Exercise training improves hypertension-induced autonomic dysfunction without influencing properties of peripheral cardiac vagus nerve

We examined the vagal transfer function of autonomic heart rate (HR) control in anesthetized sedentary and exercise-trained Spontaneously Hypertensive Rats (SHR). To this end, male SHR and Wystar-Kyoto (WKY) rats with 48-50 weeks of age-old were divided into 4 groups: sedentary (SHRS, n = 12) and trained (SHRT, n = 14) hypertensive rats, sedentary (WKYS, n = 13) and trained (WKYT, n = 13) normotensive rats. The trained groups were submitted to swimming protocol for 9 weeks. Blood pressure (BP), HR, HR variability (HRV), BP variability (BPV), baroreflex sensitivity and cardiac tonus were recorded in baseline conditions. Following, electric stimulation of peripheral vagus nerve was performed in anesthetized conditions. Resting bradycardia was observed in SHRT and WKYT when compared to their respective sedentary groups (p < 0.001). The BP was lower in SHRT than in SHRS (p < 0.001). The SHRT and WKYT rats showed higher baroreflex-mediated tachycardia values when compared to their respective sedentary counterparts (p < 0.001). Baroreflex bradycardic response in SHRT was higher than in SHRS (p < 0.005). The SHRT and WKYT rats showed a decreased sympathetic activity in comparison to their respective sedentary groups (p < 0.05). The cardiac vagal tonus was higher in SHRT than in SHRS (p < 0.05). Regarding the dynamic transducer properties of peripheral vagus nerve to the heart no difference was observed among the groups. In conclusion, our results demonstrate that exercise training decreased BP in SHR and improved cardiovascular autonomic balance to the heart without changes in transduction properties of peripheral cardiac vagus nerve.Federal University of Triangulo MineiroUniv Fed Triangulo Mineiro, Dept Sport Sci, Human Performance & Sport Res Grp, Av Tutunas 490, BR-38061500 Uberaba, MG, BrazilUniv Fed Triangulo Mineiro, Dept Endocrinol & Metab, Postgrad Course Hlth Sci, Uberaba, BrazilUniv Fed Juiz de Fora, Dept Physiol, Juiz De Fora, BrazilUniv Fed Sao Paulo, Dept Biosci, Santos, SP, BrazilUniv Fed Triangulo Mineiro, Inst Biol & Nat Sci, Dept Physiol, Uberaba, BrazilUniv Fed Sao Paulo, Dept Biosci, Santos, SP, BrazilWeb of Scienc

Genotoxic studies in hypertensive and normotensive rats treated with amiodarone

Amiodarone, a benzofuran derivative. is a very effective antiarrhythmic medication, but has potential to cause side effects. Although its cytotoxicity potential is very well-known, there are few reports about its genotoxicity effects. Since amiodarone has not been investigated in genotoxicity studies, and the spontaneously hypertensive rat (SHR) is a well-characterized model for hypertension, the aim of the present study was to perform cytogenetic analysis on chromosome aberrations in bone marrow cells of SHRs and normotensive Wistar-Kyoto rats (WKYs) that received oral amiodarone treatment for 4 weeks. Amiodarone activity was also monitored using electrocardiograms. The presence of bradycardia in amiodarone-treated rats confirmed that this drug was really active. Metaphase analysis on bone marrow cells showed that there were significant differences in total chromosomal damage and percentage abnormal metaphase between WKY and SHR negative controls. In the SHR negative control, the frequencies of basal chromosomal aberrations and abnormal metaphases were significantly higher (p < 0.05). There were high numbers of chromosomal aberrations in all amiodarone-treated groups, compared with negative controls. In amiodarone-treated groups, the most frequent chromosomal aberration was chromatid breaks. More chromosomal aberrations were found in WKYs that received amiodarone, with a statistically significant difference in comparison with negative controls (p < 0.05). However, in SHR rats there was no significant difference between the amiodarone and negative groups regarding chromosomal damage induction. These results showed that treatment with amiodarone was genotoxic in WKYs, but not in SHRs. Further studies are needed to confirm whether amiodarone is genotoxic or efficient and harmless, among humans undergoing therapy. (c) 2008 Published by Elsevier B.V.PIBIC/CNPq (Conselho Nacional de Desenvolvimento Cientifico a Tecnologico)BIC/FAPEMIG (Fundaqao de Apoio a Pesquisa do Estado de Minas Gerais

Acute adenosine increases cardiac vagal and reduces sympathetic efferent nerve activities in rats

Adenosine is the first drug of choice in the treatment of supraventricular arrhythmias. While the effects of adenosine on sympathetic nerve activity (SNA) have been investigated, no information is available on the effects on cardiac vagal nerve activity (VNA). We assessed in rats the responses of cardiac VNA, SNA and cardiovascular variables to intravenous bolus administration of adenosine. In 34 urethane-anaesthetized rats, cardiac VNA or cervical preganglionic sympathetic fibres were recorded together with ECG, arterial pressure and ventilation, before and after administration of three doses of adenosine (100, 500 and 1000 mu g kg-1). The effects of adenosine were also assessed in isolated perfused hearts (n= 5). Adenosine induced marked bradycardia and hypotension, associated with a significant dose-dependent increase in VNA (+204 +/- 56%, P &lt; 0.01; +275 +/- 120%, P &lt; 0.01; and +372 +/- 78%, P &lt; 0.01, for the three doses, respectively; n= 7). Muscarinic blockade by atropine (5 mg kg-1, i.v.) significantly blunted the adenosine-induced bradycardia (-56.0 +/- 4.5%, P &lt; 0.05; -86.2 +/- 10.5%, P &lt; 0.01; and -34.3 +/- 9.7%, P &lt; 0.01, respectively). Likewise, adenosine-induced bradycardia was markedly less in isolated heart preparations. Previous barodenervation did not modify the effects of adenosine on VNA. On the SNA side, adenosine administration was associated with a dose-dependent biphasic response, including overactivation in the first few seconds followed by a later profound SNA reduction. Earliest sympathetic activation was abolished by barodenervation, while subsequent sympathetic withdrawal was affected neither by baro- nor by chemodenervation. This is the first demonstration that acute adenosine is able to activate cardiac VNA, possibly through a central action. This increase in vagal outflow could make an important contribution to the antiarrhythmic action of this substance.Ministero dell' Istruzione, Universita' e della Ricerca ScientificaConselho Nacional de Desenvolvimento Cientifico e Technologico (CNPq) - Brazil [308016/20092

N, N ', N ''-trisubstituted guanidines: Synthesis, characterization and evaluation of their leishmanicidal activity

Leishmaniasis is a group of diseases caused by protozoan parasites from the genus Leishmania. There are estimated 1.3 million new cases annually with a mortality of 20,000-30,000 per year, when patients are left untreated. Current chemotherapeutic drugs available present high toxicity and low efficacy, the latter mainly due to the emergence of drug-resistant parasites, which makes discovery of novel, safe, and efficacious antileishmanial drugs mandatory. The present work reports the synthesis, characterization by ESI-MS, H-1 and C-13 NMR, and FTIR techniques as well as in vitro and in vivo evaluation of leishmanicidal activity of guanidines derivatives presenting lower toxicity. Among ten investigated compounds, all being guanidines containing a benzoyl, a benzyl, and a substituted phenyl moiety, LQOF-G2 (IC50-ama 5.6 mu M: SI = 131.8) and LQOF-G7 (IC50-ama 7.1 mu M; SI = 87.1) were the most active against L. amazonensis intracellular amastigote, showing low cytotoxicity to the host cells according to their selectivity index. The most promising compound, LQOF-G2, was further evaluated in an in vivo model and was able to decrease 60% of the parasite load in foot lesions at a dose of 0.25 mg/kg/day. Moreover, this guanidine derivative demonstrated reduced hepatotoxicity compared to other leishmanicidal compounds and did not show nephrotoxicity, as determined by the analyses of biomarkers of hepatic damage and renal function, which make this compound a potential new hit for therapy against leishmaniasis. (C) 2019 Elsevier Masson SAS. All rights reserved171116128COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informação2013/24487-6; 2013/08248-1; 2016/19289-9; 2017/03552-

Chronic treatment with ivabradine does not affect cardiovascular autonomic control in rats

A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine – a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels– has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p=0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11bpm, p=0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p>0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p>0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p=0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p<0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/sec, p=0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p=0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart