Central Integration of Left Versus Right Baroreceptor Afferent Input in Female Spontaneously Hypertensive Rats

Abstract

Objective: Neuromodulation of blood pressure using baroreflex activation therapy is an effective means to control hypertension in resistant hypertensive patients. In a genetic rat model of essential hypertension, the spontaneously hypertensive rats (SHRs); we were able to demonstrate in male rats that preferential central integration of left baroreceptor afferent input exists relative to that of the right afferents. It remains unknown whether laterality also influences baroreflex responses in female SHRs. Accordingly, the differences in cardiovascular responses triggered by stimulation of the left and right baroreceptor afferents, as assessed by direct electrical stimulation of the aortic depressor nerve (ADN), were studied in female SHRs. Design and method: Pentobarbital-anesthetized female SHRs (25–29 weeks, n = 6–8) were instrumented for left and right ADN stimulation (1–40 Hz, 0.2 ms, 0.4 mA for 20 s) and recording of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were also matched for the diestrus phase of the estrus cycle. Results: Both left and right ADN stimulation resulted in frequency-dependent reductions (P < 0.001) in MAP, HR, MVR and FVR. Reflex reductions in MAP, HR, MVR and FVR were comparable for both left-sided and right-sided stimulation. Conclusions: Unlike males, female SHRs express no differential central modulation of baroreceptor afferent input as evidenced by the comparable left versus right baroreflex-mediated depressor responses. Similar depressor responses in the left versus right stimulation may have been contributed to by the lack of differences in baroreflex-driven changes in HR and vascular resistance. Clinically, targeting either the left or right aortic nerves may equally provide adequate reductions in blood pressure in female hypertensive subjects. Future studies should elucidate the mechanisms responsible for sex differences in the central processing of baroreflex between male and female SHRs.

Functional symmetry of the aortic baroreflex in female spontaneously hypertensive rats

“…Unexpectedly, peak reflex depressor responses to left and right ADN stimulation and the immediacy of those responses were relatively similar, hence suggesting that central integration of left versus right aortic baroreceptor afferent input is not differentially regulated in female SHRs. These findings notably contrast with our previous observation of a left-sided dominance in the expression of aortic baroreflex function in male SHRs [22] and normotensive rats of either sex [21]. Together, these findings indicate a sexual dimorphism in the processing of the aortic baroreflex relative to male SHRs and the loss of functional asymmetry that would otherwise be observed under normotensive conditions in females.…”

“…Indeed, our studies have shown that normotensive rats of either sex tend to exhibit a left-sided dominance in the central integration of baroreceptor afferent input; however, in females, baroreflex processing of the left or bilateral baroreceptor afferent input appears to contribute to higher reflex depressor responses compared with males [21]. Using the same experimental approach, we have also identified an identical functional asymmetry in aortic baroreflex function in male SHRs [22]. However, it remains undetermined if the hypertensive state would alter the expression of laterality in female SHRs.…”

“…All raw data traces were smoothed over a 1 s time constant and subsequently converted into 5 s bins. Measures of vascular resistance were calculated by dividing MAP by the blood flow values recorded from the mesenteric and femoral vascular beds, as described previously [21,22,25,28]. Resting baseline levels were recorded over a 40 s period prior to starting the neurostimulation protocol.…”

“…The surgical approach used to instrument rats for unilateral and bilateral ADN stimulation whilst recording BP, HR, and regional blood flows have been described elsewhere [21,22,25]. Briefly, pentobarbital (Diamondback, Arizona, USA) anesthesia was delivered using an intraperitoneal injection of 50 mg/kg of the anesthetic followed by a continuous infusion (Harvard Apparatus Ltd., Massachusetts, USA) into the right femoral vein at a dose of 10 mg/kg/h and an infusion rate of 2 ml/h.…”

“…Optimal charge parameters were chosen in accordance with our previous studies [21,22,25,27]. Briefly, left, right and bilateral ADN stimulations were delivered continuously for 20 s, with the pulse intensity and width kept at 0.4 mA and 0.2 ms, respectively, and pulse frequency varied (1, 2.5, 5, 10, 20, and 40 Hz) and applied in a random sequence.…”