Hypothalamic angiotensinergic-noradrenergic systems interaction in fructose induced hypertension.

OBJECTIVE: Several studies suggest the importance of the interaction between the renin angiotensin and sympathetic nervous systems in blood pressure control, especially in clinical situations such as the metabolic syndrome. Previously, we have demonstrated changes in noradrenergic hypothalamic control of blood pressure in an animal model of insulin resistance and hypertension. The aim of the present study was to evaluate the effects of the interaction between the noradrenergic and angiotensinergic systems on hypothalamic blood pressure regulation in fructose hypertensive rats. METHODS: In control (C) and fructose-fed hypertensive (F) rats, we studied: 1) the effects of hypothalamic perfusion of irbesartan (AT(1) angiotensin receptor antagonist, 50 and 500 microg ml(-1)) and metoprolol (beta(1) adrenergic receptor antagonist, 10 and 100 microg ml(-1)) on blood pressure, heart rate and noradrenaline intrahypothalamic levels, by means of the microdialysis technique; and 2) the effects of intrahypothalamic microinjection of angiotensin II alone or after metoprolol pre-administration, on blood pressure and heart rate. RESULTS: Meanwhile irbesartan perfusion did not modify neither mean arterial pressure (MAP) nor heart rate or noradrenaline hypothalamic levels in the C group, its highest dose diminished MAP (DeltaMAP: F: - 16.3+/-1 mm Hg, p<0.05) and noradrenaline levels (% of basal levels: 58+/-7%, p<0.05) in the F group, without affecting heart rate. Intrahypothalamic perfusion of metoprolol diminished MAP only in the F group (DeltaMAP: F: -12.1+/-1.1 mm Hg, p<0.05), but did not modify heart rate in both groups. On the other hand, it diminished noradrenaline hypothalamic levels in C (% of basal levels: 53+/-6%, p<0.05) but not in the F group. The pressor response to angiotensin II microinjection was increased in F rats (DeltaMAP: F: 13.3+/-1.5 mm Hg vs. C: 6.9+/-1.8 mm Hg; p<0.05). Previous administration of metoprolol markedly abolished this increment. CONCLUSIONS: Our results suggest the existence of an increase in AT(1) and beta(1) adrenergic receptors tone in the hypothalamus of F rats, which could be related to the increase in blood pressure present in this experimental model. On the other hand, considering that the enhanced pressor response to angiotensin II intrahypothalamic injection in F rats was abolished by previous administration of a beta(1) adrenergic receptor antagonist, these results would indicate that beta(1) adrenergic receptors activation participates in the pressor response to angiotensin II in this experimental model of insulin resistance and hypertension.

Participación del hipotálamo en la regulación de la presión arterial en un modelo de hipertensión e insulinorresistencia / Role of the hypothalamus in blood pressure regulation in a model of hypertension and insulin resistance

Objetivo: Evaluar el papel del área hipotalámica anterior en la regulación de la presión arterial en un modelo en ratas de hipertensión arterial (HTA) e insulinorresistencia. Material y métodos: Se utilizaron ratas Sprague-Dawley macho (n = 72) que fueron divididas en dos grupos: F,fructosa (10 por ciento p/v por 6 semanas) y C, grupo control. Se canuló la arteria carótida izquierda para la medición de la presión arterial media (PAM) y la frecuencia cardíaca (FC). Se colocó una sonda de microdiálisis en el área hipotalámica anterior (AHA) para la perfusión de yohimbina (10 y 100 µg/ml) o de clonidina (100 y 300 µg/ml), antagonista y agonista α2-adrenérgicos, respectivamente, y se evaluaron los cambios hemodinámicos. Resultados: Los animales del grupo F presentaron niveles mayores de presión arterial sistólica que los del grupo C (F: 131 ± 3 mm Hg versus C: 112 ± 4 mm Hg; p < 0,05). La perfusión intrahipotalámica de yohimbina indujo un incremento en la PAM en C, en tanto que no modificó los valores en F. No se encontraron cambios en la FC en ninguno de los grupos. La clonidina en dosis de 100 µg/ml indujo una disminución de la PAM sólo en F, mientras que en dosis de300 µg/ml la disminuyó en ambos grupos y fue mayor en F que en C. Sólo la clonidina en dosis de 300 µg/ml disminuyó la FC en el grupo F, sin modificar los valores en C. Conclusiones: Existiría un tono α2-adrenérgico menor en el AHA de las ratas F, que podría relacionarse con el incremento de la presión arterial presente en este grupo. Por otra parte, la respuesta exacerbada a la clonidina en F evidenciaría la existencia de una supersensibilidad de receptores adrenérgicos hipotalámicos, posiblemente como consecuencia de niveles extracelulares reducidos de noradrenalina en el AHA en este modelo de HTA e insulinorresistencia.

Hypothalamic cardiovascular effects of angiotensin-(1-7) in spontaneously hypertensive rats.

The objective of the present work was to study the cardiovascular actions of the intrahypothalamic injection of Ang-(1-7) and its effects on the pressor response to Ang II in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals. In anaesthetized SH and WKY rats, a carotid artery was cannulated for mean arterial pressure (MAP) measurement and a stainless-steel needle was inserted into the anterior hypothalamus for drug administration. The cardiovascular effects of the intrahypothalamic administration of Ang-(1-7) were determined in SH and WKY rats. In SH rats, the effect of irbesartan and D-Ala-Ang-(1-7) on Ang-(1-7) cardiovascular effect was also evaluated. Ang II was administered in the hypothalamus of SH and WKY rats and changes in blood pressure and heart rate were measured followed by the administration of Ang II, Ang II+Ang-(1-7) or Ang II+D-Ala-Ang-(1-7). Ang-(1-7) did not the change basal MAP in WKY rats, but induced a pressor response in SH animals. Whilst the co-administration of D-Ala-Ang-(1-7) did not affect the response to Ang-(1-7), the previous administration of irbesartan prevented the effect of the peptide. The intrahypothalamic injection of Ang II induced a significantly greater pressor response in SH animals compared to normotensive rats. The co-administration of Ang-(1-7) with Ang II did not affect the pressor response to Ang II in the WKY group. In SH rats, whilst the co-administration of Ang-(1-7) with Ang II reduced the pressor response to Ang II, the concomitant application of D-Ala-Ang-(1-7) with Ang II increased the pressor response to the octapeptide after 5 and 10 min of intrahypothalamic administration. In conclusion, our result demonstrated that the biologically active peptide Ang-(1-7) did not participate in the hypothalamic blood pressure regulation of WKY animals. In SH rats, Ang-(1-7) exerted pleiotropic effects on blood pressure regulation. High dose of the heptapeptide produced a pressor response because of an unspecific action by activation of AT1 receptors. The concomitant administration of lower doses of Ang-(1-7) with Ang II reduced the pressor response to the octapeptide. Finally, the effect of AT(1-7) antagonist on Ang II pressor response suggested that hypothalamic formed Ang-(1-7) are implicated in the regulation of the cardiovascular effects of Ang II.

Hypothalamic antihypertensive effect of irbesartan in chronic aortic coarctated rats.

The aim of the present work was to study the central and plasma pharmacokinetics of irbesartan (IRB) and its possible hypothalamic antihypertensive effect in sham-operated (SO) and aortic-coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. Anesthetized Wistar rats were used 42 days after ACo or SO. For the study of plasma pharmacokinetics, a vascular shunt probe was inserted into the carotid artery. In a separated experiment, a concentric probe was placed into the anterior hypothalamus for the study of IRB distribution in the central nervous system. Based on the hypothalamic concentrations of IRB reached in ACo rats, the anterior hypothalamus of SO and ACo animals was perfused with a Ringer solution containing approximately 6 microg x ml(-1) of the drug. IRB (10 mg x kg(-1) i.v.) induced a late decrease of heart rate (HR) in ACo animals (DeltaHR: -42 +/- 10 bpm, n = 5, p < 0.05 vs. SO rats) but not in SO rats (DeltaHR: 11 +/- 13 bpm, n = 5). Systemic administration of the drug reduced the mean arterial pressure (MAP) of both experimental groups, but the hypotensive effect was greater in ACo (DeltaMAP: -39.9 +/- 5.0 mm Hg, n = 5, p < 0.05 vs. SO rats) than in SO rats (DeltaMAP: -25.4 +/- 2.1 mm Hg, n = 5). A similar pharmacokinetic profile was observed in both experimental groups. Hypothalamic distribution of IRB was greater in ACo (AUC: 730 +/- 130 ng x ml(-1) h(-1), n = 5, p < 0.05 vs. SO rats) than in SO animals (AUC: 283 +/- 87 ng x ml(-1) h(-1), n = 5). The IRB hypothalamic perfusion induced an antihypertensive effect in ACo (DeltaMAP: -15.1 +/- 1.0 mm Hg, n = 5, p < 0.05 vs. Ringer perfusion) but not in SO rats. In conclusion, the chronic aortic coarctation did not modify the plasma pharmacokinetics of IRB, but it increased the distribution of the drug in the central nervous system. The greater hypotensive effect of IRB observed in ACo animals suggests the involvement of AT1 receptors in the maintenance of the hypertensive stage in chronic ACo rats. The hypotensive effect of IRB in ACo animals could be explained, at least in part, due an action on the anterior hypothalamic angiotensin system.

Pharmacokinetic profile of methyldopa in the brain of sinaortic-denervated rats.

Pharmacokinetics of methyldopa (MD) and the effect on the dopaminergic metabolism was studied in anesthetized sham-operated (SO) and sinoaortic-denervated (SAD) rats by using the microdialysis technique. A concentric microdialysis probe was placed in the striatum or in the posterior hypothalamus. Levels of MD, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC). Following the i.p. administration of MD (50 mg x kg(-1), i.p.), striatal dialysates showed that this drug rapidly reaches the brain. However, in SAD rats the MD levels of dialysates were lower and decreased more rapidly compared to SO rats. On the other hand, dialysates of posterior hypothalamus showed that in SAD animals the accumulation of MD was significantly greater than in SO rats.MD does not significantly reduce the striatal production of dopaminergic metabolite DOPAC in both groups of rats. The drug also induces a decrease of DOPAC levels in hypothalamic dialysates of SO and SAD animals. On the other hand, a no significative decay of HVA levels was seen in the striatal dialysate of both groups of experimental animals. In conclusion, this study by using a microdialysis technique shows that MD has different kinetic profiles in dialysates from posterior hypothalamus and striatum of SO and SAD rats at a dose that alters dopaminergic metabolism.