Properties of angiotensin-converting enzyme in intact cerebral microvessels.

Brecher, Peter; Tercyak, Anna M.; Chobanian, Aram V.

doi:10.1161/01.hyp.3.2.198

Cited by 35 publications

(10 citation statements)

References 26 publications

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“…19 Studies of the effect of ACE inhibition in healthy volunteers have shown reductions in blood pressure with increased cerebral blood flow. 20 These findings are supported by the recognized pressor effects of angiotensin II in the cerebral vasculature of experimental animals 21 and suggest that ACE inhibitors exert a more marked vasodilatory effect in the cerebral circulation compared with other vascular beds. This is the first study to demonstrate the effect of ACE inhibition on cerebral vasomotor reactivity in patients with cerebrovascular disease.…”

Section: Discussionmentioning

confidence: 76%

Effect of Perindopril on Cerebral Vasomotor Reactivity in Patients With Lacunar Infarction

Walters

Muir

Shah

et al. 2004

Stroke

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Background and Purpose-There is growing evidence that pharmacologic interference with the renin-angiotensin system may reduce risk of stroke, although the mechanism is unclear. Impaired reactivity of cerebral vessels has recently been recognized as a risk factor for stroke. We examined the effect of the angiotensin-converting enzyme (ACE) inhibitor perindopril on cerebral vasomotor reactivity to acetazolamide in patients with lacunar cerebral infarction. Methods-We studied a cohort of male patients between 3 and 12 months after lacunar infarction confirmed on computed tomography. Each patient received perindopril 4 mg daily or matching placebo for 2 weeks in a randomized, double-blind, placebo-controlled crossover fashion. A 1-week washout period was observed between dosing periods. Cerebral vasomotor reactivity (increase in middle cerebral artery mean flow velocity in response to intravenous injection of 15 mg/kg acetazolamide) was measured before and after each dosing period using standard Doppler ultrasound techniques. Results-Twelve patients (mean age 63.2Ϯ2.3 years) completed the protocol. There was no treatment order effect.Cerebral vasomotor reactivity was significantly greater after perindopril treatment (percent change from baseline ϩ18.8Ϯ10.1% after perindopril, Ϫ4.6Ϯ4.1% after placebo; Pϭ0.032). Dosing with perindopril did not affect resting cerebral blood flow velocity (percent change from baseline ϩ3.1Ϯ9.5% after perindopril, Ϫ0.6Ϯ5.4% after placebo), nor was there a change in resting blood pressure (ϩ1.8 mm HgϮ3.1 after perindopril, ϩ1.4 mm HgϮ2.5 after placebo). Conclusions-This study provides evidence of a significant improvement in cerebral vasomotor reactivity induced by perindopril, beyond any effect on blood pressure. The results suggest a possible mechanism for the beneficial effect of ACE inhibition on stroke risk observed in recent clinical trials, and suggest a role for the renin-angiotensin axis in the pathophysiology of subcortical small vessel disease.

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Section: Discussionmentioning

confidence: 76%

Effect of Perindopril on Cerebral Vasomotor Reactivity in Patients With Lacunar Infarction

Walters

Muir

Shah

et al. 2004

Stroke

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“…Ang II modulates blood flow to peripheral tissues and increases systemic blood pressure by AT 1 receptor stimulation in peripheral arteries followed by vasoconstriction (Timmermans et al, 1995). In the brain, circulating or locally formed Ang II, through AT 1 and perhaps AT 2 (Tsutsumi and Saavedra, 1991c) receptor stimulation in cerebral vessels and sympathetic nerves, exerts a profound influence in the control of cerebrovascular flow (Edvinsson, 1975;Edvinsson et al, 1979;Brecher et al, 1981;Speth and Harik, 1985;Tsutsumi and Saavedra, 1991c;Saavedra and Nishimura, 1999). In the spontaneously hypertensive rats (SHR) both the brain Ang II and sympathetic systems are stimulated (Saavedra, 1992).…”

Section: Novel Central Functions Of Angiotensin IImentioning

confidence: 99%

Brain Angiotensin II: New Developments, Unanswered Questions and Therapeutic Opportunities

2005

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1. There are two Angiotensin II systems in the brain. The discovery of brain Angiotensin II receptors located in neurons inside the blood brain barrier confirmed the existence of an endogenous brain Angiotensin II system, responding to Angiotensin II generated in and/or transported into the brain. In addition, Angiotensin II receptors in circumventricular organs and in cerebrovascular endothelial cells respond to circulating Angiotensin II of peripheral origin. Thus, the brain responds to both circulating and tissue Angiotensin II, and the two systems are integrated. 2. The neuroanatomical location of Angiotensin II receptors and the regulation of the receptor number are most important to determine the level of activation of the brain Angiotensin II systems. 3. Classical, well-defined actions of Angiotensin II in the brain include the regulation of hormone formation and release, the control of the central and peripheral sympathoadrenal systems, and the regulation of water and sodium intake. As a consequence of changes in the hormone, sympathetic and electrolyte systems, feed back mechanisms in turn modulate the activity of the brain Angiotensin II systems. It is reasonable to hypothesize that brain Angiotensin II is involved in the regulation of multiple additional functions in the brain, including brain development, neuronal migration, process of sensory information, cognition, regulation of emotional responses, and cerebral blood flow. 4. Many of the classical and of the hypothetical functions of brain Angiotensin II are mediated by stimulation of Angiotensin II AT1 receptors. 5. Brain AT2 receptors are highly expressed during development. In the adult, AT2 receptors are restricted to areas predominantly involved in the process of sensory information. However, the role of AT2 receptors remains to be clarified. 6. Subcutaneous or oral administration of a selective and potent non-peptidic AT1 receptor antagonist with very low affinity for AT2 receptors and good bioavailability blocked AT1 receptors not only outside but also inside the blood brain barrier. The blockade of the complete brain Angiotensin II AT1 system allowed us to further clarify some of the central actions of the peptide and suggested some new potential therapeutic avenues for this class of compounds. 7. Pretreatment with peripherally administered AT1 antagonists completely prevented the hormonal and sympathoadrenal response to isolation stress. A similar pretreatment prevented the development of stress-induced gastric ulcers. These findings strongly suggest that blockade of brain AT1 receptors could be considered as a novel therapeutic approach in the treatment of stress-related disorders. 8. Peripheral administration of AT1 receptor antagonists strongly affected brain circulation and normalized some of the profound alterations in cerebrovascular structure and function characteristic of chronic genetic hypertension. AT1 receptor antagonists were capable of reversing the pathological cerebrovascular remodeling in hypertension and the shift to the ...

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“…Ang II receptors and angiotensin-converting enzyme (ACE) are present in cerebral microvessels and large cerebral arteries. [1][2][3][4] The brain autoregulates the levels of cerebral blood flow within normal limits by compensating alterations in the calibre of large and of resistance cerebral vessels in response to changes in systemic BP. 5 Resistance arteries have a higher potential vasodilatory capacity during decreases in BP, and a lower vasoconstricting capacity during increases in BP.…”

Section: Introductionmentioning

confidence: 99%

Pre-treatment with candesartan protects from cerebral ischaemia

Ito

Nishimura

Saavedra

2001

J Renin Angiotensin Aldosterone Syst

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Angiotensin II (Ang II) regulates cerebral blood flow by stimulating cerebral vasoconstriction via AT1-receptors. In adult spontaneously hypertensive rats (SHR), the cerebrovascular autoregulatory curve is shifted to the right, in the direction of higher blood pressures, an indication of excessive cerebrovascular vasoconstriction. A restricted capacity to dilate cerebral blood vessels may be responsible for the enhanced vulnerability to cerebrovascular ischaemia during hypertension. We found that chronic treatment with the AT1-receptor antagonist, candesartan, (0.5 mg/kg/day for 14 days, via osmotic minipumps implanted in the subcutaneous tissue) blocked Ang II binding to AT1-receptors in cerebral blood vessels and in brain areas involved in the regulation of cerebrovascular flow, and increased the ratio of lumen-wall area in the middle cerebral artery. Candesartan treatment normalised the lower part of the autoregulatory curve in SHR, and markedly decreased cerebral ischaemia as a consequence of middle cerebral artery occlusion with reperfusion. Protection from ischaemia is related to arterial remodelling, enhanced compensatory vasodilatation in the peripheral area of ischaemia, decreased reduction in cerebral blood flow following the occlusion of a major cerebral blood vessel, and protection from injury in the periphery of the lesion. Our results indicate that pre-treatment with AT1-antagonists such as candesartan could be of benefit in the prevention and treatment of brain ischaemia.

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Properties of angiotensin-converting enzyme in intact cerebral microvessels.

Cited by 35 publications

References 26 publications

Effect of Perindopril on Cerebral Vasomotor Reactivity in Patients With Lacunar Infarction

Effect of Perindopril on Cerebral Vasomotor Reactivity in Patients With Lacunar Infarction

Brain Angiotensin II: New Developments, Unanswered Questions and Therapeutic Opportunities

Pre-treatment with candesartan protects from cerebral ischaemia

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