Reply to Willie

J Appl Physiol 115: 1216, 2013; doi:10.1152/japplphysiol.00862.2013.

Reply

Reply to Willie Paola Maggio,1 Angela S. M. Salinet,2 Ronney B. Panerai,2,3 and Thompson G. Robinson2,3 1

Neurologia Clinica, Universita` Campus Bio-Medico, Rome, Italy; 2Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; and 3National Institutes for Health Research, Biomedical Research Unit in Cardiovascular Sciences, Glenfield Hospital, Leicester, United Kingdom TO THE EDITOR:

We are grateful to Dr. Willie (6) for his letter, which is a welcome contribution to the debate on the complex interaction between cerebrovascular regulatory mechanisms, namely neurovascular coupling (NVC), cerebral autoregulation (CA), and CO2 vasoreactivity (CO2-VR). A relatively large number of independent studies have confirmed that cerebral blood flow (or velocity) reaches zero for values of arterial blood pressure (BP) significantly greater than zero, which defines the critical closing pressure (CrCP) (2). The corresponding inverse slope of the instantaneous pressure-flow relationship has been termed the resistance-area product (RAP) (2). CrCP is considered to play a major role in controlling cerebral blood flow (CBF) (2). One issue raised by Dr. Willie is the extent to which it is possible to identify the main determinants of CrCP and RAP and what role they play in the interaction between NVC, CA, and CO2-VR. The effects of PaCO2 on CBF may be explained by changes in CrCP (2). The influence of metabolic pathways on CrCP is reinforced by studies of NVC (2– 4). However, neural activation usually induces simultaneous changes in BP and PaCO2, activating CA and CO2-VR responses, which can then confound the NVC response. To clarify these issues, we have proposed the use of subcomponent analysis (4) and dynamic multivariate modeling (3). The former identifies the separate contributions of BP, CrCP, and RAP to CBF changes. With this method, a strong association was found between concomitant changes in BP and RAP, ascribed to myogenic mechanisms, and between CrCP and the NVC response, assumed to reflect metabolic pathways (4). Although hypercapnia-induced depression of CA led to NVC impairment via insufficient changes in CrCP (1), in acute stroke it was the RAP response that was altered (5). These results suggest that hypercapnia should not be considered a general model for CA impairment because it seems to affect only its metabolic component. Whether the attenuated NVC response in hypercapnia (1) could be due to an attenuated BP increase cannot be completely ruled out by our study. However, it would depend on a causal link between BP and CrCP, something that hitherto has not been described. Furthermore, Address for reprint requests and other correspondence: T. Robinson, Dept. of Cardiovascular Sciences, Robert Kilpatrick Clinical Sciences Bldg., Univ. of Leicester, Leicester LE1 5WW, UK (e-mail: [email protected]).

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even if the BP increase was attenuated in the hypercapnic condition, its contribution was not significantly different compared with normocapnia. Dr. Willie also mentions multivariate dynamic modeling (3). This is a much more computationally intensive technique to quantify the influences of BP, PaCO2, and neural activation, separating the contributions of CrCP and RAP. The influence of BP was confirmed to be effected through changes in RAP (3). However, RAP was also influenced by neural activation and could then also reflect metabolic pathways. Therefore, to address Dr. Willie’s second question, we do not encourage generalizing RAP and CrCP as selective indicators of myogenic and metabolic cerebrovascular regulation, and we have only made such broad associations in the context of each individual study. We strongly advocate further research, including animal studies, to identify the role of CrCP and RAP in different physiological conditions. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). AUTHOR CONTRIBUTIONS Author contributions: P.M., A.S.S., and T.R. edited and revised manuscript; P.M., A.S.S., and T.R. approved final version of manuscript; R.B.P. drafted manuscript. REFERENCES 1. Maggio P, Salinet ASM, Panerai RB, Robinson TG. Does hypercapniainduced impairment of cerebral autoregulation affect neurovascular coupling? A functional TCD study. J Appl Physiol 115: 491–497, 2013. 2. Panerai RB. The critical closing pressure of the cerebral circulation. Med Eng Phys 25: 621–632, 2003. 3. Panerai RB, Eyre M, Potter JF. Multivariate modeling of cognitive-motor stimulation on neurovascular coupling: transcranial Doppler used to characterize myogenic and metabolic influences. Am J Physiol Regul Integr Comp Physiol 303: R395–R407, 2012. 4. Panerai RB, Moody M, Eames PJ, Potter JF. Cerebral blood flow velocity during mental activation: Interpretation with different models of the passive pressure-velocity relationship. J Appl Physiol 99: 2352–2362, 2005. 5. Salinet ASM, Robinson TG, Panerai RB. Cerebral blood flow response to neural activation after acute ischemic stroke: a failure of myogenic autoregulation? J Neurol 2013 Jul 4 [Epub ahead of print]. 6. Willie CK. Uncoupling neurovascular coupling: putative pathways of cerebrovascular regulation? J Appl Physiol; doi:10.1152/japplphysiol.00813.2013.

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