Angiotensin-converting enzyme 2 (ACE2) is a newly discovered carboxy-peptidase responsible for the formation of vasodilatory peptides such as angiotensin-(1-7). We hypothesized that ACE2 is part of the brain renin-angiotensin system, and its expression is regulated by the other elements of this system. ACE2 immunostaining was performed in transgenic mouse brain sections from neuron-specific enolase-AT(1A) (overexpressing AT(1A) receptors), R(+)A(+) (overexpressing angiotensinogen and renin), and control (nontransgenic littermates) mice. Results show that ACE2 staining is widely distributed throughout the brain. Using cell-type-specific antibodies, we observed that ACE2 staining is present in the cytoplasm of neuronal cell bodies but not in glial cells. In the subfornical organ, an area lacking the blood-brain barrier and sensitive to blood-borne angiotensin II, ACE2 was significantly increased in transgenic mice. Interestingly, ACE2 mRNA and protein expression were inversely correlated in the nucleus of tractus solitarius/dorsal motor nucleus of the vagus and the ventrolateral medulla, when comparing transgenic to nontransgenic mice. These results suggest that ACE2 is localized to the cytoplasm of neuronal cells in the brain and that ACE2 levels appear highly regulated by other components of the renin-angiotensin system, confirming its involvement in this system. Moreover, ACE2 expression in brain structures involved in the control of cardiovascular function suggests that the carboxypeptidase may have a role in the central regulation of blood pressure and diseases involving the autonomic nervous system, such as hypertension.

Abstract-Angiotensin-converting enzyme 2 (ACE2), a new component of the brain renin-angiotensin system, has been suggested to participate in the central regulation of blood pressure (BP). To clarify the relationship between ACE2 and other brain renin-angiotensin system components, we hypothesized that central angiotensin II type 1 receptors reduce ACE2 expression/activity in hypertensive mice, thereby impairing baroreflex function and promoting hypertension. To test this hypothesis, chronically hypertensive mice (RA) with elevated angiotensin II levels were treated with losartan (angiotensin II type 1 receptor blocker) or PD123319 (angiotensin II type 2 antagonist; 10 mg/kg per day, SC) for 2 weeks. Baseline spontaneous baroreflex sensitivity and brain ACE2 activity were dramatically decreased in RA compared with nontransgenic mice, whereas peripheral ACE2 activity/expression remained unaffected. Losartan, but not PD123319, increased central ACE2 activity, spontaneous baroreflex sensitivity, and normalized BP in RA mice. To confirm the critical role of central ACE2 in BP regulation, we generated a triple-transgenic model with brain ACE2 overexpression on a hypertensive RA background. Triple-transgenic-model mice exhibit lower BP and blunted water intake versus RA, suggesting lower brain angiotensin II levels. Moreover, the impaired spontaneous baroreflex sensitivity, parasympathetic tone, and increased sympathetic drive, observed in RA, were normalized in tripletransgenic-model mice. These data suggest that angiotensin II type 1 receptors inhibit ACE2 activity in RA mice brain, thus contributing to the maintenance of hypertension. In addition, overexpression of ACE2 in the brain reduces hypertension by improving arterial baroreflex and autonomic function. Together, our data suggest that angiotensin II type 1 receptor-mediated ACE2 inhibition impairs baroreflex function and support a critical role for ACE2 in the central regulation of BP and the development of hypertension. Key Words: angiotensin Ⅲ baroreflex Ⅲ blood pressure Ⅲ transgenic mice Ⅲ nervous system I t is well established that tissue renin-angiotensin systems (RASs) play an important role in the regulation of blood pressure (BP), and hyperactivity of these systems results in the development and maintenance of hypertension. 1 Angiotensin (Ang) II, the major actor of the RAS, acts via 2 receptor subtypes: Ang II type 1 (AT 1 R) and type 2 (AT 2 R) receptors. Activation of AT 1 R leads to elevated BP through vasoconstriction, increased cardiac output, aldosterone release, and sodium reabsorption. In addition to these peripheral effects, AT 1 R also mediates the central effects of Ang II, including vasopressin release, water and salt intakes, and increased sympathetic drive, contributing to the development of high BP. However, Ang II binding to the AT 2 R is thought to counteract the AT 1 R-mediated effects. 2,3 In the brain, AT 2 R overexpression has been reported to decrease nocturnal BP and norepinephrine excretion partially by reducing sympathetic ou...

The oral administration of 3% hydrogen peroxide solution in cats can result in necroulcerative gastritis as a possible sequel. While hydrogen peroxide is considered a safe emetic agent in dogs, its use in cats is not recommended. As a result, the use of emetic agents in cats should be limited to veterinary administration, using alternative, safer emetic agents such as alpha-adrenergic agonists.

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