Itzell Gallardo-Ortiz

Evidence for the role of α1D- and α1A-adrenoceptors in contraction of the rat mesenteric artery

Abstract We investigated the α 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≥PHE>OXY>MET; p A 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; α 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 α 1D -adrenoceptors predominate for contraction in mesenteric artery of the Wistar rat, with a second population of α 1A -adrenoceptors responding at high agonist concentrations.

Synthesis, in vitro and computational studies of protein tyrosine phosphatase 1B inhibition of a small library of 2-arylsulfonylaminobenzothiazoles with antihyperglycemic activity

The 2-arylsulfonylaminobenzothiazole derivatives 1-27 were prepared using a one step reaction. The in vitro inhibitory activity of the compounds against protein tyrosine phosphatase 1B (PTP-1B) was evaluated. Compounds 4 and 16 are rapid reversible (mixed-type) inhibitors of PTP-1B with IC(50) values in the low micromolar range. The most active compounds (4 and 16) were docked into the crystal structure of PTP-1B. Docking results indicate potential hydrogen bond interactions between the nitro group in both compounds and the catalytic amino acid residues Arg 221 and Ser 216. Both compounds were evaluated for their in vivo antihyperglycemic activity in a type 2 diabetes mellitus rat model, showing significant lowering of plasma glucose concentration, during the 7h post-intragastric administration.

Antihypertensive and vasorelaxant activities of Laelia autumnalis are mainly through calcium channel blockade

The aim of the present study was to evaluate the possible mechanism of the vasorelaxant action of methanol extract from Laelia autumnalis (MELa) in isolated rat aortic rings, and to establish its antihypertensive activity in vivo. MELa (0.15-->50 microg/mL) induced relaxation in aortic rings pre-contracted with KCl (80 mM), showing an IC50 value of 34.61+/-1.41 microg/mL and E max value of 85.0+/-4.38% (in endothelium-intact rings) and an IC50 value of 45.11+/-4.17 microg/mL and E max value of 80.0+/-12.1% (in endothelium-denuded rings). Serotonin (5-HT, 1 x 10(-4) M) provoked sustained contraction, which was markedly inhibited by MELa (0.15-->50 microg/mL) in a concentration-dependent and endothelium-independent manner. Pretreatment with MELa (15, 46, 150, 300 and 1500 microg/mL) also inhibited contractile responses to norepinephrine (NE 1 x 10(-11) M to 1 x 10(-5.5) M). In endothelium-denuded rings, the vasorelaxant effect of MELa was reduced partially by ODQ (1 microM), but not by tetraethylammonium (5 microM), glibenclamide (10 microM), and 2-aminopyridine (100 microM). The extract also reduced NE-induced transient contraction in Ca2+-free solution, and inhibited contraction induced by increasing external calcium in Ca2+-free medium plus high KCl (80 mM). The antihypertensive effect of MELa was determined in spontaneously hypertensive rats (SHR). A single oral administration of the extract (100 mg/kg) exhibited a significant decrease in systolic and diastolic blood pressure and heart rate (p<0.05) in SHR rats. Our results suggest that MELa induces relaxation in rat aortic rings through an endothelium-independent pathway, involving blockade of Ca2+ channels and a possible cGMP enhanced concentrations and also causes an antihypertensive effect.

Vasorelaxant and antihypertensive effects of methanolic extract from roots of Laelia anceps are mediated by calcium-channel antagonism.

RMELanc-induced relaxation in aortic rings precontracted with NE, 5-HT and KCl. It also reduced NE-induced transient contraction in Ca(2+)-free solution and inhibited contraction induced by increasing external calcium. Nevertheless, the vasorelaxant effect of RMELanc was not reduced by ODQ, 1-alprenolol, TEA, glibenclamide, and 2-AP. Oral administration of 100 mg/kg of RMELanc exhibited a significant decrease in systolic and diastolic blood pressures in SHR rats. HPLC analysis allowed us to detect the presence of 2,7-dihydroxy-3,4,9-trimethoxyphenantrene (1), which induced a significant relaxation effect. Therefore, our results suggest that RMELanc induces vasorelaxant and antihypertensive effects by blockade of Ca(2+) channels.

Evidence that NAN-190-induced hypotension involves vascular α1-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.

Differential role of cyclooxygenase-1 and -2 on renal vasoconstriction to α1-adrenoceptor stimulation in normotensive and hypertensive rats

AIMS Hypertension is associated with the impairment of renal cyclooxygenase (COX) activity, which regulates vascular tone, salt and water balance and renin release. We aimed to evaluate the functional role of COX isoforms in kidneys isolated from spontaneously hypertensive rats (SHR) after α1-adrenoceptor (α1-AR) stimulation. MAIN METHODS Male six-month-old SHR and normotensive Wistar-Kyoto rats (WKY) were used. The kidneys were isolated to measure perfusion pressure and COX-1- or COX-2-derived prostanoids in response to α1-AR activation. KEY FINDINGS The basal perfusion pressure was higher in SHR kidneys compared with WKY kidneys (95 ± 11 vs. 68 ± 6 mmHg, P<0.05). Phenylephrine induced a greater vasopressor response in SHR kidneys (EC50 of 1.89 ± 0.58 nmol) than WKY kidneys (EC50 of 3.30 ± 0.54 nmol, P<0.05 vs. SHR). COX-1 inhibition decreased the α1-AR-induced vasoconstrictor response in WKY but did not affect SHR response, while COX-2 inhibition diminished the response in SHR. Both basal prostacyclin (PGI2) and thromboxane A2 (TxA2) values were higher in SHR kidney perfusates (P<0.05) and were reduced by COX-1 and COX-2 inhibitors in both strains. Furthermore, phenylephrine increased PGI2 through COX-2 in WKY and through COX-1 in SHR, but the agonist did not significantly modify TxA2 in both strains. SIGNIFICANCE The data suggest that COX-1 contributes to vasoconstrictor effects in WKY kidneys and that COX-2 has the same effect in SHR kidneys. The results also suggest that basal release of COX-2-derived vasoconstrictor prostanoids is involved in renal vascular hypersensitivity in SHR.

Does exercise increase insulin sensitivity through angiotensin 1-7?

Glucose homeostasis in humans and other mammals is regulated by the concerted contributions of several organs and systems. One of the quantitatively most important events for maintaining this equilibrium is glucose transport in skeletal muscle. The main physiological mediators that stimulate this process are insulin and exercise. Each triggers the translocation of glucose transporter type 4 (GLUT4), the predominant GLUT in muscle, from the interior of the cell to the plasma membrane by means of distinct mechanisms. In addition, exercise can increase insulin-mediated glucose transport in skeletal muscle and improve whole-body insulin sensitivity (Maarbjerg et al. 2011, Stanford & Goodyear 2014). Enhanced insulin sensitivity after an exercise session has been partially explained by the amplification of the insulin signalling pathway (distal) and GLUT4 translocation to the plasma membrane (Maarbjerg et al. 2011). Conversely, chronic exercise-induced insulin sensitization has been related to adaptations in skeletal muscle, such as improvements in mitochondrial function and increments in capillary density, oxidative fibres and GLUT4 protein expression (Stanford & Goodyear 2014). Current evidence shows that microvasculature plays a critical role in regulating insulin delivery to and action on post-exercised skeletal muscle; however, the mechanisms involved have not yet been elucidated. Here, we propose a novel hypothesis to explain how exercise through angiotensin (Ang) 1-7 signalling improves insulin sensitivity in skeletal muscle. The renin–angiotensin system (RAS), considered the master regulator of cardiovascular homeostasis, promotes the formation of two physiologically relevant peptides: Ang II and Ang 1-7. The synthesis process begins when the renin enzyme, released by juxtaglomerular cells in the kidney, cleaves angiotensinogen, which is synthesized and secreted by the liver, to form the inactive decapeptide Ang I. Subsequently, the angiotensin-converting enzyme (ACE), which is released by the lungs, cleaves Ang I to the active octapeptide Ang II. This peptide mediates its effects through two types of G-protein-coupled receptors. Some biological actions of Ang II via the Ang II type 1 receptor (AT1R) include vasoconstriction, inflammation, hypertrophy, oxidative stress and insulin resistance. Contrariwise, Ang II-mediated effects through the Ang II type 2 receptor (AT2R) involve vasodilatory, anti-inflammatory, antihypertrophic, antioxidant and insulin-sensitizing effects (Dominici et al. 2014). Thus, this ACE/Ang II/AT1R pathway represents the classical axis of the RAS. Ang 1-7, the other major active peptide of RAS, is formed in three distinct ways. It can be directly synthesized from Ang I by thimet oligopeptidase (TOP), neutral endopeptidase (NEP) or prolyl endopeptidase (PEP), or from Ang II by the ACE homolog, ACE2, which constitutes the most important enzyme for Ang 1-7 generation. Indirectly, this heptapeptide may also be formed from Ang I by ACE2, producing the intermediary peptide Ang 1-9, which in turn is cleaved by ACE or NEP. Ang 1-7, once formed, can interact with the G-protein-coupled Mas receptor (MasR) and, at a lesser proportion, AT2R. Last, Ang 1-7 is metabolized to Ang 1-5 by ACE. The majority of biological responses of Ang 1-7 through Mas and AT2 receptors are similar to each other, but dissimilar to those induced by Ang II via AT1R. Thus, the ACE2/Ang 1-7/MasR pathway, considered the new RAS axis, exerts counter-regulatory actions on the classical pathway, the ACE/Ang II/AT1R axis (Dominici et al. 2014). In addition to its systemic expression, local RAS is localized in several tissues, such as brain, heart, blood vessels, pancreas, liver, adipose tissue and skeletal muscle, where it regulates diverse functions. Recent studies show that RAS participates in some exercise-induced beneficial effects. After one or several exercise sessions, insulin-induced vasorelaxant responses are increased in isolated arteries from healthy and insulin-resistant rats (Fontes et al. 2014, Wang et al. 2015). In a similar fashion, swimming training improved the vasodilator effect of Ang 1-7 in thoracic aortae from spontaneous hypertensive rats (SHR) through a nitric oxide (NO)and prostacyclin (PGI2)-dependent mechanism (Silva et al. 2011). In addition, Ang II-mediated vasoconstrictor responses were attenuated in several vascular beds from postexercised rats and humans (Adams et al. 2005, Chies et al. 2013). These vascular adaptations after exercise have been associated with downregulation of the ACE/Ang II/AT1R axis and/or upregulation of the ACE2/Ang 1-7/MasR axis of RAS (Adams et al. 2005, Silva et al. 2011, Gu et al. 2014). Moreover, as in the vasculature and blood (Silva et al. 2011, Gomes-Santos et al. 2014, Gu et al. 2014), exercise training shifts the RAS towards the

An Internet System to Self-monitoring and Assess Feeding in Young Mexicans

Obesity and metabolic syndrome pave the way to type 2 diabetes and cardiovascular disease. Obesity and metabolic syndrome prevalence are high (39% and 13%, respectively) in young Mexican population where feeding habits are one of the main factors leading to these maladies. So, a plausible strategy to address the problem is to suggest young to review and control their feeding habits. We present an internet system to register, self-monitoring, and assess feeding habits for young Mexican to review and control them. This system is organized in eight questionnaires, one of them about food frequencies. Also anthropometrics data such as weight, height, waist and hip circumference are registered to assess and follow-up weight condition, through body mass index, and waist/hip ratio. The user could generate a pdf report that automatically summarizes all the data captured in the questionnaires in two pages. A follow up charts of some parameters are also available for monthly data collection once the user fills the system. More than 2,000 young students have used this system since 2013 and is open universally (www.misalud.abacoac.org) to all young people wanting to self-monitoring her/his feeding habits, and obtaining general health recommendations.