Central inhibition of AT1 receptors by eprosartan -: In vitro autoradiography in the brain

All components of the renin-angiotensin system have been demonstrated in the brain and AT(1) receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT(1) receptor antagonists, which are increasingly used in the treatment of arterial hypertension and chronic heart failure, have the potential to mediate action via the central renin-angiotensin system. Therefore, we tested the in vivo access of the non-peptide AT(1) receptor antagonist, eprosartan (30 and 60 mg per kg of body weight (BW) for 4 weeks, i.p. administered by osmotic minipumps), to angiotensin II receptors in the rat brain by in vitro autoradiography with I-125-(Sar(1)-Ile(8)) angiotensin II as a ligand. Eprosartan significantly increased plasma renin activity by four-fold and six-fold at doses of 30 and 60 mg kg(-1), respectively (P < 0.05 vs CTRL). In the brain, eprosartan produced a dose-dependent inhibition of AT receptor binding in the median cerebral artery (850 +/- 249 and 650 +/- 106 vs 1072 +/- 116 dpm mm(-2) of CTRL: P < 0.05). Furthermore, eprosartan inhibited angiotensin II receptor binding in discrete brain areas, which express exclusively, or predominantly, AT(1) receptors both outside and within the blood-brain barrier, such as the paraventricular nucleus (180 +/- 47 and 130 +/- 18 vs 545 +/- 99 dpm mm(-2) of CTRL, P < 0.05), the subfornical organ (106 +/- 26 and 112 +/- 17 vs 619 +/- 256 dpm mm-2 of CTRL; P < 0.05), and the organum vasculosum laminae terminalis (461 +/- 110 and 763 +/- 136 vs 1033 +/- 123 dpm mm(-2) of CTRL; P < 0.05), These results emphasize that eprosartan readily crosses the blood-brain barrier in vivo and selectively inhibits binding to AT(1) receptors in specific brain nuclei. The modulation of central regulatory mechanisms might contribute to AT(1) receptor antagonists overall therapeutic efficacy in cardiovascular disease, (C) 2001 Academic Press.