Each heartbeat originates from a specialized region in the heart called the sinoatrial node (SAN) that is highly regulated by the autonomic nervous system (ANS). Hypertensive heart disease is the most common form of cardiovascular disease and impairs heart rate (HR) regulation. Inability to increase HR in response to various stressors is known as chronotropic incompetence and is linked to increased mortality risk in this population. Nevertheless, the mechanisms for chronotropic incompetence in this setting are unclear. As such, the first aim of this thesis was to characterize the mechanisms for impaired HR regulation in a mouse model of angiotensin II (AngII)-induced hypertensive heart disease. AngII-infused mice had intrinsic SAN dysfunction, increased sympathetic nervous system activity, and reduced SAN responsiveness to ANS stimulation. Mechanistically, reduced SAN responsiveness to sympathetic signaling in AngII-infused mice occurred due to upregulation of the enzyme phosphodiesterase 4D (PDE4D) in SAN myocytes, blunting catecholamine signalling. Inhibiting PDE4D activity and expression increased HR and SAN responses to catecholamine stimulation in AngII-infused mice, suggesting it may be a target for improving sympathetically mediated HR regulation in disease. Atrial fibrillation (AF) is the most common arrhythmia and frequently coexists with SAN dysfunction. While the ANS plays an important role in the generation of SAN and atrial arrhythmogenesis, endocrine factors can also contribute. Natriuretic peptides (NPs) are a family of cardioprotective hormones that act partially through NP receptor B (NPR-B), but NPR-B’s role in SAN function and atrial arrhythmogenesis is poorly understood. Thus, the second aim of this thesis was to characterize the role of NPR-B signaling on HR regulation and AF. NPR-B-deficient mice demonstrated intrinsic SAN dysfunction with reduced in vivo HR secondary to alterations in ion channel function in SAN cells. NPR-B-deficient mice were also highly susceptible to AF due to enhanced atrial catecholamine responses. Correspondingly, atrial NPR-B expression was reduced in humans with AF. Interestingly, activation of NPR-B antagonized catecholamine signaling in both mouse and human atrial myocytes. These studies highlight that NPR-B stimulation may be a novel approach for treatment and prevention of both SAN dysfunction and catecholamine-induced AF through distinct pathways.