Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia

Abstract

Blood flow and vasodilatory responses are altered by age in a number of vascular beds, including the cerebral circulation. To test the role of prostaglandins as regulators of cerebral vascular function, we examined cerebral vasodilator responses to CO(2) (cerebrovascular reactivity) in young (26 ± 5 yr; 6 males/6 females) and older (65 ± 6 yr, 5 males/5 females) healthy humans before and after cyclooxygenase inhibition (using indomethacin). Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured before and 90 min after indomethacin. Changes in MCAv during the recovery from hypercapnia (vasoconstrictor responses) were also evaluated before and after indomethacin. Cerebrovascular reactivity was calculated using linear regression between MCAv and end-tidal CO(2). Young adults demonstrated greater MCAv (55 ± 6 vs. 39 ± 5 cm/s: P < 0.05) and MCAv reactivity (1.67 ± 0.20 vs. 1.09 ± 0.19 cm·s(-1)·mmHg(-1); P < 0.05) to hypercapnia compared with older adults (P < 0.05). In both groups MCAv and MCAv reactivity decreased between control and indomethacin. Furthermore, the age-related differences in these cerebrovascular variables were abolished by indomethacin. During the recovery from hypercapnia, there were no age-related differences in MCAv reactivity; however, indomethacin significantly reduced the MCAv reactivity in both groups. Taken together, these results suggest that cerebral blood flow velocity and cerebrovascular reactivity are attenuated in aging humans, and may be due to a loss of prostaglandin-mediated vasodilation.

Fig. 1.

Timeline of experimental study day. FiCO₂, fractional concentration of inspired CO₂; HR, heart rate; ETCO₂, end-tidal CO₂; MAP, mean arterial pressure; MCAv, middle cerebral artery velocity.

Fig. 2.

MCAv and cerebrovascular conductance index (CVCi) before (control trial) and 90 min after indomethacin (indomethacin trial). Measurements were taken while subjects were breathing room air. *P < 0.05 vs. young; †P < 0.05 vs. control.

Fig. 3.

MCAv vs. ETCO₂ before (control trial) and 90 min after indomethacin (indomethacin trial) in young subjects (left panel) and older subjects (middle panel). Calculated reactivity slope for MCAv is on the right. *P < 0.05 vs. young. †P < 0.05 vs. control.

Fig. 4.

The slope of the relationship between percent change from baseline in CVCi (cm·s⁻¹·mmHg⁻¹) and percent change from baseline in ETCO₂ (mmHg). *P < 0.05 vs. young. †P < 0.05 vs. control.

Fig. 5.

MCAv vs. ETCO₂ during the recovery from hypercapnia in young and old subjects (left panel) before (control) and after (indomethacin) cyclooxygenase inhibition and the calculated reactivity slopes (right panel). †P < 0.05 vs. control.