Electroacupuncture modulation of reflex hypertension in rats: role of cholecystokinin octapeptide

Abstract

Acupuncture or electroacupuncture (EA) potentially offers a nonpharmacological approach to reduce high blood pressure (BP). However, ~70% of the patients and animal subjects respond to EA, while 30% do not. EA acts, in part, through an opioid mechanism in the rostral ventrolateral medulla (rVLM) to inhibit sympathoexcitatory reflexes induced by gastric distention. CCK-8 opposes the action of opioids during analgesia. Therefore, we hypothesized that CCK-8 in the rVLM antagonizes EA modulation of sympathoexcitatory cardiovascular reflex responses. Male rats anesthetized with ketamine and α-chloralose subjected to repeated gastric distension every 10 min were examined for their responsiveness to EA (2 Hz, 0.5 ms, 1-4 mA) at P5-P6 acupoints overlying median nerve. Repeated gastric distension every 10 min evoked consistent sympathoexcitatory responses. EA at P5-P6 modulated gastric distension-induced responses. Microinjection of CCK-8 in the rVLM reversed the EA effect in seven responders. The CCK1 receptor antagonist devazepide microinjected into the rVLM converted six nonresponders to responders by lowering the reflex response from 21 ± 2.2 to 10 ± 2.9 mmHg (first vs. second application of EA). The EA modulatory action in rats converted to responders with devazepide was reversed with rVLM microinjection of naloxone (n = 6). Microinjection of devazepide in the absence of a second application of EA did not influence the primary pressor reflexes of nonresponders. These data suggest that CCK-8 antagonizes EA modulation of sympathoexcitatory cardiovascular responses through an opioid mechanism and that inhibition of CCK-8 can convert animals that initially are unresponsive to EA to become responsive.

Repetitive Electroacupuncture Attenuates Cold-Induced Hypertension through Enkephalin in the Rostral Ventral Lateral Medulla

“…Microinjection of ICI 174,864, the δ opioid receptor antagonist, or DADLE, the δ-opioid agonist, into the rVLM of normotensive rats did not influence blood pressure. This result is consistent with our and other previous studies and indicates that there is no tonic action resulting from δ-opioid receptor stimulation 19 20 23 24 43 44 45 . Thus it appears that under normal physiological conditions endogenous opioids in the rVLM do not participate in BP regulation.…”

CME Article:Long-Lasting Reduction of Blood Pressure by Electroacupuncture in Patients with Hypertension: Randomized Controlled Trial

“…Experimental studies suggest that responsiveness may be related to cholecystokinin-8 in the brain, which antagonizes EA-related opioid actions in brain stem regions that regulate sympathetic outflow during EA. 27 , 56 Experimental studies have shown that EA-associated reductions in reflex elevations in BP are related to decreased sympathetic outflow. 31 , 57 , 58 The present study also found that, compared with low responders, highly responsive patients began the study with higher baseline plasma levels of norepinephrine and responded to EA with decreases in circulating norepinephrine and renin activity.…”

What do we understand from clinical and mechanistic studies on acupuncture treatment for hypertension?

“…Non-responsiveness to acupuncture treatment occurred in about 30 % of subjects, and an EA analgesic response occurred in about 70 % of patients [ 71 , 72 ]. Similar acupuncture effectiveness in terms of sympathoexcitatory cardiovascular responses [ 40 , 73 ] and effects on hypertension [ 41 ] were observed. We investigated the neurotransmitter that antagonizes the actions of opioids, and found that, within the rVLM, cholecystokinin 8 reversed the effects of EA, while blockade of its receptor converted an EA non-responsive subject to an EA responder [ 73 ].…”

“…Similar acupuncture effectiveness in terms of sympathoexcitatory cardiovascular responses [ 40 , 73 ] and effects on hypertension [ 41 ] were observed. We investigated the neurotransmitter that antagonizes the actions of opioids, and found that, within the rVLM, cholecystokinin 8 reversed the effects of EA, while blockade of its receptor converted an EA non-responsive subject to an EA responder [ 73 ]. Neurotransmitter mechanisms might be involved in the effectiveness of acupuncture.…”