Bradykinin-mediated estrogen-dependent depressor response by direct activation of female-specific distribution of myelinated Ah-type baroreceptor neurons in rats

Abstract

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^st -order) and nucleus tractus solitarius (NTS, 2^nd -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 EC₅₀ in females. B₂ R agonist mediated more dramatic MAP reduction with long-lasting effect compared with B₁ 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 B₂ R/B₁ R expression in baroreflex afferent pathway.

Keywords: baroreceptor activation; bradykinin; depressor response; neurocontrol of blood pressure regulation; nodose.