Alterations in dynamic heart rate control in the β₁-adrenergic receptor knockout mouse

Abstract

β1-Adrenergic receptors (β1-ARs) are key targets of sympathetic nervous system activity and play a major role in the beat-to-beat regulation of cardiac chronotropy and inotropy. We employed a β1-AR gene knockout model to test the hypothesis that β1-AR function is critical for maintenance of resting heart rate and baroreflex responsiveness and, on the basis of its important role in regulating chronotropy and inotropy, is also required for maximal exercise capacity. Using an awake unrestrained mouse model, we demonstrate that resting heart rate and blood pressure are normal in β1-AR knockouts and that the qualitative responses to baroreflex stimulation are intact. Chronotropic reserve in β1-AR knockouts is markedly limited, with peak heart rates ∼200 beats/min less than wild types. During graded treadmill exercise, heart rate is significantly depressed in β1-AR knockouts at all work loads, but despite this limitation, there are no reductions in maximal exercise capacity or metabolic indexes. Thus, in mice, the β1-AR is not essential for either maintenance of resting heart rate or for maximally stressed cardiovascular performance.

Knockout of the α1A/C-adrenergic receptor subtype: The α1A/C is expressed in resistance arteries and is required to maintain arterial blood pressure

“…The ␣1B KO mouse has normal basal blood pressure but, similar to the ␣1A͞C KO, demonstrates a reduced pressor response to PE (9). However, measurement in the ␣1B KO was made shortly after anesthesia (9), which can alter AR responses (14,20), and further study is warranted.…”

Cardiovascular and Metabolic Alterations in Mice Lacking Both β1- and β2-Adrenergic Receptors

“…4B, demonstrating that whereas both wild types and ␤1/␤2-AR double knockouts have virtually identical levels of O 2 consumption and CO 2 production at rest, consistent deficits in both of these indices are revealed at all exercise levels in the double knockout. This metabolic deficit appears to result from the combined deficiency of ␤1-and ␤2-ARs, since neither the ␤1-AR knockout nor the ␤2-AR knockout display such deficits (17,18). Interestingly, however, there are differences in total exercise capacity between wild type mice and ␤2-AR knockouts, with the ␤2-AR knockout demonstrating a slight enhancement of total exercise capacity and reduced respiratory exchange ratios (17).…”

“…Interestingly, however, there are differences in total exercise capacity between wild type mice and ␤2-AR knockouts, with the ␤2-AR knockout demonstrating a slight enhancement of total exercise capacity and reduced respiratory exchange ratios (17). In contrast, ␤1-AR ablation has no effect on total exercise capacity (18).…”

“…In the companion article (17), the functional consequences of ␤2-AR disruption are described. We have previously described the functional consequences of ␤1-AR gene disruption (13,18). We have now produced mice that lack both ␤1-and ␤2-ARs.…”

Adrenergic Receptor Polymorphisms Associated with Resting Heart Rate: The HyperGEN Study

“…Heart rate is under the control of both the parasympathic and sympathetic nervous systems (SNS), with the latter more active among hypertensive subjects (Rahn et al 1999). In the mouse SNS, beta1-adrenergic receptors have been implicated as the largest contributor to cardiac chronotropic responses (Rohrer et al 1998). Two common polymorphisms in ADRB1 have been studied for association to heart rate in humans, Ser49Gly and Arg389Gly.…”