Sex-Related Differences in Acetazolamide-Induced Cerebral Vasomotor Reactivity
Background and Purpose Cerebral vasomotor reactivity can easily be assessed reliably by measuring vasodilatory response to acetazolamide by transcranial Doppler sonography. The aim of this study was to confirm the hypothesis that female sex is associated with an increased cerebrovascular flow reserve.
Methods Blood flow velocity of the middle cerebral artery was measured by transcranial Doppler sonography in 36 healthy sex- and age-matched subjects. After the initial blood flow velocities were recorded, the subjects received 14.3 mg/kg body wt acetazolamide, ie, 1 g/70 kg, intravenously. The measurements were repeatedly performed at 5-minute intervals starting 10 minutes after injection and lasting for 30 minutes. The highest measured flow velocities were used for further analysis.
Results In both groups mean blood flow velocity increased significantly after acetazolamide (women, from 60.2±12.5 to 89.9±14.4 cm/s, P<.006; men, from 54.5±18.8 to 75.7±24.5 cm/s, P<.02). The difference in mean blood flow velocity after acetazolamide between groups of women and men was statistically significant (P<.02).
Conclusions Female subjects show an increased vasodilatory response to the acetazolamide test compared with men.
Cerebral vasomotor reactivity can easily be assessed reliably by measuring vasodilatory response to acetazolamide by TCD.1 Acetazolamide inhibits carboanhydrase, an enzyme that catalyzes either the dissociation or the formation of carbonic acid, thereby causing a marked cerebral acidosis.2 This effect develops rather slowly, peaking after 10 minutes, and is a very strong vasodilatory stimulus.3 Dahl and coworkers4 found a positive correlation between the increase in blood flow velocity in the MCA and the increase in CBF. In a previous study we examined 104 patients with internal carotid artery occlusions and 100 healthy control subjects by TCD and the acetazolamide test.5 Analyzing factors that influence vasomotor reactivity, we observed a sex-related difference in both patients with internal carotid artery occlusions (n=104) and healthy control subjects (n=100).
The aim of the present study was to confirm the hypothesis that female sex is associated with an increased cerebrovascular flow reserve as measured by an increased vasodilatory response to the acetazolamide test.
Subjects and Methods
After we obtained informed consent, 36 healthy sex- and age-matched subjects (18 women and 18 men) were admitted to the study. The basic clinical characteristics—age, blood pressure, heart rate, Po2, and Pco2—of both groups were comparable. However, the female study group showed a significantly lower body weight (P<.0001) as well as a lower hematocrit value (P<.03). The female group comprised 5 smokers, and hyperlipemia (cholesterol >200 mg/dL) was present in 2 subjects. The male group comprised 4 cigarette smokers and 2 men with hyperlipemia.
Rigid exclusion criteria were established to avoid any bias by an unbalanced distribution of concomitant diseases or drug therapy: subjects with hypertension, diabetes mellitus, congestive heart failure (>New York Heart Association grade I), chronic obstructive lung disease, cerebrovascular disease (transient ischemic attack, stroke, or carotid artery stenoses >25% evaluated by duplex sonography), hematologic disease, and cancer were excluded from the study as well as patients being treated with nitrates, β-blocking agents, calcium channel blockers, anticoagulants, and vasodilatory drugs.
A three-dimensional TCD scanner (Trans-Scan, EME) as described by Aaslid et al6 7 was used for the TCD examination. The recorded color-coded frequency spectra were drawn by the computer in three projections. Spectral information was displayed as velocity in centimeters per second. CBF velocity from Doppler shift frequency was calculated assuming an angle of 0° between probe and blood vessel.
All subjects were studied in the morning in a supine resting state with their eyes closed. The probe of the Trans-Scan was placed against the side of the skull just above the zygomatic arch. The MCA on both sides was insonated at a depth of 45 to 60 mm. After an optimal signal of either the right or left MCA was obtained, the probe was fixed in this position and the spots marked for further evaluation. Systolic, diastolic, and mean blood flow velocities were recorded. After the initial blood flow velocities were recorded, the subjects received 14.3 mg/kg body wt acetazolamide, ie, 1 g/70 kg, intravenously. The measurements were repeatedly performed at 5-minute intervals starting 10 minutes after injection and lasting for 30 minutes. The highest measured CBF velocities were used for further analysis.
PI was calculated according to the formula of Gosling and King8 : PI=(Vsystolic−Vdiastolic)/Vmean, where V indicates blood flow velocity. Flow acceleration was calculated as the difference between Vmean at rest and the highest Vmean after acetazolamide. Blood pressure was measured by the cuff method, and the mean blood pressure was calculated by standard formulas.
The statistical analysis was performed by an IBM mainframe 3090-400E/2VF with vector facilities installed at the University of Vienna. The statistical software used was sas (Statistical Analysis System) and spss (Statistical Package for the Social Sciences) release 4.0. The data are expressed as mean±SD. A correlation analysis of the variables depicted in Table 2⇓ was performed with the use of Pearson correlation coefficients. Spearman’s correlation coefficients were used as a check test. The Mann-Whitney U and Wilcoxon rank-sum W tests were used to analyze differences between the variables. We assumed statistical significance at P<.05.
Table 1⇓ summarizes Vmean and PI at rest and after acetazolamide in both groups. The difference in Vmean at rest between female and male groups was statistically nonsignificant. In both groups Vmean increased significantly after acetazolamide (women, from 60.2±12.5 to 89.9±14.4 cm/s, P<.006; men, from 54.5±18.8 to 75.7±24.5 cm/s, P<.02). The difference in Vmean after acetazolamide between female and male groups was statistically significant (P<.02). The difference in PI at rest as well as after acetazolamide between female and male groups was statistically nonsignificant. In both groups PI decreased significantly after acetazolamide (women, from 0.94±0.15 to 0.79±0.15, P<.007; men, from 0.93±0.15 to 0.79±0.23, P<.001).
The results of the correlation analysis in which Pearson correlation coefficients were used are depicted in Table 2⇓. Sex displayed a significant correlation with Vmean after acetazolamide (P<.04). A further strong correlation was found between age and Vmean at rest (P<.001) and after acetazolamide (P<.02) as well as between age and PI at rest (P<.006) and after acetazolamide (P<.002). Pco2 showed a significant correlation with Vmean after acetazolamide (P<.02), but there was no significant correlation between Pco2 and flow acceleration. A statistically significant negative correlation was displayed between cigarette smoking and Vmean at rest (P<.03) and flow acceleration (P<.04).
No statistically significant correlations were found between blood pressure (systolic, diastolic, and mean), heart rate, body weight, hematocrit, Po2, and the cerebral blood flow parameters (Vmean and PI at rest and after acetazolamide and flow acceleration).
Our study was designed to confirm the results of a former uncontrolled study that showed significantly increased vasoreactivity after acetazolamide in women compared with men. However, in that patient population we administered 1 g IV acetazolamide to all subjects independent of their body weight. In the present study dosage of acetazolamide was related to body weight, ie, 1 g/70 kg IV. Therefore, the significant differences in body weight between the study groups (P<.001) probably have not influenced the results of this study. According to Maren,9 who found full inhibition of carboanhydrase after administration of acetazolamide at a dose greater than 10 mg/kg IV in humans, we assumed that by administration of a dose of 14.3 mg/kg, full inhibition of carboanhydrase in both sexes is reached. The strict exclusion criteria may have eliminated any bias by concomitant drug therapy or diseases that may influence cerebral vasomotor reactivity. We measured blood flow velocities 10 to 30 minutes after the administration of acetazolamide at 5-minute intervals. By study design the highest Vmean in the MCA was used for further evaluation. However, all subjects showed constant increased blood flow velocities during the measurement period. This is in accordance with the findings of Piepgras et al,1 who studied 12 normal subjects by this method and found a significant increase in flow velocity after injection, reaching a plateau after 5 minutes and lasting for at least 30 minutes. In this study the acetazolamide-induced increases in blood velocity in the MCA and in CBF measured by 133Xe dynamic single-photon emission CT correlated significantly in both hemispheres. Ehrenreich et al,10 studying 10 patients with various disorders, described a more marked increase in CBF by acetazolamide than that induced by 5 minutes of 5% CO2 inhalation. Vorstrup et al11 reported an increase in mean CBF after acetazolamide of 13% to 47%. However, in all these studies vasodilatory reserve capacity was not compared between women and men.
To the best of our knowledge, the present study is the first that was designed to test the hypothesis that there is a sex-related difference in acetazolamide-induced cerebral vasomotor reactivity. Correlation coefficients of the study group showed a significant correlation between age and Vmean at rest (P<.001) as well as Vmean after acetazolamide (P<.02) and between cigarette smoking and Vmean at rest (P<.03). However, the study group was age-matched (mean age of women, 53.1±11.9 years; mean age of men, 53.8±11.2 years). There were 5 smokers in the female group and 4 smokers in the male group. Pco2 showed a significant correlation with Vmean after acetazolamide (P<.02). However, the Pco2 values were comparable between the study groups (women, 39.0±3.5 mm Hg; men, 38.4±3.9 mm Hg). Female sex was associated with a significantly lower hematocrit value; however, this variable showed no significant correlation with blood flow velocity at rest and after acetazolamide. Therefore, all these variables could be excluded as cause for the increased vasomotor reactivity in the female study group. Sex was found to be the only variable between the study groups to correlate with differences in acetazolamide-induced vasomotor reactivity (P<.04).
It may be speculated that the administration of acetazolamide in women results in pronounced CO2 tension, leading to a higher CBF or blood flow velocity than in men, or that the vascular smooth muscle of women is more sensitive to that stimulus than that of men. A more advanced stage of arteriosclerosis may be further argument for the reduced vasodilatory capacity in men compared with women.
Our results suggest that women have a significantly increased vasodilatory capacity after the acetazolamide test compared with men. The mechanisms of increased vasomotor reactivity in women and the clinical significance of this phenomenon are currently undefined.
Selected Abbreviations and Acronyms
|CBF||=||cerebral blood flow|
|MCA||=||middle cerebral artery|
|TCD||=||transcranial Doppler sonography|
|Vmean||=||mean blood flow velocity|
- Received April 20, 1995.
- Revision received September 21, 1995.
- Accepted September 25, 1995.
- Copyright © 1996 by American Heart Association
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