The vasodilatory effect of a synthetic polymer-based root canal material on thoracic aorta.

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 Ca(2+)channel antagonistic effect of the Epiphany, the effect of these compounds in Ca(2+)-free solution on extracellular Ca(2+)(CaCl(2))-induced contraction in high-K(+) pre-challenged rings (in K(+)-depolarized rings) was examined to determine whether the direct inhibition of [Ca(2+)] influx increase accounted for the vasodilatory effects of these compounds. For comparison, L-type Ca(2+)channel blocker nifedipine (1 micromol 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 CaCl(2)-induced contractions (P < 0.05), the base of Epiphany did not inhibit CaCl(2)-induced contractions significantly (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.

Vasodilating mechanisms of testosterone.

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.

Assessment of concomitant versus sequential trastuzumab on radiation-induced cardiovascular toxicity.

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.

Systemic morphine produce antinociception mediated by spinal 5-HT7, but not 5-HT1A and 5-HT2 receptors in the spinal cord.

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 microg) and metergoline (20 microg) 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 microg) and metergoline (1, 5, 10 and 20 microg) 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 microg) or ketanserine (20 microg) 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.

High-dose testosterone and dehydroepiandrosterone induce cardiotoxicity in rats: Assessment of echocardiographic, morphologic, and oxidative stress parameters.

The aim of this study is to assess cardiotoxic effect of testosterone (TES) and dehydroepiandrosterone (DHEA) in Sprague Dawley rats. We compared the impact of subacute (14 days) and subchronic (90 days) administration of suprapharmacologic doses of TES and DHEA on body weight, locomotor activity, muscle strength, echocardiographic parameters, heart histopathology, and oxidative stress markers with the control group. Testosterone (10, 30, and 100 mg/100 g body weight) and DHEA (10 mg/100 g body weight) administration decreased the body weights and locomotor activity (p < 0.05), and the combination of both increased muscle strength (p < 0.05) in rats. In our histopathological evaluation, misshapen cell nuclei, disorganized myocardial fibers, and leukocytic infiltrates were observed in high-dose TES (100 mg/100 g)-treated rats, especially on day 14. On day 90, mild changes such as misshapen cell nuclei, disorganized myocardial fibers, and leukocytic infiltrates were observed in TES and DHEA-treated groups. According to our echocardiographic study on day 14 and day 90, TES, especially at high doses, induced increase in left ventricular posterior wall diameter and ejection fraction (p < 0.05). In this study, blood oxidative stress marker malondialdehyde was increased slightly but not significantly in TES and DHEA groups. On the other hand, antioxidant enzymes such as SOD and glutathione peroxidase (GSH-Px) levels were slightly but not significantly increased in TES and DHEA groups. These data demonstrate that the potential risk to cardiac health due to exogenous androgen use may be related to oxidative stress in rats.

The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension-induced visceral pain models in Rodents.

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 & 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.

Effects of taurine on contractions of human internal mammary artery: a potassium channel opening action.

OBJECTIVE: Taurine is an abundant amino acid that is widely distributed in human and animal tissues. Pharmacodynamic studies show that taurine has hypotensive and myocardial protective effects. Studies in isolated tissue baths show that taurine relaxes precontracted arteries. This study aimed to show the effects of taurine on human internal mammary artery (IMA) in vitro and to explain the mechanisms of its effects. METHODS: The response in the IMA was recorded isometrically by a force displacement transducer in isolated organ baths. Taurine (20, 40, 80 mM) was added to organ baths after precontraction with KCl (45 mM) or serotonin (5-HT, 30 µM). Taurine-induced relaxations were also tested in the presence of the cyclooxygenase inhibitor indomethacin (10 µM), the nitric oxide synthase inhibitor L-NAME (100 µM), the large conductance Ca2+-activated K+ channel inhibitor tetraethylammonium (TEA, 1 mM), the ATP-sensitive K+ channel inhibitor glibenclamide (GLI, 10 µM), the voltage-sensitive K+ channel inhibitor 4-aminopyridine (4-AP, 1 mM) and the inward rectifier K+ channel inhibitor barium chloride (BaCl2, 30 µM). RESULTS: Taurine did not affect the resting tone of IMA. However, it produced relaxation in the 5-HT and KCl -precontracted preparations. The relaxation to IMA was not affected by GLI, 4-AP, BaCl2, indomethacin and L-NAME. But, TEA inhibited taurine -induced relaxations significantly (p < 0.05). CONCLUSIONS: The preincubation of IMA with taurine antagonized KCl and 5-HT induced contractions in a concentration dependent manner, while it did not affect the resting tone. The relaxations to taurine were significantly antagonized by pretreatment with TEA. These results suggest that mechanism of vasodilator effect of taurine in IMA may be the activation of large conductance Ca2+-activated K+ channels.