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1.
Clin Exp Hypertens ; 39(3): 210-219, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28448188

RESUMO

In endothelium-denuded abdominal (but not thoracic) aortas of rats, the nonselective cyclooxygenase (COX) inhibitor, indomethacin, suppressed contractions evoked by α-adrenergic agonists hypothetically mediated by prostanoids. We aimed to identify these non-endothelial-derived contractile prostanoids released by α-adrenergic receptors activation. Endothelium-denuded abdominal and thoracic aortas of Wistar rats were used for biochemical and functional analyses. Western blot analysis showed that COX-1 and COX-2 protein levels were respectively equivalent in endothelium-denuded abdominal and thoracic aortas. Enzyme immunoassay data supported direct evidence of phenylephrine-stimulated release of prostanoids (PGI2, PGE2, and PGF2α) by thoracic and abdominal aortas without endothelium, and their almost complete inhibition by 1 µM indomethacin. Isometric force measurements established that 10 µM indomethacin-but no lower concentrations-inhibited the contractions evoked by phenylephrine in endothelium-denuded abdominal aorta. In this preparation, 10 µM indomethacin also depressed the contractions provoked by angiotensin II and high K+ (80 mM). In fact, indomethacin (up to 1 mM) caused concentration-dependent reductions in all abovementioned contractile responses. In endothelium-denuded thoracic aortas, however, only 1 mM indomethacin significantly depressed the contractile activity stimulated by either phenylephrine, angiotensin II, or high K+. Hence, there was a clear quantitative difference in response to indomethacin between abdominal and thoracic aortas without endothelium. Altogether, the results indicate that prostanoids induced by phenylephrine in abdominal and thoracic aortas were derived from non-endothelial COX-mediated metabolism; notably, the decrease in prostanoid synthesis could not account for the inhibition of vasoconstrictor responses by indomethacin: Through COX-independent actions, indomethacin inhibited aortic smooth muscle contractility.


Assuntos
Aorta Abdominal/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Vias Biossintéticas/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Indometacina/farmacologia , Contração Muscular/efeitos dos fármacos , Angiotensina II/farmacologia , Animais , Aorta Abdominal/metabolismo , Aorta Torácica/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/biossíntese , Epoprostenol/biossíntese , Técnicas In Vitro , Masculino , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Potássio/farmacologia , Ratos , Ratos Wistar , Vasoconstritores/farmacologia
2.
Clin Exp Hypertens ; 37(4): 271-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25271908

RESUMO

Our aim was to determine whether angiotensin type 2 receptors (AT2R) are involved in the depression of carotid pulse pressure (PP) in rats with suprarenal aortic coarctation (SrC). We tested the effects of losartan, PD123319, and CGP42112 on PP in SrC and Sham-operated anesthetized rats. PP increased in SrC rats. Neither losartan nor PD123319 affected PP in SrC and Sham-operated rats. CGP42112 reduced PP, in SrC rats, combined with losartan. Moreover, PD123319 blocked this effect. AT2R protein increased in the thoracic aortas of SrC rats. Thus, upregulated AT2R stimulation by CGP42112 mediates depression of PP in rats under pressure overloading.


Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Coartação Aórtica/genética , Pressão Sanguínea/fisiologia , Regulação da Expressão Gênica , Hipertensão/etiologia , Receptor Tipo 2 de Angiotensina/genética , Regulação para Cima/efeitos dos fármacos , Animais , Coartação Aórtica/complicações , Coartação Aórtica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Western Blotting , Artérias Carótidas/fisiopatologia , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Oligopeptídeos/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/metabolismo
3.
Iran J Basic Med Sci ; 23(8): 1091-1099, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32952957

RESUMO

OBJECTIVES: To determine the effects of triiodothyronine (T3) intracoronary perfusion in isolated hearts and short-term administration in rats on the left ventricular (LV) phosphorylation patterns of Akt and ERK1/2. MATERIALS AND METHODS: Cardiodynamic and hemodynamic parameters were evaluated in Langendorff-perfused hearts. Left ventricles were used for histomorphometric and Western blot analyses. Short-term hyperthyroidism was established by T3 (500 µg.kg-1.d-1; subcutaneous injection) for 1 (T31d), 3 (T33d), and 10 (T310d) days. RESULTS: Isolated hearts receiving T3 perfusion did not modify LV developed pressure, +dP/dtmax, -dP/dtmin, heart rate, and coronary perfusion pressure compared with vehicle-perfused hearts. P-ERK1/2 and p-Akt levels in LV tissues after 5, 15, or 60 min of T3 or vehicle perfusion were similar. Compared with their time-matched controls, isolated hearts of T33d and T310d rats exhibited LV hypertrophy and increased absolute values of +dP/dtmax and -dP/dtmin (i.e., positive inotropic and lusitropic effects). P-ERK1/2 decreased in LV tissues of T31d and T310d but not in those of T33d rats, and p-Akt levels augmented in left ventricles of T33d and stayed unaltered in those of T31d and T310d rats. CONCLUSION: T3 intracoronary perfusion did not alter cardiodynamics and hemodynamics nor influence the activation of Akt and ERK of normal hearts. Accordingly, the rapid non-genomic effects of T3 were not evident. Short-term T3 treatment provoked cardiac hypertrophy coincidental with increased LV function and associated with transient Akt activation and cyclic ERK1/2 inhibition; which implies activation of physiological hypertrophy signaling and deactivation of pathological hypertrophy signaling, respectively.

4.
Vascul Pharmacol ; 50(1-2): 14-9, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18778795

RESUMO

In this work, the possibility that isometric contraction activates endothelial nitric oxide synthase (eNOS) in a calcium/calmodulin (Ca2+/CaM)-dependent manner was examined in rat thoracic aorta. Step-wise stable contractile responses (precontractions) to phenylephrine were obtained in endothelium-intact and endothelium-denuded aortic rings. The subsequent addition of the NO synthase inhibitor, N(G)nitro-l-arginine methyl ester (l-NAME), or the soluble guanylyl cyclase inhibitor, ODQ, further augmented precontractions in a concentration-dependent manner. The amplitude of l-NAME- and ODQ-induced increases in tone were dependent on the level of precontraction; the maximal increments for l-NAME and ODQ were observed in arteries precontracted with phenylephrine at 67% of its maximal effect. Likewise, in endothelium-intact non-contracted arteries, l-NAME and ODQ induced small but significant increases in tone. Neither l-NAME nor ODQ had any effect in endothelium-denuded preparations. In endothelium-intact aortic rings precontracted with high K+ solutions, l-NAME also elicited supplementary contractions dependent on precontraction level. The CaM antagonist, calmidazolium, inhibited in a concentration-dependent, noncompetitive, manner the effects of l-NAME on the tone of endothelium-intact phenylephrine-precontracted aortic rings. These results suggest that isometric contraction increases the activity of eNOS by means of the Ca2+/CaM complex in rat aorta.


Assuntos
Aorta Torácica/fisiologia , Calmodulina/antagonistas & inibidores , Endotélio Vascular/fisiologia , Contração Isométrica/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Aorta Torácica/citologia , Cálcio/metabolismo , Calmodulina/metabolismo , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Imidazóis/farmacologia , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Guanilil Ciclase Solúvel
5.
J Cardiovasc Pharmacol Ther ; 13(3): 207-13, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18635753

RESUMO

Rosuvastatin was tested on rat aortic rings in the presence and absence of K(+) channel blockers, mevalonic acid, and inhibitors of nitric oxide, prostaglandins, or endothelial-derived hyperpolarizing factor synthesis. The direct vascular effects of rosuvastatin were then evaluated by obtaining dose-response curves. Rosuvastatin relaxed aortic rings with and, to a lesser degree, without endothelium. Under both these conditions this effect was partially inhibited by L-NAME, tetraethylammonium, apamin + charybdotoxin (only administered together), or mevalonic acid. The combination of L-NAME with any of the other 3 treatments completely inhibited the effect of rosuvastatin, but indomethacin, clotrimazol, glibenclamide, charybdotoxin, or apamin alone had no effect. Therefore, the relaxation induced by rosuvastatin, even in the absence of endothelium, is partially related to 2 different mechanisms, one that is isoprenoid dependent and NO mediated and the other that is tied to the opening of Ca( 2+)-dependent K(+) channels of the slow subfamily.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Fluorbenzenos/farmacologia , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta Torácica/enzimologia , Aorta Torácica/metabolismo , Fatores Biológicos/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/enzimologia , Endotélio Vascular/metabolismo , Técnicas In Vitro , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/metabolismo , Prostaglandinas/metabolismo , Ratos , Ratos Wistar , Rosuvastatina Cálcica
6.
Fundam Clin Pharmacol ; 20(4): 339-49, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16867017

RESUMO

In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.


Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Aorta Torácica/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Aorta Torácica/metabolismo , Azepinas/farmacologia , Tartarato de Brimonidina , Clonidina/farmacologia , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Técnicas In Vitro , Masculino , Metoxamina/farmacologia , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Piperazinas/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Serotonina/farmacologia , Vasoconstritores/farmacologia , Ioimbina/farmacologia
7.
Gac Med Mex ; 142(1): 1-8, 2006.
Artigo em Espanhol | MEDLINE | ID: mdl-16548285

RESUMO

Using endothelium-denuded rat aortic rings incubated in Ca2+ -free solution, we assessed the ability of testosterone to influence the contractile effect of phenylephrine, and the increase in resting tone (IRT) associated with Ca2+ ability to cross the plasma membrane. The addition of testosterone [10(-5)-10(-4) 5 min before phenylephrine [10(-6) M], inhibited both phenylephrine-induced contraction and IRT. These changes were not affected by cycloheximide (10(-5) M; a protein synthesis inhibitor of), flutamide (10(-5) M; an androgenic receptor antagonist), or by adding aminoglutethimide (10(-5) M; an aromatase inhibitor). Testosterone also blocked the contractile response to serotonin [10(-5) M] but not to caffeine [10(-2) M]. On the other hand, testosterone inhibited the contractile responses to cyclopiazonic acid (10(-6) M; a selective Ca2+ -ATPase inhibitor) or ryanodine (10(-5 M; an activator of sarcoplasmic reticulum Ca2+ -release channels) associated with capacitative Ca2+ influx through non-L-type Ca2+ channels. These data suggest that by acting on the cellular membrane, testosterone interferes with the signal transduction pathway of G(q-11) protein-coupled receptors, and inhibits capacitative Ca2+ influx through both L-type and non-L-type Ca2+ channels. These effects are non-genomic, non-mediated by the intracellular androgen receptor, and not due to the conversion of testosterone to estrogens.


Assuntos
Aorta/efeitos dos fármacos , Aorta/fisiologia , Cálcio/metabolismo , Células/metabolismo , Fenilefrina/farmacologia , Testosterona/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Técnicas In Vitro , Masculino , Contração Muscular , Ratos , Ratos Wistar
8.
Fundam Clin Pharmacol ; 18(6): 669-77, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15548238

RESUMO

In this study, we aimed to elucidate whether the daily hypertensive dose of long-term N(G)-nitro-l-arginine methyl ester (l-NAME) treatment, could make a difference between endothelial and smooth muscle functions in rat thoracic aorta. We test the hypothesis that high-dose, long-term l-NAME treatment has a depressive effect on vascular smooth muscle contractile activity which is not related with nitric oxide (NO) synthesis inhibition. After 14 days of treatment, isometric tension and (45)Ca(2+) influx were measured in aortic tissues isolated from l-NAME(10) and l-NAME(100) hypertensive (10 and 100 mg/kg/day, systolic blood pressures 167 +/- 7 and 172 +/- 10 mmHg, respectively) and control normotensive rats (132 +/- 7 mmHg). In l-NAME(10)- and l-NAME(100)-treated rats, acetylcholine-induced relaxation in aortic rings was suppressed with no significant difference between the treatments. l-NAME(100) (but not l-NAME(10)) treatment, significantly inhibited contractile responses to phenylephrine, angiotensin II, and K(+) (80 mm) in endothelium-intact tissues. The effect of l-NAME(100) on phenylephrine-induced contractile responses was not observed after 3 days of treatment. In endothelium-denuded aortic tissues of l-NAME(100) (but not l-NAME(10))-treated rats, phenylephrine (1 x 10(-6) m)- and K(+) (80 mm)-induced contractions and (45)Ca(2+) influxes were significantly reduced. In Ca(2+)-free medium (0.1 mm EDTA), on the contrary, the transient contractions obtained by either phenylephrine (1 x 10(-6) m) or caffeine (1 x 10(-2) m), or the sustained contractions induced by 12-o-tetradecanoylphorbol-13-acetate (1 x 10(-6) m; a protein kinase C activator) in endothelium-denuded aortic rings, were not modified by both l-NAME treatments. These results indicate that in aortic rings from l-NAME hypertensive rats, low and high doses, long-term l-NAME administration may be associated with equivalent inhibition in NO-dependent vasodilator tone (corresponding to equivalent hypertension values); whereas only high-dose, long-term l-NAME administration produces an endothelium-independent decrease in vasocontrictor activity, at least partly explained by a reduction in extracellular Ca(2+) influx.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Radioisótopos de Cálcio , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Potássio/metabolismo , Ratos , Ratos Wistar , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
9.
Vascul Pharmacol ; 38(3): 169-75, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12402516

RESUMO

The cyclooxygenase inhibitor, indomethacin, depresses adrenergic agonist constriction of endothelium-denuded rat abdominal, but not thoracic, aorta. In order to explain this finding, we explored the possibility of segmental differences in the population of alpha 1-adrenoceptor (AR) subtypes. In endothelium-denuded tissues, phenylephrine elicited concentration-dependent contractions in the thoracic and abdominal aortic rings with potencies and maximal effects that, respectively, did not differ significantly (P > .05). Indomethacin (1 x 10(-5) M) inhibited phenylephrine-induced contractions only in abdominal aorta. The subtype-selective alpha 1D-AR antagonist, BMY 7378, was found to antagonize contractions to phenylephrine competitively in abdominal (pA2 8.44) and thoracic (pA2 8.56) aortic rings. These data are consistent with published alpha 1D-AR functional potency and clonal alpha 1D-AR binding affinity. In addition, cumulative concentration-contraction curves for phenylephrine were competitively antagonized in the rat abdominal and thoracic aortae by prazosin, 5-methylurapidil and WB 4101, with pA2 values of 9.39 and 9.61, 7.64 and 7.85, and 9.43 and 9.58, respectively. These compounds with varying degrees of subtype selectivity inhibited contractions of the thoracic and abdominal aortae with affinities consistent with those determined at the alpha 1D-AR subtype. The results of this study suggest that the contraction to phenylephrine of the rat abdominal and thoracic aorta is mediated via the same alpha 1D-AR subtype.


Assuntos
Aorta Abdominal/fisiologia , Aorta Torácica/fisiologia , Músculo Liso Vascular/fisiologia , Receptores Adrenérgicos alfa 1/fisiologia , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Análise de Variância , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/fisiologia , Técnicas In Vitro , Indometacina/farmacologia , Contração Isométrica/efeitos dos fármacos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Vasoconstritores/farmacologia
10.
Vascul Pharmacol ; 54(1-2): 29-35, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21122823

RESUMO

We tested whether heterologous receptor desensitization induced by activation of AT1 receptors may explain the purported relaxation produced by angiotensin II in normal rat aorta. Also, the role for AT2 receptors in the promotion of vasodilation was studied. In endothelium-intact and endothelium-denuded aortic rings, angiotensin II elicited biphasic contractions, which were significantly depressed when repeated in each tissue. Angiotensin II produced biphasic responses on phenylephrine preconstricted endothelium-intact and endothelium-denuded tissues, without reducing precontractile tone. These responses were abolished in the presence of the AT1 receptor antagonist losartan, but no relaxing responses to angiotensin II were uncovered. PD123319 did not influence angiotensin II responses in endothelium-intact tissues precontracted with phenylephrine; thus, under AT2 receptors blockade the contractile effects of angiotensin II were not overexposed. In conclusion, angiotensin II-induced biphasic responses can be attributed to AT1 receptors activation and rapid desensitization with time. Desensitization proved to be homologous in nature, since precontractile tone induced by phenylephrine was not depressed by angiotensin II (i.e., angiotensin II did not induce heterologous α1-adrenergic receptors desensitization). We found no functional evidence of the participation of AT2 receptors in angiotensin II elicited biphasic contractions. Angiotensin II does not exert relaxant effects in normal rat aorta.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Angiotensina II/fisiologia , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 2 de Angiotensina II/administração & dosagem , Animais , Aorta Torácica/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Técnicas In Vitro , Losartan/administração & dosagem , Losartan/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/farmacologia , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologia
11.
Fundam Clin Pharmacol ; 25(3): 313-22, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20584208

RESUMO

This work was aimed to determine whether isometric contraction in Wistar rat aorta is related to the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent activation of endothelial nitric oxide synthase (eNOS). Basically, we hypothesized that additional increases in active tone occur after the pharmacological inhibition of a transduction pathway involved in NO synthesis or action. In intact aortic rings contracted with phenylephrine or high K(+), the cumulative administration of the PI3K inhibitor, LY294002, elicited significant decreases--but not supplementary increases--in tone. In endothelium-intact tissues, on the other hand, the Akt1/2 kinase inhibitor did not alter phenylephrine- and K(+)-induced isometric contractions. The PI3K inhibitor wortmannin (1 × 10(-7) m) produced a significant supplementary contraction only in endothelium-intact aortic rings precontracted with phenylephrine. Higher concentrations of this inhibitor produced relaxations of phenylephrine and high K(+)-constricted endothelium-intact and endothelium-denuded aortic rings. LY294002 and wortmannin did not cause any potentiating effect on phenylephrine- and angiotensin II-induced concentration-dependent contractile responses in endothelium-intact tissues. In intact aortic rings contracted with phenylephrine or high K(+), the addition of the NOS inhibitor, L-NAME, or the guanylyl cyclase inhibitor, ODQ, further augmented tone in a concentration-dependent manner, and these supplementary contractions were significantly reduced by endothelium removal. Taken together, our data suggest that the PI3K/Akt pathway is not counteracting aortic isometric contractions by activation of the eNOS. It appears, on the other hand, that the smooth muscle PI3K can stimulate contraction without activation of the protein kinase Akt in response to GPCR agonists and high K(+).


Assuntos
Guanilato Ciclase/antagonistas & inibidores , Contração Isométrica/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Androstadienos/farmacologia , Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Cromonas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Guanilato Ciclase/metabolismo , Contração Isométrica/fisiologia , Masculino , Morfolinas/farmacologia , Músculo Liso Vascular/enzimologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Oxidiazóis/farmacologia , Fenilefrina/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Potássio/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Wortmanina
12.
Fundam Clin Pharmacol ; 25(3): 333-42, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20608990

RESUMO

In experiments in vivo, we studied whether the endothelial dysfunction induced by nitric oxide (NO) synthesis inhibition is simultaneously or sequentially manifested as a reduced level of endothelium-dependent agonist-induced vasodilatation, an increased responsiveness to vasoconstrictors, and hypertension. Vascular responses to acetylcholine, phenylephrine, and angiotensin II were measured in pithed rats after acute intravenous injection (100 mg/kg) and short-term oral administration of N(G) -nitro-L-arginine methyl ester (L-NAME; 60 mg/kg per day) for 1 and 3 days (L-NAME(1d) and L-NAME(3d), respectively). Pithed rats were chosen because drug-induced cardiovascular responses reflect only peripheral effects. Parallel experiments examined mean arterial pressure (MAP) values in anesthetized rats. After short-term L-NAME(1d) and L-NAME(3d) treatments, the MAP was significantly elevated in anesthetized but not pithed rats. Acute intravenous administration of L-NAME elevated MAP in pithed rats. Intravenous infusion of phenylephrine was used to compensate for the pressor response induced by L-NAME in pithed animals. The maximum decrease and duration of the hypotensive responses to acetylcholine were unaltered by the acute and both short-term L-NAME treatments in pithed rats. These treatments, on the other hand, increased phenylephrine- and angiotensin II-induced pressor responses in pithed animals. In isolated aortic rings prepared from pithed rats treated acutely and short-term with L-NAME, acetylcholine-induced relaxations were inhibited. Thus, the inhibition of NO-dependent vasodilator tone after acute intravenous injection and short-term oral L-NAME administration may be associated with vascular smooth muscle hyper-responsiveness to pressor agonists and hypertension, whereas the hypotensive responses to acetylcholine could not be associated with the L-NAME-induced endothelial dysfunction in pithed rats.


Assuntos
Acetilcolina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipotensão/induzido quimicamente , NG-Nitroarginina Metil Éster/administração & dosagem , Acetilcolina/antagonistas & inibidores , Administração Oral , Angiotensina II/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/administração & dosagem , Hipotensão/tratamento farmacológico , Técnicas In Vitro , Injeções Intravenosas , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
13.
Fundam Clin Pharmacol ; 22(1): 45-52, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18251721

RESUMO

The objective of this study was to re-examine whether the effect of the nitric oxide synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), on blood pressure depends on peripheral vascular tone. The effects of L-NAME (10 mg/kg, i.v.) on diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP) and heart rate (HR) were studied in pithed rats. Sal-pithed rats received 0.9% NaCl, 10 microl/kg/min. Vascular tone was step-wise increased with 3, 10 and 30 microg/kg/min intravenous phenylephrine infusion (LPhe-pithed, MPhe-pithed and HPhe-pithed rats respectively). L-NAME elicited vasopressor responses in all the animals studied. L-NAME increases in SBP and DBP in Sal-pithed rats were significantly smaller than the ones obtained in phenylephrine infused rats. The increases in DBP elicited by L-NAME were greater in LPhe-pithed rats compared with those of MPhe-pithed and HPhe-pithed rats (i.e. the step-wise rises in DBP obtained with phenylephrine were inversely related to the increases in DBP produced by L-NAME); however, the increases in SBP were similar between these experimental groups. The PP increased during L-NAME-induced pressor responses in phenylephrine-infused rats. l-NAME increases in PP showed the following order: Sal-pithed < LPhe-pithed < MPhe-pithed < or = HPhe-pithed rats. HR was not modified by L-NAME. In conclusion, the vasopressor responses produced by L-NAME in pithed rats are influenced by the pre-existing vasomotor tone in complex form. We did not find a simple positive correlation between the vascular tone or level of arterial pressure, and the magnitude of the diastolic and systolic pressor responses elicited by L-NAME. Interestingly, the increase in PP induced by l-NAME was greater in accordance with the increasing value of baseline arterial pressure. NO synthesis inhibition in the arterial endothelium may possibly explain the increase in PP caused by L-NAME, as resulting from the reduction in proximal conduit artery compliance.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Animais , Masculino , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Wistar
14.
Am J Physiol Cell Physiol ; 291(6): C1388-94, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16885392

RESUMO

The ability of estradiol to affect phenylephrine-induced contraction and the subsequent increase in resting tone, associated with capacitative Ca(2+) entry across the plasma membrane, was evaluated in rat aortic rings incubated in Ca(2+)-free solution. The incubation with estradiol (1-100 nM, 5 min) inhibited both the phenylephrine-induced contraction and the IRT. Neither cycloheximide (1 microM; inhibitor of protein synthesis) nor tamoxifen (1 microM; blocker of estrogenic receptors) modified the effects of estradiol. Estradiol (100 microM) also blocked the contractile response to serotonin (10 microM) but not to caffeine (10 mM). In addition, estradiol (100 microM) inhibited the contractile responses to cyclopiazonic acid (1 microM; selective Ca(2+)-ATPase inhibitor) associated with capacitative Ca(2+) influx through non-L-type Ca(2+) channels. Finally, estradiol inhibited the Ca(2+)-induced increases in intracellular free Ca(2+) (after pretreatment with phenylephrine) in cultured rat aorta smooth muscle cells incubated in Ca(2+)-free solution. In conclusion, estradiol interfered in a concentration-dependent manner with Ca(2+)-dependent contractile effects mediated by the stimuli of alpha(1)-adrenergic and serotonergic receptors and inhibited the capacitative Ca(2+) influx through both L-type and non-L-type Ca(2+) channels. Such effects are in essence nongenomic and not mediated by the intracellular estrogenic receptor.


Assuntos
Aorta/efeitos dos fármacos , Cálcio/metabolismo , Estradiol/farmacologia , Fenilefrina/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/fisiologia , Animais , Aorta/anatomia & histologia , Aorta/metabolismo , Cafeína/farmacologia , Células Cultivadas , Cicloeximida/farmacologia , Relação Dose-Resposta a Droga , Estradiol/análogos & derivados , Antagonistas de Estrogênios/farmacologia , Feminino , Fulvestranto , Indóis/farmacologia , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Progesterona/farmacologia , Inibidores da Síntese de Proteínas/farmacologia , Ratos , Ratos Wistar , Serotonina/farmacologia , Tamoxifeno/farmacologia , Testosterona/farmacologia , Tetraetilamônio/farmacologia , Vasodilatadores/farmacologia
15.
Gac. méd. Méx ; 142(1): 1-8, ene.-feb. 2006. ilus
Artigo em Espanhol | LILACS | ID: lil-571159

RESUMO

Utilizando segmentos de aorta de rata sin endotelio inmersos en solución sin Ca2+, evaluamos la capacidad de la testosterona para modificar el efecto contráctil del agonista adrenérgico fenilefrina, así como el incremento en el tono de reposo (ITR) asociado con la entrada capacitativa de calcio por el sarcoplasma. La testosterona [10-5–10- 4 M] inhibió significativamente la contracción activada por la fenilefrina [10-6 M] y el ITR. Estos efectos no fueron modificados con cicloheximida [10-5 M] (inhibidor de la síntesis protéica), flutamida [10-5 M] (antagonista de receptores androgénicos), o aminoglutetimida [10-5 M] (inhibidor de la citocromo P450 aromatasa). La testosterona también inhibió las respuestas contráctiles de la serotonina [10-5 M], pero no de la cafeína [10-2 M]. Además, la testosterona inhibió las contracciones del ácido ciclopiazónico [10-6 M] y de la ryanodina [10- 5 M] asociadas con el ingreso capacitativo de Ca2+ mediante canales de Ca2+ tipo no L. Estos datos sugieren que la testosterona interfiere con la vía de transducción de los receptores acoplados a proteínas Gq- 11, e inhibe la entrada capacitativa de Ca2+ a través de canales de Ca2+ tipo L y tipo no L; los efectos son no genómicos, independientes de receptores androgénicos, y de la conversión testosterona en estrógenos.


Using endothelium-denuded rat aortic rings incubated in Ca2+ -free solution, we assessed the ability of testosterone to influence the contractile effect of phenylephrine, and the increase in resting tone (IRT) associated with Ca2+ ability to cross the plasma membrane. The addition of testosterone [10(-5)-10(-4) 5 min before phenylephrine [10(-6) M], inhibited both phenylephrine-induced contraction and IRT. These changes were not affected by cycloheximide (10(-5) M; a protein synthesis inhibitor of), flutamide (10(-5) M; an androgenic receptor antagonist), or by adding aminoglutethimide (10(-5) M; an aromatase inhibitor). Testosterone also blocked the contractile response to serotonin [10(-5) M] but not to caffeine [10(-2) M]. On the other hand, testosterone inhibited the contractile responses to cyclopiazonic acid (10(-6) M; a selective Ca2+ -ATPase inhibitor) or ryanodine (10(-5 M; an activator of sarcoplasmic reticulum Ca2+ -release channels) associated with capacitative Ca2+ influx through non-L-type Ca2+ channels. These data suggest that by acting on the cellular membrane, testosterone interferes with the signal transduction pathway of G(q-11) protein-coupled receptors, and inhibits capacitative Ca2+ influx through both L-type and non-L-type Ca2+ channels. These effects are non-genomic, non-mediated by the intracellular androgen receptor, and not due to the conversion of testosterone to estrogens.


Assuntos
Animais , Masculino , Ratos , Aorta/efeitos dos fármacos , Aorta/fisiologia , Cálcio/metabolismo , Células/metabolismo , Fenilefrina/farmacologia , Testosterona/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Contração Muscular , Ratos Wistar
18.
Arch. med. res ; 28(3): 361-7, sept. 1997. ilus
Artigo em Inglês | LILACS | ID: lil-225240

RESUMO

Effects of pretreatment with thipental on endothelium-dependent vasodilatador responses elicited by drugs in rat aortic rings were investigated. The vasodilators employed were acetylcholine and histamine (endothelium-and receptor-dependent), A23187 (endothelium-dependent but receptor-independent) and sodium nitroprusside (endothelium-independent); they were tested 15 or 60 min to thiopental. Pretreatment with the barbiturate reversibly inhibitied relaxation elicited by either acetylcholine and histamine, but a high concentration of the anesthetic was needed (3.1 mg/ml). On the contrary, thiopental did not modify the relaxation elicited by sodium nitroprusside or A23187. In addition, the barbiturate inhibited basal and acetylcholine-stimulated production of nitrites (an indicator of nitric oxide output) in aortic rings. In conclusion, thiopental inhibited the endothelium-dependent relaxation elicited by either acetylcholine or histamine. Although the bariturate also inhibited nitric oxide production, the reduction in the relaxant response provoked by it does not seem to be the result of direct guanylate cyclase or nitric oxide synthase alterations, since thiopental did not modify the effect of sodium nitroprusside or A23187. Disturbances elicited by thiopenatal on endothelial receptors or on signal transduction elements may indirectly provoke nitric oxide synthase inhibition


Assuntos
Animais , Masculino , Aorta Torácica , Aorta Torácica/fisiologia , Aorta Torácica/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Hipnóticos e Sedativos/farmacologia , Técnicas In Vitro , Óxido Nítrico/biossíntese , Tiopental/farmacologia , Ratos Wistar
19.
Rev. mex. anestesiol ; 18(3): 109-14, jul.-sept. 1995. tab
Artigo em Espanhol | LILACS | ID: lil-162053

RESUMO

En este trabajo se investigó si los receptores cardiovasculares de la serotonina (5-HT) son antagonizados por el droperidol. Los efectos de este fármaco sobre la vasopresión y el cronotropismo positivo obtenidos con la infusión intravenosa de noradrenalina (NA; 1 µg.kg-1.min-1), angiotensina II (1 µg.kg-1.min-1) y quipazina (100 µg.kg-1.min-1) se estudiaron en ratas desmeduladas. El droperidol (0.01 - 1 mg.kg-1,i.v.) revirtió los efectos presores de la NA y la quipazina en forma dependiente de la dosis. El pretratamiento con propranolol, bromefeniramina o atropina (1 mg.kg-1, i.v.; cada uno), no previno los efectos del neuroléptico. Por otra parte, el droperidol no modificó la respuesta presora de la angiotensina II, ni el cronotropismo de las drogas estudiadas. Se observó que los efectos inhibitorios del droperidol (DI50 141 µg/kg; LC 105-191) y de la ketanserina (Di50 110 µg/kg; LC 91-132) sobre la vasopresión de la quipazina, son similares; sin embargo, esta última no fue modificada por la prazosina. Estos resultados indican una interacción del droperidol con los reeptores vasculares 5-HT y confirman su capacidad para bloquear Ó-adrenoceptores


Assuntos
Animais , Masculino , Propranolol/farmacocinética , Quipazina/farmacocinética , Bromofeniramina/farmacocinética , Angiotensina II/efeitos dos fármacos , Norepinefrina/administração & dosagem , Norepinefrina/farmacocinética , Sistema Nervoso Central/efeitos dos fármacos , Receptores de Serotonina/antagonistas & inibidores , Receptores de Serotonina/efeitos dos fármacos , Ratos Wistar , Droperidol/administração & dosagem , Droperidol/farmacocinética , Interações Medicamentosas/fisiologia , Frequência Cardíaca , Pressão Sanguínea
20.
Rev. mex. anestesiol ; 19(4): 159-66, oct.-dic. 1996. ilus
Artigo em Espanhol | LILACS | ID: lil-187757

RESUMO

Se evaluaron los efectos del tiopental en anillos de aorta de rata. El anestésico produjo contracción que aumentó al quitar el endotelio y no se inhibió con indometacina (10-5M). Prazosina (10-6M) o idazoxan (10-6M) o diltiazem (10-6M) pero disminuyó en un medio sin calcio. Por otra parte, el tiopental relajó anillos aórticos precontraídos con fenilefrina (10-6M), angiotensina II (10-7), serotonina (3.1 x 10-5 M) o KCI (40 mM), en forma independiente del endotelio. Finalmente, la exposición al tiobarbitúrico (3.1 mg/ml) inhibió reversiblemente la relajación ocasionada por histamina, pero no por el nitroprusiato de sodio o por el A23187. Los resultados permiten concluir que, en la aorta de rata, el tiopental produce: a) contracción modulada inhibitoriamente por el endotelio y dependiente del calcio extracelular que ingresa a través de canales insensibles a diltiazem, y que no es mediada por prostaglandinas o receptores adrenérgicos; b) relajación independiente tanto del endotelio como del agente contráctil empleado; c) inhibición de la relajación dependiente de endotelio ocasionada por histamina. Efecto que no parece deberse a alteración de la guanilato ciclasa o de la sintasa de óxido nítrico, puesto que el anestésico no inhibió el efecto del nitropusiato de sodio o del A23187. Por lo anteriormente expuesto, consideramos posible que los diversos efectos vasculares del tiopental se asocien con su capacidad para disolverse en las membranas del músculo liso y del endotelio de la aorta, alterando componentes funcionales de las mismas


Assuntos
Animais , Ratos , Aorta/efeitos dos fármacos , Fenilefrina/administração & dosagem , Tiopental/administração & dosagem , Tiopental/farmacologia , Nitroprussiato , Endotélio Vascular/efeitos dos fármacos , Relaxamento
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