PROSTAGLANDINS WORK IN PROGRESS
VASODILATORY ACTION OF ARACHIDONIC ACID IN HUMANS FOLLOWING INDOMETHACIN TREATMENT Ake Wennmalm Department of Clinical Physiology, Karolinska Institutet at Huddinge Hospital, S-141 86 Huddinge, Sweden. has been Arachidonic acid (AA), the precursor of PGE2 and PGF shown to produce a marked vasodepressor response in many &$cies (1,2, 3). Most authors assume that AA exerts this effect through its conversion to PGE2 or to some undefined intermediate in the biosynthesis of this ccmpound. The lack of effect by AA when given to animals treated with aspirin or indomethacin supports such a view. In the present communication some preliminary data are presented which indicate that AA in part maintains its vasodilatory properties also when the cyclooxygenase system necessary for the conversion of AA to PGE2 is probably inhibited.
In four healthy male volunteers, oleic acid (OA), and subsequently AA, were infused at increasing rates, up to 3.8 mg/min, into the brachial artery. The forearm blood flow was measured using venous occlusion plethysmography (4). All subjects were studied twice, with an interval of seven days. During the 72 hrs preceding the first, but not the second, occasion the subjects were given indomethacin (50 mg x 4/24 hrs, orally). Aspirin (3 g) was given to the subjects 70-75 hrs before both occasions to counteract an increase in platelet aggregability during the infusion of AA (5). When no indomethacin was given, AA and OA, at an infusion rate of 3.8 mg/min during 4 min, increased the forearm blood flow from 5.7rl.O (mean + SE) to 21.3k3.1 and 8.Ok1.3 ml/ min/lOO ml tissue, respectively. After pretreatment with indomethacin, the same infusion rate increased the forearm blood flow from 5.320.8 to 15.4k1.8 and 8.9kl.O ml/min/lOO ml tissue, respectively. The increase in flow by AA after indomethacin, which thus reached almost 50 % of the increase without drug, is significant (PcO.01, paired t-test). The current dose of indomethacin has been shown to reduce the renal excretion of PGE metabolites in man by 77-98 % (6). Such a marked fall in this excretion indicates that the synthesis of PGE is almost completely inhibited. Nevertheless, in the present experiments a substantial increase in the forearm blood flow developed during the infusion of AA also after indomethacin. The moderate increase in forearm
APRIL 1977 VOL. 13 NO. 4
809
PROSTAGLANDINS
blood flow during OA infusion, unchanged by indomethacin, rules out the possibility of an unspecific fatty acid vasodilatory action. It cannot at present be excluded that the present dose of indomethacin, in contrast to Hamberg's observation, was insufficient to inhibit the formation of PGE completely. However, the more spectacular possibility, that the vasodilatory capacity of AA only in part is due to its conversion to PGE, should be the subject of further studies. Acknowledgements This study was supported by the Swedish Medical Research Council, project 04X-4341. REFERENCES 1.
Larsson, C. and Anggbrd, E. Arachidonic acid lowers and indomethatin increases the blood pressure of the rabbit. J. Pharm. Pharmac. 25: 653, 1973.
2.
Cohen, M., J. Sztokalo and E. Hinsch. The antihypertensive action of arachidonic acid in the spontaneous hypertensive rat and its antagonism by anti-inflammatory agents. Life Sci. 13: 317, 1973.
3.
Rose, J.C., M. Johnson, P.W. Ramwell and P.A. Kot. Effects of arachidonic acid on systemic arterial pressure, myocardial contractility and platelets in the dog (38408). Proc. Sot. Exp.Biol. Med. 147: 652, 1974.
4.
Dohn, K. Plethysmographs usable during functional states recording volume changes in ml. per 100 ml. of extremity. Rep. Stenomeml Hosp. 6: 147, 1956.
5.
Kocsis. Arachidonic Silver, M.J., J.B. Smith, C. Ingerman and J.J. acid-induced human platelet aggregation and prostaglandin formation. Prostaglandins. 4: 863, 1973.
6.
Hamberg, M. Inhibition of prostaglandin synthesis in man. Biochem. Biophys. Res. Commun. 49: 720, 1972.
Received
810
2/l/77
-
Approved
2/14/JJ
APRIL 1977 VOL. 13 NO. 4
VASODILATORY ACTION OF ARACHIDONIC ACID IN HUMANS FOLLOWING INDOMETHACIN TREATMENT Ake Wennmalm Department of Clinical Physiology, Karolinska Institutet at Huddinge Hospital, S-141 86 Huddinge, Sweden. has been Arachidonic acid (AA), the precursor of PGE2 and PGF shown to produce a marked vasodepressor response in many &$cies (1,2, 3). Most authors assume that AA exerts this effect through its conversion to PGE2 or to some undefined intermediate in the biosynthesis of this ccmpound. The lack of effect by AA when given to animals treated with aspirin or indomethacin supports such a view. In the present communication some preliminary data are presented which indicate that AA in part maintains its vasodilatory properties also when the cyclooxygenase system necessary for the conversion of AA to PGE2 is probably inhibited.
In four healthy male volunteers, oleic acid (OA), and subsequently AA, were infused at increasing rates, up to 3.8 mg/min, into the brachial artery. The forearm blood flow was measured using venous occlusion plethysmography (4). All subjects were studied twice, with an interval of seven days. During the 72 hrs preceding the first, but not the second, occasion the subjects were given indomethacin (50 mg x 4/24 hrs, orally). Aspirin (3 g) was given to the subjects 70-75 hrs before both occasions to counteract an increase in platelet aggregability during the infusion of AA (5). When no indomethacin was given, AA and OA, at an infusion rate of 3.8 mg/min during 4 min, increased the forearm blood flow from 5.7rl.O (mean + SE) to 21.3k3.1 and 8.Ok1.3 ml/ min/lOO ml tissue, respectively. After pretreatment with indomethacin, the same infusion rate increased the forearm blood flow from 5.320.8 to 15.4k1.8 and 8.9kl.O ml/min/lOO ml tissue, respectively. The increase in flow by AA after indomethacin, which thus reached almost 50 % of the increase without drug, is significant (PcO.01, paired t-test). The current dose of indomethacin has been shown to reduce the renal excretion of PGE metabolites in man by 77-98 % (6). Such a marked fall in this excretion indicates that the synthesis of PGE is almost completely inhibited. Nevertheless, in the present experiments a substantial increase in the forearm blood flow developed during the infusion of AA also after indomethacin. The moderate increase in forearm
APRIL 1977 VOL. 13 NO. 4
809
PROSTAGLANDINS
blood flow during OA infusion, unchanged by indomethacin, rules out the possibility of an unspecific fatty acid vasodilatory action. It cannot at present be excluded that the present dose of indomethacin, in contrast to Hamberg's observation, was insufficient to inhibit the formation of PGE completely. However, the more spectacular possibility, that the vasodilatory capacity of AA only in part is due to its conversion to PGE, should be the subject of further studies. Acknowledgements This study was supported by the Swedish Medical Research Council, project 04X-4341. REFERENCES 1.
Larsson, C. and Anggbrd, E. Arachidonic acid lowers and indomethatin increases the blood pressure of the rabbit. J. Pharm. Pharmac. 25: 653, 1973.
2.
Cohen, M., J. Sztokalo and E. Hinsch. The antihypertensive action of arachidonic acid in the spontaneous hypertensive rat and its antagonism by anti-inflammatory agents. Life Sci. 13: 317, 1973.
3.
Rose, J.C., M. Johnson, P.W. Ramwell and P.A. Kot. Effects of arachidonic acid on systemic arterial pressure, myocardial contractility and platelets in the dog (38408). Proc. Sot. Exp.Biol. Med. 147: 652, 1974.
4.
Dohn, K. Plethysmographs usable during functional states recording volume changes in ml. per 100 ml. of extremity. Rep. Stenomeml Hosp. 6: 147, 1956.
5.
Kocsis. Arachidonic Silver, M.J., J.B. Smith, C. Ingerman and J.J. acid-induced human platelet aggregation and prostaglandin formation. Prostaglandins. 4: 863, 1973.
6.
Hamberg, M. Inhibition of prostaglandin synthesis in man. Biochem. Biophys. Res. Commun. 49: 720, 1972.
Received
810
2/l/77
-
Approved
2/14/JJ
APRIL 1977 VOL. 13 NO. 4
