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Increased brain angiotensin receptor in rats with chronic high-output heart failure
R Yoshimura1, T Sato, T Kawada
1Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Insights
Chronic heart failure (CHF) activates the brain renin-angiotensin system (RAS). Angiotensin II receptor type 1 (AT1) expression increases in key brain areas, suggesting the brain is a therapeutic target for CHF treatments.
Area of Science:
- Cardiovascular Physiology
- Neuroendocrinology
- Renal Physiology
Background:
- The renin-angiotensin system (RAS) is crucial in chronic heart failure (CHF) pathophysiology.
- Previous studies in rats showed CHF enhances thirst responses to central angiotensin I.
- Central angiotensin-converting enzyme (ACE) inhibition prevented cardiac hypertrophy in CHF, suggesting brain RAS activation.
Purpose of the Study:
- To investigate the mechanism of central RAS activation in rats with CHF.
- To examine the expression of brain ACE and angiotensin receptors (AT) in a rat model of CHF.
Main Methods:
- High-output heart failure was induced in Sprague-Dawley rats via aortocaval shunt.
- ACE mRNA levels were quantified using reverse transcriptase polymerase chain reaction (RT-PCR).
- Angiotensin receptor (AT) binding densities were assessed using binding autoradiography.
Main Results:
- ACE mRNA levels did not significantly increase in the subfornical organ, hypothalamus, or lower brainstem of CHF rats compared to sham-operated controls.
- Binding densities for type 1 AT (AT1) were significantly higher in the subfornical organ, paraventricular hypothalamic nuclei, and solitary tract nuclei of CHF rats.
- These brain regions are critical for regulating water intake, vasopressin release, and hemodynamic control.
Conclusions:
- Upregulation of AT1 expression in key brain regions involved in body fluid control highlights the brain as a significant site of RAS action in CHF.
- These findings suggest the brain is a potential therapeutic target for ACE-inhibitors in managing CHF.
Background:
The renin-angiotensin system (RAS) plays a key role in the pathophysiology of chronic heart failure (CHF). In rats, we reported that CHF enhances dipsogenic responses to centrally administered angiotensin I, and central inhibition of the angiotensin-converting enzyme (ACE) prevents cardiac hypertrophy in CHF. This suggests that the brain RAS is activated in CHF. To clarify the mechanism of the central RAS activation in CHF, we examined brain ACE and the angiotensin receptor (AT) among rats with CHF.
Methods And Results:
We created high-output heart failure in 22 male Sprague-Dawley rats by aortocaval shunt. Four weeks after surgery, we examined ACE mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and AT by binding autoradiography. ACE mRNA levels were not significantly increased in the subfornical organ (SFO), the hypothalamus, or in the lower brainstem of CHF rats (n = 5) compared with sham-operated rats (SHM) (n = 6). Binding densities for type 1 AT (AT1) in the SFO (P < .05), paraventricular hypothalamic nuclei (P < .05), and solitary tract nuclei (P < .05) were higher in rats with CHF (n = 5) than in SHM rats (n = 6). Thus, in rats with CHF, AT1 expression is increased in brain regions that are closely related to water intake, vasopressin release, and hemodynamic regulation.
Conclusions:
The fact that AT1 expression was upregulated in important brain regions related to body fluid control in CHF rats indicates that the brain is a major site of RAS action in CHF rats and, therefore, a possible target site of ACE-inhibitors in the treatment of CHF.