Daniel Godínez-Hernández

Protective effects of resveratrol on calcium-induced oxidative stress in rat heart mitochondria

Trans-resveratrol is a nutraceutical with known antioxidant, anti-inflammatory, cardioprotective, and anti-apoptotic properties. The aim of this study was to evaluate the effects of resveratrol on heart mitochondria. Resveratrol significantly decreased Fe2+ + ascorbate oxidant system-induced lipid peroxide levels, preserved physiological levels of glutathione, and increased nitric oxide (NO) levels in mitochondria. Under calcium-mediated stress, there was a 2.7-fold increase in the NO levels, and a mild decoupling in the mitochondrial respiratory chain. These results provide a mechanism for and support the beneficial effects of resveratrol under pathological conditions induced by oxidative stress and calcium overload. In addition, these findings underscore the usefulness of resveratrol in the prevention of cardiovascular diseases.

Angiotensin-II-Dependent Changes in Alpha-1 Adrenoceptor Vascular Expression in Pregnant Rats

Vessels from pregnant animals show a blunted response to adrenergic agonists. In this work, we explored if pregnancy reduces α₁-adrenergic receptor (α₁-AR)-mediated vascular smooth muscle protein expression as well as agonist-induced contraction in rat aorta, and if angiotensin II (Ang II) levels during pregnancy are related to these changes. Female Wistar rats were divided randomly into nonpregnant (NP) and pregnant groups (first week: P1, second week: P2, third week: P3). Subsets of animals were treated with captopril (5 mg kg^–1 day^–1 for 7 days; n = 6). Phenylephrine (PHE) concentration-response curves were constructed (1 × 10^–9 to 3.1 × 10^–5 mol/l) and α_1A-, α_1B- and α_1D-AR were measured in the aorta by immunoblot. Captopril decreased α-AR expression in the NP group. In contrast, pregnancy decreased α_1A-, α_1B- and α_1D-AR levels and captopril prevented this reduction. PHE sensitivity was decreased in the thoracic and abdominal aorta in the P2 group, with no changes in E_max, and E_max was decreased in the abdominal aorta in all experimental groups. Our results suggest that Ang II levels during pregnancy are related to a decrease in aortic α₁-AR expression. The physiological meaning of this finding remains to be established.

Increased alpha-1 Adrenoceptor Expression in Pregnant Rats with Subrenal Aortic Coarctation

The progression of pregnancy is associated with attenuation in vasopressor response to adrenergic agonists. In pregnancy-induced hypertension this attenuation is reverted. It is not known if this reversion involves alpha-1 adrenoceptor expression. Objective. In this work we propose that in pregnant rats with subrenal aortic coarctation there are changes in the expression of alpha-1 adrenergic receptors in the thoracic and abdominal aorta during pregnancy. Methods. We used non-pregnant, normal pregnant and pregnant with subrenal aortic coarctation female Wistar rats. Pregnancy-induced hypertension indicators, systolic blood pressure, 24 hours proteinuria, pup weight and maternal weight were measured. Dose response curves to phenylephrine were carried out to determine vascular reactivity along pregnancy. Alpha 1-adrenoceptors were detected from thoracic and abdominal aorta using immunoblot. Results. Results show significant increases in arterial pressure and proteinuria in pregnant rats with SRAC at the end of the third week. Pregnancy reduces alpha-1-A, -B and -D adrenoceptor expression and this event is reverted by subrenal aortic coarctation. This phenomenon is more apparent in the abdominal segment of the aorta. Conclusions. These findings suggest that subrenal aortic coarctation is a good animal model of pregnancy-induced hypertension and that α1-adrenoceptors participate in its physiopathology increasing their expression in a segment-dependent manner.

Von Willebrand Factor: Multimeric Structure and Functional Activity in Patients With Atrial Fibrillation With and Without Oral Anticoagulation

von Willebrand factor (vWF) is a multimeric glycoprotein present in blood plasma. It is synthesized in megakaryocytes and endothelial cells, secreted into circulation in the form of high-molecular-weight multimers (HMWMs), and cleaved into shorter, less active multimers by ADAMTS13. It is essential for platelet adhesion and aggregation. Previous studies have investigated the relationship between vWF levels and thromboembolic events with little regard to vWF multimeric structure. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 levels. One hundred seven patients with AF, 51 anticoagulated and 56 nonanticoagulated, were eligible for the study. Plasma samples were analyzed for vWF antigen, vWF activity, and ADAMTS13; vWF multimers were analyzed by Western blot in 1% to 1.3% sodium dodecyl sulfate agarose gel electrophoresis. Patients with AF without oral anticoagulation (OAC) had significantly higher vWF plasma levels (154.00 [75-201] UI/dL) and vWF activity (60.00% [20%-210%]) compared to patients with OAC (133.50 [90-192] UI/dL, P = <.001; 50.00% [20%-160%], P = .02). Both were specially decreased in patients treated with acenocumarin. Patients without OAC also showed lower ADAMTS13 levels and presence of vWF HMWMs. Patients with AF show higher plasma levels and vWF activity. Moreover, treatment with traditional OAC (acenocumarin) significantly reduced vWF levels. Patients without OAC might have an increased risk of thrombotic events showing lower ADAMTS13 and higher vWF levels. Patients with stroke had higher plasma levels, vWF activity, and HMWMs. Our study suggests that increased vWF levels and presence of HMWMs could be related to cerebrovascular disease and may represent useful biomarkers for stroke in AF.

Toluene exposure enhances acute and chronic formalin-induced nociception in rats: Participation of 5-HT3 receptors

HighlightsToluene exposure enhanced formalin‐induced acute and long‐lasting nociception.Alosetron reduced toluene pronociceptive effect on formalin‐induced nociception.m‐CPBG further enhanced the effect of toluene on formalin‐induced nociception.Alosetron blocked m‐CPBG pronociceptive effect on formalin‐induced nociception.Methiothepin did not affect toluene effect on formalin‐induced nociception. &NA; The purpose of this study was to evaluate the effect of acute toluene exposure on formalin (0.5% and 1%)‐induced acute and long‐lasting nociceptive hypersensitivity in rats. In addition, we sought to investigate the role of peripheral 5‐HT3 receptors in the pronociceptive effect of toluene. Toluene exposure (6000 ppm) for 30 min enhanced 0.5% or 1% formalin‐induced acute nociception and long‐lasting secondary allodynia and hyperalgesia. In contrast, exposition to toluene for 30 min in rats previously injected (six days before) with 1% formalin did not affect long‐lasting hypersensitivy. Local peripheral pre‐treatment with alosetron (5‐HT3 receptor antagonist, 10–100 nmol) reduced the pronociceptive effect of toluene in acute nociception and long‐lasting secondary allodynia and hyperalgesia. Alosetron (100 nmol) was also able to reduce the nociceptive effects of 1% formalin in absence of toluene. Moreover, local peripheral injection of m‐CPBG (5‐HT3 receptor agonist, 300 nmol) enhanced 0.5% formalin‐induced acute and long‐lasting nociception in air‐ and toluene‐exposed rats. Alosetron (10 nmol) blocked the pronociceptive effects of m‐CPBG (300 nmol) on 0.5% formalin‐induced acute and long‐lasting hypersensitivity in rats exposed to toluene. Alosetron (at 10 nmol) did not modify formalin‐induced nociceptive behaviors. Finally, local peripheral pre‐treatment with methiothepin (non‐selective 5‐HT receptor antagonist, 1.5 nmol), did not affect the pronociceptive effect of toluene on 1% formalin‐induced acute and long‐lasting hypersensitivity. Our data demonstrate that acute exposure to toluene has pronociceptive effects in formalin‐induced acute nociception and long‐lasting hypersensitivity. Our data suggest that this pronociceptive effect depend on activation of peripheral 5‐HT3, but not methiothepin‐sensitive 5‐HT, receptors.

The Effects of 17β-Oestradiol on Increased α1-Adrenergic Vascular Reactivity Induced by Prolonged Ovarian Hormone Deprivation: The Role of Voltage-Dependent L-type Ca2+ Channels

The present study investigated the hypothesis that the duration of ovarian hormone deprivation before reintroduction of oestrogen affects the role of oestrogen as a mediator of the contractile function of α1-adrenergic receptors. Rats underwent ovariectomy (OVX) or were sham-operated, and the OVX rats were treated with vehicle (corn oil) or 17β-oestradiol (E2) for 5 days either 10, 28 or 60 days after OVX. The OVX increased phenylephrine- and Ca2+-induced contractions. Interestingly, the phenylephrine-induced contractions were increased at each of the three time points, whereas the Ca2+-induced contractions were only increased in the 60-day group. E2 had biphasic effects on phenylephrine- and Ca2+-induced contractility. Indeed, E2 increased contractions in the 10-day group and diminished contractions in the other groups (the increased contractions were avoided by verapamil). These results indicate that E2 controls α1-adrenergic receptor-mediated contractility through effects on L-type Ca2+ channels in a way that depends on the timing in which the treatment with E2 is initiated.

Participation of voltage-gated sodium and calcium channels in the acute cardiac effects of toluene

Abstract Inhaling solvents can lead to occurrence of cardiac arrhythmias and sudden sniffing death. Mechanisms related to this phenomenon are not fully understood. The purpose of this study was to investigate the effect of acute toluene exposure on heart reactivity to epinephrine and the participation of voltage-gated sodium and calcium channels. We found that acute toluene exposure increased perfusion pressure, left ventricular developed pressure, and heart rate. These actions were inhibited by lidocaine and nifedipine. Our results suggest that acute toluene exposure modify voltage-gated sodium and calcium channel function and expression likely due to a cardiac adrenergic mechanism and these effects could be participating, at least in part, in the presence of cardiac arrhythmias. To our best knowledge, this is the first report to establish a direct participation of voltage-gated Na+ and Ca2+ channels, toluene and epinephrine on cardiac function in rats.

Comparative effects of avocado oil and losartan on blood pressure, renal vascular function, and mitochondrial oxidative stress in hypertensive rats

OBJECTIVE Angiotensin II (Ang-II) antagonism alleviates hypertensive kidney damage by improving mitochondrial function and decreasing oxidative stress. This condition also is associated with altered renal vascular tone due to enhanced constriction by Ang-II. Thus, approaches ameliorating these events are desirable to alleviate kidney damage. Avocado oil, a source of antioxidants and oleic acid, is known to improve mitochondrial function, while oleic acid has antihypertensive effects. Therefore, the aim of this study was to test whether avocado oil counteracts, to a similar degree as the Ang-II blocker losartan, the deleterious effects of hypertension on blood pressure, renal vascular performance, kidney mitochondrial function, and oxidative stress. METHODS Hypertensive rats induced with Nω-nitro-l-arginine methyl ester (L-NAME) were supplemented during 45 d with avocado oil or losartan. Vascular responses were analyzed in perfused kidney. Membrane potential, reactive oxygen species levels, and glutathione were analyzed in isolated kidney mitochondria. RESULTS In hypertensive rats, avocado oil decreased 21.2% and 15.5% diastolic and systolic blood pressures, respectively, and alleviated impaired renal vasodilation. Hypertension decreased membrane potential by 83.7% and augmented reactive oxygen species levels by 51% in mitochondria fueled with a complex I substrate, whereas it augmented the levels of oxidized glutathione in 48%. These alterations were normalized by avocado oil at a comparable degree to losartan. CONCLUSIONS Because avocado oil mimicked the effects of losartan, we propose that the effects of avocado oil might be mediated by decreasing the actions of Ang-II on mitochondria. These results suggest that avocado oil intake might be a nutritional approach to attenuate the deleterious effects of hypertension on kidney.

Acknowledgement to Referees for Pharmacology 2009

www.karger.com/pha J. Ahamed, New York, N.Y., USA Jörg Ahrens, Hannover, Germany Reiko Akagi, Hiroshima, Japan Satoshi Akiba, Kyoto, Japan Y. Akiba, Los Angeles, Calif., USA Naohiko Anzai, Tochigi, Japan H. Aso, Sendai, Japan Jean Bastin, Paris, France Melvin L. Billingsley, Hershey, Pa., USA F. Boulle, Maastricht, Netherlands William Bowen, Rochester, N.Y., USA J. Breslin, Tampa, Fla., USA Keith K. Burkhart, Silver Spring, Md., USA Frederic Canini, La Tronche, France De-Liang Cao, Springfield, Ill., USA Kejiang Cao, Nanjing, China Rong Chu, Little Rock, Ark., USA George Crystal, Chicago, Ill., USA S.J. Czuczwar, Lublin, Poland Sergio De Marchi, Verona, Italy Carina Denny, Piracicaba, Brazil Le Ding, Kansas, Mo., USA Patrick D’Silva, Bangalore, India Michele Emdin, Pisa, Italy Qingfeng Fan, Philadelphia, Pa., USA J. Faridi, Stockton, Calif., USA Silvia Franchi, Milan, Italy Masanori Fujii, Kyoto, Japan M. Fujimuro, Kyoto, Japan Fenghua Fu, Yantai, China Stefano Fumagalli, Firenze, Italy Li Gan, Madison, Wis., USA Chantal Gauthier, Nantes, France Huiming Ge, Nanjing, China A. Gentilini, Firenze, Italy Lisa Giocomo, Palo Alto, Calif., USA Javier González-Maeso, New York, N.Y., USA Joseph Granchelli, Rochester, N.Y., USA Luis Granero, Valencia, Spain Xiu-Li Guo, Jinan, China E. Gussoni, Boston, Mass., USA Ki Baik Hahm, Seongnam, Korea R. Hardeland, Göttingen, Germany Noriyasu Hirasawa, Sendai, Japan Michael Holzer, Graz, Austria Martin Hönigl, Graz, Austria Lai S. Hooi, Johor Bahru, Malaysia Shigeo Horinaka, Tochigi, Japan Longshuang Huang, Chicago, Ill., USA Christian Humpel, Innsbruck, Austria Yoshimi Imura, Fujisawa, Japan N. Inagaki, Gifu, Japan Makoto Inui, Yamaguchi, Japan Keiichi Ishihara, Kyoto, Japan Yoichiro Isohama, Kumamoto, Japan Kazumi Iwata, Kyoto, Japan Yangfu Jiang, Sichuan, China Melanie S. Joy, Aurora, Colo., USA K. Kadoyama, Himeji, Japan Ira Kass, Brooklyn, N.Y., USA H. Katsuki, Kumamoto, Japan Atsufumi Kawabata, Higashiosaka, Japan Naoyuki Kawao, Osaka, Japan Zunji Ke, Shanghai, China Frieder Keller, Ulm, Germany H.R. Kim, Chungnam, Korea Yoshihisa Kitamura, Kyoto, Japan Yasuo Kizawa, Chiba, Japan T. Kobayashi, Tokyo, Japan J. Komano, Osaka, Japan Vasilios Kouloulias, Athens, Greece Toshiaki Kume, Kyoto, Japan Solene Le Douairon Lahaye, Rennes, France M-T. Lin, Tainan, Taiwan Yi-Wen Liu, Chiayi, Taiwan Zhen-Guo Liu, Columbus, Ohio, USA Pamela Lucchesi, Columbus, Ohio, USA Denisa Margina, Bucharest, Romania Xianfang Meng, Wuhan, China Francesca Menniti, Rome, Italy I. Mérida, Madrid, Spain Jing Miao, Philadelphia, Pa., USA S. Minagawa, Kyoto, Japan Keiji Miyata, Tsukuba, Japan Mizuo Miyazaki, Nagaokakyo, Japan Nobuaki Mizutani, Kobe, Japan M.J. Moshi, Dar es Salaam, Tanzania H. Motohashi, Kyoto, Japan Nariya Mukeshkumar, Jamnagar, India T. Murayama, Kanazawa, Japan H. Murota, Osaka, Japan