Low voltage vagal nerve stimulation reduces bronchoconstriction in guinea pigs through catecholamine release

Abstract

Objective: Electrical stimulation of the vagus nerve at relatively high voltages (e.g., >10 V) can induce bronchoconstriction. However, low voltage (≤2 V) vagus nerve stimulation (VNS) can attenuate histamine-invoked bronchoconstriction. Here, we identify the mechanism for this inhibition.

Methods: In urethanea-nesthetized guinea pigs, bipolar electrodes were attached to both vagus nerves and changes in pulmonary inflation pressure were recorded in response to i.v. histamine and during VNS. The attenuation of the histamine response by low-voltage VNS was then examined in the presence of pharmacologic inhibitors or nerve ligation.

Results: Low-voltage VNS attenuated histamine-induced bronchoconstriction (4.4 ± 0.3 vs. 3.2 ± 0.2 cm H(2) O, p < 0.01) and remained effective following administration of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, and after sympathetic nerve depletion with guanethidine, but not after the β-adrenoceptor antagonist propranolol. Nerve ligation caudal to the electrodes did not block the inhibition but cephalic nerve ligation did. Low-voltage VNS increased circulating epinephrine and norepinephrine without but not with cephalic nerve ligation.

Conclusion: These results indicate that low-voltage VNS attenuates histamine-induced bronchoconstriction via activation of afferent nerves, resulting in a systemic increase in catecholamines likely arising from the adrenal medulla.

Figure 1

Pulmonary inflation pressure (Ppi) was monitored during histamine (N = 26) or acetylcholine (N = 6) administration (control) and compared with the response when low-voltage vagus nerve stimulation (VNS) treatment was applied 20 sec before and during the administration of histamine or acetylcho-line (VNS). *p < 0.05 and **p < 0.01 compared with respective controls.

Figure 2

Following treatment with chemical inhibitors or ligation of the vagus nerve, the pulmonary inflation pressure (Ppi) response to histamine was compared without and during low-voltage vagus nerve stimulation (VNS). N_G-nitro-L-arginine methyl ester (L-NAME), N = 7, Guanethidine, N = 6, Propranolol, N = 6, Caudal Ligation, N = 7, Cephalic Ligation, N = 3. *p < 0.05.

Figure 3

Representative traces of the airway pressure responses to i.v. histamine alone (H) and during low-voltage vagus nerve stimulation (VNS). Upper trace demonstrates responses before propranolol was administered. Bottom trace shows the responses in the presence of propranolol.

Figure 4

Representative traces of the airway pressure responses to i.v. histamine (H) alone and during vagus nerve stimulation (VNS). Upper trace shows responses prior to placement of a ligature around the vagus nerve. Bottom trace shows i.v. histamine responses without and during low voltage VNS after the vagus nerve was ligated cephalic to the electrodes.

Figure 5

Pulmonary inflation pressure (Ppi) was monitored in five animals and the responses to i.v. histamine and to i.v. histamine plus a low-voltage vagus nerve stimulation (VNS) treatment compared. In the comparisons on the left, VNS was applied for 20 sec before and continued through the administration of i.v. histamine (Continuous VNS). In the comparisons on the right, the low-voltage VNS treatment was applied for 30 sec and then discontinued for 10 sec prior to administration of i.v. histamine (Interrupted VNS). *p < 0.05.

Figure 6

Arterial epinephrine (Epi) and norepinephrine (Noepi) levels were measured at baseline and during vagus nerve stimulation (VNS), N = 4. Three of these animals underwent ligation of the vagus nerve cephalic to the electrodes. Following ligation, epinephrine (Cephalic Ligation Epi) and norepinephrine (Cephalic Ligation Norepi) levels were remeasured at baseline and during VNS. *p < 0.05.