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Background:While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. These mechanisms, which have a dynamic structure, are key to homeostasis. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases.Objectives:To evaluate the effect of anti-atherosclerotic liquid (AAL), anti-inflammatory capsules (AIC) and anti-oxidant liquid (AOL) supplementation on the flow-mediated dilatation (FMD), inflammatory, oxidative stress and endothelial dysfunction markers in patients with selected chronic diseasesMethods:We analyzed data of 178 patients from cohorts with selected chronic diseases (Rheumatoid arthritis, familial Mediterranean fever, DM type-2, Hypertension, Multiple sclerosis, Chronic obstructive pulmonary disease, Alzheimer disease and Cancer) in this quasi-experimental study. Endothelial dysfunction was determined by FMD and serum asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (AAL, 3 ml once per day), omega-3 (AIC, 3 capsules once per day) and extract with Alaskan blueberry and 21 different red purple fruit vegetables (AOL, 30 ml once per day). Stepwise multivariate regression analysis evaluated the association of FMD with clinical and serologic parameters.Results:Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased and CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. FMD was negatively correlated with serum ADMA, MDA, PTX3, hsCRP levels, SBP and DBP and positively correlated to CuZn-SOD and eGFR levels both at baseline and after the 12-weeks treatment period. Multivariate regression analysis revealed that ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies (Table 1, Figure 1).Conclusion:Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. Short-term AAL, AIC and AOL therapies significantly improves FMD and normalizes ADMA, PTX3, hsCRP and MDA. This may have implications for adjunctive therapy in a number of chronic disorders.References:[1] Yilmaz MI, Saglam M, Caglar K, Cakir E, Sonmez A, Ozgurtas T et al. The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis. 2006;47(1):42-50. doi:10.1053/j.ajkd.2005.09.029.Disclosure of Interests:None declared

While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases. We analyzed data of 178 patients from cohorts with selected chronic diseases in this quasi-experimental study. Endothelial dysfunction was determined by flow-mediated dilatation (FMD) and asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL). Stepwise multivariate regression analysis was used to evaluate the association of FMD with clinical and serologic parameters. Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. The FMD was negatively correlated with serum ADMA, MDA, PTX3, and hsCRP levels and positively correlated with CuZn-SOD and eGFR levels. ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies. Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. In addition, short-term AAL, AIC and AOL therapies significantly improves a number of parameters in our cohort and can normalize ADMA, PTX3, hsCRP and MDA levels.

The increase of endocannabinoid tonus by inhibiting fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) represents a promising therapeutic approach in a variety of disease to overcome serious central side effects of exocannabinoids. Recent studies reported that systemic administration of FAAH and MAGL inhibitors produce antipruritic action. Dual FAAH/MAGL inhibitors have also been described to get enhanced endocannabinoid therapeutic effect. In this study, we examined and compared dose-related antipruritic effects of systemic (intraperitoneal; ip) or intrathecal (it) administration of selective FAAH inhibitor PF-3845 (5, 10, and 20 mg/kg, i.p.; 1, 5, and 10 µg, i.t.), MAGL inhibitor JZL184 (4, 20, and 40 mg/kg, i.p.; 1, 5, and 10 µg, i.t.) and dual FAAH/MAGL inhibitor JZL195 (2, 5, and 20 mg/kg, i.p.; 1, 5, and 10 µg, i.t.) on serotonin (5-HT)-induced scratching model. Serotonin (25 μg) was injected intradermally in a volume of 50 μl into the rostral part of skin on the back of male Balb-C mice. Both systemic or intrathecal administration of PF-3845, JZL184 or JZL195 produced similar dose-dependent antipruritic effects. Our results suggest that endocannabinoid-degrading enzymes FAAH and MAGL are involved in pruritic process at spinal level. FAAH, MAGL or dual FAAH/MAGL inhibitors have promising antipruritic effects, at least, in part through spinal site of action.

GUNDUZ, Ozgur/0000-0002-2470-3021; Ulugol, Ahmet/0000-0003-4643-1124; Gunaydin, Caner/0000-0002-8304-832X; Gunaydin, Caner/0000-0002-8304-832X WOS: 000385338800008 PubMed: 27685776 Intradermal injection of pruritogens such as serotonin, histamine and compound 48/80 into the skin and then, the evaluation of the scratching behavior is the commonly used animal model to advance pruritic research and drug development. However, predictive validity of this model is poorly documented. There is a close interaction between itch and pain sensations with regard to mediation through an anatomically and functionally identical neuronal pathway. One approach is whether the existing animal model of itch differentiates itch or pain to show efficacy of clinically effective analgesic drugs as a back translation. In this study, we explored the effects of different group of analgesic drugs on serotonin and compound 48/80-induced scratching behavior in Balb-C mice. Serotonin (25 mu g) and compound 48/80 (100 mu g) was injected intradermally in a volume of 50 mu l into the rostra! part of skin on the back of male mice and scratches were counted for a 30-min observation period. Morphine (1, 3, 10 mg/kg), tramadol (20, 40, 80 mg/kg), cannabinoid agonist CP 55,940 (0.1, 0.3, 1 mg/kg), paracetamol (100, 200, 300 mg/kg) and diclofenac (50, 100, 200 mg/kg) were given intraperitoneally 30 min prior to pruritogen injection. The analgesic drugs dose dependently blocked serotonin and compound 48/80-induced straching behavior with exerting complete inhibition at certain doses. Our data suggests that intradermal pruritogen-induced scratching models may not discriminate pain and itch sensations and give false positive results when standard analgesic drugs are used.

There are limited data regarding effect of trastuzumab on radiation-induced cardiovascular toxicity when used sequentially or concomitantly. This experimental study aims to investigate effect of trastuzumab on radiation-induced cardiovascular toxicity with respect to the treatment sequence. One hundred and eight female Wistar albino rats were divided into six groups (G): G1 was control, G2 was trastuzumab, and G3 was radiotherapy (RT); G4 and G6 were sequential RT and trastuzumab; and G5 was concomitant RT and trastuzumab groups, respectively. Rats were killed at 6th h, 21st and 70th days after RT; thoracic aorta and heart samples were obtained. Transthoracic echocardiography and functional studies evaluating relaxation of thoracic aorta were performed. Subendothelial edema scores of thoracic aorta samples at 21st and 70th days were higher in RT groups (G3, G4, G5, and G6) ( p < 0.001). There was a deterioration of relaxation responses of thoracic aorta samples in RT groups ( p < 0.001). Cardiac fibrosis (CF) scores revealed detrimental effect of RT beginning from 6th h and trastuzumab from 21st day. RT groups showed further deterioration of CF at 70th day. Ejection fraction, left ventricular mass, and fractional shortening were significantly decreased in G4, G5, and G6. Trastuzumab may increase pathological damage in cardiovascular structures when used with RT regardless of timing.

The most recently identified serotonin (5-HT) receptor is the 5-HT7 receptor. The antinociceptive effects of a 5-HT7 receptor agonist have been shown in neuropathic and inflammatory animal models of pain. A recent study demonstrated the functional expression of 5-HT7 receptors in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis, which receives and processes orofacial nociceptive inputs. Objective To investigate the antinociceptive effects of pharmacological activation of 5-HT7 receptors on orofacial pain in mice. Material and Methods Nociception was evaluated by using an orofacial formalin test in male Balb-C mice. Selective 5-HT7 receptor agonists, LP 44 and LP 211 (1, 5, and 10 mg/kg), were given intraperitoneally 30 min prior to a formalin injection. A bolus of 10 µl of 4% subcutaneous formalin was injected into the upper lip of mice and facial grooming behaviors were monitored. The behavioral responses consisted of two distinct periods, the early phase corresponding to acute pain (Phase I: 0–12 min) and the late phase (Phase II: 12–30 min). Results LP 44 and LP 211 (1, 5, and 10 mg/kg) produced an analgesic effect with reductions in face rubbing time in both Phase I and Phase II of the formalin test. Conclusion Our results suggest that 5-HT7 receptor agonists may be promising analgesic drugs in the treatment of orofacial pain.

Cannabinoids produce antinociceptive and antihyperalgesic effects mainly through activation of the inhibitory CB1 receptors. The demonstration that antinociceptive effects of systemic cannabinoids are significantly diminished following surgical dorsolateral funiculus lesion provides evidence that supraspinal sites and descending pain modulatory pathways play crucial roles in systemic cannabinoid analgesia. In this review, we will firstly provide a background, brief overview of descending modulatory pathways followed by descending pathways implicated in cannabinoid analgesia. We will then describe the recent evidence of the involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception. This review will provide evidences that systemically administered cannabinoids reinforce the descending serotonergic and noradrenergic pathways to produce acute antinociceptive effects via spinal 5-HT7, 5-HT2A and alpha-2 adrenoceptors activation.

We researched the survival of bone marrow-derived mesenchymal stem cells (MSCs) and the results of MSCs' injected into decompensated bladders in a rabbit model.Partial bladder neck obstruction (PBNO) and subsequent decompensation of the bladder was achieved by wrapping the bladder neck with autologous rectus fascia. In the first aspect of the experiment 18 rabbits underwent MSC injection into the decompensated bladder to prove the survivability of injected MSCs. For this purpose MSCs were isolated, transfected with Green Fluorescent Protein (GFP), and injected into the detrusor layer. Once viability was assessed in the first phase, an additional 10 rabbits underwent PBNO in the second phase. Five of these animals underwent subsequent MSC injection (group 3, stem cell) and 5 did not (group 2, obstruction). Both groups were compared to 5 controls (group 1). Urodynamics were performed in all groups. After the animals were sacrificed the groups were compared via morphometric analysis, contractile response to carbachol and KCl, and muscarinic receptor type analysis.On morphometric analysis, collagenous area rates were 43, 53 and 37% in group 1, 2 and 3, respectively. There was no statistically significant difference between groups in terms of bladder weight, bladder capacity and vesical pressure. The contractile effects of KCl and muscarinic agonist carbachol were significantly higher in groups 1 and 3 than group 2. The response to carbachol was antagonized by muscarinic M(1) and M(3) receptor antagonist pirenzepine and abolished by muscarinic M(3) receptor antagonist 4-DAMP in all groups.The injection of MSCs decreased the collagenous area, increased detrusor contractility. Functional M(3) receptors were also expressed in MSCs-injected bladder smooth muscle as well as in control group.

Although some studies have shown the essential role of descending serotonergic pathways and spinal 5-HT1A, 5-HT2A, or 5-HT3 receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced analgesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT7 receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending serotonergic pathways and spinal 5-HT7 receptors compared with 5-HT3 and 5-HT2A receptors in the antinociceptive and antihyperalgesic effects of paracetamol. Tail-flick, hot plate and plantar incision tests were used to determine nociception in male BALB/c mice. Lesion of serotonergic bulbospinal pathways was performed by intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT), and spinal 5-HT levels were measured by HPLC. To evaluate the particular subtypes of the spinal 5-HT receptors, the selective 5-HT7, 5-HT3 and 5HT(2A) receptor antagonists SB 269970, ondansetron and ketanserin, respectively, were given i.th. after oral administration of paracetamol. Oral paracetamol (200, 400 and 600 mg/kg) elicits dose-dependent antinociceptive and antihyperalgesic effects. I.th. pretreatment with 5,7-DHT (50 mu g) sharply reduced 5-HT levels in the spinal cord. Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10 mu g) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10 mu g) did not. Our findings suggest that systemic administration of paracetamol may activate descending serotonergic pathways and spinal 5-HT7 receptors to produce a central antinociceptive and antihyperalgesic effects. (C) 2011 Elsevier B.V. All rights reserved.

Objectives. Cyclosporine A (CyA), tacrolimus (TRL), sirolimus (SIR), and everolimus (RAD) are immunosuppressive drugs frequently used in organ transplantation. Our aim was to confirm a robust sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of CyA, TRL, SIR, and RAD in whole-blood samples.Materials and Methods. We used an integrated online solid-phase extraction-LC-MS/MS system and atmospheric pressure ionization tandem mass spectrometry (API-MS/MS) in the multiple reaction monitoring (MRM) detection mode. CyA, TRL, SIR, and RAD were simultaneously analyzed in whole blood treated with precipitation reagent taken from transplant patients.Results. System performance parameters were suitable for using this method as a high-throughput technique in clinical practice. The high concentration of one analyte in the sample did not affect the concentration of other analytes. Total analytical time was 2.5 min, and retention times of all analytes were shorter than 2 minutes.Conclusion. This LC-MS/MS method can be preferable for therapeutic drug monitoring of these immunosuppressive drugs (CyA, TRL, SRL, and RAD) in whole blood. Sample preparation was too short and simple in this method, and it permits robust, rapid, sensitive, selective, and simultaneous determination of these drugs.

Aims To examine whether obstruction changes the expression of prostaglandins (PGs) in bladder, intravesical low-dose aspirin could be used as a new route of drug administration, this way of administration influences PGs' expression, and contractile function of the bladder is protected after treatment. Methods Eighteen rabbits were divided into three groups. Sham-operated group (group 1) included 6 rabbits. Twelve rabbits were partially obstructed for 70 days. Six of these 12 rabbits not receiving any treatment constituted obstructed group (group 2). The remaining six rabbits received 2 mg/kg/day aspirin (group 3). One rabbit in each group was evaluated on 1st, 7th, 14th, 28th, 42nd, and 70th days following obstructive surgery. After scarification, the percentage of collagenous area and concentrations of PGE2 and PGF2-alpha were measured. Contractile responses to field stimulation (EFS), carbachol, and potassium chloride (KCl) were determined. Results Wet tissue PGE2 and PGF2-alpha levels were higher in obstructed group than the other groups. Aspirin decreased the percentage of collagenous area in group 3 compared to the group 2, but this difference was not statistically significant. The strips from aspirin groups resulted in better contractile response to cholinergic stimulation with KCl, but this difference was not statistically significant between the obstructed and aspirin groups. Similarly, carbachol did not elicit significantly greater concentration-dependent contraction in strips from obstructed group compared to those from aspirin groups. Maximum responses to EFS were not significant in aspirin group compared to those from obstructed group. Conclusions Intravesical aspirin may have protective effect on partially obstructed bladder. Neurourol. Urodynam. Neurourol. Urodynam. 30: 1646–1651, 2011. © 2011 Wiley Periodicals, Inc.

Introduction Resin-based dental materials contain various diluent monomers that can interfere with vascular function by causing vasodilation. In this study, we evaluated the vasoactive potential of hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) and the possible mechanism of their vascular action on isolated rat aorta. Methods Responses of thoracic aorta rings were recorded isometrically by using force displacement transducers. After precontracting aorta rings with phenylephrine, relaxations to HEMA and TEGDMA were recorded in the absence and presence of nitric oxide synthase inhibitor N ω -nitro-L-arginine methyl ester, cyclooxygenase inhibitor indomethacin, and K + channel inhibitors tetraethylammonium, glibenclamide, and 4-aminopyridine. To investigate the Ca 2+ -channel antagonistic effect of HEMA and TEGDMA in different aorta rings, concentration-response curves to CaCl 2 were obtained in the absence and presence of the test monomers. Results Both HEMA and TEGDMA elicited concentration-dependent relaxations. The vasorelaxant effect of HEMA and TEGDMA was not mediated via endothelium-dependent nitric oxide and prostanoid-dependent mechanisms or by K + efflux through K + channels. Both monomers significantly inhibited the contractions induced by CaCl 2 . Conclusions Our results showed that HEMA and TEGDMA induce vasodilation via Ca 2+ -antagonistic action, whereas nitric oxide and cyclooxgenase pathway and K + channels were not responsible for this vasoactive effect.

Neopterin is synthesized in macrophage/Kupffer cells by interferon-gamma and other cytokines. This study aimed to evaluate the utility of using neopterin as a biomarker of acetaminophen (APAP)-induced liver injury. Wistar rats, randomly divided into two groups (APAP and normal), received APAP (1.0 g/kg) and distilled water, respectively, by gastric tube. The APAP group had a higher degree of liver necrosis than the control group. The APAP group also had significantly higher serum neopterin levels than the normal group. Serum neopterin levels correlated with serum AST, ALT activities, and degree of necrosis. This study demonstrates the preclinical utility of neopterin as a biomarker for the animal model of APAP-induced liver injury. Further research studies are required to determine the preclinical opportunities of using neopterin as a marker of APAP-induced liver injury.

Serotonin (5-HT) plays an important role in the descending control of pain. We evaluated the role of descending serotonergic pathways and spinal 5-HT₇ and 5-HT(2A) receptors in comparison to that of 5-HT(1A) and 5-HT₃ receptors in the antinociceptive effects of systemically administered cannabinoids. Antinociceptive effects were evaluated by radiant heat tail-flick and hot plate tests in Balb-C mice. The selective CB₁ receptor agonist, ACEA; a mixed CB₁ and CB₂ receptor agonist, WIN 55,212-2; and a selective CB₂ receptor agonist, GW405833, were given systemically to induce antinociception. Spinal 5-HT was depleted with intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT). Bilateral surgical lesions of the dorsolateral funiculus were performed. Selective 5-HT₇, 5-HT(2A), 5-HT(1A) and 5-HT₃ antagonists-SB-269970, ketanserin, WAY 100635 and ondansetron, respectively-were administered i.th. Risperidone, an atypical antipsychotic displaying 5-HT(2A) antagonism, also irreversibly binds to and inactivates the 5-HT₇ receptors. Thus, we also injected risperidone i.th. to elucidate the role of spinal 5-HT₇ and 5-HT(2A) receptors in cannabinoid-mediated antinociception. WIN 55,212-2 and ACEA produced dose-dependent antinociception, which were reversed by selective CB₁ receptor antagonist rimonabant. GW405833 did not produce any antinociception. The antinociceptive effects of WIN 55,212-2 and ACEA were totally absent in spinal 5-HT depleted and dorsolateral funiculus lesioned mice. I.th. administration of SB-269970, ketanserin, and risperidone, but not WAY 100635 or ondansetron, blocked both WIN 55,212-2- and ACEA-induced antinociception. These findings suggest that systemically administered cannabinoids interact with descending serotonergic pathways via CB₁-mediated mechanisms and exert a central antinociceptive effect involving spinal 5-HT₇ and 5-HT(2A) receptors.

Seyrek M, Vural IM, Tunca YM, Aydin C, Ulku C, Demirkaya K, Inal A, Yildiz O. The vasodilatory effect of a synthetic polymer-based root canal material on thoracic aorta. International Endodontic Journal 43, 590–599, 2010. Abstract Aim To test the hypothesis that, Epiphany, either in its mixed form or as separate components, can alter the vascular reactivity of isolated rat thoracic aorta. The possible mechanism of its vascular action was also investigated. Methodology The relaxant effect of the base, the catalyst and mixed Epiphany on isolated rat aortic rings pre-contracted with phenylephrine (PE) was tested. The aortic rings were then incubated with either nitric oxide synthase (NOS) inhibitor, cyclooxygenase (COX) inhibitor or K+ channel inhibitors; after pre-contraction with PE, relaxations to the various compounds of Epiphany were examined. In another set of experiments, to investigate the Ca2+channel antagonistic effect of the Epiphany, the effect of these compounds in Ca2+-free solution on extracellular Ca2+(CaCl2)-induced contraction in high-K+ pre-challenged rings (in K+-depolarized rings) was examined to determine whether the direct inhibition of [Ca2+] influx increase accounted for the vasodilatory effects of these compounds. For comparison, L-type Ca2+channel blocker nifedipine (1 μmol L−1), instead of Epiphany compounds, was assayed in adjacent rat aortic rings in parallel. Results The catalyst and the mixture of Epiphany induced concentration-dependent relaxations. However, the base of Epiphany did not cause relaxation in rat aorta. The relaxation responses were not significantly altered by incubation of aorta with NOS, COX and potassium channel inhibitors. Whilst nifedipine, the catalyst and the mixture of Epiphany inhibited CaCl2-induced contractions (P 0.05). Conclusion Epiphany induced relaxation of rat aorta via a calcium antagonistic effect. Provided that the vasodilatory effect elicited by Epiphany can be reversed by the circulation, its haemorrhagic potential by virtue of permanent vascular dilatation can be ignored.

Background Tramadol is an analgesic drug, and its mechanism of action is believed to be mediated by the mu-opioid receptor. A further action of tramadol has been identified as blocking the reuptake of serotonin (5-HT). One of the most recently identified subtypes of 5-HT receptor is the 5-HT7 receptor. Thus, the authors aimed to examine the potential role of serotonergic descending bulbospinal pathways and spinal 5-HT7 receptors compared with that of the 5-HT2A and 5-HT3 receptors in the antinociceptive and antihyperalgesic effects of tramadol and its major active metabolite O-desmethyltramadol (M1) on phasic and postoperative pain models. Methods Nociception was assessed by the radiant heat tail-flick and plantar incision test in male Balb-C mice (25-30 g). The serotonergic pathways were lesioned with an intrathecal injection of 5,7-dihydroxytryptamine. The selective 5-HT7, 5-HT2, and 5-HT3 antagonists; SB-269970 and SB-258719; ketanserin and ondansetron were given intrathecally. Results Systemically administered tramadol and M1 produced antinociceptive and antihyperalgesic effects. The antinociceptive effects of both tramadol and M1 were significantly diminished in 5-HT-lesioned mice. Intrathecal injection of SB-269970 (10 microg) and SB-258719 (20 microg) blocked both tramadol- and M1-induced antinociceptive and antihyperalgesic effects. Ketanserin (20 mumicrog) and ondansetron (20 microg) were unable to reverse the antinociceptive and antihyperalgesic effects of tramadol and M1. Conclusions These findings suggest that the descending serotonergic pathways and spinal 5-HT7 receptors play a crucial role in the antinociceptive and antihyperalgesic effects of tramadol and M1.

Dental adhesives can alter the contractility of vascular tissue via different mechanisms. The aim of this study was to investigate and compare the vascular action of two self-etch adhesive systems, Clearfil SE Bond (CSEB) and Clearfil S(3) Bond (CS3B). Responses of isolated rat thoracic aorta rings were recorded isometrically by force displacement transducers. Following pre-contraction of aorta rings, relaxations to the independent and mixed components of CSEB and CS3B were recorded in the absence and presence of nitric oxide synthase (NOS) inhibitor (N(omega)-nitro-L-arginine methyl ester (N-LAME)), cyclooxygenase (COX) inhibitor (indomethacin) and K+ channel inhibitors (tetraethylammonium, glibenclamide and 4-aminopyridine). We also tested the effects of CSEB and CS3B in endothelium-intact and -denuded rat thoracic aorta rings. To investigate the Ca2+-channel antagonistic effect of adhesive components, concentration-response curves to CaCl2 were obtained in the absence and presence of the components. The primer, the bond, and the mixture of CSEB and CS3B elicited concentration-dependent relaxations. Mechanical rubbing of the endothelium did not significantly modify the extent of vasorelaxation induced by the test materials. The vasorelaxant effect was mediated neither by NOS and COX inhibition nor by the tested K+ channel antagonists. Mechanical removal of the endothelium did not alter the vasodilatory effect induced by the self-etch adhesives. Both CSEB and CS3B significantly inhibited the contractions induced by CaCl2. These results demonstrate the vasodilatory effect induced by the self-etch adhesive systems through a Ca2+-antagonistic effect.

Molecular, genetic and epigenetic pathways of peroxynitrite-induced cellular toxicityOxidative stress plays a key role in the pathogenesis of cancer and many metabolic diseases; therefore, an effective antioxidant therapy would be of great importance in these circumstances. Nevertheless, convincing randomized clinical trials revealed that antioxidant supplementations were not associated with significant reduction in incidence of cancer, chronic diseases and all-cause mortality. As oxidation of essential molecules continues, it turns to nitro-oxidative stress because of the involvement of nitric oxide in pathogenesis processes. Peroxynitrite damages via several distinctive mechanisms; first, it has direct toxic effects on all biomolecules and causes lipid peroxidation, protein oxidation and DNA damage. The second mechanism involves the induction of several transcription factors leading to cytokine-induced chronic inflammation. Finally, it causes epigenetic perturbations that exaggerate nuclear factor kappa-B mediated inflammatory gene expression. Lessons-learned from the treatment of several chronic disorders including pulmonary diseases suggest that, chronic inflammation and glucocorticoid resistance are regulated by prolonged peroxynitrite production.

Objectives To investigate the effect of testosterone on contractile tone of endothelium-denuded human corpus cavernosum strips. Human studies designed to examine a possible relaxant effect of testosterone on corpus cavernosal circulation are lacking. Methods Testosterone (0.1-300 μM) was added cumulatively to organ baths after precontraction of isolated human corpus cavernosum strips (n = 5) with KCl (45 mM). Testosterone-induced responses were tested in the presence of nonselective, large, conductance Ca 2+ -activated and voltage-sensitive K + channel inhibitor tetraethylammonium (1 mM), adenosine triphosphate-sensitive K + channel inhibitor glibenclamide (10 μM), voltage-dependent inward rectifier K + channel inhibitor barium chloride (30 μM) and voltage-sensitive K + channel inhibitor 4-aminopyridine (1 mM). Results Testosterone (0.1-300 μM) produced relaxation in human corpus cavernosum (maximum relaxation 65.4% ± 3.3% of KCl-induced contraction) that reached a maximum at a concentration of 300 μM. Testosterone-induced relaxation was significantly attenuated by glibenclamide, but it was not affected by the other K + channel inhibitors (tetraethylammonium, barium chloride, or 4-aminopyridine). Conclusions Testosterone might induce relaxation in human isolated corpora cavernosa strips by activation of smooth muscle adenosine triphosphate-sensitive K + channels. This finding suggests that testosterone, in addition to its known endothelial action, might regulate erectile function locally by its action on the smooth muscle of the human corpus cavernosum.

Etch-and-rinse adhesives can cause vasorelaxation via mechanisms occurring in the endothelium and smooth muscle, including the release of nitric oxide (NO). This effect might promote or aggravate bleeding if such adhesives are placed inadvertently on iatrogenic pulp microexposures. The present study assessed the vasoactive potential of a newer generation self-etch adhesive, Clearfil Protect Bond (CPB), on isolated rat aorta. Cumulative concentrations of the primer, bond, and mixture of CPB elicited concentration-dependent relaxation of phenylephrine-induced active tonus in the rat aorta, demonstrating that the tested self-etch adhesive can lead to vasorelaxation of pulp vessels that is mediated by Ca(2+) antagonistic effect. The vasorelaxant effect of CPB or its components was mediated neither via endothelium-dependent NO and prostanoid-dependent mechanisms nor by K(+) efflux through K(+) channels. Mechanical removal of the endothelium did not significantly alter the relaxation induced by CPB. Assuming these data can be extrapolated to the clinical situation, CPB, either in mixed form or by its components, can lead to vasorelaxation of pulp vessels that is mediated by a Ca(2+) antagonistic effect. If CPB is placed inadvertently on pulp microexposures during direct pulp capping, this effect might promote bleeding that might impair healing and, via plasma exatravasation, might compromise resin infiltration and polymerization.

Preliminary clinical studies of testosterone therapy in male patients with coronary artery disease obtained promising results. However, little is known about the in vitro effects of testosterone in human isolated arteries. We investigated the effect of testosterone on contractile tone of human isolated radial artery (RA). Testosterone was added (0.1 – 300 µM ) cumulatively to organ baths after precontraction with KCl (45 mM) and phenylephrine (PE, 10 µM). Testosterone-induced relaxations were tested in the presence of the cyclooxygenase inhibitor indomethacin (10 µM), nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 100 µM), non-selective large conductance Ca2+-activated and voltage-sensitive K+ channel inhibitor tetraethylammonium (TEA, 1 mM), ATP-sensitive K+ channel inhibitor glibenclamide (GLI, 10 µM), and voltage-sensitive K+ channel inhibitor 4-aminopyridine (4-AP, 1 mM). Testosterone produced relaxation in human RA (Emax: 53.03 ± 2.76% and 66.83 ± 1.97% of KCl and PE-induced contraction, respectively). Except for GLI, the relaxation to testosterone is affected by neither K+ channel inhibitors (TEA, BaCl2, and 4-AP), L-NAME, nor indomethacin. We report for the first time that supraphysiological concentrations of testosterone induces relaxation in RA. This response may occur in part via ATP-sensitive K+ channel opening action. Keywords:: human radial artery, testosterone, vasodilation, potassium channel

Background and purpose: The serotonergic system within the spinal cord have been proposed to play an important role in the analgesic effects of systemic morphine. Currently, seven groups of 5-HT receptors (5-HT1–7) have been characterized. One of the most recently identified subtypes of 5 HT receptor is the 5-HT7 receptor. We aimed to examine the role of spinal 5-HT7 receptors in the antinociceptive effects of systemic morphine. Experimental approach: The involvement of spinal 5-HT7 receptor in systemic morphine antinociception was compared to that of the 5-HT1A and 5-HT2 receptors by using the selective 5-HT7 receptor antagonist, SB-269970, the selective 5-HT1A receptor antagonist, WAY 100635, the selective 5-HT2 antagonist ketanserin as well as the non-selective 5-HT1,2,7 receptor antagonist, metergoline. Nociception was evaluated by the radiant heat tail-flick test. Key results: I.t. administration of SB-269970 (10 μg) and metergoline (20 μg) completely blocked the s.c. administered morphine-induced (1, 3, 5 and 10 mg kg−1) antinociception in a time-dependent manner. Additionally, i.t. administration of SB-269970 (1, 3, 10 and 20 μg) and metergoline (1, 5, 10 and 20 μg) dose dependently inhibited the antinociceptive effects of a maximal dose of morphine (10 mg kg−1, s.c.). I.t. administration of WAY 100635 (20 μg) or ketanserine (20 μg) did not alter morphine-induced (1, 3, 5 and 10 mg kg−1, s.c.) antinociception. Conclusion and implications: These findings indicate that the involvement of spinal 5-HT7, but not of 5-HT1A or of 5-HT2 receptors in the antinociceptive effects of systemic morphine. British Journal of Pharmacology (2006) 149, 498–505. doi:10.1038/sj.bjp.0706854

Levosimendan is a calcium-sensitizing agent and inodilator working via potassium channels, which is under current investigation in the treatment of heart failure. We investigated the type of potassium channels that play a role on the dilatating effect of levosimendan on the contractile tones of the isolated human umbilical artery (HUA).The response in the HUA was recorded isometrically by a force displacement transducer in isolated organ baths. Levosimendan was added to organ baths after precontraction with serotonin (5-HT, 1 microM). Levosimendan-induced relaxations were tested in the presence of the large conductance Ca2+-activated K+ channel inhibitor tetraethylammonium (TEA, 1 mM), the adenosine triphosphate (ATP)-sensitive K+ channel inhibitor glibenclamide (GLI, 10 microM), and the voltage-sensitive K+ channel inhibitor 4-aminopyridine (4-AP, 1 mM). All experiments were performed in solutions containing the cyclooxygenase inhibitor indomethacin (10 microM) and the nitric oxide synthase inhibitor L-NAME (100 microM).Levosimendan (10 nM to 3 microM) produced potent relaxation in the HUA. Vehicle had no significant relaxant effect. The relaxation to levosimendan was not affected by the K+ channel inhibitor, GLI. However, 4-AP (1 mM) and TEA (1 mM) inhibited levosimendan-induced relaxation significantly (P.05).These results show that levosimendan effectively and directly decreases the tone of the HUA. The mechanism of this levosimendan-induced relaxation in the HUA appears in part to be due to voltage-gated and large conductance Ca2+-activated K+ channel opening action.

Background Levosimendan is a potent inotropic and vasodilator drug used in the treatment of decompensated heart failure. There is no study on in vitro effects of levosimendan in human isolated arteries. Methods We investigated the effect of levosimendan on contractile tone of human isolated internal mammary artery (IMA). The responses in IMA were recorded isometrically by a force-displacement transducer in isolated organ baths. Levosimendan was added to organ baths either at rest or after precontraction with phenylephrine (1 μmol/L). Levosimendan-induced relaxations were tested in the presence of cyclooxygenase inhibitor indomethacin (10 μmol/L), nitric oxide synthase inhibitor N 122 -nitro-l-arginine methyl ester (100 μmol/L), large-conductance calcium-activated potassium-channel inhibitor tetraethylammonium (1 mmol/L), adenosine triphosphate–sensitive potassium-channel inhibitor glibenclamide (10 μmol/L), and voltage-sensitive potassium-channel inhibitor 4-aminopyridine (1 mmol/L). Results Levosimendan (10 nmol/L to 3 μmol/L) produced potent relaxation in human IMA (maximal effect, 75.3% ± 4.9% of phenylephrine maximum contraction, 6.8 ± 0.1, n=15; −log 10 of 50% effective concentration). Vehicle had no significant relaxant effect. The relaxation to levosimendan is not affected by either potassium-channel inhibitors (tetraethylammonium and 4-aminopyridine) or cyclooxygenase and nitric oxide synthase inhibitors. Glibenclamide (10 μmol/L) inhibited levosimendan-induced relaxation significantly ( p Conclusions Levosimendan effectively and directly decreases the tone of IMA. The mechanism of levosimendan-induced relaxation in IMA appears in part to be adenosine triphosphate–sensitive potassium-channel opening action. Levosimendan may be a cardiovascular protective agent by its relaxing action on the major arterial graft, IMA.

To investigate the antimuscarinic effect of oxybutynin in the rat detrusor muscle after estrogen pretreatment because, to our knowledge, no study has been done on the interaction of estrogen with antimuscarinic drugs. Estrogen has been shown to affect muscarinic receptors in the detrusor muscle of animals. In addition, oxybutynin has been shown to block muscarinic receptors in the bladder.Estradiol benzoate (150 microg/kg) or saline was given subcutaneously to virgin female Wistar albino rats (n = 6, each group) for 10 consecutive days. On the 11th day, isolated detrusor muscle strips were taken, and acetylcholine (ACh)-induced contractions were evaluated in the absence or presence of oxybutynin (10 and 100 nM).ACh induced concentration-dependent contractions in the detrusor muscle. In the estradiol-pretreated group, the maximum of the ACh-induced contractions was diminished compared with that in the control group (P0.05). Oxybutynin (10 and 100 nM) inhibited ACh-induced contractions competitively (pK(B) 8.85). In the estradiol-pretreated group, the concentration-response curve to ACh was shifted further to the right in the presence of oxybutynin (100 nM).We have demonstrated for the first time that oxybutynin further inhibits ACh-induced and muscarinic receptor-mediated contractions in rat detrusor muscle after pretreatment with estrogen.

In human internal mammary artery (IMA), testosterone induces vasodilation that shows marked variability among patients. We aimed to investigate the relationship of this variability with cardiovascular risk factors. Cumulative relaxations to testosterone after precontraction with KCl were examined in IMA segments from patients with identified cardiovascular risk factors such as hypercholesterolemia, diabetes, hypertension, smoking, age, gender, body mass index (BMI), and number of occluded vessels. Testosterone responses were significantly diminished in subjects with 3 compared with 1 risk factor. Hypercholesterolemia independently influenced testosterone responses by significantly decreasing its maximum, and smoking significantly decreased the sensitivity to testosterone. Thus, the variability observed in testosterone-induced vascular relaxations may in part be related to differences in risk factors present among the individuals studied.

The opioid and non-opioid types of stress-induced analgesia have been well defined. One of the non-opioid type involve the endocannabinoid system. We previously reported that the spinal serotonin 7 receptor (5-HT7) blockers inhibit both morphine and cannabinoid-induced analgesia, thus we hypothesized that descending serotonergic pathways-spinal 5-HT7 receptor loop might contribute to stress-induced analgesia. Stress-induced analgesia was induced with warm (32°C) or cold (20°C) water swim stress in male Balb-C mice. The effects of intrathecal injection of a selective 5-HT7 receptor antagonist, SB 269970, of the denervation of serotonergic neurons by intrathecal administration of 5,7-dihydroxytryptamine (5,7-DHT) and of lesions of the dorsolateral funiculus on opioid and non-opioid type stress-induced analgesia were evaluated with the tail-flick and hot plate tests. The expression of 5-HT7 receptors mRNA in the dorsal lumbar region of spinal cord were analyzed by RT-PCR following spinal serotonin depletion or dorsolateral funiculus lesion. The effects of the selective 5-HT7 receptor agonists LP 44 and AS 19 were tested on nociception. Intrathecal SB 269970 blocked both opioid and non-opioid type stress-induced analgesia. Dorsolateral funiculus lesion or denervation of the spinal serotonergic neurons resulted in a marked decrease in 5-HT7 receptor expression in the dorsal lumbar spinal cord, accompanied by inhibition of opioid and non-opioid type stress-induced analgesia. However, the systemic or intrathecal LP 44 and AS 19 alone did not produce analgesia in unstressed mice. These results indicate that descending serotonergic pathways and the spinal 5-HT7 receptor loop play a crucial role in mediating both opioid and non-opioid type stress-induced analgesia.

WOS: 000364744700005 PubMed: 25869205 Background Recent studies showed that the pharmacological inhibition of endocannabinoid degrading enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) elicit promising analgesic effects in a variety of nociceptive models without serious side effects. However, the full spectrum of activities is not observed upon inhibition of either FAAH or MAGL enzymes alone and thus dual FAAH and MAGL inhibitors have been described. Visceral pain is strongly associated with inflammation and distension of the gut. Thus, we explored the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on inflammatory and mechanically evoked visceral pain models. Methods Visceral inflammatory and distension-induced pain were assessed with the 0.6% acetic acid writhing test in mice and colorectal distension (CRD) test in rats, respectively. The selective FAAH inhibitor PF 3845, MAGL inhibitor JZL 184, dual inhibitor JZL 195, and the cannabis analog CP 55,940 were given systemically 30 min prior to nociceptive testing. Key Results PF 3845 (5, 10, and 20 mg/kg), JZL 184 (5, 10, and 20 mg/kg), and JZL 195 (5, 10, and 20 mg/kg) elicit dose-dependent antinociceptive in the acetic acid writhing test. In the CRD model, while JZL 195 (5, 10, or 20 mg/kg) and PF3845 (10, 20, and 40 mg/kg) produced dose-dependent antinociceptive effects comparable to those of CP 55,940 (0.1, 0.3, or 1 mg/kg), JZL 184 (10, 20, and 40 mg/kg) alone did not alter the visceromotor response (VMR). Conclusions (sic) Inferences The selective FAAH inhibitor and dual FAAH/MAGL inhibitors were effective in both inflammatory and mechanically evoked visceral pain, while the MAGL inhibitor elicited an analgesic effect in inflammatory, but not in distension-induced, visceral pain. Scientific and Technological Research Council of TurkeyTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S403] This study is supported by a grant 112S403 from The Scientific and Technological Research Council of Turkey.

Interest has increased in the use of arterial conduits for CABG significantly in most major cardiac surgery centers around the world, because the number of patients receiving arterial grafts and our knowledge about the biologic characteristics of arterial grafts have increased. In addition, more advanced clinical protocols for the use of grafts have been developed and midterm results with alternative arterial grafts are encouraging.

Plant cannabinoids have been used historically as a therapeutic agent in some folk medicine for the treatment of headache, fibromyalgia, and irritable bowel and related conditions in which serotonergic pathways are considered to play a crucial role in pathogenesis and treatment modalities. Serotonergic system has important modulatory role in acute and chronic pain conditions. The analgesic efficacy of cannabinoids in acute and chronic pain appear to be mediated, at least in part, through the regulation of the serotonergic system. In this chapter, we review the interaction between cannabinoids and serotonergic system in the peripheral, spinal and supraspinal sites with special emphasis on serotonin in central sites by which cannabinoid CB1 receptor activation reinforce descending serotonergic pathways to produce antinociceptive effects.

p Dexmedetomidine (DEX) is a new methylol derivative with high affinity to 2-adrenergic receptors. It causes analgesia and sympatholysis, and has sedative, anxiolytic, and hypnotic effects. The use of DEX and its affinity to 2-adrenergic eceptors in the body should not only be limited to sedation and nesthesia, because 2-adrenergic receptors are scattered hroughout the body. In 1948, Ahlquist et al1 first reported and subtypes of adrenergic receptors that were activated by noradrenalin, the mediator of sympathetic nervous system stimulation in mammals. In light of this preliminary report, numerous studies were performed on this topic and, in 1973, 1 and 2 subtypes of -adrenergic receptors were determined.2 In subsequent investigations, gene studies were developed, and 3 subtypes, called aA, 1B, and 1c, or 1-adrenergic receptors2 and 4 subtypes, called 2A, 2B, 2C, and 2D, for 2-adrenergic receptors were isolated.3,4 Studies perormed on isolated organ samples from several experimental anmals showed that both subtypes of -adrenergic receptors are present in postsynaptic membranes in many animal species, including rabbits and guinea pigs; 1-adrenergic receptors are domnant.5 In contrast, 2-adrenergic receptors were reported to be enser only in a number of tissues, such as human saphenous vein6 and femoral vein tissue.7 Experimental findings show that localization of -adrenergic receptor subtypes can differ among species nd vessel segments, so the responses that occur after activation of hese receptors vary.

Although some studies have shown the essential role of descending serotonergic pathways and spinal 5-HT(1A), 5-HT(2A), or 5-HT(3) receptors in the antinociceptive effects of paracetamol, other studies have presented conflicting results, and the particular subtype of spinal 5-HT receptors involved in paracetamol-induced analgesia remains to be clarified. Recent studies have demonstrated the importance of spinal 5-HT(7) receptors in descending serotonergic pain inhibitory pathways. In this study, we investigated the role of descending serotonergic pathways and spinal 5-HT(7) receptors compared with 5-HT(3) and 5-HT(2A) receptors in the antinociceptive and antihyperalgesic effects of paracetamol. Tail-flick, hot plate and plantar incision tests were used to determine nociception in male BALB/c mice. Lesion of serotonergic bulbospinal pathways was performed by intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT), and spinal 5-HT levels were measured by HPLC. To evaluate the particular subtypes of the spinal 5-HT receptors, the selective 5-HT(7), 5-HT(3) and 5-HT(2A) receptor antagonists SB 269970, ondansetron and ketanserin, respectively, were given i.th. after oral administration of paracetamol. Oral paracetamol (200, 400 and 600 mg/kg) elicits dose-dependent antinociceptive and antihyperalgesic effects. I.th. pretreatment with 5,7-DHT (50 μg) sharply reduced 5-HT levels in the spinal cord. Depletion of spinal 5-HT totally abolished the antinociceptive and antihyperalgesic effects of paracetamol. I.th. injection of SB 2669970 (10 μg) blocked the antinociceptive and antihyperalgesic effects of paracetamol, but ondansetron and ketanserin (10 μg) did not. Our findings suggest that systemic administration of paracetamol may activate descending serotonergic pathways and spinal 5-HT(7) receptors to produce a central antinociceptive and antihyperalgesic effects.

To examine whether obstruction changes the expression of prostaglandins (PGs) in bladder, intravesical low-dose aspirin could be used as a new route of drug administration, this way of administration influences PGs' expression, and contractile function of the bladder is protected after treatment.Eighteen rabbits were divided into three groups. Sham-operated group (group 1) included 6 rabbits. Twelve rabbits were partially obstructed for 70 days. Six of these 12 rabbits not receiving any treatment constituted obstructed group (group 2). The remaining six rabbits received 2 mg/kg/day aspirin (group 3). One rabbit in each group was evaluated on 1st, 7th, 14th, 28th, 42nd, and 70th days following obstructive surgery. After scarification, the percentage of collagenous area and concentrations of PGE2 and PGF2-alpha were measured. Contractile responses to field stimulation (EFS), carbachol, and potassium chloride (KCl) were determined.Wet tissue PGE2 and PGF2-alpha levels were higher in obstructed group than the other groups. Aspirin decreased the percentage of collagenous area in group 3 compared to the group 2, but this difference was not statistically significant. The strips from aspirin groups resulted in better contractile response to cholinergic stimulation with KCl, but this difference was not statistically significant between the obstructed and aspirin groups. Similarly, carbachol did not elicit significantly greater concentration-dependent contraction in strips from obstructed group compared to those from aspirin groups. Maximum responses to EFS were not significant in aspirin group compared to those from obstructed group.Intravesical aspirin may have protective effect on partially obstructed bladder.

Several animal and human studies in vivo and in vitro indicate that testosterone has vasodilatory effects on different vessels. However, the effect of testosterone on the internal spermatic vein is not clear. In addition, the role of testosterone in the pathophysiology of varicocele is not established. We investigated the effect of testosterone on the internal spermatic vein in vitro in patients with varicocele and analyzed its relation to varicocele grade.Isolated internal spermatic veins were collected from patients who underwent varicocelectomy and orchiectomy. The preparations (3 to 4 mm rings) were mounted in an organ bath containing 10 ml Krebs-Henseleit solution on an L-shaped brace for tension measurement along the former circumferential axis. Changes in venous tension in the presence of testosterone (0.1 to 300 microM) were recorded isometrically by a force displacement transducer.Cumulative concentrations of testosterone (0.1 to 300 microM) elicited concentration dependent relaxation of 45 mM KCl induced active tone in the internal spermatic vein (mean +/- SEM 60.97% +/- 5.05% of the KCl induced contraction). Relaxation to testosterone (1 to 300 microM) was significantly higher in 5 cases of grades 0 and 1 varicocele than in 15 of grades 2 and 3 varicocele (maximum relaxation response 78.58% +/- 8.25% vs 55.10% +/- 5.3% of the KCl induced contraction).To our knowledge the current report is the first to describe testosterone induced relaxation of the human internal spermatic vein. The vasodilatory effect of testosterone on the human internal spermatic vein decreases in high grade varicoceles.

The increased incidence of cardiovascular disease in man compared with premenopausal women suggests an unfavourable effect of male sex hormone testosterone on the cardiovascular system. However, numerous clinical and epidemiological studies reported a controversial relationship between testosterone and cardiovascular disease. Furthermore, an increasing amount of evidence indicate that testosterone can exert acute vasorelaxing effects, VIA non-genomic mechanisms. These effects involve primarily the vascular smooth muscle, without requiring the presence of endothelium, although an endothelial contribution is apparent in some studies. To date, the mechanism behind the vasodilatory action of testosterone is still under debate and might be through either activation of K (+) channels or blockade of Ca (2+) channels in vascular muscle cells. The purpose of this article is to review the evidence regarding the vasodilating effect of testosterone as well as its mechanism of action.

Mineral trioxide aggregate (MTA) is being advocated for vital pulp therapy. In the case of direct pulp capping, hemorrhage control is an important step on success, but little is known about the effect of MTA on pulpal bleeding. In addition, there has been a lack of information on the effect of MTA on smooth muscle contraction, such as can occur in the blood vessels of dental pulp. The present study assessed the vascular effects of MTA, using the rat aortic ring preparations as a tissue model. MTA (100–500 mg) induced dose–dependent contraction in rat thoracic aorta. The contractile effect of MTA was blocked by calcium channel blocker nifedipine (1 μM). These data suggest that the vasoconstrictor property of MTA is related to calcium influx and it may allow proper control of hemorrhage which is critical for the success of any pulp-capping treatment.

Objective: To investigate the direct effects of dexmedetomidine (DEX) on isolated human internal mammary artery (IMA). Design: In vitro experimental study. Setting: Cardiovascular Pharmacology Laboratory, Department of Pharmacology, Gulhane School of Medicine, Ankara, Turkey. Participants: IMA segments were obtained from 18 patients undergoing coronary artery bypass surgery. Interventions: The response in IMA was recorded isometrically by a force displacement transducer in isolated organ baths. DEX-induced contractions were tested in the presence of the α2-adrenoceptor antagonist yohimbine (10−7 mol/L) and the α1-adrenoceptor antagonist prazosin (10−8 M). The effect of DEX (10−7, 10−6, and 10−5 mol/L) on phenylephrine (10−9-3 × 10−4 mol/L)-induced contactions was also tested. Measurement and Main Results: DEX (10−9 mol/L-3 × 10−5 mol/L) caused contraction in IMA segments. The contraction at lower concentrations of DEX (10−9 mol/L-3 × 10−7 mol/L) was attenuated by yohimbine (10−7 mol/L), whereas prazosin (10−8 mol/L) attenuated the contractions at higher concentrations of DEX (10−6 mol/L-3 × 10−5 mol/L). Incubation of IMA segments with high concentrations of DEX (10−6 mol/L and 10−5 mol/L) caused an inhibition of phenylephrine (10−9 mol/L-3 × 10−4 mol/L)-induced contraction. Conclusion: These data suggest that DEX causes contraction by activating α2-adrenoceptors at lower concentrations, but it may also activate α1-adrenoceptors at higher concentrations in IMA. The action of DEX on phenylephrine-induced contraction may be related to an α1-adrenoceptor antagonistic effect produced via partial α1-adrenoceptor agonistic action.