Effect of targeted deletions of !1- and !2-adrenergic-receptor subtypes on heart rate variability

Ecker, Phillip M., Chu-Chuan Lin, Jennifer Powers, Brian K. Kobilka, Anne M. Dubin, and Daniel Bernstein. Effect of targeted deletions of !1and !2-adrenergic-receptor subtypes on heart rate variability. Am J Physiol Heart Circ Physiol 290: H192–H199, 2006. First published August 19, 2005; doi:10.1152/ajpheart.00032.2005.— !-Adrenergic receptors (!-ARs) play a major role in regulating heart rate (HR) and contractility in the intact cardiovascular system. Three subtypes (!1, !2, and !3) are expressed in heart tissue, and the role of each subtype in regulating cardiac function has previously been determined by using both pharmacological and gene-targeting approaches. However, previous studies have only examined the role of !-ARs in the macrolevel regulation of HR. We employed three knockout (KO) mouse lines, !1-KO, !2-KO, and !1/!2 double KO (DL-KO), to examine the role that !-AR subtypes play in HR variability (HRV) and in the sympathetic and parasympathetic inputs into HR control. Fast Fourier transformation (FFT) in frequency domain methods of ECG spectral analysis was used to resolve HRV into highand low-frequency (HF and LF) powers. Resting HR (in beats/min) was decreased in !1-KO [488 (SD 27)] and DL-KO [495 (SD 12)] mice compared with wild-type [WT; 638 (SD 30)] or !2-KO [656 (SD 51)] (P " 0.0005) mice. Mice lacking !1-ARs (!1-KO and DL-KO) had increased HRV (as illustrated by the standard deviation of normal R-R intervals) and increased normalized HF and LF powers compared with mice with intact !1-ARs (WT and !2-KO). These results demonstrate the differential role of !-AR subtypes in regulating autonomic signaling.