Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD

Spreading depolarization (SD) occurs in a plethora of clinical conditions including migraine aura, delayed ischemia after subarachnoid hemorrhage and malignant hemispheric stroke. It describes waves of near-breakdown of ion homeostasis, particularly Na+ homeostasis in brain gray matter. SD induces tone alterations in resistance vessels, causing either hyperperfusion in healthy tissue; or hypoperfusion (inverse hemodynamic response = spreading ischemia) in tissue at risk. Observations from mice with genetic dysfunction of the ATP1A2-encoded alpha(2)-isoform of Na+/K+-ATPase (alpha(2)NaKA) suggest a mechanistic link between (1) SD, (2) vascular dysfunction, and (3) salt-sensitive hypertension via alpha(2)NaKA. Thus, alpha(2)NaKA-dysfunctional mice are more susceptible to SD and show a shift toward more inverse hemodynamic responses. alpha(2)NaKA-dysfunctional patients suffer from familial hemiplegic migraine type 2, a Mendelian model disease of SD. alpha(2)NaKA-dysfunctional mice are also a genetic model of salt-sensitive hypertension. To determine whether SD thresholds and hemodynamic responses are also altered in other genetic models of salt-sensitive hypertension, we examined these variables in stroke-prone spontaneously hypertensive rats (SHRsp). Compared with Wistar Kyoto control rats, we found in SHRsp that electrical SD threshold was significantly reduced, propagation speed was increased, and inverse hemodynamic responses were prolonged. These results may have relevance to both migraine with aura and stroke.

Automated summary

Spreading depolarization (SD) is a phenomenon that occurs in various clinical conditions, such as migraine, delayed ischemia, and stroke. It involves disturbances in ion homeostasis, particularly sodium homeostasis, in the brain. SD can cause changes in resistance vessels, leading to either increased blood flow in healthy tissue or decreased blood flow in at-risk tissue. Research suggests a possible link between SD, vascular dysfunction, and salt-sensitive hypertension through genetic dysfunction of the α(2)-isoform of Na+/K+-ATPase. Genetic models of salt-sensitive hypertension, such as stroke-prone spontaneously hypertensive rats (SHRsp), also show altered SD thresholds and hemodynamic responses. These findings have implications for understanding migraine with aura and stroke.