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No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation
T M Estrup1, O B Paulson, S Strandgaard
1Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.
Insights
Blocking angiotensin AT2-receptors with PD 123319 did not alter cerebral blood flow (CBF) autoregulation limits in spontaneously hypertensive rats. This suggests AT2-receptors do not play a significant role in regulating CBF autoregulation acutely.
Area of Science:
- Neuroscience
- Cardiovascular Physiology
- Pharmacology
Background:
- The renin-angiotensin system influences cerebral blood flow (CBF) autoregulation.
- Angiotensin-converting enzyme inhibitors and AT1-receptor antagonists affect CBF autoregulation limits.
- The specific role of AT2-receptors in cerebral circulation regulation remains unclear.
Purpose of the Study:
- To investigate the effect of blocking angiotensin AT2-receptors on cerebral blood flow (CBF) autoregulation.
- To determine if AT2-receptor blockade influences the limits of CBF autoregulation in spontaneously hypertensive rats (SHR).
Main Methods:
- Administration of PD 123319 (an AT2-receptor antagonist) to anesthetized, ventilated spontaneously hypertensive rats (SHR).
- Measurement of cerebral blood flow (CBF) using the intracarotid 133xenon injection method.
- Determination of autoregulation limits by altering blood pressure (BP) via noradrenaline infusion and controlled hemorrhage, followed by least-sum-of-squares analysis.
Main Results:
- PD 123319 did not affect baseline CBF but caused a minor decrease in blood pressure.
- No significant differences were observed in the lower or upper limits of CBF autoregulation between PD 123319-treated rats and control animals.
- The lower limit of autoregulation was 102±4 mmHg (treated) vs. 94±4 mmHg (control), and the upper limit was 171±10 mmHg (treated) vs. 162±7 mmHg (control).
Conclusions:
- Acute blockade of angiotensin AT2-receptors does not significantly influence the autoregulation of cerebral blood flow in spontaneously hypertensive rats.
- These findings suggest that AT2-receptors may not play a critical role in the acute regulation of cerebral circulation under these experimental conditions.
Abstract:
Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral circulation is uncertain. Hence, the present study investigated the effect on CBF autoregulation of blocking of angiotensin AT2-receptors with PD 123319 in spontaneously hypertensive rats (SHR). Anaesthetised and ventilated SHR were given PD 123319, 0.36 mg/kg/min, intravenously, and compared with a control group. CBF was measured by the intracarotid 133xenon injection method and BP was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. PD 123319 did not influence baseline CBF, but resulted in a minor BP decrease (10 control and 10 treated rats). The lower limit of CBF autoregulation (eight treated and eight control) as well as the upper limit of CBF autoregulation (eight treated and eight control) were not significantly different in PD 123319 and control animals (lower limit treated 102+/-4 mmHg and control 94+/-4; NS, and upper limit treated 171 +/- 10 mmHg and control 162+/-7; NS). These findings indicate that acute AT2-receptor blockade does not influence CBF autoregularion.