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GENETICALLY MODIFIED ANIMALS AND MODEL ORGANISMS

Cardiovascular autonomic control in mice lacking angiotensin AT1a receptors

¹Wright State University School of Medicine, Department of Pharmacology and Toxicology, Dayton, Ohio; and ²University of Sao Paulo School of Medicine, Ribeirão Preto-SP, and ³Federal University of Sao Paulo School of Medicine, Sao Paulo, Brazil

Submitted 6 April 2004 ; accepted in final form 30 November 2004

Studies examined the role of angiotensin (ANG) AT1a receptors in cardiovascular autonomic control by measuring arterial pressure (AP) and heart rate (HR) variability and the effect of autonomic blockade in mice lacking AT1a receptors (AT1a –/–). Using radiotelemetry in conscious AT1a +/+ and AT1a –/– mice, we determined 1) AP and pulse interval (PI) variability in time and frequency (spectral analysis) domains, 2) AP response to ₁-adrenergic and ganglionic blockade, and 3) intrinsic HR after ganglionic blockade. Pulsatile AP was recorded (5 kHz) for measurement of AP and PI and respective variability. Steady-state AP responses to prazosin (1 µg/g ip) and hexamethonium (30 µg/g ip) were also measured. AP was lower in AT1a –/– vs. AT1a +/+, whereas HR was not changed. Prazosin and hexamethonium produced greater decreases in mean AP in AT1a –/– than in AT1a +/+. The blood pressure difference was marked after ganglionic blockade (change in mean AP of –44 ± 10 vs. –18 ± 2 mmHg, AT1a –/– vs. AT1a +/+ mice). Intrinsic HR was also lower in AT1a –/– mice (431 ± 32 vs. 524 ± 22 beats/min, AT1a –/– vs. AT1a +/+). Beat-by-beat series of systolic AP and PI were submitted to autoregressive spectral estimation with variability quantified in low-frequency (LF: 0.1–1 Hz) and high-frequency (HF: 1–5 Hz) ranges. AT1a –/– mice showed a reduction in systolic AP LF variability (4.3 ± 0.8 vs. 9.8 ± 1.3 mmHg²), with no change in HF (2.7 ± 0.3 vs. 3.3 ± 0.6 mmHg²). There was a reduction in PI variability of AT1a –/– in both LF (18.7 ± 3.7 vs. 32.1 ± 4.2 ms²) and HF (17.7 ± 1.9 vs. 40.3 ± 7.3 ms²) ranges. The association of lower AP and PI variability in AT1a –/– mice with enhanced AP response to ₁-adrenergic and ganglionic blockade suggests that removal of the ANG AT1a receptor produces autonomic imbalance. This is seen as enhanced sympathetic drive to compensate for the lack of ANG signaling.

heart rate; blood pressure; baroreflex; autonomic nervous system; spectral analysis

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