Bradykinin-mediated Estrogen-dependent Depressor Response by Direct Activation of Female-specific Distribution of Myelinated Ah-type Baroreceptor Neurons in Rats

Aim: To understand the direct impact of bradykinin in autonomic control of circulation through baroreflex afferent pathway.

Methods: The mean arterial pressure (MAP) was monitored while bradykinin and its agonists were applied via nodose (NG) microinjection, the expression of bradykinin receptors (BRs) in the NG (1 -order) and nucleus tractus solitarius (NTS, 2 -order) were tested in adult male, age-matched female, and ovariectomized rats under physiological and hypertensive conditions. Additionally, bradykinin-induced depolarization was also tested in identified baroreceptor and baroreceptive neurons using whole-cell patch-clamp technique.

Results: Under physiological condition, bradykinin-induced dose- and estrogen-dependent reductions of MAP with lower estimated EC in females. B R agonist mediated more dramatic MAP reduction with long-lasting effect compared with B R activation. These functional observations were consistent with the molecular and immunostaining evidences. However, under hypertensive condition, the MAP reduction was significantly less dramatic in N -Nitro-L-Arginine-methyl ester (L-NAME) induced secondary and spontaneous hypertension rats in males compared with female rats. Electrophysiological data showed that bradykinin-elicited concentration-dependent membrane depolarization with discharges during initial phase in identified myelinated Ah-types baroreceptor neurons, not myelinated A-types; while, higher concentration of bradykinin was required for depolarization of unmyelinated C-types without initial discharges.

Conclusion: These datasets have demonstrated for the first time that bradykinin mediates direct activation of baroreflex afferent function to trigger estrogen-dependent depressor response, which is due mainly to the direct activation/neuroexcitation of female-specific myelinated Ah-type baroreceptor neurons leading to a sexual dimorphism in parasympathetic domination of blood pressure regulation via activation of B R/B R expression in baroreflex afferent pathway.