Investigating the hypotensive effect of focused ultrasound neuromodulation and barbiturate-loaded nanodroplets in healthy and hypertensive rats.

Current strategies for reducing blood pressure (BP) are ineffective and unsafe for many patient populations, including drug-resistant hypertension and during pregnancy. Stimulating the periaqueductal grey (PAG) region has shown promise in treating drug-resistant hypertension in patients using deep brain stimulation. To develop a minimally invasive neuromodulation technique for the sustained treatment of hypertension. We have investigated BP reduction using focused ultrasound (FUS) (540 kHz) and anesthetic-loaded ultrasound-responsive nanodroplets to deliver pentobarbital to the PAG in normotensive (N = 27) and hypertensive (N = 20) male and female rats. BP, heart rate and plasma hormone content were collected before and after FUS exposure, and neuronal activity was mapped in the PAG using C-Fos and neuron subtype staining. Cavitation activity was monitored by detecting acoustic emissions from vaporizing nanodroplets, and neuromodulation was verified with immunohistochemistry. Systolic and diastolic BP were reduced for 6 h following a single sonication of the PAG (-37/-28 mmHg systolic/diastolic), and the offline effect was extended to 4 days with consecutive sonications combined with systemically injected pentobarbital-loaded nanodroplets. In contrast, FUS applied to the frontal cortex had no effect on BP. Immunohistochemistry revealed stimulation of inhibitory neurons in the PAG region, indicating that the hypotensive effect was associated with a GABAergic pathway. The acoustic emissions from vaporizing droplets were found to correlate with neuron activity and change in BP, offering the potential for real-time treatment monitoring using ultrasound. This work has implications for developing a new treatment for hypertension that has greater safety and broader applicability for vulnerable patient populations.