Jean-Marc Chillon

Effects of Endothelin Receptor Inhibition on Cerebral Arterioles in Hypertensive Rats

The purpose of this study was to examine the effects of endothelin receptor inhibition on cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP). Structure and mechanics of cerebral arterioles were examined in untreated Wistar-Kyoto rats (WKY) and SHRSP that were either untreated or treated for 3 months with bosentan, an inhibitor of endothelin receptors (100 mg/kg per day). We measured pressure, external diameter, and cross-sectional area of the vessel wall (histologically) in maximally dilated (EDTA) arterioles on the cerebrum. Bosentan reduced but did not normalize arteriolar mean pressure (103 +/- 3 and 81 +/- 5 mm Hg in untreated and treated SHRSP versus 51 +/- 4 mm Hg in WKY, P < .05; mean +/- SEM) and pulse pressure (40 +/- 2 and 33 +/- 2 mm Hg in untreated and treated SHRSP versus 25 +/- 3 mm Hg in WKY, P < .05) in SHRSP. Cross-sectional area of the vessel wall (CSA) was increased in untreated SHRSP (1627 +/- 173 microm2), and CSA in treated SHRSP (1287 +/- 78 microm2) was similar to that in WKY (1299 +/- 65 microm2). Bosentan had no effect on reductions in external diameter (remodeling) of cerebral arterioles (104 +/- 7 and 96 +/- 4 microm in untreated and treated SHRSP compared with 126 +/- 7 microm in WKY, P < .05). Stress-strain curves indicate that bosentan had no significant effect on distensibility of arterioles on the cerebrum in SHRSP. The results suggest that endothelin-1 may contribute to the development of hypertrophy, but not remodeling or changes in distensibility, of cerebral arterioles in SHRSP.

Effects of an Angiotensin-Converting Enzyme Inhibitor and a β-Blocker on Cerebral Arterioles in Rats

We examined the effects of an angiotensin-converting enzyme inhibitor, perindopril, and a beta-blocker, propranolol, on cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP). The structure and mechanics of cerebral arterioles were examined in untreated Wistar-Kyoto rats (WKY) and SHRSP that were untreated or treated for 3 months with a high (2 mg/kg per day) or a low (0.3 mg/kg per day) dose of perindopril or propranolol (250 mg/kg per day) alone or in combination with the low dose of perindopril. We measured pressure, external diameter, and cross-sectional area of the vessel wall (CSA) in maximally dilated (with EDTA) cerebral arterioles. Treatment of SHRSP with the high dose of perindopril or the combination of propranolol and the low dose of perindopril normalized cerebral arteriolar mean pressure (50+/-1 [mean+/-SEM] and 43+/-2 mm Hg vs 50+/-1 mm Hg in WKY and 94+/-3 mm Hg in untreated SHRSP; P<0.05), pulse pressure (15+/-1 and 16+/-1 mm Hg vs 13+/-1 mm Hg in WKY and 35+/-1 mm Hg in untreated SHRSP; P<0.05), and CSA (1103+/-53 and 1099+/-51 microm2, respectively, vs 1057+/-49 microm2 in WKY and 1281+/-62 microm2 in untreated SHRSP; P<0.05). In contrast, treatment of SHRSP with the low dose of perindopril or propranolol alone did not normalize arteriolar pulse pressure (24+/-1 and 21+/-1 mm Hg) and failed to prevent increases in CSA (1282+/-77 and 1267+/-94 microm2). Treatment with either dose of perindopril or the combination of propranolol and perindopril significantly increased external diameter in cerebral arterioles of SHRSP (99+/-3, 103+/-2, and 98+/-3 microm vs 87+/-2 microm in untreated SHRSP; P<0.05), whereas propranolol alone did not (94+/-3 microm; P>0.05). These findings suggest that effects of angiotensin-converting enzyme inhibitors on cerebral arteriolar hypertrophy in SHRSP may depend primarily on their effects on arterial pressure, particularly pulse pressure, whereas their effects on cerebral arteriolar remodeling (defined as a reduction in external diameter) may be pressure independent.

Comparative effects of the angiotensin II receptor blocker, telmisartan, and the angiotensin-converting enzyme inhibitor, ramipril, on cerebrovascular structure in spontaneously hypertensive rats.

Objective 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. Design 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). Methods 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. Results 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). Conclusion 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.

Effects of an Angiotensin-Converting Enzyme Inhibitor and a β-Blocker on Cerebral Arteriolar Dilatation in Hypertensive Rats

Abstract—We examined the effects of the angiotensin-converting enzyme inhibitor perindopril and the &bgr;-blocker propranolol on dilator responses of cerebral arterioles in chronic hypertension. Dilator responses to acute hypotension were examined in untreated Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) that were untreated or treated for 3 months with a low (0.3 mg · kg−1 · day−1) or a high (2 mg · kg−1 · day−1) dose of perindopril or a dose of propranolol (250 mg · kg−1 · day−1) alone or in combination with the low dose of perindopril. Pressure (servo-null) and diameter were measured in cerebral arterioles during acute reductions in arterial pressure both before and during maximal dilatation (EDTA). The high dose of perindopril or the combination of propranolol and perindopril normalized cerebral arteriolar pressure (52±2 [mean±SEM], 49±2 mm Hg versus 50±2 mm Hg in WKY and 96±3 mm Hg in untreated SHRSP;P <0.05). In contrast, the low dose of perindopril or propranolol alone did not normalize arteriolar pressure (74±2 mm Hg and 58±3 mm Hg). Both the low and high doses of perindopril improved autoregulatory dilatation, maximal dilatation, and dilator reserve of cerebral arterioles in SHRSP, with the low dose of perindopril being almost as effective as the high dose of perindopril. Propranolol alone did not significantly improve dilator function of cerebral arterioles. Furthermore, dilator function of cerebral arterioles was not further improved by the addition of propranolol to the low dose of perindopril. These findings suggest that angiotensin-converting enzyme inhibitors, such as perindopril, may be more effective than propranolol in attenuating the impairment of cerebral autoregulatory vasodilatation, maximal dilatation, and dilator reserve during treatment of chronic hypertension.

Effects of Chronic Nitric Oxide Synthase Inhibition on Cerebral Arterioles in Rats

We examined the effects of nitric oxide (NO) synthase inhibition on the structure and mechanics of cerebral arterioles. We measured pressure, diameter, and cross-sectional area of the vessel wall (histologically) in maximally dilated cerebral arterioles in Sprague-Dawley rats that were untreated or treated for 3 months with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg per day). Treatment with L-NAME increased cerebral arteriolar mean (87+/-6 versus 42+/-2 mm Hg, P<.05) and pulse (25+/-2 versus 13+/-2 mm Hg, P<.05) pressures, as well as cross-sectional area of the vessel wall (1839+/-70 versus 1019+/-58 microm2, P<.05) and external diameter (101+/-4 versus 87+/-2 microm, P<.05). These findings suggest that hypertension induced by NO synthase inhibition is accompanied by hypertrophy of the vessel wall and enlargement of cerebral arterioles in rats. To determine the role of cerebral arteriolar pulse pressure in hypertrophy of cerebral arterioles during inhibition of NO synthase, we measured the cross-sectional area of the vessel wall in rats treated with L-NAME that underwent unilateral carotid clipping. Unilateral carotid clipping failed to prevent increases in cross-sectional area of the vessel wall (1507+/-173 and 1613+/-148 microm2 in the clip and sham sides, respectively) in rats treated with L-NAME, even though increases in pulse pressure were prevented (16+/-1 and 27+/-1 mm Hg in the clip and sham sides, respectively, P<.05). These findings suggest that inhibition of NO synthase may promote hypertrophy of cerebral arterioles independently of increases in arteriolar pulse pressure.

Presence of Intracranial Artery Calcification Is Associated With Mortality and Vascular Events in Patients With Ischemic Stroke After Hospital Discharge A Cohort Study

Background and Purpose— Although intracranial artery calcification (IAC) has been reported to be a risk factor for ischemic stroke, the prognostic implications of IAC in stroke outcome are unknown. The purpose of this study was to determine the association between IAC and risk of vascular events and death in patients with stroke after hospital discharge. Methods— All patients with ischemic stroke over a 1-year period were included (n=302). IAC, assessed by multidetector CT, was defined as hyperdense foci (peak density >130 Hounsfield units) and assessed in the 7 major cerebral arteries. The IAC scores ranged from 0 (no calcification) to 7. Follow-up information on major clinical events (including fatal or nonfatal ischemic stroke, cardiac and peripheral artery events, and all-cause death) was obtained by means of a structured phone interview. Results— IAC was present in 260 patients (83%). With a mean follow-up of 773±223 days, 88 major clinical events occurred in 67 patients (22%): 45 new ischemic vascular events (ischemic stroke: n=22; cardiac event: n=15; peripheral artery event: n=8) and 43 deaths from any cause. Patients with the highest IAC scores had significantly higher rates of death and vascular events than those with the lowest IAC scores (log rank test, P=0.029). In the Cox proportional hazards regression model, the IAC score was significantly associated with major clinical events (hazard ratio, 1.34; 95% CI, 1.11–1.61; P=0.002). Conclusions— In patients with ischemic stroke, IAC detection may constitute a simple marker of a high risk of future major clinical events.

Constrictor and Dilator Effects of Angiotensin II on Cerebral Arterioles

Background and Purpose— In light of the equivocal data on the cerebral vasoconstrictor and vasodilator actions of angiotensin II (Ang II) and the potential clinical importance of this, we investigated the effects of Ang II on rat pial arterioles. Methods— We determined the effect of Ang I (3.10−6 mol/L) in the absence and presence of the converting enzyme inhibitor, captopril (10−5 mol/L) in cerebral arterioles of male Wistar rats (open-skull preparation), and those of Ang II (3.10−12 to 3.10−6 mol/L) in the absence and presence of the Ang II receptor (AT1) antagonist, telmisartan (10−5 mol/L) or the AT2 antagonist, PD123319 (10−5 mol/L). We examined the effect of PD123319 (10−5 mol/L) and the Ca2+-activated K+ (BKCa) channel blocker, tetraethylammonium (10−4 mol/L) on the Ang II responses in the presence of telmisartan (10−5 mol/L). Results— Ang II-induced dose-dependent constriction with a maximum decrease of −20.1±1.0% at 10−6 mol/L. Captopril significantly decreased Ang I-induced vasoconstriction (−4.0±0.9 versus −21.3±2.5%; n=4). Telmisartan reversed Ang II-induced vasoconstriction (9.5±2.5 versus −20.1±1% at 10−6 mol/L; n=5). PD123319 significantly increased Ang II-induced vasoconstriction (−12.9±0.8 versus −10.2±0.4% at 10−6 mol/L; n=5). PD123319 abolished (−2.6±0.7 versus 9.3±1.1% at 10−6 mol/L; n=5) whereas tetraethylammonium reversed (−12.1±1.6 versus 9.9±1.0% at 10−6 mol/L; n=4) Ang II-induced vasodilatation in the presence of telmisartan. Conclusion— Angiotensin is converted locally into Ang II; the overall effect of Ang II is vasoconstrictor following stimulation of the AT1 receptor, but a vasodilator response can be evoked following stimulation of the AT2 receptor and activation of BKCa.

Captopril improves cerebrovascular structure and function in old hypertensive rats

1 We examined the effects of an angiotensin‐converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR). 2 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. 3 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). 4 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. 5 Thus, ACEIs attenuate eutrophic and hypertrophic inward remodeling of cerebral arterioles in young and old SHR, thus decreasing the lower limit of CBF autoregulation.

Chronic renal failure alters endothelial function in cerebral circulation in mice

We examined structure, composition, and endothelial function in cerebral arterioles after 4 wk of chronic renal failure (CRF) in a well-defined murine model (C57BL/6J and apolipoprotein E knockout female mice). We also determined quantitative expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (on serine 1177 and threonine 495), and caveolin-1; quantitative expression of markers of vascular inflammation or oxidative stress [Rock-1, Rock-2, VCAM-1, and peroxisome proliferator-activated receptor-γ (PPARγ)]; and the plasma concentration of L-arginine and asymmetric dimethylarginine (ADMA). Our hypothesis was that endothelial function would be impaired in cerebral arterioles during CRF following either a decrease in NO production (through alteration of eNOS expression or regulation) or an increase in NO degradation (due to oxidative stress or vascular inflammation). Endothelium-dependent relaxation was impaired during CRF, but endothelium-independent relaxation was not. CRF had no effect on cerebral arteriolar structure and composition. Quantitative expressions of eNOS, eNOS phosphorylated on serine 1177, caveolin-1, Rock-1, Rock-2, and VCAM-1 were similar in CRF and non-CRF mice. In contrast, quantitative expression of PPARγ (which exercises a protective role on blood vessels) was significantly lower in CRF mice, whereas quantitative expression of eNOS phosphorylated on the threonine 495 (the inactive form of eNOS) was significantly higher. Lastly, the plasma concentration of ADMA (a uremic toxin and an endogenous inhibitor of eNOS) was elevated and plasma concentration of L-arginine was low in CRF. In conclusion, endothelial function is impaired in a mouse model of early stage CRF. These alterations may be related (at least in part) to a decrease in NO production.

Effects of Indapamide, a Thiazide-Like Diuretic, on Structure of Cerebral Arterioles in Hypertensive Rats

Abstract—We examined the effects of indapamide, a thiazide-like diuretic, on cerebral arterioles in spontaneously hypertensive rats (SHR). The structure and mechanics of cerebral arterioles were examined in untreated Wistar Kyoto rats (WKY) and SHR that were untreated or treated for 3 months with a low (1 mg/kg per day) or a high (10 mg/kg per day) dose of indapamide. We measured pressure, diameter, and cross-sectional area of the vessel wall (CSA) in maximally-dilated (EDTA) cerebral arterioles. Treatment of SHR with the high dose of indapamide normalized cerebral arteriolar mean pressure (62±4 [mean±SEM] versus 59±3 mm Hg in WKY and 88±6 mm Hg in untreated SHR; P <0.05), pulse pressure (13±1 versus 10±1 mm Hg in WKY and 20±1 mm Hg in untreated SHR; P <0.05), and CSA (1080±91 versus 1100±48 μm2 in WKY and 1439±40 μm2 in untreated SHR; P <0.05). In contrast, treatment of SHR with the low dose of indapamide did not normalize arteriolar mean (72±3) and pulse pressure (20±1 mm Hg), but did normalize CSA (1091±52 μm2). Treatment with either dose of indapamide failed to increase external diameter in cerebral arterioles of SHR (89±4 and 92±4 μm, respectively, versus 103±6 μm in WKY and 87±4 μm in untreated SHR). Finally, treatment with indapamide attenuated the rightward shift of the stress-strain curve in SHR, suggesting that treatment with indapamide attenuated increases in distensibility of cerebral arterioles in SHR. These findings suggest that, whereas thiazide-like diuretics may not attenuate eutrophic inward remodeling of cerebral arterioles in SHR, they may attenuate hypertrophic inward remodeling via a mechanism unrelated to their pressor effects.