La Angiotensina II y la respuesta neurohumoral frente al estrés / The angiotensin II and the neurohumoral response mediated stress

El estímulo eléctrico plantar (EEP) aplicado a ratas conscientes, incrementa la presión arterial media (PAM) y la frecuencia cardíaca (FC). En el presente trabajo evaluamos la hipótesis que la angiotensina II (ANG II) endógena media la respuesta simpática frente al EEP. Nuestros resultados muestran que el bloqueo del receptor AT1 con losartan, valsartan o eprosartan previene la respuesta vasopresora inducida por el EEP. La nefrectomía bilateral (NFX), la cual reduce los niveles circulantes de ANG, suprimió el incremento de la PAM y de las catecolaminas plasmáticas observada durante el EEP. La administración de una dosis subpresora de angiotensina II restauró la respuesta vasopresora inducida por el estrés en las ratas nefrectomizadas. La modulación de los niveles circulantes de angiotensina II alteró la respuesta presora frente al estrés. Así, la reducción de los niveles circulantes de ANG mediante una ingesta elevada de sodio, inhibió la respuesta presora frente al EEP. Por el contrario, el incremento del sistema renina-angiotensina inducido por una dieta baja en sal, facilitó la respuesta presora frente al estrés. Nuestros resultados indican que la angiotensina II endógena soporta la respuesta simpática frente al estrés, a través de la estimulación de los receptores AT1 presinápticos

Angiotensin II supports sympathetically mediated vasopressor response to footshock-stress.

The present study was carried out to assess whether endogenous angiotensin II (Ang II) supports sympathetically mediated cardiovascular response to stress in conscious unrestrained rats, using experimental models in which the renin-angiotensin-system was reduced or blocked. Footshock-stress increased mean arterial pressure (MAP) and heart rate (HR). Inhibition of angiotensin-converting enzyme with captopril or blockade of AT(1)angiotensin receptor with losartan, attenuated vasopressor responses to footshocks, while heart rate response was not altered. Bilateral nephrectomy suppressed vasopressor response as well the elevation of plasma noradrenaline and adrenaline induced by footshocks, and reduced heart rate response. Cardiovascular response to stress in nephrectomised rats was restored by exogenous administration of a subpressor dose of Ang II. Our results demonstrate that in conscious rats cardiovascular response to footshocks is dependent on an active renin-angiotensin system and they indicate that endogenous Ang II supports the sympathetically mediated vasopressor response to footshocks.

Angiotensin II receptor antagonists role in arterial hypertension.

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT(1) receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT(1) receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT(1) receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT(1) receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60-70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT(1) receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.

Role of bradykinins and nitric oxide in the AT2 receptor-mediated hypotension.

Footshocks increases mean arterial pressure and heart rate. Systemic or intracerebroventricular (IVT) administration of losartan, a specific angiotensin AT1 receptor antagonist, not only inhibited the pressor response to footshocks but resulted in vasodepression. Peripheral or IVT administration of PD 123319, a specific angiotensin AT2 receptor antagonist, did not alter the haemodynamic response to footshocks. However, simultaneous blockade of angiotensin AT1 and AT2 receptors by combined systemic or central administration of losartan and PD 12319, eliminated the vasodepressor response to footshocks unmasked in losartan pretreated rats. Our data suggest that activation of peripheral or brain angiotensin AT2 receptor mediated the vasodepressor response to footshocks in the presence of angiotensin AT1 receptor antagonist. We studied the role of kinins and nitric oxide in the vasodepressor response observed after footshocks. The decrease in mean arterial pressure observed after footshocks in losartan treated rats was blunted by systemic or IVT administration of icatibant (HOE 140) or N(G)-nitro-L-arginine-methyl ester, indicating that peripheral or brain kinins and nitric oxide are involved in the hypotensor response to footshocks during angiotensin AT1 receptor blockade. Our results suggest a role for angiotensin AT2 receptor in the regulation of arterial blood pressure, possibly through the release of vasodilator autacoids such as bradykinins and nitric oxide.