Reply to "Letter to the editor: Sympathetically mediated increases in cardiac output, or peripheral vasoconstriction as primary regulator of BP during hyperinsulinemia?"

REPLY: We thank Dr. Fadel and colleagues (2) for their complimentary comments and insightful interpretations in regard to our recent article (4), published in the American Journal of Physiology-Heart and Circulatory Physiology. Below we provide our response to the authors’ three main points. First, the authors expressed some concern that increases in femoral vascular conductance (FVC) following 5-s pulses of neck suction (NS, 60 Torr) were not observed under basal, noninsulin conditions. Important to this point, we did not expect a fall in sympathetic nervous system activity (SNA) to elicit much vasodilation at baseline in the healthy young adults studied. In fact, the lack of effect of NS on peripheral blood flow in young women agrees with prior work from the Fadel group (1) and others (5). In contrast, an acute reduction of SNA with NS in a cohort of primarily men showed an increase in FVC under basal conditions (3). At first glance, it is logical to deduce that divergent findings could be attributed to differences between young men and women. However, we observed no obvious sex differences in the effect of NS on FVC under basal, noninsulin conditions (main effect of sex, P 0.651; interaction of sex and NS, P 0.983). This lack of sex differences was noted in the initial article (4). Most importantly, any apparent lack of an effect of NS on FVC at baseline (when SNA is relatively low) is inconsequential to addressing our main hypothesis, which was that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and that this would be manifested with the NS maneuver. As displayed in Figs. 1 and 2 of our article (4), it is clear that there is no effect of NS on FVC during hyperinsulinemia despite significant increases in SNA; notably, this observation is not sex specific (interaction of insulin and NS: men, P 0.929; women, P 0.980). In contrast, we do observe an effect of NS on cardiac output that is amplified during hyperinsulinemia in both men and women (interaction of insulin and NS: men, P 0.017; women, P 0.015). Altogether, these data in young healthy adults cannot be used to support the role of SNA in restraining insulin-induced peripheral vasodilation. Second, as nicely pointed out by Fadel and colleagues, to consider the robust sympathoexciation during hyperinsulinemia, in the experiments in isolated arteries, it seems appropriate to compare the degree of vasoconstriction between a low dose of phenylephrine without insulin (mimicking the low SNA under basal conditions) versus a higher dose of phenylephrine with insulin (mimicking the high SNA during hyperinsulinemia). As reported in the original article (4), aortic rings from healthy mice exhibited the same degree of constriction under these two conditions. Fadel and colleagues interpreted this finding as evidence to suggest that “central sympathoexcitatory actions of insulin offset the effect of any attenuating actions of local vascular insulin signaling on sympathetic vasoconstriction and [blood pressure]. ” We concur with this interpretation, which does not differ from ours, that in the healthy state, insulin actions in the vasculature can blunt the vasoconstriction normally associated with increasing -adrenergic stimulation. Notably, the fact that insulin attenuates -adrenergic vasoconstriction in healthy isolated arteries could theoretically explain why in our cohort of young healthy participants, we do not provide evidence that sympathoexcitation during hyperinsulinemia restrains peripheral vasodilation. Indeed, it is possible that vascular insulinization lessens sympathetic vasoconstriction and that, consequently, maintenance of blood pressure becomes more reliant on increases in cardiac output, a notion that has been underappreciated. Third, the authors highlight a classic article from David Robertson’s group in patients with autonomic insufficiency (6) and point to the results showing such patients cannot maintain blood pressure following meal-induced hyperinsulinemia. We similarly referenced this article and acknowledged a sometimes-overlooked aspect of Robertson’s findings—the fall in blood pressure after a meal was attenuated by indomethacin (a -adrenergic receptor agonist) (6). These data lend further support to our conclusion that the increased cardiac output cannot be dismissed as an important component of blood pressure regulation during hyperinsulinemia. In short, we thank Fadel and colleagues for their constructive remarks and appreciation of our somewhat unexpected findings. While we remain in support of the final conclusion of the article (4), we agree with the assertion by Fadel and colleagues that is difficult to conceive a scenario in which sympathetic vasoconstriction is not important for the maintenance of blood pressure. Certainly, additional work is warranted to better understand sympathetic control of blood flow and blood pressure during hyperinsulinemia, an important and complex question that we continue to interrogate using the combination of reductionist and integrative approaches. Correspondence: J. K. Limberg (limbergj@missouri.edu); J. Padilla (padillaja@missouri.edu). Am J Physiol Heart Circ Physiol 319: H394–H395, 2020; doi:10.1152/ajpheart.00578. 2020.