Abstract 305: Activation of Central Angiotensin II type 2 Receptors Attenuates Neurogenic Hypertension.

Abstract

Aim: The role of the angiotensin II type-2 receptor (AT2R) in hypertension is under debate and the expression can be modulated in different pathological states. In hypertension AT2R are upregulated, therefore we hypothesize that central AT2R stimulation will lower blood pressure in conscious spontaneously hypertensive rats (SHR). Methods: SHR were implanted with a radio-telemetry device and an icv cannula connected to a miniosmotic pump delivering saline vehicle, AT2R agonist Compound 21 (C21) (0.002μg/μl/hr) alone or in combination with AT2R antagonist PD123319. MAP was assessed for 21 days: 7 days baseline (saline), 14 days treatment (e.g. C21). To assess the role of the angiotensin II type-1 receptor (AT1R) and NO in these responses, AT1R blocker losartan or NO synthase inhibitor L-NAME were administered centrally with C21. (n=5-7/group). Results: Icv C21-infusion blocked the increase in MAP seen in the vehicle group (MAP (mmHg): baseline: vehicle 153±5 vs C21 157±4; day 21 (D21): vehicle 164±5 vs C21 155±5;p<0.05). PD123319 abolished this blood pressure lowering effect (MAP (mmHg): baseline 154±5; D21 163±5;p<0.05). Co-infusion of C21 and losartan did not reinforce the MAP lowering effect seen with C21 alone (MAP (mmHg): baseline 157±2; D21 153±1;p<0.05). Simultaneous L-NAME administration abolished the effects of C21 (MAP (mmHg): baseline 156±4; D21 190±5;p<0.05). Mechanistically, an improved parasympathetic control of HR was seen in the C21-treated group (change in HR after i.p. propranolol (bpm): vehicle -68.2±2.4 vs C21 -36.3±4.1;p<0.05). Impaired baroreflex sensitivity (BRS) also improved under C21-infusion (BRS (ms/mmHg) D21: vehicle 1.81±0.16 vs C21 3.15±0.07;p<0.05) Conclusion: Selective central AT2R stimulation with C21 attenuates hypertension and corrects autonomic dysfunction in SHR. These effects are mediated through a NO-dependent mechanism. In contrast to an enhanced peripheral AT2R effect following AT1R blockade, concomitant central AT1R blockade did not enhance these responses to central AT2R stimulation. These findings suggest activation of the central AT2R represent a possible new therapeutic target for the treatment of neurogenic hypertension.