Rosa A. Bobadilla-Lugo

Effects of leukotriene synthesis inhibition on acute liver damage induced by carbon tetrachloride.

Administration of the leukotriene synthesis inhibitors nordihydroguaiaretic acid (NDHGA, 30 mg/kg), caffeic acid (20 mg/kg) or nafazatrom (100 mg/kg) and of the phosphodiesterase inhibitor and free radical trapper dipyridamole (10 mg/kg) prevented the alterations in enzyme activity displayed by acute CCl4 administration. The effect was less evident in preventing hepatic glycogen depletion or lipid peroxidation. A synergistic protective effect between dipyridamole and NDHGA or caffeic acid was observed. In conclusion, the present results show that acute hepatic damage induced by CCl4 can be partially prevented by leukotriene synthesis inhibitors and the protection is enhanced with the simultaneous use of phosphodiesterase inhibitors.

Renal Angiotensin-II Receptors Expression Changes in a Model of Preeclampsia

The blunted response to angiotensin II (Ang II) during pregnancy is lost in patients by preeclampsia. This impaired response has been attributed to a change in one or both of the Ang II receptors, type 1 (AT1R) and type 2 (AT2R). The ratio of the Ang II receptor types in the kidney has not been studied. We postulated that an imbalance exists between AT1R/AT2R receptors in the renal cortex from rats subjected to an experimental model of preeclampsia, and that this altered ratio can modify the characteristic blunted pressor response to Ang II during pregnancy. The feto-placental units of Wistar rats were made ischemic by subrenal aortic coarctation, thus creating an experimental model of preeclampsia. We measured the AT1R and AT2R protein expression and the presence of the heterodimer AT1R/AT2R in the renal cortex and evaluated the pressor response to Ang II in an isolated kidney preparation from non-pregnant, healthy pregnant, and preeclampsia model rats. Pregnancy increased AT2R and AT1R/AT2R heterodimer expression and decreased the pressor response to Ang II. In contrast, AT1R increased, while AT2R and AT1R/AT2R heterodimer decreased in the preeclampsia model group. Thus, Ang II hypersensitivity observed in preeclampsia might be related to an increased expression of AT1R over AT2R and to a decreased presence of the AT1R/AT2R heterodimer in renal cortex.

Effects of Exercise on Oxidative Stress in Rats Induced by Ozone

Oxidative stress (OS) induced by acute exercise is reduced by chronic exercise. Ozone (O3) exposure produces OS. The aim of this study was to determine if aerobic exercise (AE) reduced OS produced by O3. A pilot experiment was performed with male Wistar rats submitted to AE (trained to swim 90 min/day). Adaptation to exercise was demonstrated three weeks after training by means of changes in reduced nitrates (NOx) in plasma. Therefore, two-week training was chosen for the following experiments. Six of twelve trained rats were exposed to O3 (0.5 ppm, 4 h/day, one hour before exercise). Two groups of sedentary animals (n = 6 each) were used as controls, one of which was exposed to O3. At the end of the experiments NOx, 8-isoprostane (8-IP), malondialdehyde (MDA), superoxide dismutase (SOD) activity, and carbonyls (CBs) were measured in plasma. CBs did not change in any group. O3-induced OS was manifested by reduced NOx and SOD activity, as well as increased 8-IP and MDA. Exercise significantly blocked O3 effects although SOD was also decreased by exercise (a greater drop occurring in the O3 group). It is concluded that AE protects against OS produced by O3 and the effect is independent of SOD.

Oxychlorine species suppress postsurgical adhesions in rats

BACKGROUND Surgically induced adhesions complicate up to 100% of abdominal surgeries. Food and Drug Administration-approved treatments are generally not only less effective than desired but they also have major contraindications. Oxychlorine species, including chlorine dioxide (ClO2), suppress scar formation in infected wounds without affecting keratinocytes while reducing fibroblast proliferation. The aim of the present study was to evaluate the effect of oxychlorine solutions containing ClO2 on adhesion formation. METHODS Male Wistar rats were subjected to Buckenmaier model of surgical adhesions and treated with either oxychlorine solutions containing ClO2 (40-150 ppm) or isotonic saline solution. To increase the severity of adhesions, peritonitis was produced by intraperitoneal administration of a diluted nonlethal dose of feces (50 mg/kg). Wound strength of the healed wound was measured to evaluate the effects of oxychlorine solutions. In addition, an oxychlorine solution of lesser efficacy (at 100 ppm) was compared with three available anti-adhesion materials. RESULTS Reproducibility of the model was validated in 26 rats. Oxychlorine solutions containing ClO2 (40-110 ppm) significantly reduced postsurgical adhesion formation without affecting the strength of the healed wound. Higher concentrations (120 and 150 ppm) had no effect. Fecal peritonitis significantly increased, and solutions with ClO2 at 110 ppm significantly reduced adhesion formation. The effect of the oxychlorine solution was significantly greater than that of Interceed, Guardix, Seprafilm, and isotonic saline solution. CONCLUSIONS ClO2-containing oxychlorine solutions could be an innovative strategy for the suppression of surgical adhesion formation, with the additional advantage of contributing antiseptic properties.

Experimental Gestational Diabetes Mellitus Induces Blunted Vasoconstriction and Functional Changes in the Rat Aorta

Diabetic conditions increase vascular reactivity to angiotensin II in several studies but there are scarce reports on cardiovascular effects of hypercaloric diet (HD) induced gestational diabetes mellitus (GDM), so the objective of this work was to determine the effects of HD induced GDM on vascular responses. Angiotensin II as well as phenylephrine induced vascular contraction was tested in isolated aorta rings with and without endothelium from rats fed for 7 weeks (4 before and 3 weeks during pregnancy) with standard (SD) or hypercaloric (HD) diet. Also, protein expression of AT1R, AT2R, COX-1, COX-2, NOS-1, and NOS-3 and plasma glucose, insulin, and angiotensin II levels were measured. GDM impaired vasoconstrictor response (P < 0.05 versus SD) in intact (e+) but not in endothelium-free (e−) vessels. Losartan reduced GDM but not SD e− vasoconstriction (P < 0.01 versus SD). AT1R, AT2R, and COX-1 and COX-2 protein expression were significantly increased in GDM vessels (P < 0.05 versus SD). Results suggest an increased participation of endothelium vasodilator mediators, probably prostaglandins, as well as of AT2 vasodilator receptors as a compensatory mechanism for vasoconstrictor changes generated by experimental GDM. Considering the short term of rat pregnancy findings can reflect early stage GDM adaptations.

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.

Beneficial effects of phycobiliproteins from Spirulina maxima in a preeclampsia model

Aims: Considering phycobiliproteins of Spirulina maxima has shown a wide margin of security in pregnant and non‐pregnant animals as well as antioxidant properties, present study aimed to investigate if the cardiovascular and metabolic effects of an experimental model of preeclampsia can be prevented by the administration of this compound. Main methods: Subrenal aortic coarctation (SRAC) practiced to female Wistar rats of 8 weeks of age. Animals were divided randomly to conform non‐pregnant and pregnant groups and pregnant with SRAC showed fetoplacental ischemia and were considered preeclamptic (PE). Groups were treated with saline solution (control group) or phycobiliproteins solution (100 mg/kg/day ig) for the last 7, 14 or 20 days of pregnancy. Key findings: PE animals showed increased systolic blood pressure, weight gain, glucose and GTT as well as vascular contractility. Also, PE animals showed decreased SOD, GPx activities while MDA was increased. Phycobiliproteins oral treatment for 3 weeks significantly decreased systolic blood pressure and reestablished glucose, weight gain and vascular contractility as well as enzyme activities of PE rats to those of normal pregnant animals. Significance: Our results show that phycobiliproteins can prevent the damage produced by fetoplacental ischemia and provides evidence of free radical species contribution to the physiopathology of the disease. Also, we conclude phycobiliproteins can be an alternative to reduce preeclampsia manifestations, however, more studies are recommended.

Evidence of changes in alpha-1/AT1 receptor function generated by diet-induced obesity

To study whether hypercaloric diet–induced obesity deteriorates vascular contractility of rat aorta through functional changes in α1 adrenergic and/or AT1 Angiotensin II receptors. Angiotensin II- or phenylephrine-induced contraction was tested on isolated aorta rings with and without endothelium from female Wistar rats fed for 7 weeks with hypercaloric diet or standard diet. Vascular expression of Angiotensin II Receptor type 1 (AT1R), Angiotensin II Receptor type 2 (AT2R), Cyclooxygenase-1 (COX-1), Cyclooxygenase-2 (COX-2), inducible Nitric Oxide Synthase (iNOS) and endothelial Nitric Oxide Synthase (eNOS), as well as blood pressure, glucose, insulin and angiotensin II blood levels were measured. Diet-induced obesity did not significantly change agonist-induced contractions (Emax and pD2 hypercaloric diet vs standard diet n.s.d.) of both intact (e+) or endothelium free (e−) vessels but significantly decrease both phenylephrine and angiotensin II contraction (Emax p < 0.01 hypercaloric diet vs standard diet) in the presence of both prazosin and losartan but only in endothelium-intact vessels. Diet-induced obesity did not change angiotensin II AT1, AT2 receptor proteins expression but reduced COX-1 and NOS2 (p < 0.05 vs standard diet). Seven-week hypercaloric diet–induced obesity produces alterations in vascular adrenergic and angiotensin II receptor dynamics that suggest an endothelium-dependent adrenergic/angiotensin II crosstalk. These changes reflect early-stage vascular responses to obesity.

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