RESUMO

Cancer results from a complex interplay of different biological, chemical, and physical phenomena that span a wide range of time and length scales. Computational modeling may help to unfold the role of multiple evolving factors that exist and interact in the tumor microenvironment. Understanding these complex multiscale interactions is a crucial step towards predicting cancer growth and in developing effective therapies. We integrate different modeling approaches in a multiscale, avascular, hybrid tumor growth model encompassing tissue, cell, and sub-cell scales. At the tissue level, we consider the dispersion of nutrients and growth factors in the tumor microenvironment, which are modeled through reaction-diffusion equations. At the cell level, we use an agent based model (ABM) to describe normal and tumor cell dynamics, with normal cells kept in homeostasis and cancer cells differentiated apoptotic, hypoxic, and necrotic states. Cell movement is driven by the balance of a variety of forces according to Newton's second law, including those related to growth-induced stresses. Phenotypic transitions are defined by specific rule of behaviors that depend on microenvironment stimuli. We integrate in each cell/agent a branch of the epidermal growth factor receptor (EGFR) pathway. This pathway is modeled by a system of coupled nonlinear differential equations involving the mass laws of 20 molecules. The rates of change in the concentration of some key molecules trigger proliferation or migration advantage response. The bridge between cell and tissue scales is built through the reaction and source terms of the partial differential equations. Our hybrid model is built in a modular way, enabling the investigation of the role of different mechanisms at multiple scales on tumor progression. This strategy allows representating both the collective behavior due to cell assembly as well as microscopic intracellular phenomena described by signal transduction pathways. Here, we investigate the impact of some mechanisms associated with sustained proliferation on cancer progression. Specifically, we focus on the intracellular proliferation/migration-advantage-response driven by the EGFR pathway and on proliferation inhibition due to accumulation of growth-induced stresses. Simulations demonstrate that the model can adequately describe some complex mechanisms of tumor dynamics, including growth arrest in avascular tumors. Both the sub-cell model and growth-induced stresses give rise to heterogeneity in the tumor expansion and a rich variety of tumor behaviors.

RESUMO

Hypoxia-ischemia (HI) is characterized by a reduced supply of oxygen during pregnancy, which leads to both central nervous system and peripheral injuries in the foetus, resulting in impairment in its development. The purpose of this study was to investigate behavioural changes and systemic oxidative stress in adult animals that have been affected by HI during pregnancy. HI was induced by the occlusion of the maternal uterine artery with aneurysm clamps for a period of 45 min on the 18th gestational day. Animals from the sham group were submitted to same surgical procedure as the HI animals, without occlusion of the maternal uterine artery. The control group consisted of non-manipulated healthy animals. At postnatal day 90, the pups were submitted to behavioural tests followed by blood collection. HI adult animals presented an increase in anxiety behaviour and a lack of habituation compared to both sham and control groups. Oxidative damage, assessed by protein and lipid oxidation in serum, did not differ between HI and sham-operated animals. However, HI animals presented reduced activity of the glutathione peroxidase enzyme and increased formation of nitrite, indicating alterations in the systemic antioxidant repair system. Our results suggest an association among HI, systemic oxidative stress and behavioural alterations.

Assuntos

Habituação Psicofisiológica , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/psicologia , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Estresse Oxidativo , Complicações na Gravidez/metabolismo , Complicações na Gravidez/psicologia , Animais , Antioxidantes/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Peroxidação de Lipídeos , Masculino , Aprendizagem em Labirinto , Nitritos/metabolismo , Gravidez , Proteínas/metabolismo , Ratos

RESUMO

BACKGROUND: Propofol is an alternative to thiopental for induction of general anaesthesia for cesarean section. It crosses the placenta and induces vasodilatation of isolated vessels and may therefore alter fetal placental vascular resistance. The direct effect of propofol on the fetal placental circulation was studied in vitro. The actions of propofol on vasoconstrictive effects induced by angiotensin II (Ang II), bradykinin (BK), prostaglandin F(2alpha) (PGF(2alpha)) and potassium chloride (KCl) were evaluated. METHODS: Full-term healthy human placentas (n=48) were perfused with modified Tyrode's solution using a pulsatile pump. Placental perfusion pressure was measured in response to injection of Ang II, BK, KCl and PGF(2alpha) before and after perfusion with propofol (1.7 x 10(-5) and 5.6 x 10(-5) M). RESULTS: BK, Ang II, KCl and PGF(2alpha) induced a dose-dependent increase in placental perfusion pressure. Propofol induced a concentration-dependent decrease in placental perfusion pressure, but this was not observed with the propofol solvent (Intralipid). Propofol, but not Intralipid, reduced the vasoconstrictor effects of BK, KCl and PGF(2alpha), while the effect of Ang II was not changed. The effect of KCl was abolished in placentas perfused with Ca(2+)-free solution, while the effect of Ang II was not altered. CONCLUSIONS: Propofol induced vasodilatation and inhibited the vasoconstrictive effects of BK and PGF(2alpha), in the human placenta. These findings suggest that propofol may not reduce fetal placental blood flow. Since propofol reduced the vasoconstricting effect of KCl but not that of AngII, we propose that the vasodilatory effect of propofol in the human placenta involves inhibition of Ca(2+) channels.

Assuntos

Anestésicos Intravenosos/efeitos adversos , Feto/irrigação sanguínea , Placenta/irrigação sanguínea , Propofol/efeitos adversos , Adulto , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Cloreto de Potássio/farmacologia , Gravidez , Circulação Pulmonar/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos

RESUMO

1. The vasodilator action of angiotensin (Ang) II has not yet been demonstrated in spontaneously hypertensive rats (SHR), nor have any possible changes in this response during the development of hypertension. 2. In the present study, the vasodilator effect of AngII was evaluated in the rat isolated, preconstricted mesenteric arterial bed (MAB) from 6- (young) and 24-week-old (adult) SHR and compared with effects on MAB from age-matched normotensive rats (control). 3. Angiotensin II (10-300 nmol) induced vasodilation in noradrenaline (NA)-preconstricted MAB that was greater in vessels from young compared with adult rats in both the control and SHR groups. Angiotensin II-induced vasodilation was reduced by the angiotensin AT(2) receptor antagonist PD 123319 (10 micromol/L), the angiotensin-(1-7) receptor antagonist A779 (1 micromol/L) and the bradykinin B(2) receptor antagonist HOE-140 (0.01 micromol/L), but not by the AT(1) receptor antagonist losartan (30 micromol/L). Expression of AT(2) receptors was weak in vessels from adult control rats compared with that in young control rats, whereas in young SHR AT(2) receptor expression was increased compared with that in young control rats. This increased expression of AT(2) receptors was maintained in adult SHR and there was no significant difference in AT(2) receptor expression between young and old SHR. 4. The findings of the present suggest that AngII induces an AT(2) receptor-mediated vasodilator effect in the MAB via activation of angiotensin-(1-7) and bradykinin receptors, an action that is reduced in adult control rats and adult SHR. In adult control rats, the attenuated response of AngII is probably due to endothelial dysfunction and reduced expression of AT(2) receptors, whereas in adult SHR it is associated with endothelial dysfunction alone. Increased expression of AT(2) receptors in SHR may represent a counteracting response for modulating blood pressure.

Assuntos

Angiotensina II/metabolismo , Regulação da Expressão Gênica/fisiologia , Receptor Tipo 2 de Angiotensina/metabolismo , Vasodilatação/fisiologia , Acetilcolina/farmacologia , Envelhecimento , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Animais , Western Blotting , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Imidazóis/farmacologia , Losartan/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Fragmentos de Peptídeos/farmacologia , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 2 de Angiotensina/genética

RESUMO

The mechanisms involved in the vasodilation action of clonidine have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the clonidine vasodilator effect using rat isolated mesenteric arterial bed (MAB). In precontracted MAB, clonidine (10-300 pmol) induced a dose-dependent relaxation, that was inhibited by endothelium removal (deoxycholic acid - 2.5 mM) and reduced by the alpha(2) adrenoceptor inhibitors yohimbine (1-3 microM) and rauwolscine (1 microM). The endothelium-dependent vasodilation induced by clonidine was reduced by the nitric oxide (NO) synthase inhibitor L-NAME (0.3 mM) and guanylyl cyclase inhibitor ODQ (10 microM) but was not affected by indomethacin (3-10 microM) alone. High K+ (25 mM) solution reduced the vasodilator effect of clonidine that was further attenuated by L-NAME. In the presence of high K+ plus L-NAME, the residual vasodilator effect of clonidine was further reduced by indomethacin (3 microM). The Ca(2+)-dependent K+ channel (K+(Ca2+)) inhibitors, charybdotoxin (ChTx; 0.1 microM) plus apamin (0.1 microM), also reduced the vasodilation induced by clonidine, however this response was not further reduced in the presence of L-NAME as observed with acetylcholine (10 pmol). In the presence of ATP-dependent K+ channel (K+(ATP)) blocker, glibenclamide (10 microM), the inhibitory effect of ChTx plus apamin plus L-NAME was increased. In contrast, the vasodilation induced by clonidine was not affected by voltage-dependent K+ channels (K(V)) blocker, 4-aminopyridine (4-AP, 1 mM). In conclusion, our results demonstrate that clonidine activates alpha(2)-adrenoceptors in rat MAB and that the endothelium-dependent vasodilation is mediated by activation of NO-cGMP pathway, hyperpolarization due to activation of K+(Ca) and K+(ATP) channels. Prostaglandins might participate in the vasodilator effect of clonidine when NO and EDHF mechanisms are blunted.

Assuntos

Agonistas alfa-Adrenérgicos/farmacologia , Clonidina/farmacologia , GMP Cíclico/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Canais de Potássio/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Fatores Biológicos/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Técnicas In Vitro , Masculino , Artérias Mesentéricas/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Canais de Potássio Cálcio-Ativados/metabolismo , Prostaglandinas/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo

RESUMO

Açai (Euterpe oleracea Mart.) a fruit from the Amazon region, largely consumed in Brazil is rich in polyphenols. Experiments were undertaken to determine whether hydro-alcoholic extract obtained from stone of açaí induces a vasodilator effect in the rat mesenteric vascular bed precontracted with norepinephrine (NE) and, if so, to elucidate the underlying mechanism. Açai stone extract (ASE, 0.3-100 microg) induced a long-lasting endothelium-dependent vasodilation that was significantly reduced by N(G)-nitro-l-arginine methyl ester (l-NAME) and (1)H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-l-one (ODQ) and abolished by KCl (45 mM) plus l-NAME. In vessels precontrated with NE and KCl (45 mM) or treated with K(Ca)(+2) channel blockers (charybdotoxin plus apamin), the effect of ASE was significantly reduced. However this effect is not affect by indomethacin, glybenclamide and 4-aminopiridine. Atropine, pyrilamine, yohimbine and HOE 140 significantly reduced the vasodilator effect of acetylcholine, histamine, clonidine and bradykinin, respectively, but did not change the vasodilator effect of ASE. In cultured endothelial cells ASE (100 microg/mL) induced the formation of NO that was reduced by N(G)-nitro-l-arginine (l-NA, 100 microM). The present study demonstrates that the vasodilator effect of ASE is dependent on activation of NO-cGMP pathway and may also involve endothelium-derived hyperpolarizing factor (EDHF) release. The vasodilator effect suggest a possibility to use ASE as a medicinal plant, in the treatment of cardiovascular diseases.

Assuntos

Arecaceae , Endotélio Vascular/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Arecaceae/química , Fatores Biológicos/metabolismo , Brasil , Células Cultivadas , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/metabolismo , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Frutas , Guanilato Ciclase/metabolismo , Masculino , Mesentério/irrigação sanguínea , Óxido Nítrico/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Plantas Medicinais , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo , Vasoconstritores/farmacologia , Vasodilatadores/isolamento & purificação

RESUMO

Alpinia zerumbet (K. Schum), a medicinal plant originated from West Asia, is used in the northeast and southeast of Brazil as infusions or decoctions as a diuretic, antihypertensive, and antiulcerogenic. Experiments were undertaken to determine whether a hydroalcoholic extract obtained from leaves of Alpinia zerumbet (AZE) induces vasodilation in the mesenteric vascular bed (MVB), and an antihypertensive effect was also assessed in rats with DOCA-salt hypertension. In MVB precontracted with norepinephrine, AZE induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3]oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of AZE. In vessels precontracted with norepinephrine, the vasodilator effect of AZE was not changed by 4-aminopyridine, glibenclamide, or by charybdotoxin plus apamin. Concentrations of atropine, pyrilamine, and yohimbine that significantly reduced the vasodilator effect of acetylcholine, histamine, and clonidine, respectively, did not change the vasodilator effect of AZE. HOE 140, which significantly reduced the vasodilator effect of bradykinin, induced a slight but significant reduction on the vasodilator effect of AZE. Chronic oral administration of AZE induced a significant reduction in systolic, mean, and diastolic arterial pressure in rats with DOCA-salt hypertension. Probably the vasodilator effect of AZE is dependent on the activation of the NO-cGMP pathway and independent of activation of ATP-dependent, voltage-dependent, and calcium-dependent K+ channels. Bradykinin receptors may also participate in the vasodilator effect of AZE. Finally, the vasodilator and antihypertensive effects of AZE demonstrated in the present study provide experimental support for the indication of Alpinia zerumbet as an antihypertensive medicinal plant.

Assuntos

Alpinia/química , Anti-Hipertensivos/farmacologia , Endotélio Vascular/fisiologia , Vasodilatadores/farmacologia , Acetilcolina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos

RESUMO

1. Pregnancy in rats is characterized by a reduction in arterial pressure that is associated with a decreased response to vasoconstrictors. However, the responses to vasodilators in isolated vessels remain controversial and are not well established in hypertensive pregnant rats. 2. In the present study, we investigated the effect of pregnancy on the bradykinin (BK)-induced vasodilator responses of the isolated mesenteric arterial bed (MAB) from Wistar normotensive and spontaneously hypertensive rats (SHR) and determined the role of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and angiotensin-converting enzyme (ACE) in these responses. 3. Mean arterial pressure (MAP) in pregnant normotensive and pregnant hypertensive rats (93 +/- 1 and 122 +/- 2 mmHg, respectively) was lower than in non-pregnant controls (128 +/- 1 and 163 +/- 2 mmHg, respectively; P < 0.05). In MAB isolated from normotensive rats and precontracted with phenylephrine, the effects of bradykinin, acetylcholine (ACh) and nitroglycerine (NG) were not influenced by pregnancy. In contrast, the vasodilator responses to BK were significantly reduced in pregnant compared with non-pregnant SHR and seemed to be specific to BK. 4. The ACE inhibitor captopril potentiated BK vasodilator responses and abolished the differences between pregnant and non-pregnant SHR. Inhibition of nitric oxide (NO) synthase by N(G)-nitro-L-arginine methyl ester (l-NAME) significantly reduced the vasodilator effect of BK in all groups. In the presence of l-NAME plus high K+ solution (47 mmol/L), BK-induced vasodilation was completely blocked. The NO-dependent component of the responses seems to be more important in hypertensive rats and pregnancy does not modify this profile. 5. Our results suggest that increased ACE activity may be involved in the pregnancy associated reduction in vasodilator responses to BK in the MAB of hypertensive rats. Pregnancy does not modify the relative contribution of the EDHF and NO to the vasodilator effect of BK.

Assuntos

Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/antagonistas & inibidores , Bradicinina/farmacologia , Captopril/farmacologia , Hipertensão/fisiopatologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Vasodilatação/efeitos dos fármacos , Acetilcolina/antagonistas & inibidores , Acetilcolina/farmacologia , Animais , Fatores Biológicos/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Técnicas In Vitro , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III , Peptidil Dipeptidase A/metabolismo , Gravidez , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Circulação Esplâncnica/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/farmacologia

RESUMO

1. The mechanisms involved in the vasodilator actions of angiotensin II (Ang II) have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the Ang II vasodilator effect using rat isolated mesenteric vascular bed (MVB). 2. Under basal conditions, Ang II does not affect the perfusion pressure of MVB. However, in vessels precontracted with norepinephrine, Ang II induces vasodilation followed by vasoconstriction. Vasoconstrictor, but not the vasodilation of Ang II, is inhibited by AT(1) antagonist (losartan). The vasodilator effect of Ang II was not inhibited by AT(2), angiotensin IV and angiotensin 1-7 receptor antagonists alone (PD 123319, divalinal, A 779, respectively). 3. The vasodilator effect of Ang II is significantly reduced by endothelial removal (deoxycholic acid), but not by indomethacin. Inhibition of NO-synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ) reduces the vasodilator effect of Ang II. This effect is also reduced by tetraethylammonium (TEA) or l-NAME, and a combination of l-NAME plus TEA increases the inhibitory effect of the antagonists alone. However, indomethacin does not change the residual vasodilator effect observed in vessels pretreated with l-NAME plus TEA. 4. In vessels precontracted with norepinephrine and depolarized with KCl 25 mm or treated with Ca(2+)-dependent K(+) channel blockers (charybdotoxin plus apamin), the effect of Ang II was significantly reduced. However, this effect is not affected by ATP and voltage-dependent K(+) channel blockers (glybenclamide and 4-aminopyridine). 5. Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin (BK) and Ang II in the rat MVB. The inhibitory effect of the B(2) receptor antagonist HOE 140 on the vasodilator effect of Ang II is further enhanced by PD 123319 and/or A 779. 6. The present findings suggest that BK plays an important role in the endothelium-dependent vasodilator effect of Ang II. Probably, the link between Ang II and BK release is modulated by receptors that bind PD 123319 and A 779.

Assuntos

Angiotensina II/farmacologia , Angiotensina I/fisiologia , Bradicinina/fisiologia , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Fragmentos de Peptídeos/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Vasodilatação/fisiologia , Animais , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/fisiologia , Ratos , Ratos Wistar , Receptores de Angiotensina/fisiologia , Vasodilatação/efeitos dos fármacos

RESUMO

UNLABELLED: The mechanism underlying the Niteroi, Rio de Janeiro sedative effect of clonidine, an alpha2-adrenoceptor agonist, remains uncertain. Because activation of alpha2-adrenoceptors induces release of nitric oxide (NO), we tested the hypothesis that the sedative effect of clonidine depends on NO-related mechanisms. The effect of 7-nitro indazole on the sleeping time induced by clonidine was studied in Wistar rats. In addition, we examined the effect of clonidine, alpha-methyldopa, and midazolam on the thiopental-induced sleeping time in rats pretreated with N(G)-nitro-L-arginine-methyl-ester (L-NAME). The sleeping time induced by clonidine was significantly decreased by 7-nitro indazole. Thiopental sleeping time was increased by clonidine, alpha-methyldopa, and midazolam. L-NAME reduced the prolongation effect of clonidine and alpha-methyldopa, but did not alter the effect of midazolam on the thiopental-induced sleeping time. The inhibitory effect of L-NAME on clonidine-dependent prolongation of thiopental-induced sleeping time was reversed by L-arginine. These results suggest that NO-dependent mechanisms are involved in the sedative effect of clonidine. In addition, this effect seems to be specific for the sedative action of alpha2-adrenoceptors agonists. IMPLICATIONS: Clonidine, an antihypertensive drug, is also a sedative. This sedative effect, although an adverse event in the treatment of hypertensive patients, can be helpful for sedation of surgical patients. The mechanism of this effect, however, is unknown. In this study, we show that the sedative effect of clonidine is mediated by nitric oxide, because it could be prevented by pretreatment with nitric oxide synthase inhibitors.

Assuntos

Agonistas alfa-Adrenérgicos/farmacologia , Clonidina/farmacologia , Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hipnóticos e Sedativos/farmacologia , Masculino , Metildopa/farmacologia , Midazolam/farmacologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo I , Ratos , Sono/efeitos dos fármacos , Tiopental/farmacologia

RESUMO

The antihypertensive mechanism of alpha2-adrenoceptor agonists, such as clonidine and rilmenidine, is not completely elucidated, although it is probably due to reduction of sympathetic tone mediated by stimulation of central alpha2-adrenoceptors. Because activation of alpha2-adrenoceptors on endothelial cells induces release of endothelium-derived relaxing factor (EDRF), we determined whether nitric oxide (NO) release is involved in the antihypertensive action of clonidine and rilmenidine. In chloralose-anesthetised Wistar rats, systolic and diastolic arterial blood pressures were recorded on a polygraph. Intravenous injection of clonidine or rilmenidine (control group) caused a rapid increase of arterial blood pressure. followed by a long-lasting hypotensive effect. The hypotensive effects, estimated as the area enclosed by the decrease in diastolic pressure during the 20 min after clonidine and rilmenidine injections, were 574+/-60 and 410+/-59 mm Hg/min, respectively. The delta decrease in diastolic arterial blood pressure observed 20 min after intravenous injections of clonidine and rilmenidine was 48+/-5 and 34+/-3 mm Hg, respectively. Clonidine and rilmenidine injected 5-10 min after intravenous pretreatment with L-NAME (2 and 1 mg/kg) or methylene blue (10 mg/kg) induced hypotensive effects that were significantly smaller than that observed for the control group. These results suggest that the antihypertensive effects of clonidine and rilmenidine also may be modulated by the NO-cyclic guanosine monophosphate (cGMP) pathway at the level of the central nervous system and/or at the vascular peripheral circulation.

Assuntos

Anti-Hipertensivos/farmacologia , Clonidina/farmacologia , Hipotensão/prevenção & controle , Azul de Metileno/uso terapêutico , NG-Nitroarginina Metil Éster/uso terapêutico , Oxazóis/farmacologia , Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/metabolismo , Interações Medicamentosas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Hipotensão/induzido quimicamente , Masculino , Azul de Metileno/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Rilmenidina

RESUMO

The most conspicuous effect of bradykinin following its administration into the systemic circulation is a transient hypotension due to vasodilation. In the present study most of the available evidence regarding the mechanisms involved in bradykinin-induced arterial vasodilation is reviewed. It has become firmly established that in most species vasodilation in response to bradykinin is mediated by the release of endothelial relaxing factors following the activation of B2-receptors. Although in some cases the action of bradykinin is entirely mediated by the endothelial release of nitric oxide (NO) and/or prostacyclin (PGI2), a large amount of evidence has been accumulated during the last 10 years indicating that a non-NO/PGI2 factor accounts for bradykinin-induced vasodilation in a wide variety of perfused vascular beds and isolated small arteries from several species including humans. Since the effect of the non-NO/PGI2 endothelium-derived relaxing factor is practically abolished by disrupting the K+ electrochemical gradient together with the fact that bradykinin causes endothelium-dependent hyperpolarization of vascular smooth muscle cells, the action of such factor has been attributed to the opening of K+ channels in these cells. The pharmacological characteristics of these channels are not uniform among the different blood vessels in which they have been examined. Although there is some evidence indicating a role for KCa or KV channels, our findings in the mesenteric bed together with other reports indicate that the K+ channels involved do not correspond exactly to any of those already described. In addition, the chemical identity of such hyperpolarizing factor is still a matter of controversy. The postulated main contenders are epoxyeicosatrienoic acids or endocannabinoid agonists for the CB1-receptors. Based on the available reports and on data from our laboratory in the rat mesenteric bed, we conclude that the NO/PGI2-independent endothelium-dependent vasodilation induced by BK is unlikely to involve a cytochrome P450 arachidonic acid metabolite or an endocannabinoid agonist.

Assuntos

Animais , Bradicinina/farmacologia , Fatores Relaxantes Dependentes do Endotélio/fisiologia , Ácido Nítrico/metabolismo , Prostaglandinas/metabolismo , Vasodilatação/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Bradicinina/efeitos adversos , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/metabolismo , Hipotensão/induzido quimicamente , ômega-N-Metilarginina/farmacologia , Canais de Potássio/efeitos dos fármacos

RESUMO

The most conspicuous effect of bradykinin following its administration into the systemic circulation is a transient hypotension due to vasodilation. In the present study most of the available evidence regarding the mechanisms involved in bradykinin-induced arterial vasodilation is reviewed. It has become firmly established that in most species vasodilation in response to bradykinin is mediated by the release of endothelial relaxing factors following the activation of B2-receptors. Although in some cases the action of bradykinin is entirely mediated by the endothelial release of nitric oxide (NO) and/or prostacyclin (PGI2), a large amount of evidence has been accumulated during the last 10 years indicating that a non-NO/PGI2 factor accounts for bradykinin-induced vasodilation in a wide variety of perfused vascular beds and isolated small arteries from several species including humans. Since the effect of the non-NO/PGI2 endothelium-derived relaxing factor is practically abolished by disrupting the K+ electrochemical gradient together with the fact that bradykinin causes endothelium-dependent hyperpolarization of vascular smooth muscle cells, the action of such factor has been attributed to the opening of K+ channels in these cells. The pharmacological characteristics of these channels are not uniform among the different blood vessels in which they have been examined. Although there is some evidence indicating a role for KCa or KV channels, our findings in the mesenteric bed together with other reports indicate that the K+ channels involved do not correspond exactly to any of those already described. In addition, the chemical identity of such hyperpolarizing factor is still a matter of controversy. The postulated main contenders are epoxyeicosatrienoic acids or endocannabinoid agonists for the CB1-receptors. Based on the available reports and on data from our laboratory in the rat mesenteric bed, we conclude that the NO/PGI2-independent endothelium-dependent vasodilation induced by BK is unlikely to involve a cytochrome P450 arachidonic acid metabolite or an endocannabinoid agonist.

Assuntos

Bradicinina/farmacologia , Ácido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Prostaglandinas/metabolismo , Vasodilatação/efeitos dos fármacos , Sistema Vasomotor/efeitos dos fármacos , Animais , Bradicinina/efeitos adversos , Moduladores de Receptores de Canabinoides , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores Enzimáticos/metabolismo , Hipotensão/induzido quimicamente , Canais de Potássio/efeitos dos fármacos , ômega-N-Metilarginina/farmacologia

RESUMO

We investigated the angiotensin II (Ang II)-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin J (Ang I), and tetradecapeptide (TDP) renin substrate in the absence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM). The angiotensin converting enzyme (ACE) inhibitor captopril (36 microM) completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 microM) significantly reduced (80-90%) the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95%) the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistance but not in large vessels during ACE inhibition.

Assuntos

Angiotensina II/biossíntese , Aorta/metabolismo , Endotélio/metabolismo , Artérias Mesentéricas/metabolismo , Acetilcolina/metabolismo , Animais , Captopril/farmacologia , Masculino , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Wistar , Sistema Renina-Angiotensina/efeitos dos fármacos , Saralasina/farmacologia

RESUMO

We investigated the angiotensin II (Ang II)-generating system by analyzing the vasoconstrictor effect of Ang II, angiotensin I (Ang I), and tetradecapeptide (TDP) renin substrate in the abscence and presence of inhibitors of the renin-angiotensin system in isolated rat aortic rings and mesenteric arterial beds with and without functional endothelium. Ang II, Ang I, and TDP elicited a dose-dependent vasoconstrictor effect in both vascular preparations that was completely blocked by the Ang II receptor antagonist saralasin (50 nM). The angiotensin converting enzyme (ACE) inhibitor captopril (36 muM) completely inhibited the vasoconstrictor effect elicited by Ang I and TDP in aortic rings without affecting that of Ang II. In contrast, captopril (36 muM) significantly reduced (80-90 percent) the response to bolus injection of Ang I, without affecting those to Ang II and TDP in mesenteric arteries. Mechanical removal of the endothelium greatly potentiated (70-95 percent) the vasoconstrictor response to Ang II, Ang I, and TDP in aortic rings while these responses were unaffected by the removal of the endothelium of mesenteric arteries with sodium deoxycholate infusion. In addition, endothelium disruption did not change the pattern of response elicited by these peptides in the presence of captopril. These findings indicate that the endothelium may not be essential for Ang II formation in rat mesenteric arteries and aorta, but it may modulate the response to Ang II. Although Ang II formation from Ang I is essentially dependent on ACE in both vessels, our results suggest the existence of an alternative pathway in the mesenteric arterial bed that may play an important role in Ang II generation from TDP in resistence but not in large vessels during ACE inhibition.

Assuntos

Ratos , Animais , Masculino , Acetilcolina/metabolismo , Angiotensina II/biossíntese , Angiotensina I/metabolismo , Angiotensinogênio/análogos & derivados , Aorta/metabolismo , Captopril/farmacologia , Endotélio/metabolismo , Artérias Mesentéricas/metabolismo , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Saralasina/farmacologia , Angiotensina II/metabolismo , Ratos Wistar

RESUMO

Foram comparados os coeficientes de digestibilidade da proteína bruta (PB), matéria seca (MS), hemicelulose (HCEL), fibra em detergente neutro (FDN), fibra em detergente ácido (FDA), energia bruta (EB) e celulose (CEL), obtidos pela coleta total das fezes (CT) e pelo uso dos marcadores óxido crômico (OC) e lignina (LIG). Foram utilizados 24 animais, nove equinos, seis asininos e nove muares, em delineamento experimental inteiramente ao acaso, com nove tratamentos em esquema fatorial 3 x 3 (três espécies e três marcadores), com três repetiçöes para equinos e muares e duas para jumentos. O experimento teve duraçäo de 28 dias. A dieta era composta de feno de "Coast cross" picado (PB=7,8 por cento) e concentrado (PB=12,7 por cento) à base de milho desintegrado com sabugo, milho gräo, farelo de trigo, farelo de soja, calcário e fosfato bicálcio. A relaçäo volumoso/concentrado foi de 1:1, fornecida no equivalente a 2 por cento do peso vivo em MS/dia, de acordo com o seguinte esquema de arraçoamento: A=7h e 13h (volumoso), 9h e 15h (concentrado);B=7h e 15h (volumoso), 11h e 19h (concentrado); C=7h (concentrado total e 1/3 do volumoso), 15h (2/3 do volumoso). Näo foram encontradas diferenças significativas entre os coeficientes de digestibilidade da HCEL (67,12 e 63,55) e CEL (51,06 e 46,58) obtidos pelos indicadores CT, LIG, mas diferentes pelo indicador OC (58,34 e 38,41). Os coeficientes de digestiblidade da PB (71,01, 67,78 e 63,12), da MS (64,15, 59,03 e 52,99), da FDN (51,20, 46,53 e 38,61), da EB (64,60, 60,77 e 54,94) e da FDA (33,23, 66,03 E 18,84) obtidos respectivamente pela CT, LIG e OC diferiram entre si

Assuntos

Animais , Digestão , Equidae , Fezes , Lignina

Assuntos

Cininas/fisiologia , Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Sinergismo Farmacológico , Humanos , Dados de Sequência Molecular