Antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEIs) reverses cerebral arteriolar remodeling, thus restoring dilatation and hence the lower limit of cerebral blood flow (CBF) autoregulation (LLCBF). The objective of this study was to determine whether angiotensin II receptor AT1 blockers (ARBs) produce the same effect. We examined the effects of treatment with an ARB [telmisartan (TEL), 1.93 ± 0.04 mg/kg per day] or an ACEI [ramipril (RAM), 1.00 ± 0.02 mg/kg per day] on the cerebral circulation in spontaneously hypertensive rats (SHR). Arteriolar pressure and diameter (cranial window) and CBF (laser Doppler) were measured during stepwise hypotensive hemorrhage, before and after deactivation (ethylenediamine tetraacetic acid), in untreated Wistar–Kyoto (WKY) rats and SHR untreated or treated for 3 months with TEL or RAM in the drinking water. Treatment normalized arteriolar internal diameter (SHR, 38 ± 3 μm; TEL, 52 ± 2 μm; RAM, 50 ± 2 μm; WKY, 58 ± 4 μm), essentially by reversing eutrophic inward remodeling, and the LLCBF (SHR, 80 ± 11 mmHg; TEL, 60 ± 4 mmHg; RAM, 71 ± 6 mmHg; WKY, 57 ± 5 mmHg). The fact that the ARB (TEL) is as effective as an ACEI (RAM) in reversing cerebral arteriolar remodeling suggests that the cerebrovascular AT1 receptor is an underlying mechanism that promotes hypertensive eutrophic inward remodeling.

The AT₁ receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT₂ receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT₁ receptor. The discovery of a local RAS has highlighted the importance of the balance between AT₁/AT₂ receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT₁ receptor, homo- and heterodimerization, and the use of AT₁ receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT₁/AT₂ equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT₁ and AT₂ receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives.

We examined the effects of an angiotensin‐converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR). Animals were anesthetized with sodium pentobarbitone (60 mg kg⁻¹ day⁻¹). We measured cerebral blood flow (CBF, arbitrary units) and cerebral arteriolar internal diameter (ID, μm) prior to and during stepwise hypotension (SH) in 6‐ (WKY‐6) and 15‐month‐old (WKY‐15) Wistar Kyoto rats and in age‐matched SHR that were untreated (SHR‐6 and SHR‐15) or treated for 3 months with captopril (SHR‐6C, 105±2 mg kg⁻¹ day⁻¹ and SHR‐15C, 94±1 mg kg⁻¹ day⁻¹). ID and cross‐sectional area of the vessel wall (CSA) were measured in deactivated (EDTA) cerebral arterioles during a second SH. Captopril decreased the lower limit of CBF autoregulation (61±6 in SHR‐6C and 51±2 in SHR‐15C versus 52±6 in WKY‐6 and 62±7 in WKY‐15 and 83±14 mmHg in SHR‐6 and 120±19 mmHg in SHR‐15; P<0.05) and CSA (510±21 in SHR‐6C and 585±25 in SHR‐15C versus 529±12 in WKY‐6 and 549±20 in WKY‐15 and 644±38 mmHg in SHR‐6 and 704±38 mmHg in SHR‐15; P<0.05). Captopril increased cerebral arteriolar external diameter of SHR (105±5 in SHR‐6C and 94±4 in SHR‐15C vs 125±8 in WKY‐6 and 108±3 in WKY‐15 and 83±2 mmHg in SHR‐6 and 80±2 mmHg in SHR‐15 for a pial arteriolar pressure step of 35–39 mmHg; P<0.05). Captopril attenuated increases in cerebral arteriolar distensibility in young SHR. Thus, ACEIs attenuate eutrophic and hypertrophic inward remodeling of cerebral arterioles in young and old SHR, thus decreasing the lower limit of CBF autoregulation. British Journal of Pharmacology (2005) 144, 349–356. doi:10.1038/sj.bjp.0706001

Treatment of stroke, especially during the first hours or days, is still lacking. S-nitrosoglutathione (GSNO), a cerebroprotective agent with short life time, may help if administered early with a sustain delivery while avoiding intensive reduction in blood pressure. We developed in situ forming implants (biocompatible biodegradable copolymer) and microparticles (same polymer and solvent emulsified with an external oily phase) of GSNO to lengthen its effects and allow cerebroprotection after a single subcutaneous administration to Wistar rats. Arterial pressure was recorded for 3 days (telemetry, n = 14), whole-blood platelet aggregation up to 13 days (aggregometry, n = 58), and neurological score, cerebral infarct size and edema volume for 2 days after obstruction of the middle cerebral artery by autologous blood clots (n = 30). GSNO-loaded formulations (30 mg/kg) induced a slighter and longer hypotension (-10 vs. -56 ± 6 mmHg mean arterial pressure, 18 h vs. 40 min) than free GSNO at the same dose. The change in pulse pressure (-50%) lasted even up to 42 h for microparticles. GSNO-loaded formulations (30 mg/kg) prevented the transient 24 h hyper-aggregability observed with free GSNO and 7.5 mg/kg-loaded formulations. When injected 2 h after stroke, GSNO-loaded microparticles (30 mg/kg) reduced neurological score at 24 (-62%) and 48 h (-75%) vs. empty microparticles and free GSNO 7.5 mg/kg and, compared to free GSNO, divided infarct size by 10 and edema volume by 8 at 48 h. Corresponding implants reduced infarct size and edema volume by 2.5 to 3 times. The longer (at least 2 days) but slight effects on arterial pressures show sustained delivery of GSNO-loaded formulations (30 mg/kg), which prevent transient platelet hyper-responsiveness and afford cerebroprotection against the consequences of stroke. In conclusion, in situ GSNO-loaded formulations are promising candidates for the treatment of stroke.

Antihypertensive treatment with standard clinical doses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) reverses cerebral arteriolar remodeling, thus restoring dilatation and the lower limit of cerebral blood flow (CBF) autoregulation (LL CBF AR). In humans, a combination of standard clinical doses of the two drugs does not produce greater protection against stroke than that obtained with single-drug treatments and increases the risk of side-effects. We hypothesized that a combination of suboptimal doses of the ARB, telmisartan (TEL) and of the ACEI, ramipril (RAM), could be a well tolerated and effective treatment of hypertension-induced remodeling of cerebral arterioles. We studied the impact of 3-month oral treatment with TEL (0.5 or 0.8 mg/kg per day) or RAM (0.1 or 0.25 mg/kg per day) alone or in combination (TEL0.8 + RAM0.1 or TEL0.5 + RAM0.25) on the cerebral circulation of the spontaneously hypertensive rats (SHRs). Normotensive Wistar–Kyoto rats (WKYs) were taken as controls. Cerebral arteriolar pressure, CBF and internal diameter were measured via an open-skull preparation at baseline and during hypotension before and after deactivation (EDTA). Combinations normalized cerebral arteriolar pressure, whereas drugs alone had no significant impact. TEL0.8 + RAM0.1 showed the greatest effect on arteriolar internal diameter (SHRs 42 ± 16, WKYs 59 ± 16 μm, TEL0.5 + RAM0.25 50 ± 6, TEL0.8 + RAM0.1 62 ± 18, P < 0.05) and normalized LL CBF AR (SHRs 77 ± 28, WKYs 53 ± 17 mmHg, TEL0.8 + RAM0.1 50 ± 10, P < 0.05). The combination of suboptimal doses of TEL and RAM with an 8: 1 ratio has the greatest effect on cerebral circulation and could represent well tolerated and efficient treatment of cerebral ischemia and stroke.