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Effect of prostaglandin synthesis inhibitors on basal and CO2-stimulated cerebral blood flow in man
Gen. Pharmac. Vol. 14, pp. 179 to 180, 1983 Printed in Great Britain
0306-3623/83/01017%02503.00/0 Pergamon Press Ltd
EFFECT OF PROSTAGLANDIN SYNTHESIS INHIBITORS ON BASAL A N D CO2-STIMULATED CEREBRAL BLOOD FLOW IN MAN S. ERIKSSON1, L. HAGENFELDT2, D. LAW 3, C. PATRONO4, E. PINCA4 and A WENNMALM 3 Departments of Medicine ~, Clinical Physiology a, and Clinical Chemistry 2, Karolinska Institutet, Huddinge Hospital and Karolinska Hospital, Stockholm, Sweden and the Department of Pharmacology 4, Catholic University, Rome, Italy (Received 19 April 1982)
Abstract--The present data do not provide evidence that basal or CO2-stimulated human cerebral blood flow is under control of locally formed PG. It is suggested that the CBF decreasing effect elicited by indomethacin is separated from its inhibitory effect on PG formation.
INTRODUCTION The prostaglandin (PG) synthesis inhibitor indomethacin reduces basal cerebral blood flow (CBF) and markedly inhibits the CBF response to elevation of arterial PCO2 (hypercapnia) in animals (Pickard & Mackenzie, 1973; Sakabe & Siesj6, 1979) and in man (Wennmalm et al., 1981). It has been assumed from these data that the effect of indomethacin is related to inhibition of P G formation. However, in neither of these studies were any determinations of plasma levels of P G or of cerebral vascular P G production included. We have therefore investigated, in healthy volunteers, arterial and jugular venous plasma levels of P G precursor and of two P G metabolites, in the basal state and following CO2-stimulation of CBF, and furthermore, compared the effect of three different P G synthesis inhibitors--aspirin, indomethacin and naprosyn---on basal and CO2 stimulated CBF in these subjects. RESULTS AND DISCUSSION CBF was monitored using the N 2 0 wash-in technique (Kety & Schmidt, 1945). The cerebral 02 consumption and the cerebral uptake or release of free fatty acids (FFA)---including arachidonic acid
(AA)--was also followed. The efficacy of the P G synthesis inhibitors was monitored by following AAinduced platelet aggregation in plasma samples taken before and after drug administration. All drugs completely inhibited AA-induced aggregation, indicating that the P G synthesising enzyme cyclo-oxygenase was inhibited. In the basal state no release of AA or of PGI2 metabolites occurred over the brain. Aspirin failed to affect CBF, after acute as well as after chronic administration. Indomethacin significantly depressed CBF after acute administration, but this action by the drug was not present after one week's treatment. Acute administration of naprosyn did not change the 0 2 extraction over the brain indicating that CBF was unchanged. After chronic administration naprosyn also failed to change CBF. Inhalation of CO2 was followed by a significant release of AA but not of other F F A into the cerebral venous effluent. No release of PGI2 metabolites was present. Acute and chronic administration of aspirin did not affect the CO2-induced elevation of CBF. Indomethacin considerably limited the rise in CBF induced by inhalation of CO2, after acute as well as after chronic administration. Naprosyn, after chronic administration, did not affect CO2- induced increase in CBF.
Table 1. Cerebral blood flow, expressed in ml/li)0 ml tissue/min in the basal state and during inhalation of C O 2 a s indicated. CBF recordings were performed in the absence of drug treatment (control), and during acute and chronic treatment with aspirin, indomethacin or naprosyn. * indicates that the value is significantly different from the corresponding value before drug treatment Aspirin
lndomethacin Acute Chronic
Naprosyn Chronic
Control
Acute
Chronic
Normocapnia (21% 02 in N2)
43.1 + 2.1
38.3 + 2.7
45.7 ___4.9
34.6 + 2.6*
62.5 + 10.4
38.6 + 2.7
Hypercapnia (4-6~o CO2 and 21% Oz in N2)
70.7 + 6.5
75.1 -+ 5.9
79.5 _ 14.0
43.7 + 2.6*
79.7 _+ 11.0
70.0 + 8.2
179
S. ERIKSSON et al.
180
Acknowledgement--This study was supported by the Swedish Medical Research Council, Project O4X-4341.
REFERENCES
KETY S. S. & SCHMIDT C. F. (1945) The determination of cerebral blood flow in m a n by the use of nitrous oxide in low concentrations. Am. J. Physiol. 143, 53-66. PICKARD J. D. & MACKENZIE E. T. (1973) Inhibition of
prostaglandin synthesis and the response of baboon cerebral circulation to carbon dioxide. Nature, New Biol. 245, 187-188. SAKABE T. & SIESJ6 B. K. (1979) The effect of indomethacin on the blood flow-metabolism couple in the brain under normal, hypercapnic and hypoxic conditions. Acta physiol. Scand. 107, 283 284. WENNMALM A., ERIKSSON S. • WAHREN J. (1981) Effect of indomethacin on basal and carbon dioxide stimulated cerebral blood flow in man. Clin. Physiol, 1,227--243.
0306-3623/83/01017%02503.00/0 Pergamon Press Ltd
EFFECT OF PROSTAGLANDIN SYNTHESIS INHIBITORS ON BASAL A N D CO2-STIMULATED CEREBRAL BLOOD FLOW IN MAN S. ERIKSSON1, L. HAGENFELDT2, D. LAW 3, C. PATRONO4, E. PINCA4 and A WENNMALM 3 Departments of Medicine ~, Clinical Physiology a, and Clinical Chemistry 2, Karolinska Institutet, Huddinge Hospital and Karolinska Hospital, Stockholm, Sweden and the Department of Pharmacology 4, Catholic University, Rome, Italy (Received 19 April 1982)
Abstract--The present data do not provide evidence that basal or CO2-stimulated human cerebral blood flow is under control of locally formed PG. It is suggested that the CBF decreasing effect elicited by indomethacin is separated from its inhibitory effect on PG formation.
INTRODUCTION The prostaglandin (PG) synthesis inhibitor indomethacin reduces basal cerebral blood flow (CBF) and markedly inhibits the CBF response to elevation of arterial PCO2 (hypercapnia) in animals (Pickard & Mackenzie, 1973; Sakabe & Siesj6, 1979) and in man (Wennmalm et al., 1981). It has been assumed from these data that the effect of indomethacin is related to inhibition of P G formation. However, in neither of these studies were any determinations of plasma levels of P G or of cerebral vascular P G production included. We have therefore investigated, in healthy volunteers, arterial and jugular venous plasma levels of P G precursor and of two P G metabolites, in the basal state and following CO2-stimulation of CBF, and furthermore, compared the effect of three different P G synthesis inhibitors--aspirin, indomethacin and naprosyn---on basal and CO2 stimulated CBF in these subjects. RESULTS AND DISCUSSION CBF was monitored using the N 2 0 wash-in technique (Kety & Schmidt, 1945). The cerebral 02 consumption and the cerebral uptake or release of free fatty acids (FFA)---including arachidonic acid
(AA)--was also followed. The efficacy of the P G synthesis inhibitors was monitored by following AAinduced platelet aggregation in plasma samples taken before and after drug administration. All drugs completely inhibited AA-induced aggregation, indicating that the P G synthesising enzyme cyclo-oxygenase was inhibited. In the basal state no release of AA or of PGI2 metabolites occurred over the brain. Aspirin failed to affect CBF, after acute as well as after chronic administration. Indomethacin significantly depressed CBF after acute administration, but this action by the drug was not present after one week's treatment. Acute administration of naprosyn did not change the 0 2 extraction over the brain indicating that CBF was unchanged. After chronic administration naprosyn also failed to change CBF. Inhalation of CO2 was followed by a significant release of AA but not of other F F A into the cerebral venous effluent. No release of PGI2 metabolites was present. Acute and chronic administration of aspirin did not affect the CO2-induced elevation of CBF. Indomethacin considerably limited the rise in CBF induced by inhalation of CO2, after acute as well as after chronic administration. Naprosyn, after chronic administration, did not affect CO2- induced increase in CBF.
Table 1. Cerebral blood flow, expressed in ml/li)0 ml tissue/min in the basal state and during inhalation of C O 2 a s indicated. CBF recordings were performed in the absence of drug treatment (control), and during acute and chronic treatment with aspirin, indomethacin or naprosyn. * indicates that the value is significantly different from the corresponding value before drug treatment Aspirin
lndomethacin Acute Chronic
Naprosyn Chronic
Control
Acute
Chronic
Normocapnia (21% 02 in N2)
43.1 + 2.1
38.3 + 2.7
45.7 ___4.9
34.6 + 2.6*
62.5 + 10.4
38.6 + 2.7
Hypercapnia (4-6~o CO2 and 21% Oz in N2)
70.7 + 6.5
75.1 -+ 5.9
79.5 _ 14.0
43.7 + 2.6*
79.7 _+ 11.0
70.0 + 8.2
179
S. ERIKSSON et al.
180
Acknowledgement--This study was supported by the Swedish Medical Research Council, Project O4X-4341.
REFERENCES
KETY S. S. & SCHMIDT C. F. (1945) The determination of cerebral blood flow in m a n by the use of nitrous oxide in low concentrations. Am. J. Physiol. 143, 53-66. PICKARD J. D. & MACKENZIE E. T. (1973) Inhibition of
prostaglandin synthesis and the response of baboon cerebral circulation to carbon dioxide. Nature, New Biol. 245, 187-188. SAKABE T. & SIESJ6 B. K. (1979) The effect of indomethacin on the blood flow-metabolism couple in the brain under normal, hypercapnic and hypoxic conditions. Acta physiol. Scand. 107, 283 284. WENNMALM A., ERIKSSON S. • WAHREN J. (1981) Effect of indomethacin on basal and carbon dioxide stimulated cerebral blood flow in man. Clin. Physiol, 1,227--243.