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

TO THE EDITOR: In the recent issue of the American Journal of Physiology-Heart and Circulatory Physiology, we read with interest the article by Limberg et al. (4) in which they attempt to discern the contributions of cardiac output (CO) and peripheral sympathetic vasoconstriction to the maintenance of arterial blood pressure (BP) during hyperinsulinemia in young healthy adults. We would like to applaud their translational approach, combining both in vivo and in vitro experiments to comprehensively investigate neural control of BP during hyperinsulinemia. The authors also used an innovative experimental design, applying 5-s pulses of neck suction (NS; 60 Torr) during basal and hyperinsulinemia conditions as a tool to examine the sympathetic restraint of leg blood flow. It was hypothesized that reducing sympathetic nerve activity (SNA) via NS during hyperinsulinemia would produce greater peripheral vasodilation and reduction in BP relative to NS under basal non-hyperinsulinemic conditions. The authors conclude that SNA-mediated increases in CO rather than peripheral vasoconstriction is the primary mechanism to maintain BP in the face of peripheral vasodilation caused by hyperinsulinemia. We would like to contribute to the discussion of these findings. First, the authors are to be commended for carrying out these very technically challenging and demanding experiments. However, some concerns are present in the NS data as presented. NS elicited the expected reductions in BP and heart rate (and thus, CO), and these responses were augmented during hyperinsulinemia. However, the primary end point(s) for NS in this study design, increases in femoral blood flow and vascular conductance, were not observed even under basal non-insulin conditions. In fact, it appears vasoconstriction occurred at the point when BP reached its nadir following NS. In other words, the expected vasodilation in response to reducing SNA with NS was not found. This is in contrast to prior investigations in which NS was associated with a transient increase in femoral blood flow and vascular conductance at the nadir of the BP response (1, 2). The reason(s) for the observed reduction (not expected increase) in vascular conductance presented by Limberg et al. (4) are not known, but having 50% women in this protocol may have played a role since young women rely more on increases in CO rather than vascular conductance in response to NS (1, 3). Importantly, this paradoxical response contributed to the overall conclusion for lack of contribution of SNA to support BP during hyperinsulinemia. The authors also completed in vitro studies in which mouse aortic rings were subjected to increasing concentrations of phenylephrine (PE) to pharmacologically mimic sympathetic vasoconstriction in the presence and absence of insulin. Although in the presence of insulin the PE-mediated constriction was blunted at the higher doses, these data do not consider the robust sympathoexcitation (and greater neurotransmitter release) during systemic hyperinsulinemia in vivo (6). Nevertheless, comparing the PE-mediated constriction observed in the absence of insulin to proportionately greater concentrations during the insulin treated condition may be more relevant to account for the increase in SNA with hyperinsulinemia. For example, comparison of PE-mediated constriction at 10 7 log concentration without insulin and the 10 6 concentration with insulin yields very similar percent vasoconstriction. Thus, an alternative interpretation is that the in vivo central sympathoexcitatory actions of insulin offset the effect of any attenuating actions of local vascular insulin signaling on sympathetic vasoconstriction and BP. Regardless of the interpretation of these data, it is difficult to imagine any scenario in which sympathetic vasoconstriction is not important for the maintenance of BP. As such, the conclusion that sympathetically mediated increases in CO, not restraint of peripheral vasodilation, contribute to BP maintenance during hyperinsulinemia requires careful consideration. While the reported increase in heart rate (~4 beats/min) and Modelflow-derived CO (~300 mL) during hyperinsulinemia may be important, the ability to maintain BP in the face of excessive insulin-induced peripheral vasodilation via this small increase in CO, and whether it is sympathetically mediated, seems debatable. It is noteworthy that patients with autonomic insufficiency cannot maintain BP following a meal-induced hyperinsulinemia despite increases in heart rate (5). In conclusion, we applaud Limberg et al. (4) for investigating the important and complex question regarding sympathetic control of BP during hyperinsulinemia. The innovative approach and provocative data collected clearly add to this important area of research. However, we suggest that the contribution of peripheral sympathetic vasoconstriction to BP regulation during hyperinsulinemia remains a matter of interpretation.