Chronic hypoxia impairs L-type Ca²⁺ channel-mediated myogenic vasoconstriction and cerebral autoregulation in newborn lambs

Cerebral autoregulation is a vital homeostatic mechanism that protects the brain from hypertension-induced injury by adjusting cerebrovascular tone to maintain stable cerebral blood flow (CBF). Neonates exposed to chronic hypoxia often exhibit impaired cerebral autoregulation though underlying molecular mechanisms remain unclear. Here, we investigated whether L-type calcium channels (LTCCs), known to be essential to the myogenic response in adults, also play a role in newborn cerebral autoregulation. We further examined whether chronic hypoxia impairs cerebral autoregulation in newborn lambs via LTCC-dependent pathways. Using laser Doppler flowmetry to measure cerebral blood flow during graded acute hypertensive challenges, we demonstrated that normoxic lambs maintain both steady-state (sustained control of blood flow over several minutes) and dynamic (rapid, beat-to-beat adjustments) autoregulation. By contrast, chronically hypoxic lambs exhibit pressure-passive CBF responses, consistent with cerebral autoregulation compromise. Intravenous nifedipine, a selective LTCC blocker, abolished cerebral autoregulation in normoxic lambs, mimicking the hypoxic phenotype. Conversely, nifedipine had no additional effect in hypoxic lambs, suggesting pre-existing LTCC suppression. Middle cerebral arteries isolated from hypoxic lambs exhibited reduced baseline tone and minimal responses to stretch or high-potassium depolarization, even before nifedipine administration. These results confirm hypoxia-induced loss of cerebral autoregulation via pathways involving LTCC function in neonatal cerebral arteries. Collectively, our findings establish that chronic hypoxia impairs neonatal cerebral autoregulation by attenuating LTCC-mediated myogenic reactivity. This mechanism probably contributes to cerebral vulnerability in high-risk neonates and represents a potential therapeutic target. KEY POINTS: Chronic hypoxia attenuates steady-state cerebral autoregulation in newborn lambs, making cerebral blood flow pressure-passive even after normoxia is restored. Dynamic autoregulation is significantly blunted by chronic hypoxia, resembling the loss seen in normoxic lambs after L-type calcium channel blockade. L-type calcium channels are essential for neonatal autoregulation because nifedipine disrupts cerebral blood flow control in normoxic lambs but has little effect in hypoxic lambs. Hypoxic arteries exhibit weak myogenic tone and a limited response to nifedipine, indicating that intrinsic L-type calcium channel-dependent pathway dysfunction contributes to the in vivo deficits.