Central inhibition of AT(1) receptors by eprosartan - In vitro autoradiography in the brain

All components of the renin-angiotensin system have been demonstrated in th e brain and AT(1) receptors have been localized in brain areas involved in central cardiovascular regulation. It is currently unclear whether AT(1) re ceptor antagonists, which are increasingly used in the treatment of arteria l hypertension and chronic heart failure, have the potential to mediate act ion via the central renin-angiotensin system. Therefore, we tested the in v ivo 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 autor adiography with I-125-(Sar(1)-Ile(8)) angiotensin II as a ligand. Eprosartan significantly increased plasma renin activity by four-fold and s ix-fold at doses of 30 and 60 mg kg(-1), respectively (P < 0.05 vs CTRL). I n 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 a ngiotensin II receptor binding in discrete brain areas, which express exclu sively, 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 bar rier in vivo and selectively inhibits binding to AT(1) receptors in specifi c brain nuclei. The modulation of central regulatory mechanisms might contr ibute to AT(1) receptor antagonists overall therapeutic efficacy in cardiov ascular disease, (C) 2001 Academic Press.