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In rats, blockade of the brain renin-angiotensin-aldosterone system prevents sympathetic hyperactivity and markedly attenuates LV dysfunction post-MI. We evaluated whether peripheral administration of an AT(1) receptor blocker has similar effects. In the first experiment, Wistar rats were injected subcutaneously (sc) daily with losartan at a regular or high dose (15 or 100 mg/kg/day) starting 2 days post-MI. At 4 weeks, sympathetic reactivity to air stress was enhanced, baroreflex function was impaired and cardiac function clearly decreased. Increased AT(1) receptor binding densities post-MI were decreased by losartan towards (regular dose) or well below (high dose) levels of sham rats. Losartan at the high dose prevented sympathetic hyperactivity and baroreflex impairment, and lowered LVEDP but further decreased LVPSP and dP/dt(max). In the second experiment, as of 2 days post-MI, losartan (1 mg/kg/day), spironolactone (10 microg/kg/day) or vehicle was infused intracerebroventricularly (i.c.v), or losartan (100 mg/kg/day) was injected sc for 4 weeks. LV dysfunction and increased fibrosis and cardiomyocyte diameter were clearly present at 4 weeks. Icv losartan or spironolactone improved or normalized LV diastolic and systolic function, LV dimensions, fibrosis and myocyte diameter. In contrast, although sc losartan similarly improved fibrosis and LVEDP, again it did not improve LV systolic function. These data indicate that specific central and general AT(1) receptor blockade can similarly improve sympathetic hyperactivity, cardiac fibrosis and LVEDP, but only central blockade improves LV systolic function, possibly due to differences in the extent of blockade of AT(1) receptors in cardiac myocytes and/or peripheral sympathetic nerves.

Chronic subcutaneous infusion of ouabain causes hypertension via central pathways involving angiotensin type 1 (AT(1)) receptor stimulation. The present study assessed plasma and tissue ANG I and II levels as well as AT1 receptor and angiotensin-converting enzyme (ACE) mRNA levels and binding densities by real-time PCR and in vitro autoradiography in relevant brain nuclei and peripheral tissues (heart and kidney) in rats at 1 and/or 2 wk after start of ouabain infusion at 50 microg/day. After 2 wk (but not after 1 wk), blood pressures significantly increased (+15 mmHg). At 2 wk, plasma ANG I and II levels were markedly suppressed by ouabain. In contrast, in the heart and kidneys, ANG I levels were not affected, and ANG II levels tended to decrease, whereas in the hypothalamus ANG II content clearly increased. At 1 wk, no changes in ACE and AT1 receptor densities were seen. After 2 wk, there were significant decreases in AT(1) receptor mRNA and densities in the organum vasculosum of the lamina terminalis (OVLT), subfornical organ (SFO), and paraventricular nucleus (PVN). ACE densities decreased only in the OVLT and SFO, but ACE mRNA showed more variable responses (decrease in OVLT vs. increase in PVN). In the kidneys, at 2 wk both AT1 receptor and ACE densities were decreased, but mRNA abundance did not change. The heart showed no significant changes. The increase in hypothalamic ANG II content and associated decreases in central AT1 receptor and ACE densities support the involvement of the brain renin-angiotensin system in the central hypertensive mechanism of action of ouabain.

After peripheral administration, AT(1) receptor blockers appear to be able to enter the brain and cause AT(1) receptor blockade in the central nervous system. In the current study, we investigated the effects of subcutaneous administration of embusartan versus losartan on inhibition of AT(1) receptor binding in rat brain by in vitro autoradiography. At 4 hours after single doses of 5, 30, or 100 mg/kg, both losartan and embusartan decreased iodine 125I Ang II binding dose dependently in brain structures that express AT(1) receptors both outside (e.g., organum vasculosum laminae terminalis) and within (e.g., paraventricular nucleus) the blood-brain barrier. At low doses, embusartan was twofold more potent than losartan inside but not outside the blood-brain barrier. After chronic treatment (30 mg/kg daily for 6 days), at 4 hours after the last dose, embusartan still caused more inhibition than losartan in the brain structures inside the blood-brain barrier. At 24 hours after the last dose, a modest, better inhibition for embusartan versus losartan remained: from 15% to 33% versus 10% to 24%, respectively. At 36 hours after the last dose, the inhibition for both blockers had almost completely disappeared inside the blood-brain barrier but persisted in, for example, the kidneys. These results demonstrate that-likely because of its high lipophilic character-embusartan appears to penetrate the blood-brain barrier more easily than losartan and therefore causes more effective AT(1) receptor blockade in nuclei within the blood-brain barrier.