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(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. B2R agonist mediated more dramatic MAP reduction with long-lasting effect compared with B1R 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 B2R/B1R expression in baroreflex afferent pathway.

Automated summary

The study found that under physiological conditions, bradykinin-induced reductions in mean arterial pressure were dose- and estrogen-dependent, with females showing lower estimated EC50. B2R agonist led to more significant and long-lasting MAP reduction compared to B1R activation. However, under hypertensive conditions, males with N-'-Nitro-L-Arginine-methyl ester induced hypertension showed significantly less dramatic MAP reduction compared to females.