

Immunohistochemical, pharmacovigilance, and omics analyses reveal the involvement of ATP-sensitive K+ channel subunits in cancers: role in drug-disease interactions.

Background: ATP-sensitive-K+ channels (KATP) are involved in diseases, but their role in cancer is poorly described. Pituitary macroadenoma has been observed in Cantu' syndrome (C.S.), which is associated with the gain-of-function mutations of the ABCC9 and KCNJ8 genes. We tested the role of the ABCC8/Sur1, ABCC9/Sur2A/B, KCNJ11/Kir6.2, and KCNJ8/Kir6.1 genes experimentally in a minoxidil-induced renal tumor in male rats and in the female canine breast cancer, a spontaneous animal model of disease, and in the pharmacovigilance and omics databases. Methods: We performed biopsies from renal tissues of male rats (N = 5) following a sub-chronic high dosing topical administration of minoxidil (0.777-77.7mg/kg/day) and from breast tissues of female dogs for diagnosis (N = 23) that were analyzed by immunohistochemistry. Pharmacovigilance and omics data were extracted from EudraVigilance and omics databases, respectively. Results: An elevated immunohistochemical reactivity to Sur2A-mAb was detected in the cytosol of the Ki67+/G3 cells other than in the surface membrane in the minoxidil-induced renal tumor and the breast tumor samples. KCNJ11, KCNJ8, and ABCC9 genes are upregulated in cancers but ABCC8 is downregulated. The Kir6.2-Sur2A/B-channel opener minoxidil showed 23 case reports of breast cancer and one case of ovarian cancer in line with omics data reporting, respectively, and the negative and positive prognostic roles of the ABCC9 gene in these cancers. Sulfonylureas and glinides blocking the pancreatic Kir6.2-Sur1 subunits showed a higher risk for pancreatic cancer in line with the positive prognostic role of the ABCC8 gene but low risks for common cancers. Glibenclamide, repaglinide, and glimepiride show a lower cancer risk within the KATP channel blockers. The Kir6.2-Sur1 opener diazoxide shows no cancer reactions. Conclusion: An elevated expression of the Sur2A subunit was found in proliferating cells in two animal models of cancer. Immunohistochemistry/omics/pharmacovigilance data reveal the role of the Kir6.1/2-Sur2A/B subunits as a drug target in breast/renal cancers and in C.S.

Drug Interaction of Minoxidil and Himplasia with Oral Anti Diabetic Drug Sitagliptin in Diabetic Rats

Aim and Objective: Sitagliptin is given as an oral antidiabetic drug to treat Diabetes Mellitus. Minoxidil and himplasia may be co-prescribed along with sitagliptin to treat hypertension and BPH respectively. As such no information is available regarding the interaction taking place between sitagliptin, minoxidil and himplasia. Hence the present work has been aimed to find out the interaction with among the above said drugs in rodent model, since such studies cannot be performed in humans. Methods: Studies were conducted in normal and alloxan induced diabetic rats with oral doses of 9mg/kg B.W of sitagliptin, 9mg/kg B.W of minoxidil and 54mg /k g of himplasia and their combinations with adequate washout periods in between the treatments. Blood samples were collected at regular time intervals in rats through retro orbital puncture. All the blood samples were analyzed for blood glucose by GOD/POD method in pharmacodynamic studies and the serum sitagliptin concentrations were estimated by UV Spectrophotometry. Serum insulin was estimated by chemiluminescence assay. Results: Sitagliptin showed hypoglycemic action in both normal and diabetic rats and the peak action was observed at 6 h. Hyperglycemia was observed with minoxidil at 1st hour, hypoglycemia was observed with himplasia at 4th hour and the combination of minoxidil and himplasia showed biphasic response in blood glucose levels. The same responses were observed even in combination with sitagliptin. The serum sitagliptin concentrations were not altered by the co-administration of drugs. Serum insulin levels were inhibited by administration of minoxidil and potentiated by himplasia and initial reduction followed by surge observed with combination of minoxidil and himplasia. The similar responses were observed when co-administered with sitagliptin. Conclusion: Thus it could be concluded that the combination of minoxidil and himplasia should be taken with care for clinical benefits in diabetic patients. However, further studies should be carried out in non rodent species and in clinical settings are warranted.

A Drug-Free, Hair Follicle Cycling Regulatable, Separable, Antibacterial Microneedle Patch for Hair Regeneration Therapy.

The development of painless hair loss therapy without side-effect is challenging. The dermal papilla is the signal center of hair follicles and plays a key role in the regulation of their cycling. Activation of dermal papilla cells (DPCs) would promote hair regeneration. In this study, a separable microneedle patch comprised of chitosan lactate (CL) and exosomes (EXO) from adipose-derived stem cells is fabricated. After insertion of the microneedle into the skin, the hyaluronic acid substrate dissolves fast and the swellable polyvinyl alcohol needles are retained. The EXO sustainedly released from needles can be endocytosed by DPCs and promote cell proliferation via the activation of the Wnt signaling pathway, while the L-lactate released by CL can promote cell growth by activating lactate dehydrogenase. CL and EXO synergetically facilitate hair regeneration through regulating hair follicle cycling. In animal tests, compared with topical administration of minoxidil, the drug-free microneedle patches can more significantly promote hair regeneration within 7 days with lower dosing frequency. Furthermore, the inherent antibacterial properties of CL make it possible to avoid potential infection. Such transdermally administrated drug-free microneedle patches provide a simple, safe, and efficient strategy for hair loss treatment and exhibit great potential in clinical application.

Development of minoxidil-loaded double emulsion PLGA nanoparticles for the treatment of hair loss

Topical administration of minoxidil (MXD) on the skin is a widely used method for the treatment of hair loss. To enhance the efficacy of MXD in human skin, the appendageal route through the hair follicle could be promising. Therefore, we developed MXD-loaded double emulsion nanoparticles (MXD-DE-NPs) using poly (D,L-lactide-co-glycolide; PLGA) and surfactants. The size of MXD-DE-NPs was 137.8 ± 0.814 nm and their encapsulation efficiency of MXD was approximately 43%. The MXD-DE-NPs showed no aggregation in aqueous conditions at 1% w/v MXD concentration without ethanol and propylene glycol. In human follicular dermal papilla cells, the NPs showed fast cellular uptake and no significant toxicity. After treatment on the skin of shaved mice, efficient skin penetration of the NPs could be observed on fluorescence imaging. NP treatment for three weeks resulted in efficient regrowth of hair in mice without ethanol and propylene glycol similar to the traditional MXD formula. These results demonstrated that MXD-DE-NPs are a promising carrier for MXD in the treatment of hair loss.

Efficacy of Minoxidil Combined With Photobiomodulation for the Treatment of Male Androgenetic Alopecia. A Double-Blind Half-Head Controlled Trial.

Androgenetic alopecia (AGA) is a hair loss disorder that frequently affects the male population. Conventional treatment modalities are limited to minoxidil, 5α reductase inhibitors, and hair transplantation procedures. The efficacy of low-level laser therapy (LLLT), also known as photobiomodulation, in the treatment of AGA has been reported, yet little is known about the outcomes of combining photobiomodulation with other conventional therapies. To evaluate hair growth improvement in males with AGA, during the administration of minoxidil with and without photobiomodulation, using a half-head model. Twenty-one men with AGA agreed to undergo 12 minutes of low-level laser irradiation (using a modified Capellux®), followed by topical minoxidil application (1 mlof 5% solution), to the affected scalp two times per day for 6 months. The photobiomodulation devices were modified such that the left half emitted light, and the right half did not. Efficacy was assessed by blinded analyses of clinical photos and automated phototrichograms (Trichoscan®) taken before treatment and after 3 and 6 months of therapy. None of the study participants experienced any adverse events. All patients showed improvements in hair coverage on both sides of the scalp at 3 and 6 months. On the side with combined treatments, the number of total hairs was significantly increased after 3 (P < 0.001) and 6 months (P = 0.001). A similar increase was also observed on theminoxidil-only side, at both 3 (P < 0.001) and 6 months (P < 0.001). No statistically significant differences were detected between sides (P > 0.05). Additional improvement was not observed with the association of photobiomodulation to topical minoxidil in male AGA. Differences from previous studies that might have influenced our result includenon-collimated light source, higher dosimetry, and a cohort with darker skin phototype and more severe alopecia. Lasers Surg. Med. 2021. © 2021 Wiley Periodicals LLC.

Minoxidil Cannot Be Used To Target Lysyl Hydroxylases during Postnatal Mouse Lung Development: A Cautionary Note.

The lysyl hydroxylases (procollagen-lysine 5-dioxygenases) PLOD1, PLOD2, and PLOD3 have been proposed as pathogenic mediators of stunted lung development in bronchopulmonary dysplasia (BPD), a common complication of preterm birth. In affected infants, pulmonary oxygen toxicity stunts lung development. Mice lacking Plod1 exhibit 15% mortality, and mice lacking Plod2 or Plod3 exhibit embryonic lethality. Therefore, to address any pathogenic role of lysyl hydroxylases in stunted lung development associated with BPD, minoxidil was administered to newborn mice in an oxygen toxicity-based BPD animal model. Minoxidil, which has attracted much interest in the management of systemic hypertension and androgenetic alopecia, can also be used to reduce lysyl hydroxylase activity in cultured cells. An in vivo pilot dosing study established 50 mg⋅kg-1⋅day-1 as the maximum possible minoxidil dose for intraperitoneal administration in newborn mouse pups. When administered at 50 mg⋅kg-1⋅day-1 to newborn mouse pups, minoxidil was detected in the lungs but did not impact lysine hydroxylation, collagen crosslinking, or lysyl hydroxylase expression in the lungs. Consistent with no impact on mouse lung extracellular matrix structures, minoxidil administration did not alter the course of normal or stunted lung development in newborn mice. At doses of up to 50 mg⋅kg⋅day-1, pharmacologically active concentrations of minoxidil were not achieved in neonatal mouse lung tissue; thus, minoxidil cannot be used to attenuate lysyl hydroxylase expression or activity during mouse lung development. These data also highlight the need for new and specific lysyl hydroxylase inhibitors. SIGNIFICANCE STATEMENT: Extracellular matrix crosslinking is mediated by lysyl hydroxylases, which generate hydroxylated lysyl residues in procollagen peptides. Deregulated collagen crosslinking is a pathogenic component of a spectrum of diseases, and thus, there is interest in validating lysyl hydroxylases as pathogenic mediators of disease and potential "druggable" targets. Minoxidil, administered at the maximum possible dose, did not inhibit lysyl hydroxylation in newborn mouse lungs, suggesting that minoxidil was unlikely to be of use in studies that pharmacologically target lysyl hydroxylation in vivo.

Elastic fibers in orthopedics: Form and function in tendons and ligaments, clinical implications, and future directions.

Elastic fibers are an essential component of the extracellular matrix of connective tissues. The focus of both clinical management and scientific investigation of elastic fiber disorders has centered on the cardiovascular manifestations due to their significant impact on morbidity and mortality. As such, the current understanding of the orthopedic conditions experienced by these patients is limited. The musculoskeletal implications of more subtle elastic fiber abnormalities, whether due to allelic variants or age-related tissue degeneration, are also not well understood. Recent advances have begun to uncover the effects of elastic fiber deficiency on tendon and ligament biomechanics; future research must further elucidate mechanisms governing the role of elastic fibers in these tissues. The identification of population-based genetic variations in elastic fibers will also be essential. Minoxidil administration, modulation of protein expression with micro-RNA molecules, and direct injection of recombinant elastic fiber precursors have demonstrated promise for therapeutic intervention, but further work is required prior to consideration for orthopedic clinical application. This review provides an overview of the role of elastic fibers in musculoskeletal tissue, summarizes current knowledge of the orthopedic manifestations of elastic fiber abnormalities, and identifies opportunities for future investigation and clinical application.

Finasteride and Its Potential for the Treatment of Female Pattern Hair Loss: Evidence to Date.

The currently approved treatment for female pattern hair loss (FPHL) includes topical minoxidil administration; however, this treatment fails to achieve hair regrowth in some patients. Finasteride, a selective 5α-reductase inhibitor (5-ARI), may be considered as an alternative treatment. However, because of its potential teratogenic effects, clinical studies and use of finasteride for FPHL are limited. In this review, we aim to summarize the literature regarding the pharmacology, clinical efficacy, and adverse effects of oral finasteride for the treatment of FPHL and to provide novel therapeutic options including topical finasteride and dutasteride, a new generation 5-ARI, for the treatment of FPHL.

Chronic administration of minoxidil protects elastic fibers and stimulates their neosynthesis with improvement of the aorta mechanics in mice

Arterial wall elastic fibers, made of 90% elastin, are arranged into elastic lamellae which are responsible for the resilience and elastic properties of the large arteries (aorta and its proximal branches). Elastin is synthesized only in early life and adolescence mainly by the vascular smooth muscles cells (VSMC) through the cross-linking of its soluble precursor, tropoelastin. In normal aging, the elastic fibers become fragmented and the mechanical load is transferred to collagen fibers, which are 100–1000 times stiffer than elastic fibers. Minoxidil, an ATP-dependent K+ channel opener, has been shown to stimulate elastin expression in vitro, and in vivo in the aorta of male aged mice and young adult hypertensive rats. Here, we have studied the effect of a 3-month chronic oral treatment with minoxidil (120 mg/L in drinking water) on the abdominal aorta structure and function in adult (6-month-old) and aged (24-month-old) male and female mice. Our results show that minoxidil treatment preserves elastic lamellae integrity at both ages, which is accompanied by the formation of newly synthesized elastic fibers in aged mice. This leads to a generally decreased pulse pressure and a significant improvement of the arterial biomechanical properties in female mice, which present an increased distensibility and a decreased rigidity of the aorta. Our studies show that minoxidil treatment reversed some of the major adverse effects of arterial aging in mice and could be an interesting anti-arterial aging agent, also potentially usable for female-targeted therapies.

Niosomes as a vesicular carrier for topical administration of minoxidil: formulation and in vitro assessment.

Niosomes are reported to increase the skin permeation and bioavailability of topically applied drug molecules. However, very few studies were reported for nanometer-sized niosome vesicles. The aim of the present study was to prepare minoxidil-loaded niosomal formulation using ethanol injection method. Surfactant screening showed that only Span 60, Span 20, and Tween 20 with cholesterol have capability of nano size vesicle formation. The formed niosomes were characterized for entrapment efficiency, vesicle size, scanning electron microscope, and physical stability. By modulation of surfactant and cholesterol ratio maximum entrapment up to 34.70 ± 1.1% with size of 470 ± 27nm was obtained (Span 60/cholesterol ratio of 1:2). The vesicle size obtained was between 150 and 800nm that was depending on cholesterol ratio and type of nonionic surfactant employed. The in vitro skin permeation study showed that an increase in cholesterol concentration in niosome vesicles increases minoxidil skin retention. Niosome formulation prepared with 1:2 ratio of Span 60 and cholesterol showed 17.21 ± 3.2% skin retention of minoxidil, which is more than eightfold as compared to control minoxidil gel.

Comparison of non-invasive and implanted telemetric measurement of blood pressure and electrocardiogram in conscious beagle dogs

IntroductionThe objective of this study was to evaluate the ability of a non-invasive telemetry monitoring system to detect and quantify changes in blood pressure and electrocardiogram (ECG) parameters in response to vehicle, l-NAME or minoxidil administration to freely moving beagle dogs. Data from a non-invasive telemetry monitoring system were compared to data captured from an invasive telemetry implant in the same animals. MethodsBlood pressure and ECG data were simultaneously acquired from male dogs using a non-invasive and an invasive implanted telemetry system for 2hours predose and 24hours post dosing with vehicle (n=5), minoxidil at 1mg/kg (n=4) and L-NAME at 10mg/kg (n=5) on separate test days. Values for mean blood pressure, systolic blood pressure, diastolic blood pressure, pulse pressure, heart rate, RR, PR, QRS, QT and QTcL (heart rate corrected QT interval) interval were reported for both methods. ResultsStatistically significant reductions in blood pressure and pulse pressure and increases in heart rate, with associated ECG interval changes were apparent following dosing with minoxidil using both methods. Statistically significant increases in blood pressure and pulse pressure were apparent following dosing with l-NAME when using the invasive telemetry system, changes were apparent when using the non-invasive telemetry system, however, no change was apparent for pulse pressure, they were of shorter duration and not statistically significant. Statistically significant decreases in heart rate, with associated changes in ECG intervals, were apparent following treatment with l-NAME for both invasive and non-invasive methods. DiscussionThis study shows that the non-invasive system can be successfully used to acquire both ECG and blood pressure data in freely moving jacketed dogs for at least 26hours, yet requires further technique refinement to improve system sensitivity to detect smaller changes in blood pressure.

Investigating the role of endogenous opioids and KATP channels in glycerol‐induced acute renal failure

The present study was designed to investigate the possible role of endogenous opioids and K(ATP) channels in glycerol-induced acute renal failure (ARF) in rats. The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 mL/kg), and the animals were sacrificed after 24 h of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury. Naltrexone (2.5, 5.0 and 10.0 mg/kg s.c.), glibenclamide (5.0 and 10.0 mg/kg i.p.), and minoxidil (25 and 50 mg/kg) were employed to explore the role of endogenous opioids and K(ATP) channels in rhabdomyolysis-induced ARF. Pretreatment with naltrexone and glibenclamide attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner, suggesting the role of endogenous opioids and K(ATP) channels in the pathogenesis of myoglobuniric renal failure. However, the simultaneous pretreatment with naltrexone (10 mg/kg s.c.) and glibenclamide (10 mg/kg i.p.) did not enhance the reno-protective effects of individual drugs, suggesting that release of endogenous opioids and opening of K(ATP) channels constitute a single pathway in acute renal injury triggered by hypertonic glycerol-induced rhabdomyolysis. Furthermore, administration of minoxidil abolished the attenuating effects of naltrexone in glycerol-induced renal failure, suggesting that opening of K(ATP) channels is downstream to opioid receptor activation. It is concluded that hypertonic glycerol-induced rhabdomyolysis may involve release of endogenous opioids that in turn modulate K(ATP) channels to contribute in the pathogenesis of ARF.

Lowering Arterial Pressure Delays the Oxidative Stress Generation in a Renal Experimental Model of Hypertension

Oxidative stress produced through reactive oxygen species (ROS) enhancement is considered to play a key role in the development and maintenance of hypertension. In the vasculature, the most important source of ROS is the reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase enzyme. The principal stimulus of this enzyme is angiotensin II (Ang II). However, oxidative stress seems to be present in virtually all forms of hypertension including low-renin hypertension, where the levels of Ang II are reduced. For this reason, the question is if ROS generation is induced by Ang II or it is a consequence of hypertension. We used as hypertensive model the aortic coarctated rats, which were treated with losartan or minoxidil for 7 days. Thoracic aortic segments were excised, and the NAD(P)H oxidase subunits expression, oxidative stress parameters, and heme oxygenase-1 abundance were evaluated. Hypertensive animals had an increase in the activity and expression of NAD(P)H oxidase and, as a consequence, in the oxidative stress parameters. Interestingly, either losartan or minoxidil administration blunted those parameters, indicating that arterial pressure is the key factor in the development of oxidative stress in the hypertensive aorta. We suggest that antihypertensive drug administration at the beginning of this pathology delays the oxidative stress generation, thus preventing the aggravation of this disease.

Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection

It has been recently reported that release of erythropoietin could mediate the cardioprotective effects of remote renal preconditioning. However, the mechanism of erythropoietin-mediated cardioprotection in remote preconditioning is still unexplored. Therefore, the present study was designed to investigate the possible signal transduction pathway of erythropoietin-mediated cardioprotection in remote preconditioning in rats. Remote renal preconditioning was performed by four episodes of 5 min renal artery occlusion followed by 5 min reperfusion. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120 min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. Extent of myocardial infarct size and coronary flow rate was also measured. Remote renal preconditioning and erythropoietin preconditioning (5,000 IUkg(-1), i.p.) attenuated ischemia-reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of diethyldithiocarbamic acid (150 mg kg(-1) i.p.), a selective NFkB inhibitor, and glibenclamide (5 mg kg(-1) i.p.), a selective K(ATP) channel blocker, attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning. However, administration of minoxidil (1 mg kg(-1) i.v.), a selective K(ATP) channel opener, restored the attenuated cardioprotective effects of remote preconditioning and erythropoietin preconditioning in diethyldithiocarbamic acid pretreated rats. These results suggest that K(ATP) channel is a downstream mediator of NFkB activation in remote preconditioning and erythropoietin preconditioning. Therefore, it may be concluded that erythropoietin preconditioning and remote renal preconditioning trigger similar signaling mechanisms for cardioprotection, i.e., NFkB activation followed by opening of K(ATP) channels.

Minoxidil prevents 3,4‐methylenedioxymethamphetamine‐induced serotonin depletions: role of mitochondrial ATP‐sensitive potassium channels, Akt and ERK

Preconditioning has emerged as a valid strategy against different neurotoxic insults. Although the mechanisms underlying preconditioning are not fully understood, the activation of ATP-sensitive potassium (KATP) channels has been proposed to play a pivotal role in neuronal preconditioning. In the present work we examine whether minoxidil a KATP channel activator protects against the long-term toxicity caused by the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) in rats. Our data show that intrastriatal administration of minoxidil prevents MDMA-induced long-term indole depletions in the rat striatum. This effect was not related to an effect on core temperature, as pre-treatment with minoxidil did not significantly alter MDMA-induced hyperthermia. Taking into account that minoxidil opens both sarcolemmal and mitochondrial KATP channels, we examined the role of each type of channels in the protective effects of minoxidil using specific inhibitors. The administration of HMR-1098, a blocker of the sarcolemmal KATP channels, along with minoxidil did not affect the protection afforded by the latter. On the contrary the selective mitochondrial KATP channel blocker 5-hydroxydecanoic acid completely reversed the protection afforded by minoxidil, thereby implicating the involvement of mitochondrial (but not sarcolemmal) KATP channels. Furthermore our data show the participation of Akt and extracellular signal-regulated kinases in minoxidil-afforded protection. Intrastriatal administration of wortmannin or PD98059 (inhibitors of phosphatidylinositol-3-kinase and mitogen-activated protein kinase/extracellular regulated protein kinase, respectively), along with minoxidil abolished the protective effect of minoxidil against the serotonergic toxicity caused by MDMA. These results demonstrate that minoxidil by opening mitochondrial KATP channels completely prevents MDMA toxicity and that Akt and MAP kinases are involved in minoxidil-afforded neuroprotection.

A model of orthostatic hypotension in the conscious monkey using lower body negative pressure

Introduction: Methods most commonly used for detecting susceptibility to orthostatic hypotension in humans include head-up tilt and the application of lower body negative pressure (LBNP). The objective of this study was to evaluate the use of LBNP for detecting drug-induced changes in susceptibility to orthostatic hypotension in conscious monkeys ( Macaca fascicularis). Methods: Orthostatic responses were produced using an airtight chamber, which sealed around the stomach (umbilical area) and enclosed the lower body, to which were applied successive decrements of 10 mmHg chamber pressure every 5 min until the orthostatic response was observed. Cardiovascular measurements, involving arterial pressures, heart rate, and left ventricular pressures were recorded. The hypotensive agents prazosin and minoxidil were administered to evaluate the ability of the procedure to detect drug-induced changes in the susceptibility to orthostatic hypotension. Results: A rapid decrease in systolic arterial pressure of > 20 mmHg occurring within a 30 s time period was determined to be the best indicator of an orthostatic response. The application of LBNP produced an orthostatic response in all monkeys and on all occasions (100% response). The onset, rate and magnitude of the decrease in systolic blood pressure were also consistent for each monkey. Prazosin (≥ 0.16 mg/kg, iv) produced an increase in the susceptibility to the orthostatic response, whereas minoxidil (10 mg/kg, po) had no effect. These results are consistent with previous findings in humans, where similar decreases in arterial pressures occur following the administration of prazosin and minoxidil, whereas increased susceptibility to orthostatic hypotension only occurs with prazosin. Discussion: The results of this study demonstrate that the application of the LBNP is a reliable method for producing an orthostatic hypotensive response in conscious monkeys. In addition, the use of positive (prazosin) and negative (minoxidil) controls demonstrated that the use of LBNP is a valid method for evaluating the effect of drug treatment on susceptibility to orthostatic hypotension.