AT 1 Receptors in the Subfornical Organ Modulate Arterial Pressure and the Baroreflex In Two-kidney One-clip Hypertensive Rats.

The subfornical organ (SFO), a forebrain circumventricular organ that lies outside the blood brain barrier, has been implicated in arterial pressure and baroreflex responses to angiotensin II (Ang II). We tested whether pharmacologic inhibition or selective silencing of SFO AT1 receptors (AT1 R) of two-kidney one-clip rats with elevated plasma Ang II decreases resting arterial pressure and renal sympathetic nerve activity (RSNA) and/or modulates arterial baroreflex responses of heart rate and RSNA. Male Sprague Dawley rats underwent renal artery clipping (2K-1C) or sham-clipping (Sham). Six weeks later, conscious rats instrumented with vascular catheters, renal nerve electrodes and a cannula directed to SFO were studied. Another set of experiments in rats equipped with hemodynamic and nerve radio-transmitters underwent injection of either scrambled RNA or siRNA targeted against AT1 R. MAP was significantly higher in 2K-1C rats. Acute SFO injection with the AT1 R inhibitor losartan did not change MAP in Sham or 2K-1C rats. Baroreflex curves of heart rate and RSNA were shifted rightward in 2K-1C rats. Losartan exerted no effect. SFO AT1 R knockdown did not influence MAP in Sham, but decreased MAP in 2K-1C rats despite no change in plasma Ang II or resting RSNA. AT1 R knockdown prevented the reduction in maximum gain and slope of baroreflex responses of heart rate and RSNA; the reduced RSNA response to baroreceptor unloading was partially restored by 2K-1C rats. These findings show AT1 R activation within the SFO contributes to hypertension and baroreflex dysfunction in 2K-1C rats and highlights the temporal requirement for reversal of these effects.