RESUMEN

BACKGROUND AND OBJECTIVE: Stroke, a leading cause of mortality and disability, characterized by neuronal death, can be induced by a reduction or interruption of blood flow. In this study, the role of Alamandine, a new peptide of the renin-angiotensin system, was evaluated in in-vitro and in-vivo brain ischemia models. METHODS: In the in-vitro model, hippocampal slices from male C57/Bl6 mice were placed in a glucose-free aCSF solution and bubbled with 95% N2 and 5% CO2 to mimic brain ischemia. An Alamandine concentration-response curve was generated to evaluate cell damage, glutamatergic excitotoxicity, and cell death. In the in-vivo model, cerebral ischemia/ reperfusion was induced by bilateral occlusion of common carotid arteries (BCCAo-untreated) in SD rats. An intracerebroventricular injection of Alamandine was given 20-30 min before BCCAo. Animals were subjected to neurological tests 24 h and 72 h after BCCAo. Cytokine levels, oxidative stress markers, and immunofluorescence were assessed in the brain 72 h after BCCAo. RESULTS: Alamandine was able to protect brain slices from cellular damage, excitotoxicity and cell death. When the Alamandine receptor was blocked, protective effects were lost. ICV injection of Alamandine attenuated neurological deficits of animals subjected to BCCAo and reduced the number of apoptotic neurons/cells. Furthermore, Alamandine induced anti-inflammatory effects in BCCAo animals as shown by reductions in TNFα, IL- 1ß, IL-6, and antioxidant effects through attenuation of the decreased SOD, catalase, and GSH activities in the brain. CONCLUSION: This study showed, for the first time, a neuroprotective role for Alamandine in different ischemic stroke models.

Asunto(s)

Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Daño por Reperfusión , Accidente Cerebrovascular , Animales , Isquemia Encefálica/metabolismo , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Neuroprotección , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oligopéptidos , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico

RESUMEN

Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin-(1-7) is able to block T3-induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin-(1-7) effects. Angiotensin-(1-7) treatment increased nuclear FOXO3 levels and reduced p-FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin-(1-7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor-κB (NF-κB) were observed after angiotensin-(1-7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin-(1-7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF-κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin-(1-7), which may contribute to future therapeutic targets.

Asunto(s)

Angiotensina I/farmacología , Catalasa/metabolismo , Proteína Forkhead Box O3/metabolismo , Miocitos Cardíacos/patología , FN-kappa B/metabolismo , Fragmentos de Péptidos/farmacología , Superóxido Dismutasa-1/metabolismo , Triyodotironina/efectos adversos , Regulación hacia Arriba , Animales , Antioxidantes/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Hipertrofia , Masculino , Modelos Biológicos , Miocitos Cardíacos/efectos de los fármacos , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Ratas Sprague-Dawley , Ratas Transgénicas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Regulación hacia Arriba/efectos de los fármacos

RESUMEN

OBJECTIVE: In the present study, the peripheral mechanism that mediates the pressor effect of angiotensin-(1-7) in the rostral ventrolateral medulla was investigated. METHOD: Angiotensin-(1-7) (25 pmol) was bilaterally microinjected in the rostral ventrolateral medulla near the ventral surface in urethane-anesthetized male Wistar rats that were untreated or treated (intravenously) with effective doses of selective autonomic receptor antagonists (atenolol, prazosin, methyl-atropine, and hexamethonium) or a vasopressin V1 receptor antagonist [d(CH2)5 -Tyr(Me)-AVP] given alone or in combination. RESULTS: Unexpectedly, the pressor response produced by angiotensin-(1-7) (16 ± 2 mmHg, n = 12), which was not associated with significant changes in heart rate, was not significantly altered by peripheral treatment with prazosin, the vasopressin V1 receptor antagonist, hexamethonium or methyl-atropine. Similar results were obtained in experiments that tested the association of prazosin and atenolol; methyl-atropine and the vasopressin V1 antagonist or methyl-atropine and prazosin. Peripheral treatment with the combination of prazosin, atenolol and the vasopressin V1 antagonist abolished the pressor effect of glutamate; however, this treatment produced only a small decrease in the pressor effect of angiotensin-(1-7) at the rostral ventrolateral medulla. The combination of hexamethonium with the vasopressin V1 receptor antagonist or the combination of prazosin, atenolol, the vasopressin V1 receptor antagonist and methyl-atropine was effective in blocking the effect of angiotensin-(1-7) at the rostral ventrolateral medulla. CONCLUSION: These results indicate that angiotensin-(1-7) triggers a complex pressor response at the rostral ventrolateral medulla that involves an increase in sympathetic tonus, release of vasopressin and possibly the inhibition of a vasodilatory mechanism.

Asunto(s)

Angiotensina I/farmacología , Bulbo Raquídeo/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Vasodilatadores/farmacología , Angiotensina I/administración & dosificación , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Presión Arterial/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hexametonio/administración & dosificación , Masculino , Bulbo Raquídeo/fisiopatología , Microinyecciones , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Wistar , Factores de Tiempo , Vasodilatadores/administración & dosificación

RESUMEN

OBJECTIVE: In the present study, the peripheral mechanism that mediates the pressor effect of angiotensin-(1-7) in the rostral ventrolateral medulla was investigated. METHOD: Angiotensin-(1-7) (25 pmol) was bilaterally microinjected in the rostral ventrolateral medulla near the ventral surface in urethane-anesthetized male Wistar rats that were untreated or treated (intravenously) with effective doses of selective autonomic receptor antagonists (atenolol, prazosin, methyl-atropine, and hexamethonium) or a vasopressin V1 receptor antagonist [d(CH2)5 -Tyr(Me)-AVP] given alone or in combination. RESULTS: Unexpectedly, the pressor response produced by angiotensin-(1-7) (16 ± 2 mmHg, n = 12), which was not associated with significant changes in heart rate, was not significantly altered by peripheral treatment with prazosin, the vasopressin V1 receptor antagonist, hexamethonium or methyl-atropine. Similar results were obtained in experiments that tested the association of prazosin and atenolol; methyl-atropine and the vasopressin V1 antagonist or methyl-atropine and prazosin. Peripheral treatment with the combination of prazosin, atenolol and the vasopressin V1 antagonist abolished the pressor effect of glutamate; however, this treatment produced only a small decrease in the pressor effect of angiotensin-(1-7) at the rostral ventrolateral medulla. The combination of hexamethonium with the vasopressin V1 receptor antagonist or the combination of prazosin, atenolol, the vasopressin V1 receptor antagonist and methyl-atropine was effective in blocking the effect of angiotensin-(1-7) at the rostral ventrolateral medulla. CONCLUSION: These results indicate that angiotensin-(1-7) triggers a complex pressor response at the rostral ventrolateral medulla that involves an increase in sympathetic tonus, release of vasopressin and possibly the inhibition of a vasodilatory mechanism.

Asunto(s)

Animales , Masculino , Ratas , Angiotensina I/farmacología , Bulbo Raquídeo/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Vasodilatadores/farmacología , Angiotensina I/administración & dosificación , Presión Arterial/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hexametonio/administración & dosificación , Microinyecciones , Bulbo Raquídeo/fisiopatología , Fragmentos de Péptidos/administración & dosificación , Ratas Wistar , Receptores de Vasopresinas/antagonistas & inhibidores , Factores de Tiempo , Vasodilatadores/administración & dosificación

RESUMEN

We evaluated the development of arterial hypertension, cardiac function, and collagen deposition, as well as the level of components of the renin-angiotensin system in the heart of transgenic rats that overexpress an angiotensin (Ang)-(1-7)-producing fusion protein, TGR(A1-7)3292 (TG), which induces a lifetime increase in circulating levels of this peptide. After 30 days of the induction of the deoxycorticosterone acetate (DOCA)-salt hypertension model, DOCA-TG rats were hypertensive but presented a lower systolic arterial pressure in comparison with DOCA-Sprague-Dawley (SD) rats. In contrast to DOCA-SD rats that presented left ventricle (LV) hypertrophy and diastolic dysfunction, DOCA-TG rats did not develop cardiac hypertrophy or changes in ventricular function. In addition, DOCA-TG rats showed attenuation in mRNA expression for collagen type I and III compared with the increased levels of DOCA-SD rats. Ang II plasma and LV levels were reduced in SD and TG hypertensive rats in comparison with normotensive animals. DOCA-TG rats presented a reduction in plasma Ang-(1-7) levels; however, there was a great increase in Ang-(1-7) ( approximately 3-fold) accompanied by a decrease in mRNA expression of both angiotensin-converting enzyme and angiotensin-converting enzyme 2 in the LV. The mRNA expression of Mas and Ang II type 1 receptors in the LV was not significantly changed in DOCA-SD or DOCA-TG rats. This study showed that TG rats with increased circulating levels of Ang-(1-7) are protected against cardiac dysfunction and fibrosis and also present an attenuated increase in blood pressure after DOCA-salt hypertension. In addition, DOCA-TG rats showed an important local increase in Ang-(1-7) levels in the LV, which might have contributed to the attenuation of cardiac dysfunction and prefibrotic lesions.

Asunto(s)

Angiotensina I/genética , Desoxicorticosterona/farmacología , Hipertensión/genética , Fragmentos de Péptidos/genética , Sistema Renina-Angiotensina/genética , Remodelación Ventricular/genética , Análisis de Varianza , Angiotensina I/sangre , Animales , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Pruebas de Función Cardíaca , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/genética , Hipertrofia Ventricular Izquierda/metabolismo , Inmunohistoquímica , Fragmentos de Péptidos/sangre , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Transgénicas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

The renin-angiotensin (Ang) system plays a pivotal role in the pathogenesis of cardiovascular disease, with Ang II being the major effector of this system. Multiple lines of evidence have shown that Ang-(1-7) exerts cardioprotective effects in the heart by counterregulating Ang II actions. The questions that remain are how and where Ang-(1-7) exerts its effects. By using a combination of molecular biology, confocal microscopy, and a transgenic rat model with increased levels of circulating Ang-(1-7) (TGR[A1-7]3292), we evaluated the signaling pathways involved in Ang-(1-7) cardioprotection against Ang II-induced pathological remodeling in ventricular cardiomyocytes. Rats were infused with Ang II for 2 weeks. We found that ventricular myocytes from TGR(A1-7)3292 rats are protected from Ang II pathological remodeling characterized by Ca(2+) signaling dysfunction, hypertrophic fetal gene expression, glycogen synthase kinase 3beta inactivation, and nuclear factor of activated T-cells nuclear accumulation. Moreover, cardiomyocytes from TGR(A1-7)3292 rats infused with Ang II presented increased expression levels of neuronal NO synthase. To provide a signaling pathway involved in the beneficial effects of Ang-(1-7), we treated neonatal cardiomyocytes with Ang-(1-7) and Ang II for 36 hours. Treatment of cardiomyocytes with Ang-(1-7) prevented Ang II-induced hypertrophy by modulating calcineurin/nuclear factor of activated T-cell signaling cascade. Importantly, antihypertrophic effects of Ang-(1-7) on Ang II-treated cardiomyocytes were prevented by N(G)-nitro-l-arginine methyl ester and 1H-1,2,4oxadiazolo4,2-aquinoxalin-1-one, suggesting that these effects are mediated by NO/cGMP. Taken together, these data reveal a key role for NO/cGMP as a mediator of Ang-(1-7) beneficial effects in cardiac cells.

Asunto(s)

Angiotensina I/metabolismo , GMP Cíclico/metabolismo , Miocitos Cardíacos/metabolismo , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/metabolismo , Transducción de Señal , Angiotensina I/sangre , Angiotensina II/administración & dosificación , Angiotensina II/toxicidad , Animales , Animales Recién Nacidos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Presión Sanguínea/fisiología , Calcio/metabolismo , Cardiomegalia/inducido químicamente , Cardiomegalia/genética , Cardiomegalia/fisiopatología , Tamaño de la Célula/efectos de los fármacos , Células Cultivadas , Hipertensión/inducido químicamente , Hipertensión/genética , Hipertensión/fisiopatología , Microscopía Confocal , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Factores de Transcripción NFATC/metabolismo , Fragmentos de Péptidos/sangre , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas

RESUMEN

We evaluated the effect of the nonpeptide mimic of angiotensin (Ang)-(1-7), AVE 0991, on the hypotensive effect of bradykinin (BK). Increasing doses of intra-arterial or intravenous BK were administered before and 30 minutes after the beginning of AVE 0991 infusion. The effect of AVE 0991 on plasma Ang-converting enzyme activity was tested using Hip-His-Leu as the substrate. The interaction of AVE 0991 with Ang-converting enzyme in vivo was tested by determining its effect on the pressor action of Ang I or Ang II. AVE 0991 produced a significant and similar potentiation of intra-arterial or intravenous bradykinin. AVE 0991 did not inhibit plasma Ang-converting enzyme activity in vitro or the pressor effect of Ang I in vivo. N(W)-nitro-l-arginine methyl ester or D-Ala(7)-Ang-(1-7) administration abolished the BK potentiating effect of AVE 0991. We further examined the BK-potentiating effect of AVE 0991, evaluating its effect on NO production in rabbit endothelial cells. The NO release was measured using the 4-amino-5-methylamino-2'-7'-difluorofluorescein diacetate. A synergistic effect of AVE 0991 and BK on NO release was observed. These results suggest that AVE 0991 potentiates bradykinin through an Ang-converting enzyme-independent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo.

Asunto(s)

Angiotensina I/farmacología , Bradiquinina/farmacología , Imidazoles/farmacología , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/farmacología , Peptidil-Dipeptidasa A/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Receptores Acoplados a Proteínas G/fisiología , Vasodilatadores/farmacología , Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Inhibidores Enzimáticos/farmacología , Hipotensión/metabolismo , Hipotensión/fisiopatología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Proto-Oncogenes Mas , Conejos , Ratas , Ratas Wistar

RESUMEN

The G protein-coupled receptor Mas was recently described as an angiotensin-(1-7) [ANG-(1-7)] receptor. In the present study we evaluated the anatomical localization of Mas using immunofluorescence in the central nervous system of adult male Wistar rats. An abundant labeling was found in the hippocampus, amigdala, anterodorsal thalamic nucleus, cortex, and hypoglossal nucleus. More importantly, a dense ANG-(1-7) receptor Mas immunoreactivity was observed in cardiovascular-related areas of the medulla and forebrain, shown in several previous studies as sites for the action of ANG-(1-7) in the brain. A strong staining was found in the nucleus of the solitary tract, caudal and rostral ventrolateral medulla, inferior olive, parvo and magnocellular portions of the paraventricular hypothalamic nucleus, supraoptic nucleus, and lateral preoptic area. Furthermore, Mas staining was predominantly present in neurons. At the medullary sites, a specific and high-intensity binding for rhodamine-ANG-(1-7) was also shown. The specific ANG-(1-7) binding was completely displaced by the anti-Mas antibody or by the ANG-(1-7) antagonist, A-779. The data presented provide the first anatomical basis for the physiological role of ANG-(1-7)/Mas axis in the modulation of different cardiovascular functions and give new insights for clarifying the role of ANG-(1-7) in the central nervous system.

Asunto(s)

Encéfalo/metabolismo , Fenómenos Fisiológicos Cardiovasculares , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Angiotensina I/metabolismo , Angiotensina I/fisiología , Animales , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/fisiología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/análisis , Ratas , Receptores Acoplados a Proteínas G/análisis

RESUMEN

We have described a transgenic rat line that expresses an angiotensin-(1-7)-producing fusion protein, the TGR(A1-7)3292. In these rats, testis acts as an angiotensin-(1-7) biological pump, increasing its plasma concentration 2.5-fold. In this study, we performed hemodynamic measurements in TGR(A1-7)3292 and age-matched Hannover Sprague-Dawley (SD) control rats, using fluorescent microspheres. Urethane-anesthetized transgenic rats had similar levels of baseline blood pressure (99 +/- 3 mmHg) as did SD rats (101 +/- 3 mmHg). However, pronounced differences were observed in other hemodynamic measurements. TGR(A1-7)3292 rats presented a significant increase in stroke volume (0.29 +/- 0.01 vs. 0.25 +/- 0.01 ml in SD), increased cardiac index (24.6 +/- 0.91 vs. 21.9 +/- 0.65 ml.min(-1).kg) and decreased total peripheral resistance (3.9 +/- 0.13 vs. 4.5 +/- 0.13 mmHg.ml(-1).min.100 g). The increase in stroke volume in transgenic rats may be partially explained by the small decrease in heart rate (326 +/- 7.0 vs. 359 +/- 6.0 beats/min in SD). Strikingly, TGR(A1-7)3292 rats presented a substantial decrease in the vascular resistance in lung, spleen, kidney, adrenals, brain, testis and brown fat tissue with no significant differences in the left ventricle, mesentery, skin, gastrocnemius muscle and white fat tissue. These results corroborate and extend previous results observed after acute angiotensin-(1-7) infusion, showing that chronic increase in circulating angiotensin-(1-7) produces sustained and important changes in regional and systemic hemodynamics. Moreover, our data suggest a physiological role for angiotensin-(1-7) in the tonic control of regional blood flow.

Asunto(s)

Angiotensina I/metabolismo , Velocidad del Flujo Sanguíneo/fisiología , Presión Sanguínea/fisiología , Fragmentos de Péptidos/metabolismo , Volumen Sistólico/fisiología , Resistencia Vascular/fisiología , Adaptación Fisiológica/fisiología , Angiotensina I/genética , Animales , Masculino , Fragmentos de Péptidos/genética , Ratas , Proteínas Recombinantes de Fusión/metabolismo

RESUMEN

We determined the effect of microinjection of ANG-(1-7) and ANG II into two key regions of the medulla that control the circulation [rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively)] on baroreflex control of heart rate (HR) in anesthetized rats. Reflex bradycardia and tachycardia were induced by increases and decreases in mean arterial pressure produced by intravenous phenylephrine and sodium nitroprusside, respectively. The pressor effects of ANG-(1-7) and ANG II (25 pmol) after RVLM microinjection (11 +/- 0.8 and 10 +/- 2 mmHg, respectively) were not accompanied by consistent changes in HR. In addition, RVLM microinjection of these angiotensin peptides did not alter the bradycardic or tachycardic component of the baroreflex. CVLM microinjections of ANG-(1-7) and ANG II produced hypotension (-11 +/- 1.5 and -11 +/- 1.9 mmHg, respectively) that was similarly not accompanied by significant changes in HR. However, CVLM microinjections of angiotensins induced differential changes in the baroreflex control of HR. ANG-(1-7) attenuated the baroreflex bradycardia (0.26 +/- 0.06 ms/mmHg vs. 0.42 +/- 0.08 ms/mmHg before treatment) and facilitated the baroreflex tachycardia (0.86 +/- 0.19 ms/mmHg vs. 0.42 +/- 0.10 ms/mmHg before treatment); ANG II produced the opposite effect, attenuating baroreflex tachycardia (0.09 +/- 0.06 ms/mmHg vs. 0.31 +/- 0.07 ms/mmHg before treatment) and facilitating the baroreflex bradycardia (0.67 +/- 0.16 ms/mmHg vs. 0.41 +/- 0.05 ms/mmHg before treatment). The modulatory effect of ANG II and ANG-(1-7) on baroreflex sensitivity was completely abolished by peripheral administration of methylatropine. These results suggest that ANG II and ANG-(1-7) at the CVLM produce a differential modulation of the baroreflex control of HR, probably through distinct effects on the parasympathetic drive to the heart.

Asunto(s)

Angiotensina II/farmacología , Angiotensina I/farmacología , Barorreflejo/efectos de los fármacos , Bulbo Raquídeo/anatomía & histología , Bulbo Raquídeo/fisiología , Fragmentos de Péptidos/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Microinyecciones , Modelos Biológicos , Óxido Nítrico Sintasa de Tipo I , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático

RESUMEN

OBJECTIVES: In this study, we investigated the effects of angiotensin II and angiotensin-(1-7) at the nucleus tractus solitarii (nTS) in transgenic rats with a severe deficit in brain angiotensinogen production, TGR(ASrAOGEN) (TGR). METHODS: Angiotensin II (10 pmol), angiotensin-(1-7) (10 pmol) or NaCl (0.9%/50 nl) were microinjected into the nTS of urethane-anaesthetized TGR (n = 36) and Sprague Dawley (SD) (n = 34) rats. Mean arterial pressure (MAP) and heart rate were measured via a femoral artery catheter and the baroreflex control of heart rate was evaluated after increases in MAP induced by phenylephrine (baroreflex bradycardia). RESULTS: Angiotensin II microinjections into the nTS of the TGR induced a higher decrease in MAP and heart rate (-37 +/- 5 mmHg and -69 +/- 12 b.p.m., respectively) in comparison to SD rats (-18 +/- 1 mmHg and -43 +/- 5 b.p.m., respectively). In contrast, changes after angiotensin-(1-7) microinjections into the nTS of TGR (-6 +/- 1 mmHg and -13 +/- 4 b.p.m.) were significantly smaller than that induced in SD (-11 +/- 2 mmHg and -24 +/- 6 b.p.m.). The baseline baroreflex sensitivity to phenylephrine of TGR was accentuated in comparison to SD rats (0.70 +/- 0.06 versus 0.44 +/- 0.03 ms/mmHg). Angiotensin II microinjection into the nTS produced similar attenuation in the baroreflex bradycardia in both SD (0.28 +/- 0.07 versus 0.5 +/- 0.07 ms/mmHg, before injection) and TGR (0.44 +/- 0.1 versus 0.82 +/- 0.1 ms/mmHg, before injection). In contrast, angiotensin-(1-7) microinjection elicited a facilitation of the baroreflex bradycardia in SD (0.68 +/- 0.12 versus 0.41 +/- 0.03 ms/mmHg, before injection), while in TGR, angiotensin-(1-7) induced an attenuation of baroreflex bradycardia (0.34 +/- 0.07 ms/mmHg versus 0.55 +/- 0.05 ms/mmHg, before injection). CONCLUSIONS: These results indicate that a permanent inhibition of angiotensinogen synthesis in the brain can lead to an increase in the sensitivity of the baroreflex control of heart rate (baroreflex bradycardia) and an increase in angiotensin II responsiveness at the nTS. However, the nTS effect of angiotensin-(1-7) was significantly attenuated in these transgenic rats. These data further indicate that the decrease in brain angiotensins in the transgenic rats may be functionally relevant and support the concept of differential regulatory mechanisms for the effects of the two angiotensin peptides.

Asunto(s)

Angiotensina II/farmacología , Angiotensina I/farmacología , Angiotensinógeno/deficiencia , Encéfalo/metabolismo , Fragmentos de Péptidos/farmacología , Núcleo Solitario/efectos de los fármacos , Angiotensina I/administración & dosificación , Angiotensina II/administración & dosificación , Animales , Animales Modificados Genéticamente , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea , Sistema Cardiovascular/efectos de los fármacos , Frecuencia Cardíaca , Masculino , Bulbo Raquídeo/patología , Microinyecciones , Fragmentos de Péptidos/administración & dosificación , Ratas , Ratas Sprague-Dawley , Valores de Referencia

RESUMEN

1. The contribution of the local vascular production of angiotensin-(1-7) [Ang-(1-7)] to the control of alpha-adrenergic-induced contractions in the aorta of Sprague-Dawley (SD) and TGR(mRen-2)27 [mRen-2] rats was studied. 2. In mRen-2 rats, contractile responses to phenylephrine were diminished as compared to control SD rats in endothelium containing but not in endothelium-denuded vessels. L-NAME increased contractile responses to phenylephrine in mRen-2 rats and, after nitric oxide synthase blockade, responses to phenylephrine became comparable in both strains. 3. Inhibition of angiotensin-converting enzyme (ACE) by captopril potentiated contractile responses in mRen-2 rats and diminished contractile responses in SD rats, both effects being dependent on the presence of a functional endothelium. The effect of captopril in mRen-2 rats was abolished in vessels pre-incubated with Ang-(1-7). 4. Blockade of Ang-(1-7) and bradykinin (BK) receptors by A-779 and HOE 140 respectively, increased phenylephrine-induced contraction in mRen-2, but not in SD rats. This effect was seen only in endothelium-containing vessels. 5. Angiotensin II AT(1) and AT(2) receptor blockade by CV 11974 and PD 123319 did not affect the contractile responses to phenylephrine in aortas of transgenic animals but diminished the response in SD rats. This effect was only seen in the presence of a functional endothelium. 6. It is concluded that the decreased contractile responses to phenylephrine in aortas of mRen-2 rats was dependent on an intact endothelium, the local release and action of Ang-(1-7) and bradykinin.

Asunto(s)

Angiotensina I/fisiología , Endotelio Vascular/efectos de los fármacos , Fragmentos de Péptidos/fisiología , Fenilefrina/farmacología , Vasoconstricción/efectos de los fármacos , Análisis de Varianza , Angiotensina I/farmacología , Antagonistas de Receptores de Angiotensina , Animales , Animales Modificados Genéticamente , Antihipertensivos/farmacología , Aorta/efectos de los fármacos , Aorta/fisiología , Antagonistas de los Receptores de Bradiquinina , Captopril/farmacología , Interacciones Farmacológicas , Endotelio Vascular/fisiología , Técnicas In Vitro , Masculino , Ratones , Fragmentos de Péptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores Adrenérgicos alfa/fisiología , Receptores de Angiotensina/fisiología , Receptores de Bradiquinina/fisiología , Vasoconstricción/fisiología