Differential responses to CO2 and sympathetic stimulation in the cerebral and femoral circulations in humans

Abstract

The relative importance of CO2 and sympathetic stimulation in the regulation of cerebral and peripheral vasculatures has not been previously studied in humans. We investigated the effect of sympathetic activation, produced by isometric handgrip (HG) exercise, on cerebral and femoral vasculatures during periods of isocapnia and hypercapnia. In 14 healthy males (28.1 +/- 3.7 (mean +/- S.D.) years), we measured flow velocity (VP; transcranial Doppler ultrasound) in the middle cerebral artery during euoxic isocapnia (ISO, +1 mmHg above rest) and two levels of euoxic hypercapnia (HC5, end-tidal P(CO(2)), P(ET,CO2), = +5 mmHg above ISO; HC10, P(ET,CO2) = +10 above ISO). Each P(ET,CO2) level was maintained for 10 min using the dynamic end-tidal forcing technique, during which increases in sympathetic activity were elicited by a 2-min HG at 30% of maximal voluntary contraction. Femoral blood flow (FBF; Doppler ultrasound), muscle sympathetic nerve activity (MSNA; microneurography) and mean arterial pressure (MAP; Portapres) were also measured. Hypercapnia increased VP and FBF by 5.0 and 0.6% mmHg-1, respectively, and MSNA by 20-220%. Isometric HG increased MSNA by 50% and MAP by 20%, with no differences between ISO, HC5 and HC10. During the ISO HG there was an increase in cerebral vascular resistance (CVR; 20 +/- 11%), while VP remained unchanged. During HC5 and HC10 HG, VP increased (13% and 14%, respectively), but CVR was unchanged. In contrast, HG-induced sympathetic stimulation increased femoral vascular resistance (FVR) during ISO, HC5 and HC10 (17-41%), while there was a general decrease in FBF below ISO. The HG-induced increases in MSNA were associated with increases in FVR in all conditions (r = 0.76-0.87), whereas increases in MSNA were associated with increases in CVR only during ISO (r = 0.91). In summary, in the absence of hypercapnia, HG exercise caused cerebral vasoconstriction, myogenically and/or neurally, which was reflected by increases in CVR and a maintained VP. In contrast, HG increased FVR during conditions of ISO, HC5 and HC10. Therefore, the cerebral circulation is more responsive to alterations in PCO2, and less responsive to sympathetic stimulation than the femoral circulation.

Figure 1. Schematic of the experimental protocol illustrating the time-related alterations of end-tidal P_CO2 (P_ET,CO2), end-tidal P_O2 (P_ET,O2), ventilatory responses and periods of handgrip (shaded columns)

Data represents 15 s averages (mean ± s.d.; n = 14).

Figure 2. Representative recordings from one subject (ID, 0039) during conditions of isocapnia (A), 30 s before handgrip and during the last 30 s of handgrip (shaded column); and (B) during conditions of hypercapnia (P_ET,CO2 10 mmHg above resting baseline value), 30 s before handgrip and during the last 30 s of handgrip (shaded column)

Note that during the isocapnic conditions, is maintained despite elevations in MAP, indicating strong cerebral autoregulation. Conversely, during the hypercapnic conditions, increases in MAP are reflected in parallel increases in , suggesting a loss of cerebral autoregulation.

Figure 3. Percentage changes in middle cerebral artery peak blood flow velocity, femoral blood flow and cerebral and femoral vascular resistance during the isocapnic (ISO₁ and ISO₂) and hypercapnic (HC5, P_ET,CO2 5 mmHg above ISO₁; HC10, P_ET,CO2 10 mmHg above ISO₁) protocols

Periods of handgrip are shown by the open circles and squares. *Significant within-condition difference (P < 0.05) between rest and handgrip. Cerebrovascular resistance = (n = 14) and femoral vascular resistance = MAP/FBF (n = 11). Data show the marked effect of hypercapnia alone in producing vasodilatation in the cerebral circulation (indicated by the decrease in CVR and increase in , •), whereas there is little change in FVR and FBF in the limb with hypercapnia (▪). In the femoral circulation, handgrip-induced muscle sympathetic nerve activity elicited a marked increase in FVR during isocapnic and hypercapnic conditions (□); in the cerebral circulation, the change in CVR is only evident in the isocapnic conditions (○). Arrows (→) denote significant impact of handgrip.

Figure 4. Relationship between handgrip-induced increases in muscle sympathetic nerve activity (MSNA) and cerebral vascular resistance (CVR, left panel) and femoral vascular resistance (FVR, right panel) during isocapnic and hypercapnic conditions

Note the strong relationships between MSNA and CVR are lost during periods of hypercapnia.