Effect of exercise duration on toluene-induced locomotor sensitization in mice: a focus on the Renin Angiotensin System.

RATIONALE: Exercise attenuates addictive behavior; however, little is known about the contribution of exercise duration to this positive effect. The Renin Angiotensin System (RAS) has been implicated both in addictive responses and in the beneficial effects of exercise; though, its role in the advantageous effects of exercise on toluene-induced addictive responses has not been explored. OBJECTIVES: To evaluate the impact of different exercise regimens in mitigating the expression of toluene-induced locomotor sensitization and to analyze changes in RAS elements' expression at the mesocorticolimbic system after repeated toluene exposure and following voluntary wheel running in toluene-sensitized animals. METHODS: Toluene-induced addictive-like response was evaluated with a locomotor sensitization model in mice. Toluene-sensitized animals had access to running wheels 1, 2, 4 or 24 h/day for 4 weeks; thereafter, locomotor sensitization expression was evaluated after a toluene challenge. RAS elements (ACE and ACE2 enzymes; AT1, AT2 and Mas receptors) expression was determined by Western blot in the VTA, NAc and PFCx of toluene-sensitized mice with and without exercise. RESULTS: Individual differences in toluene-induced locomotor sensitization development were observed. Access to wheel running 1 and 2 h/day reduced but 4 and 24 h/day completely blocked locomotor sensitization expression. Repeated toluene exposure changed RAS elements' expression in the VTA, NAc and PFCx, while exercise mainly modified ACE and AT1 in air-exposed and toluene-sensitized mice. CONCLUSIONS: Inhalant-exposed animals show different sensitization phenotypes. Exercise duration determined its efficacy to attenuate the addictive-like response. Toluene exposure and exercise each modified RAS, the latter also modifying toluene-induced changes.

Participation of angiotensin-(1-7) in exercise-induced analgesia in rats with neuropathic pain.

Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.

COVID-19: enfoque básico para entender sus tratamientos / COVID-19: a basic approach to understanding potential treatments

Resumen El virus SARS-CoV-2 ha sido identificado como el agente patológico causante de la pandemia de COVID-19. Aun cuando no se cuenta con un tratamiento estándar, se han probado antivirales como remdesivir y otros fármacos como cloroquina e ivermectina, que interfieren con la replicación del virus. También se han intentado algunas estrategias encaminadas a disminuir los mecanismos inmunitarios, como el uso de tocilizumab y antioxidantes naturales. Los fármacos relacionados con el sistema renina-angiotensina han resultado controversiales. Aún se debe estudiar con detalle los mecanismos de patogenicidad, así como los tratamientos controlados para proponer alguna opción terapéutica viable que evite la entrada y replicación del virus o que aumente los sistemas inmunitarios del huésped.

Abstract SARS-CoV-2 virus has been identified as the causative agent of the COVID-19 pandemic. Even when no standard treatment is available, antivirals such as remdesivir and other drugs such as chloroquine and ivermectin, which interfere with viral replication, have been assayed. Some strategies aimed to reduce immune mechanisms, such as the use of tocilizumab and natural antioxidants, have also been tested. The use of drugs related to the renin-angiotensin system has been controversial. Pathogenicity mechanisms, as well as controlled treatments, still have to be studied in detail in order to propose a viable therapeutic option that prevents the entry and replication of the virus or enhances the host immune system.

The α1D-adrenoreceptor antagonist BMY 7378 reverses cardiac hypertrophy in spontaneously hypertensive rats.

OBJECTIVE: The α1D-adrenoreceptor (α1D-AR) is involved in angiotensin II-induced vascular remodeling and hypertension. Whether α1D-AR plays a role in hypertension-associated cardiac hypertrophy is unclear. Here we investigated effects of BMY 7378, a selective α1D-AR antagonist, on cardiac status in aged spontaneously hypertensive rats (SHR). METHODS: Male SHR were studied during the phase of developing hypertension (5 and 10 weeks old) and once hypertension was established (20 and 30 weeks old) to assess the evolution of cardiac hypertrophy. Age-matched WKY rats were studied as controls. Thirty-week-old SHR were treated for 4 weeks with BMY 7378 (10 mg/kg per day, o.a.), or captopril (angiotensin-converting enzyme inhibitor, 40 mg/kg per day, o.a.) (as a positive control). Blood pressure and cardiac function were measured in vivo, cardiac hypertrophy by histology, and α1D-AR protein expression by immunofluorescence. RESULTS: By 30 weeks of age, SHR exhibited significant hypertension and cardiac hypertrophy. BMY 7378 and captopril decreased blood pressure and improved hemodynamic parameters and cardiac function in treated SHR vs. untreated SHR (P < 0.05). Histology showed increased cardiomyocyte size, fibrosis, and left ventricular hypertrophy in SHR hearts. BMY 7378 ameliorated fibrosis and cardiac hypertrophy, but had no effect on cardiomyocyte size in SHR. Effects of BMY 7378 were associated with increased α1D-AR protein expression in SHR. CONCLUSION: Our data indicate that pharmacological antagonism of α1D-AR reduces blood pressure and associated cardiac hypertrophy in aged SHR. These findings suggest that the α1D-AR plays a pathophysiological role in the development of hypertension and cardiac target organ damage in SHR.

Potential role of angiotensin-(1-7) in the improvement of vascular insulin sensitivity after a bout of exercise.

NEW FINDINGS: What is the central question of this study? What is the mechanism by which a bout of exercise increases subsequent insulin-stimulated vasodilatation? What is the main finding and its importance? Angiotensin-(1-7) through the Mas receptor participates in enhanced insulin-induced vasorelaxation after a bout of exercise in healthy rats. This new potential role of angiotensin-(1-7) could help in understanding how physical activity improves vascular insulin sensitivity in normal and insulin-resistant states. ABSTRACT: Exercise increases insulin-stimulated vasodilatation, but the mechanisms involved are unclear. This study was performed to investigate the possible involvement of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in enhanced vascular insulin sensitivity after a bout of exercise. Male Wistar rats were subjected to swimming for 2.5 h. After exercise, carbachol- or insulin-induced relaxation in aorta was assessed. Prior exercise improved insulin-stimulated vasorelaxation; however, this insulin-sensitizing effect was prevented by the selective Mas receptor (MasR; an Ang-(1-7) receptor) antagonist A779. Carbachol-mediated vascular relaxation was not modified by exercise. These results suggest that Ang-(1-7) acting through MasR participates in the enhancement of vascular insulin sensitivity after an exercise session. This new potential role of Ang-(1-7) could help in understanding how exercise improves vascular insulin sensitivity in normal and insulin-resistant states.

Angiotensin-(1-7) Participates in Enhanced Skeletal Muscle Insulin Sensitivity After a Bout of Exercise.

A single bout of exercise increases subsequent insulin-stimulated glucose uptake in skeletal muscle; however, it is unknown whether angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system, participates in this process. The aim of this study was to investigate the possible involvement of Ang-(1-7) in enhanced skeletal muscle insulin sensitivity after an exercise session. Male Wistar rats were forced to swim for 2.5 hours. Two hours after exercise, insulin tolerance tests and 2-deoxyglucose uptake in isolated soleus muscle were assessed in the absence or presence of the selective Mas receptor (MasR, Ang-(1-7) receptor) antagonist A779. Ang II and Ang-(1-7) levels were quantified in plasma and soleus muscle by HPLC. The protein abundance of angiotensin-converting enzyme (ACE), ACE2, Ang II type 1 receptor (AT1R), and MasR was measured in soleus muscle by Western blot. Prior exercise enhanced insulin tolerance and insulin-mediated 2-deoxyglucose disposal in soleus muscle. Interestingly, these insulin-sensitizing effects were abolished by A779. After exercise, the Ang-(1-7)/Ang II ratio decreased in plasma, whereas it increased in muscle. In addition, exercise reduced ACE expression, but it did not change the protein abundance of AT1R, ACE2, and MasR. These results suggest that Ang-(1-7) acting through MasR participates in enhanced insulin sensitivity of skeletal muscle after a bout of exercise.

COVID-19: a basic approach to understanding potential treatments.

SARS-CoV-2 virus has been identified as the causative agent of the COVID-19 pandemic. Even when no standard treatment is available, antivirals such as remdesivir and other drugs such as chloroquine and ivermectin, which interfere with viral replication, have been assayed. Some strategies aimed at reducing immune mechanisms, such as the use of tocilizumab and natural antioxidants, have also been tested. The use of drugs related to the renin-angiotensin system has been controversial. Pathogenicity mechanisms, as well as controlled treatments, still have to be studied in detail in order to propose a viable therapeutic option that prevents the entry and replication of the virus or enhances the host immune system.El virus SARS-CoV-2 ha sido identificado como el agente patológico causante de la pandemia de COVID-19. Aun cuando no se cuenta con un tratamiento estándar, se han probado antivirales como remdesivir y otros fármacos como cloroquina e ivermectina, que interfieren con la replicación del virus. También se han intentado algunas estrategias encaminadas a disminuir los mecanismos inmunitarios, como el uso de tocilizumab y antioxidantes naturales. Los fármacos relacionados con el sistema renina-angiotensina han resultado controversiales. Aún se debe estudiar con detalle los mecanismos de patogenicidad, así como los tratamientos controlados para proponer alguna opción terapéutica viable que evite la entrada y replicación del virus o que aumente los sistemas inmunitarios del huésped.

Abdominal obesity is strongly associated to blood pressure in young Mexicans.

OBJECTIVE: The objective of this study was to determine associations between abdominal obesity (AOb) and the other components of metabolic syndrome (MetS) in young Mexicans in a cross-sectional survey completed during a 4 year period. METHODS: This cross-sectional study reports on components and prevalence of MetS by using Alberti et al. (16) criteria, as well as association between AOb and elevated blood pressure (BP) of 2,993 Mexican university students, ages 17 to 25 years (66% women) from central and northern Mexico, over a 4-year survey (2010-2013). RESULTS: The most prevalent MetS components in the total sample were low HDL-C concentration (43.6%) and AOb (41.1%). MetS prevalence was 11.8%, more men than women were classified with MetS (14.3% vs. 10.5%, p < 0.01). BP was the MetS component with the lowest prevalence (8.6%). A strong association between AOb and altered BP with in both men and women was found (OR 4.3, IC95% 2.5-7.4). CONCLUSIONS: Even BP was the component with the lowest prevalence, AOb was more strongly associated with it. This fact, could explain the prevalence of hypertension among young Mexican adults.

Cardiometabolic risk in young adults from northern Mexico: Revisiting body mass index and waist-circumference as predictors.

BACKGROUND: A body mass index (BMI) ≥30 kg/m(2) and a waist circumference (WC) ≥80 cm in women (WCF) or ≥90 cm in men (WCM) are reference cardiometabolic risk markers (CMM) for Mexicans adults. However, their reliability to predict other CMM (index tests) in young Mexicans has not been studied in depth. METHODS: A cross-sectional descriptive study evaluating several anthropometric, physiological and biochemical CMM from 295 young Mexicans was performed. Sensitivity (Se), specificity (Sp) and Youden's index (J) of reference BMI/WC cutoffs toward other CMM (n = 14) were obtained and their most reliable cutoffs were further calculated at Jmax. RESULTS: Prevalence, incidence and magnitude of most CMM increased along the BMI range (p < 0.01). BMI explained 81 % of WC's variance [Se (97 %), Sp (71 %), J (68 %), Jmax (86 %), BMI = 30 kg/m(2)] and 4-50 % of other CMM. The five most prevalent (≥71 %) CMM in obese subjects were high WC, low HDL-C, and three insulin-related CMM [Fasting insulin, HOMA-IR, and QUICKI]. For a BMI = 30 kg/m(2), J ranged from 16 % (HDL-C/LDL-C) to 68 % (WC), being moderately reliable (Jmax = 61-67) to predict high uric acid (UA), metabolic syndrome (MetS) and the hypertriglyceridemic-waist phenotype (HTGW). Corrected WCM/WCF were moderate-highly reliable (Jmax = 66-90) to predict HTGW, MetS, fasting glucose and UA. Most CMM were moderate-highly predicted at 27 ± 3 kg/m(2) (CI 95 %, 25-28), 85 ± 5 cm (CI 95 %, 82-88) and 81 ± 6cm (CI 95 %, 75-87), for BMI, WCM and WCF, respectively. CONCLUSION: BMI and WC are good predictors of several CMM in the studied population, although at different cutoffs than current reference values.

Effect of inter-renal aortic coarctation-induced hypertension on function and expression of vascular α(1A)- and α(1D)-adrenoceptors.

We investigated the effect of inter-renal aortic coarctation on the function and expression of vascular α(1A)- and α(1D)-adrenoceptors and plasma angiotensin II (ATII) in rats. Male Wistar rats, either sham operated (SO), or with aortic coarctation for 7 (AC7) and 14 days (AC14) were used for agonist-induced pressor responses in vehicle (physiological saline)- and antagonist-treated anesthetized animals, immunoblot analysis (α(1A)- and α(1D)-adrenoceptor in aorta and caudal arteries), and immunoassay (plasma ATII). The α(1D)-adrenoceptor antagonist, BMY-7378 (BMY) blocked noradrenaline-induced responses in the order SO > AC7 â‰« AC14; in contrast, the α(1A)-adrenoceptor antagonist RS-100329 (RS), produced a marginal shift to the right of the dose-response curve to noradrenaline, along with a strong decrease of the maximum pressor effect in the order SO > AC7 = AC14. The potency of the α(1A)-adrenoceptor agonist A-61603 increased in rats with AC14, and responses were inhibited by RS in the order AC14 > AC7 > SO. In aorta, α(1D)-adrenoceptor protein increased in AC7 and decreased in AC14; α(1A)-adrenoreceptor protein increased in the caudal artery of AC7 and returned to control values in AC14. Plasma ATII increased in AC7 and AC14, compared with SO rats. These results suggest an early and direct relationship between ATII and α(1D)-adrenoreceptors in the development of hypertension in this experimental model.

Angiotensin II pressor response in the L-NAME-induced hypertensive pithed rat: role of the AT1 receptor.

The blockade of renin-angiotensin system by pharmacological interventions with angiotensin converting-enzyme (ACE) inhibitors or AT1 receptor antagonists in the juvenile critical age may attenuate or even prevent the development of hypertension. In this work, we determined the Ang II type 1 (AT1) receptor role in L-NAME-induced hypertension in pithed rats. Male Wistar rats (250-300 g) were used. Rats were divided into the following groups: Control (tap water) and N(omega)-Nitro-L-arginine methyl ester (L-NAME, 60 mg/kg/day/2 weeks). Dose-response curves to Ang II were constructed in the pithed rat. The results show that Ang II evoked blood pressure increase in pithed rats in a dose-related manner. In L-NAME-treated rats a greater maximal effect was observed, indicating that L-NAME promotes Ang II hypersensitivity. In L-NAME-treated rats, Ang II response was blocked by losartan (1 and 3 mg/kg), a selective AT1 receptor antagonist, indicating that AT1 receptor influence L-NAME hypertensive mechanism. Our results suggest that Ang II hypersensitivity in L-NAME-induced hypertension can be due to increased AT1 receptor expression or sensitivity changes.

The hypotensive effect of BMY 7378 involves central 5-HT1A receptor stimulation in the adult but not in the young rat.

BACKGROUND: Stimulation of central 5-hydroxytryptamine-1A (5-HT(1A)) receptors produces hypotension and bradycardia. We describe BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9 dione) effects in cardiovascular function and [(3)H] 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-amino) tetralin) binding sites in rat brain of different ages. METHODS: BMY 7378 was administered to anesthetized male Wistar rats (1, 3 and 6 months old) and blood pressure and heart rate were continuously recorded. Saturation of [(3)H] 8-OH-DPAT binding to 5-HT(1A) sites in brain membranes was determined. RESULTS: Basal diastolic blood pressure increased with age, 85 +/- 2, 106 +/- 3, and 113 +/- 2 mmHg for 1-, 3- and 6-month-old rats, respectively (p <0.05 among groups). BMY 7378 induced significant dose- and age-dependent hypotension. The selective 5-HT(1A) receptor antagonist, WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexanecarboxamide), antagonized BMY 7378 effects in 6 month-old but not in younger rats. [(3)H] 8-OH-DPAT binding sites decreased in hippocampi and brainstem with maturation. CONCLUSIONS: Data suggest that BMY 7378 is a hypotensive agent in the rat, but that its actions are mediated, in part, by central 5-HT(1A) receptor stimulation in the adult and by a nonserotonergic mechanism in the young rat.

Evidence for the role of alpha1D- and alpha1A-adrenoceptors in contraction of the rat mesenteric artery.

We investigated the alpha(1)-adrenoceptor subtype(s) involved in contraction of the isolated rat mesenteric artery by the use of the agonists noradrenaline (NA), phenylephrine (PHE), oxymetazoline (OXY), and methoxamine (MET), the competitive antagonists 8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4.5)decane-7,9-dione dihydrochloride (BMY 7378) and 5-methylurapidil, and the alkylating agent chloroethylclonidine (CEC). Agonists showed the potency order NA> or =PHE>OXY>MET; pA(2) values for 5-methylurapidil and BMY 7378 were 7.74+/-0.11 and 8.72+/-0.28, respectively, while Schild slopes were not different than unity; alpha(1)-adrenoceptor alkylation with CEC showed a drastic decrease in maximal agonists-induced contraction and a shift to the right of about 46-, 122-, 2-, and 15-fold higher than controls for NA, PHE, OXY, and MET, respectively. Data suggest that alpha(1D)-adrenoceptors predominate for contraction in mesenteric artery of the Wistar rat, with a second population of alpha(1A)-adrenoceptors responding at high agonist concentrations.

Evidence that NAN-190-induced hypotension involves vascular alpha1-adrenoceptor antagonism in the rat.

The effect of NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido]-butyl] piperazine), described as a mixed 5-HT(1A) receptor agonist/antagonist, on cardiovascular function was studied. The i.v. injection of NAN-190 (1-300 micro/kg) dose-dependently decreased blood pressure (p<0.001), while heart rate was not significantly modified compared to saline-treated, anaesthetized adult rats. WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide), a highly selective 5-HT(1A) receptor antagonist, increased NAN-190-induced hypotension (p<0.05). In the pithed rat NAN-190 displaced the phenylephrine dose-pressor response curve to the right; ED(50) values were: approximately 14, 20, 40 and 270 microg/kg for saline and NAN-190 (1, 10 and 100 microg/kg, respectively); similar ED(50) values were obtained with prazosin ( approximately 20, 69 and 358 microg/kg for 1, 10 and 100 microg/kg of prazosin, respectively). NAN-190 shifted to the right the concentration-response curves to phenylephrine in rat tail artery (alpha(1A)-adrenoceptors), in rabbit aorta (alpha(1B)-adrenoceptors) and in rat aorta (alpha(1D)-adrenoceptors), with pA(2) values of 9.47, 9.02 and 9.99; while Schild slopes were -0.78, -1.13 and -0.90, respectively (not significantly different from unity). The results show that NAN-190 induced hypotension in the anaesthetized, adult rat and suggest that this effect could be explained by antagonism of vascular alpha(1)-adrenoceptors.