BACKGROUND: Hypertensive heart disease is associated with sinoatrial node (SAN) dysfunction and reductions in heart rate variability (HRV). Alterations in HRV could occur in association with changes in autonomic nervous system (ANS) activity, changes in SAN function and responsiveness to ANS agonists, or both. These relationships are unclear. OBJECTIVE: The purpose of this study was to investigate the roles of ANS signaling, intrinsic SAN function, and changes in HRV in a mouse model of angiotensin II (AngII)-mediated hypertensive heart disease. METHODS: Mice were treated with saline or AngII (2.5 mg/(kg鈰卍)) for 3 weeks. ANS activity was assessed through HRV analysis of electrocardiograms collected in vivo by telemetry as well as direct recordings of vagal nerve activity and renal sympathetic nerve activity from anesthetized mice. The effects of the ANS agonists isoproterenol and carbachol on SAN function and beating interval variability were assessed from electrogram recordings in intact isolated atrial preparations and from spontaneous action potential recordings in isolated SAN myocytes. RESULTS: Time and frequency domain analysis demonstrates that mice infused with AngII had reduced HRV. AngII-infused mice had elevated renal sympathetic nerve activity while resting vagal nerve activity was unchanged. AngII caused an increase in SAN beating interval variability in isolated atrial preparations and isolated SAN myocytes. Furthermore, isolated atrial preparations and SAN myocytes from AngII-infused mice had impaired responses to both isoproterenol and carbachol. CONCLUSION: Reduced HRV in hypertension occurs in association with altered sympathovagal balance as well as intrinsic SAN dysfunction and reduced responsiveness of SAN myocytes to ANS agonists.