Fig. 4.

The centrally controlled, parallel sympathetic nerve and slow neurohumoral pathways that regulate both arterial and cardiac function, and participate in the pathogenesis of hypertension and heart failure (HF). Angiotensin II (Ang II) and high dietary salt (↑[Na⁺]) are convergent signals that act via hypothalamic Ang-type 1 receptors (AT₁R) to activate central nervous system (CNS) sympathetic pathways; the role of the kidneys in the retention of salt has been omitted for the sake of simplicity. The increased sympathetic nerve activity (SNA) promotes vasoconstriction and increases cardiac rate and contractile force. Prolonged stimulation of hypothalamic AT₁R also activates a novel neurohumoral pathway (box at top right) that includes aldosterone (Aldo), mineralocorticoid receptors (MR), epithelial Na⁺ channels (ENaC), endogenous ouabain (EO), and α2 Na⁺ pumps. This hypothalamic pathway feeds back (green line, “+”) to modulate Ang II-activated SNA and also promotes adrenal secretion of EO, triggered by, e.g., ACTH, adrenal SNA, and/or Ang II. The elevated plasma EO acutely inhibits α2 Na⁺ pumps in both the heart and arteries, and the rise in intracellular Na⁺ rapidly induces Na/Ca exchanger (NCX)-mediated Ca²⁺ gain, and cardiotonic and vasotonic effects. Prolonged plasma EO elevation also activates an α2 Na⁺ pump-associated protein kinase cascade (e.g., EGFR/Src/MEK/ERK-mediated) that increases cardiac and arterial NCX expression, and arterial sarcoplasmic reticulum (SR) Ca²⁺ pump (SERCA2) expression. In arteries with tone, NCX normally favors Ca²⁺ entry and helps to sustain cytosolic Ca²⁺ ([Ca²⁺]_CYT) above contraction threshold. The EO-induced NCX and SERCA2 upregulation enhances Ca²⁺ signaling and helps the very modestly increased SNA to increase vascular tone and resistance and elevate blood pressure. In the heart, NCX promotes Ca²⁺ extrusion during diastole, but prolonged α2 pump inhibition by EO reduces the Na⁺ gradient driving force so that [Na⁺]_CYT and diastolic [Ca²⁺]_CYT are both elevated; consequently, cardiac relaxation is slow and/or incomplete. Also, cardiac SERCA2 expression is usually reduced in HF (perhaps due to the high EO), as are SR Ca²⁺ stores and [Ca²⁺]_CYT transients, and systolic function is impaired. The diastolic dysfunction and attenuated cardiac contraction and stroke volume contribute to HF. These cellular mechanisms are discussed further in a recent review (31). [Modified from Blaustein et al. (31) with permission.]