TRPV4 activates autonomic and behavioural warmth-defence responses in Wistar rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Novelty of the arena impairs the cortisol-related increase in the aggression of matrinxa (Brycon amazonicus)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Pharmacology of the glucagon-like peptide-1 analog exenatide extended-release in healthy cats

Exenatide extended-release (ER) is a microencapsulated formulation of the glucagon-like peptide 1-receptor agonist exenatide: It has a protracted pharmacokinetic profile that allows a once-weekly injection with comparable efficacy to insulin with an improved safety profile in type II diabetic people. Here, we studied the pharmacology of exenatide ER in 6 healthy cats. A single subcutaneous injection of exenatide ER (0.13 mg/kg) was administered on day 0. Exenatide concentrations were measured for 12 wk. A hyperglycemic clamp (target = 225 mg/dL) was performed on days 7 (clamp I) and 21 (clamp II) with measurements of insulin and glucagon concentrations. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the clamp. Continuous glucose monitoring was performed on weeks 0, 2, and 6 after injection. Plasma concentrations of exenatide peaked at 1 h and 4 wk after injection. Comparing clamp I with clamp II, fasting blood glucose decreased (mean standard deviation = 11 8 mg/dL, P = 0.02), glucose tolerance improved (median [range] +33% 14%-138%], P = 0.04), insulin concentrations increased (+36.5% [-9.9% to 274.1%], P = 0.02), and glucagon concentrations decreased (-4.7% [0%-12.1%], P = 0.005). Compared with preinjection values on continuous glucose monitoring, glucose concentrations decreased and the frequency of readings <50 mg/dL increased at 2 and 6 wk after injection of exenatide ER. This did not correspond to clinical hypoglycemia. No other side effects were observed throughout the study. Exenatide ER was safe and effective in improving glucose tolerance 3 wk after a single injection. Further evaluation is needed to determine its safety, efficacy, and duration of action in diabetic cats. (C) 2015 Elsevier Inc. All rights reserved.

Effect of furosemide treatment on the central and peripheral pressor responses to cholinergic and adrenergic agonists, angiotensin II, hypertonic solution and vasopressin

The present study was performed to investigate the effect of treatment with furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injections of cholinergic (carbachol) and adrenergic (norepinephrine) agonists, angiotensin II (ANGII) and hypertonic saline (HS, 2 M NaCl). The changes induced by furosemide treatment on the pressor response to intravenous (i.v.) norepinephrine, ANGII and arginine vasopressin (AVP) were also studied. Rats with a stainless-steel cannula implanted into the lateral ventricle (LV) were used. Two injections of furosemide (30 mg/kg b.wt. each) were performed 12 and 1 h before the experiments. Treatment with furosemide reduced the pressor response induced by carbachol, norepinephrine and ANGII i.c.v., but no change was observed in the pressor response to i.c.v. 2 M NaCl. The pressor response to i.v. ANGII and norepinephrine, but not AVP, was also reduced after treatment with furosemide. These results show that the treatment with furosemide impairs the pressor responses induced by central or peripheral administration of adrenergic agonist or ANGII, as well as those induced by central cholinergic activation. The results suggest that the treatment with furosemide impairs central and peripheral pressor responses mediated by sympathetic activation and ANGII, but not those produced by AVP. © 1992.

Role of central α1- and α2-adrenoceptors on the dipsogenic and cardiovascular effect of angiotensin II

We investigated the effects of previous central treatment with prazosin (an α1-adrenoceptor antagonist) or clonidine (an α2-adrenoceptor agonist) on the dipsogenic, pressor and tachycardic responses produced by intracerebroventricular (ICV) injection of angiotensin II (AII) in conscious rats. Holtzman rats with a chronic cannula implanted in the lateral ventricle were tested for dipsogenic and cardiovascular (arterial pressure and heart rate) responses in separate experiments. Previous ICV treatment with clonidine (20, 40, 80 and 120 nmol) abolished the pressor, tachycardic and dipsogenic effects of ICV AII. After all doses of prazosin (40, 80 and 120 nmol), AII induced bradycardic responses, but only the 80 and 120 nmol doses of prazosin reduced the pressor responses to AII. Prazosin produced no alteration in the dipsogenic effect of AII. The results show that the periventricular α1-adrenoceptors are involved only in the cardiovascular responses produced by central AII, whereas clonidine acting through α2-adrenergic and/or imidazole receptors can modulate all actions of AII. © 1990.

Role of alpha1 and alpha2-adrenoceptors of the lateral hypothalamic area on urinary excretion caused by centrally administered angiotensin II

To determine whether central α1 and α2-adrenergic mechanisms are involved in urinary sodium and potassium excretion and urine volume induced by angiotensin II (ANGII), these renal parameters were measured in volume-expanded Holtzman rats with cannulas implanted into lateral ventricle (LV) and lateral hypothalamus (LH). The injection of ANGII into LV in rats with volume expansion reduced the sodium, potassium and urine excretion in comparison to the control injections of isotonic saline, whereas prazosin (α1 antagonist) potentiated these effects. Clonidine (α2 agonist) and yohimbine (α2 antagonist) injected into LH previous to injection of ANGII into LV also abolished the inhibitory effect of ANGII. These results suggest that the discharge of central alpha-adrenergic receptors has dual inhibitory and excitatory effect on antinatriuretic, antikaliuretic and antidiuretic effect induced by central ANGII in volume-expanded rats. © 1995.

Role of the alfa1- and alfa2-adrenoceptors of the lateral hypothalamus in the dipsogenic response to central angiotensin II in rats

The present experiments were conducted to investigate the role of the α1- and α2-adrenergic receptors of the lateral hypothalamus (LH) on the drinking response elicited by intracerebroventricular (i.c.v) injections of carbachol and angiotensin II (AII) in rats. Clonidine (an α2-adrenergic agonist) injected into the LH produced a dose-dependent reduction of the drinking responses elicited by i.c.v. administration of carbachol and AII. The α1-adrenergic agonist phenylephrine injected into the LH reduced the dipsogenic response to i.c.v. AII, but not to carbachol. Injection of yohimbine (an α2-adrenergic antagonist) and prazosin (an α1-adrenergic antagonist) into the LH also reduced the water intake produced by i.c.v. injection of AII. Previous injection of α1- or α2-adrenergic antagonists into the LH increased the antidipsogenic effect of clonidine or phenylephrine injected into the same area on the water intake induced by i.c.v. AII. These results show that the α1- and α2-adrenergic receptors of the LH are involved in the control of drinking responses elicited by i.c.v. injection of AII in rats. They also show that clonidine, but not phenylephrine, suppresses the drinking induced by i.c.v. carbachol. The data suggest that the discharge of central α-adrenergic receptors has a dual (inhibitory and excitatory) effect on water intake induced by central AII. © 1991.

Role of cholinergic and adrenergic pathways of the medial septal area in the control of water intake and renal excretion in rats

In this study, we investigated an interaction between noradrenergic and cholinergic pathways of the medial septal area (MSA) on the control of water intake and urinary electrolyte excretion by means of injection of their respective agonists. Noradrenaline (a nonspecific α-adrenergic agonist) and clonidine (an α2-adrenergic agonist), but not phenylephrine (an α1-adrenergic agonist), induced natriuresis and kaliuresis. α-Adrenergic activation had no effect on the natriuresis and kaliuresis induced by carbachol (a cholinergic agonist) and it inhibited the antinatriuresis and antikaliuresis induced by isoproterenol (a ß-adrenergic agonist). Interactions related to volume excretion are complex. α-Adrenergic activation induced a mild diuresis and inhibited the antidiuresis induced by isoproterenol, but phenylephrine combined with carbachol induced antidiuresis. The water intake induced by carbachol was inhibited by clonidine and noradrenaline, but not phenylephrine. These results show an asymmetry in the interaction between α-adrenergic and cholinergic receptors concerning water intake and electrolyte excretion. © 1992.

Role of the adrenergic pathways of the lateral hypothalamus on water intake and pressor response induced by the cholinergic activation of the medial septal area in rats

In the present experiments, we investigated a possible involvement of noradrenergic receptors of the lateral hypothalamus (LH) in the water intake and pressor response induced by cholinergic stimulation of the medial septal area (MSA) in rats. The cholinergic agonist carbachol (2 nmol) injected into the MSA induced water intake and pressor response. The injection of an α2-adrenergic agonist, clonidine (20 and 40 nmol), but not of an α1-adrenergic agonist, phenylephrine (80 and 160 nmol), into the LH inhibits the water intake induced by carbachol injected into the MSA. The injection of clonidine or phenylephrine into the LH produced no change in the MAP increase induced by carbachol injected into the MSA. The present results suggest that adrenergic pathways involving the LH are important for the water intake, but not for the pressor response, induced by cholinergic activation of the MSA. © 1994.

Alpha 1-adrenoceptor subtypes mediating the norepinephrine-induced contractile response in the rat vas deferens

The effects of chlorethylclonidine (CEC), 5-methyl-urapidil (5-MU), ryanodine and prolonged exposition to norepinephrine (NE) on the concentration-response curves (CRC) to this agonist on the bisected rat vas deferens (RVD) were investigated. 2. CEC did not affect the 50% effective concentration (EC50) of NE in either the prostatic (PP) or the epididymal (EP) portions of the RVD. 3. 5-MU did not alter the EC50 of NE in the PP but caused a significant and concentration-dependent rightward shift of the CRC to NE in the EP. 4. Ryanodine caused a shift to the right of the CRC to NE in the PP associated to a decrease in maximal response, but did not affect the CRC to NE in the EP. 5. Incubation of the EP with NE for 6 hr elicited a significant decrease in the maximal response with no changes in the EC50. Similar treatment of the PP was associated with a significant shift to the right of the CRC to NE without modifications in the maximal response. 6. These results suggest that in the RVD, NE interacts with two different alpha 1-adrenoceptors subtypes which are disposed in a selective manner along the RVD: the alpha 1(a) subtype in the EP, and non-alpha 1b-non-alpha 1a adrenoceptor subtype mainly located at the PP.

Ayahuasca alters structural parameters of the rat aorta

Ayahuasca is a hallucinogenic brew traditionally used by Northwestern Amazonian indigenous groups for therapeutic purposes. It is prepared by the decoction of Banisteriopsis caapi with the leaves of Psychotria viridis. Banisteriopsis caapi contains β-carbolines that are inhibitors of monoamine oxidase and P. viris is rich in dimethyltryptamine, a 5-HT(1A/2A/2C) agonist. Acute ayahuasca administration produces moderate cardiovascular effects in healthy volunteers, but information regarding long-term use is lacking. This study investigated the effects of ayahuasca (2-4 mL/kg) in the rat aorta after acute and chronic (14 days) administration. Ayahuasca caused flattening and stretching of vascular smooth muscle cells and changes in the arrangement and distribution of collagen and elastic fibers. Chronic treatment with the higher dose significantly increased media thickness and the ratio of media thickness to lumen diameter. More research is needed on the cardiovascular function of long-term ayahuasca consumers.

Importance of the central nucleus of the amygdala on sodium intake caused by deactivation of lateral parabrachial nucleus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3-adrenoceptor activation and α1-adrenoceptor blockade

Mirabegron is the first β3-adrenoceptor (AR) agonist approved for treatment of overactive bladder syndrome (OAB). This study aimed to investigate the effects of β3-adrenoceptor (AR) agonist mirabegron in mouse urethra. The possibility that mirabegron exerts α1-AR antagonism was also tested in rat smooth muscle preparations presenting α1A- (vas deferens and prostate), α1D- (aorta) and α1B-AR (spleen). Functional assays were carried out in mouse and rat isolated tissues. Competition assays for the specific binding of [(3) H]Prazosin to membrane preparations of HEK 293 cells expressing each of the human α1-ARs, as well as β-AR mRNA expression and cyclic AMP measurements in mouse urethra were performed. Mirabegron produced concentration-dependent urethral relaxations that were right shifted by the selective β3-AR antagonist L 748,337, but unaffected by β1- and β2-AR antagonists (atenolol and ICI 118,551, respectively). Mirabegron-induced relaxations were enhanced by the phosphodiesterase-4 inhibitor rolipram, and this agonist stimulated cAMP synthesis. Mirabegron also produced rightward shifts in urethral contractions induced by the α1-AR agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of α1-AR in urethra, vas deferens and prostate (α1A-AR, pA2  ≅ 5.6) and aorta (α1D-AR, pA2  ≅ 5.4), but not in spleen (α1B-AR). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant α1A- and α1D-ARs (pKi ≅ 6.0). The effects of mirabegron in urethral smooth muscle are the result of β3-AR agonism together with α1A / α1D-AR antagonism.

Exenatide and sitagliptin decrease interleukin 1β, matrix metalloproteinase 9, and nitric oxide synthase 2 gene expression but does not reduce alveolar bone loss in rats with periodontitis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)