109
J. Phy~tiol. (1976), 257, pp. 109-121 With 5 text -ft gure8 Printed in Great Britain
ENDOGENOUS PROSTAGLANDINS AS LOCAL REGULATORS OF BLOOD FLOW IN MAN: EFFECT OF INDOMETHACIN ON REACTIVE AND FUNCTIONAL HYPERAEMIA
By A. KILBOM AND A. WENNMALM From the Department of Clinical Physioloqjy, Karolinsia Institutet, Serafimerlasarettet, S-112 83 Stockholm and the National Board of Occupational Safety and Health, Stockholm, Sweden
(Received 4 August 1975) SUMMARY
1. The contribution of endogenously formed prostaglandins of the E series (PGE) to the development of reactive and functional hyperaemia was studied in the human forearm. 2. Forearm blood flow was recorded using venous occlusion plethysmography. The concentration of prostaglandin E-like substances (PLS) in the venous effluent from the muscle was analysed using bio-assay. For inhibition of PG biosynthesis, indomethacin (1.25 mg/kg body weight) was administered. 3. Following 5 mmn of arterial occlusion, a marked hyperaemia developed during the next 150 sec. Jndomethacin, while not affecting the resting arterial blood flow, significantly decreased the peak level as well as the duration of the hyperaemia. The total reactive hyperaemia was 25 ml./100 ml. tissue before, and 13 ml./100 ml. tissue after administration of indomethacin. 4. During sustained isometric forearm contraction, and following isometric and dynamic forearm muscle activity, a moderate hyperaemia was observed. This was significantly diminished when indomethacin had been administered, although not to the same extent as the reactive hyperaemia. The total hyperaemia in the absence and presence of indomethacin was 1 13 and 77 ml./100 nil. tissue, respectively, in connexion with isometric contraction and 206 and 120 ml./ 100 ml. tissue, respectively, following dynamic work. 5. The venous concentration of PLS was very low at rest. A significantly increased concentration was observed after ischaemia. This increased release of PbS was entirely suppressed by indomethacin. With the present
110
A. KILBOM AND A. WENNMALM
assay method, muscular activity elicited no detectable change in the venous concentration of PLS. 6. It is concluded that reactive hyperaemia depends to a considerable extent on an intact PGE synthesis. It is furthermore suggested that endogenous PGE may contribute to the functional hyperaemia that appears during and after muscle activity. INTRODUCTION
Although the physiological basis for reactive and functional hyperaemia has been studied for many years, the underlying mechanism is still incompletely known. It is generally considered that local metabolic factors, developing during muscle work and ischaemia, are mainly responsible for the associated hyperaemia (cf. Hudlicka, 1973). Changes in pH or in lactic acid concentration in the working muscle do not seem to play a major role alone, since the degree of post-exercise hyperaemia is not affected in subjects who lack the ability to break down glycogen to lactic acid and who consequently display an unchanged venous pH or lactate concentration (McArdle, 1951; Tobin & Coleman, 1965; Barcroft, Greenwood & Whelan, 1963). Increased potassium, ATP and osmolality are generally held to be possible mediators of hyperaemia (Rigler, 1932; Kjellmer, 1965; Mellander & Lundvall, 1971) since they all develop following muscular work. However, the extent to which these factors change in the venous blood in conjunction with exercise does not seem to offer a sufficient explanation for the hyperaemia either. Recently inorganic phosphate has been demonstrated as a possible mediator of functional hyperaemia in working muscles (Hilton & Vrbova', 1970). Since the factors mentioned do not afford a complete explanation for the mechanism behind functional or reactive hyperaemia, others must be considered too. Among the most potent known mediators of vasodilation are the prostaglandins of the E series (PGE) (cf. Karim & Somers, 1972), which on intra-arterial infusion have been shown to cause extensive vasodilatation in man even at very low concentrations (BevegArd & Or6, 1969). In the present study we have investigated the possibility that endogenous PGEs contribute to the functional and reactive hyperaemia in man. Forearm blood flow, recorded with and without inhibition of PG synthesis, has been studied after isometric and dynamic muscle activity as well as ischaemia, and the concentration of prostaglandin E-like substances (PLS) has been assayed in the forearm venous effluent. Part of this work has been published in abstract form (Kilbom & Wennmalm, 1974).
PROSTAGLANDINS AND FOREARM BLOOD FLOW
111
METHODS
Healthy subjects, aged 23-39, five women and five men, participated in the study. Forearm blood flow and venous PLS activity were measured at rest and during hyperaemia, induced by muscular activity or ischaemia. Venous occlusion plethysmography was used for estimating forearm blood flow. All experiments were performed twice, in the absence as well as in the presence of indomethacin (Indomee, 1-25 mg/kg body weight rectally).
Estimation of forearm blood flow The changes in forearm volume during proximal venous occlusion were measured with an air-filled rubber cuff placed around the thickest part of the forearm (Dohn, 1956; Graf & Westersten 1959). The pressure in the cuff was about 3 mmHg and the venous occlusion pressure was 60 mmHg. The pressure changes in the rubber cuff induced by venous occlusion were measured with a pressure transducer (EMT 31, Siemens-Elema) and recorded on a Mingograf 34. The recordings were calibrated with known amounts of air, inflated into the cuff. The circulation to the hand was occluded during measurements in connexion with ischaemia, but not those with muscular activity. Three series of experiments were performed, separated by an interval of at least 1 week. Some of the subjects took part in all three. The series were: Effect of indomethacin on reactive hyperaemia. After 5 min of supine rest, blood flow was measured five or six times; arterial occlusion was then applied proximally on the upper arm for 5 min, after which the post-ischaemic blood flow was measured every 15th sec for 150 sec. The subjects were given indomethacin and the procedure was repeated 1 hr later. Effect of indomethacin on functional hyperaemia following dynamic work. After repeated blood flow measurements at rest, dynamic forearm work (handgrip) was performed on a hand ergometer (Fiab, Sweden) for 5 min (Wahren, 1966). The contraction frequency was 1 Hz and the work load was 0-83 W (5 kp.m/min) for the female and 1-67 W (10 kp.m/min) for the male subjects. Immediately after this work, forearm blood flow was measured repeatedly, every 15 sec, during the first 5 min of recovery and then every 30 sec for a further 5 min. Indomethacin was then given and the procedure was repeated 1 hr later. Effect of indomethacin on functional hyperaemia induced by stained isometric contraction. After repeated flow measurements at rest, maximal isometric forearm strength (handgrip) was measured (see below). The subjects then performed a sustained isometric contraction for 5 min with an intensity corresponding to 15 % of the maximal isometric strength. During this contraction, blood flow measurements were made every 30 sec, and after the contraction every 15 sec for 2 min and then every 30 see for another 8 min. Indomethacin was administered and 1 hr later the blood flow measurements were repeated during and after isometric contraction of the same intensity. The isometric strength was measured on a strain gauge connected to a measuring bridge (Philips PT 1200/01) (Wahren, 1966). The maximal isometric strength and the intensity of the submaximal isometric contraction were monitored on a scale connected to the measuring bridge. The subjects could easily follow the deflexion on the scale and adjust the contraction to the individual intensity. The measurements in the three procedures, were also obtained twice in five subjects each, with an interval of 1 hr but without the administration of indomethacin between the measurements.
112
A. KILBOM AND A. WENNMALM
Analy8i8 of forearm venous prostaglandin E-like substances (PLS) In order to avoid the release of PG from the platelets during the sampling of blood, all subjects were pre-treated with 3 g aspirin 3 days before the investigation. This treatment, while not affecting the general PG synthesis in the tissues at the time of blood sampling (see Hamberg, 1972), inhibits the release of PG from the platelets for 3-4 days after administration of the drug (Kocsis, Hernandovich, Silver, Smith & Ingerman, 1973). Forearm venous blood wvas sampled via a 1-7 mm Teflon catheter, inserted 50 mm in the retrograde direction from the medial cubital vein on the side to be investigated. Care was taken to ensure that the tip of the catheter was positioned deep in the forearm muscle. This catheter position yields blood representative of the forearm venous effluent (Wahren, 1966). Blood samples (20 ml.) were taken at rest and during the 2 min immediately after the end of the ischaemia or work period. During sampling the blood was allowed to flow spontaneously into the test-tube, containing 0-5 ml. 0-1 M-EDTA (ethylenediaminetetra-acetate). The plasma was immediately separated by centrifuging at 2500 g for 10 min at a temperature of + 40 C. The plasma was subsequently passed over columns of Amberlite XAD-2 and PGs were elated with ethanol (Keirse & Turnbull, 1973). The eluate was purified with petrol at neutral pH and subsequently acidified and extracted twice with equal amounts of ethyl acetate. After evaporation to dryness, the residue was dissolved in 250 1L. distilled water. Quantitative estimation of PLS was performed on isolated superfused rat stomach muscle strip (Vane, 1957), mounted in a 4 ml. organ bath containing aerated Tyrode solution. The contractions of the assay organ were transferred to a Watana be Multicorder via a Harvard 0386 Heart/Smooth muscle transducer. Phentolamine (7 x 10-7 M), propranolol (7 x 10-7 m), atropine (10-6 M), methysergide (6 x 10-7 M) and diphenylhydramine (7 x 10-7 M) were added to the Tyrode solution to prevent activity in the assay organ due to the presence of noradrenaline, adrenaline, acetylcholine, serotonin or histamine in the lipid extracts of the plasma samples. Indomethacin (10-5 M) was also added to the medium in order to increase the sensitivity to PGE (Eckenfels & Vane, 1972). All samples were tested against known amounts of PGE1. The sensitivity of the assay organ was accepted when 1 ng PGE, evoked a distinct contraction. Usually 200 #sl. sample to be tested was added to the organ bath. Since each sample derived from 10-12 ml. plasma, the method permitted the accurate estimation of PLS levels equivalents to 100 pg/ml. plasma. The recovery of added PGE1 or PGE2 during the purification described was regularly checked, and was found to average 60 %. The figures given have not been corrected for losses during the purification procedure.
Calculations The total hyperaemia was estimated in each individual as the area between the blood flow curve during recovery and the preceding basal flow. The hyperaemia during isometric contraction was estimated in analogy with that during recovery and was added to the hyperaemia during recovery to give the total hyperaemia in connexion with isometric contraction. The figures given are expressed in ml./ 100 ml. tissue. Student's t-test for paired observations was used for statistical analysis. Values for resting blood flow, hyperaemia and PLS-concentration were compared in the absence and presence of indomethacin and are given as the mean + S.E. of the mean.
PROSTAGLANDINS AND FOREARM BLOOD FLOW
113
RESULTS
Reactive hyperaemia Mfter ischaemia there was a pronounced but relatively brief vasodilatation, increasing the mean forearm blood flow from 3-7 + 0'5 to a maximum of 42-0 + 4-3 ml. min-' 100 ml. tissue-' (Fig. 1). Blood flow had returned to the resting level after 150 sec. After indomethacin, the resting blood flow did not differ significantly from the pre-indomethacin value but the reactive hyperaemia was significantly decreased, the peak value being 25 % lower and blood flow being back on the resting level after only 75 sec (Fig. 1). 50 ,- rest---
ischaemiaW-
4,
recovery
~~~~~T
-
40
30 H.0J
E C> C>
0I
.20 ~-
T-
10
[-
OL
L 0
50
100
150
Time (sec)
Fig. 1. Forearm blood flow at rest and during the recovery period after 5 mini of arterial ischaemia. Mean values and S.E. of mean for ten subjects before, 0, and after indomethacin, *.
Functional hyperaemia (dynamic work) After dynamic work there was a more prolonged vasodilatation and blood flow had still not returned to the resting level after 10 min. The peak flow occurred 0-60 sec after dynamic work and the maximal values were almost as high as after ischaemia (Fig. 2). Following indomethacin, the functional hyperaemnia after dynamic work was significantly reduced but blood flow
114 A. KILBOM AND A. WENNMALM had still not returned to the resting level by the end of the 1 0 min observation period. Blood flow at rest before work was not significantly affected
by indomethacin (Fig. 2). s0
-dynamic work-'--
recovery
rest
~40 IC 30E
o 20 0 0 .0
E
E10
0 U..
01 0 5
10
15
Time (min) Fig. 2. Forearm blood flow at rest and during recovery after dynamic work. Mean values and s.E. of mean for ten subjects before, 0 and after ,
indomethacin,@0. Functional hyperaemia (isometric contraction) During isometric forearm contraction at 15 % of maximal strength, blood flow increased slowly and was about three times the resting value after 5 min. During the recovery period the blood flow went on rising at first, reaching peak values 0-60 sec after the muscular activity. These peak values, however, were lower than those after ischaemnia and after dynamic work. Blood flow had nearly returned to the resting level 10 min after -the isometric contraction (Fig. 3). After indomethacin, resting blood flow was unaffected but the hyperaemia during and after isometric work was significantly reduced and blood flow had returned to the resting level about 5 min after the contraction (Fig. 3). Total hyperaemia after ischaemia, after dynamic work or in connexion with isometric contraction was significantly higher when the PG synthesis was intact than when it was inhibited (Table 1). The duration of the hyperaemia was shorter after ischaemia than after muscular activity (Fig. 1-3). The indomethacin-induced reduction of blood flow also differed
PROSTAGLANDINS AND FOREARM BLOOD FLOW
115
TABLE 1. Reactive and functional hyperaemia in ten subjects with PG-synthesis inhibited (with indomethacin) and intact. Total reactive hyperaemia following ischaemia and functional hyperaemia after dynamic work were measured during the recovery periods of 150 sec and 10 min respectively. Functional hyperaemia at isometric contraction was measured during 5 min of contraction and during the subsequent 10 min recovery period
After ischemia After dynamic work During and following isometric contraction
PG synthesis inhibited 13±2 120 + 25
PG synthesis intact 25±4(P < 0.01) 206± 35 (P < 0.01)
% increase
77 ± 12
113±14 (P
J. Phy~tiol. (1976), 257, pp. 109-121 With 5 text -ft gure8 Printed in Great Britain
ENDOGENOUS PROSTAGLANDINS AS LOCAL REGULATORS OF BLOOD FLOW IN MAN: EFFECT OF INDOMETHACIN ON REACTIVE AND FUNCTIONAL HYPERAEMIA
By A. KILBOM AND A. WENNMALM From the Department of Clinical Physioloqjy, Karolinsia Institutet, Serafimerlasarettet, S-112 83 Stockholm and the National Board of Occupational Safety and Health, Stockholm, Sweden
(Received 4 August 1975) SUMMARY
1. The contribution of endogenously formed prostaglandins of the E series (PGE) to the development of reactive and functional hyperaemia was studied in the human forearm. 2. Forearm blood flow was recorded using venous occlusion plethysmography. The concentration of prostaglandin E-like substances (PLS) in the venous effluent from the muscle was analysed using bio-assay. For inhibition of PG biosynthesis, indomethacin (1.25 mg/kg body weight) was administered. 3. Following 5 mmn of arterial occlusion, a marked hyperaemia developed during the next 150 sec. Jndomethacin, while not affecting the resting arterial blood flow, significantly decreased the peak level as well as the duration of the hyperaemia. The total reactive hyperaemia was 25 ml./100 ml. tissue before, and 13 ml./100 ml. tissue after administration of indomethacin. 4. During sustained isometric forearm contraction, and following isometric and dynamic forearm muscle activity, a moderate hyperaemia was observed. This was significantly diminished when indomethacin had been administered, although not to the same extent as the reactive hyperaemia. The total hyperaemia in the absence and presence of indomethacin was 1 13 and 77 ml./100 nil. tissue, respectively, in connexion with isometric contraction and 206 and 120 ml./ 100 ml. tissue, respectively, following dynamic work. 5. The venous concentration of PLS was very low at rest. A significantly increased concentration was observed after ischaemia. This increased release of PbS was entirely suppressed by indomethacin. With the present
110
A. KILBOM AND A. WENNMALM
assay method, muscular activity elicited no detectable change in the venous concentration of PLS. 6. It is concluded that reactive hyperaemia depends to a considerable extent on an intact PGE synthesis. It is furthermore suggested that endogenous PGE may contribute to the functional hyperaemia that appears during and after muscle activity. INTRODUCTION
Although the physiological basis for reactive and functional hyperaemia has been studied for many years, the underlying mechanism is still incompletely known. It is generally considered that local metabolic factors, developing during muscle work and ischaemia, are mainly responsible for the associated hyperaemia (cf. Hudlicka, 1973). Changes in pH or in lactic acid concentration in the working muscle do not seem to play a major role alone, since the degree of post-exercise hyperaemia is not affected in subjects who lack the ability to break down glycogen to lactic acid and who consequently display an unchanged venous pH or lactate concentration (McArdle, 1951; Tobin & Coleman, 1965; Barcroft, Greenwood & Whelan, 1963). Increased potassium, ATP and osmolality are generally held to be possible mediators of hyperaemia (Rigler, 1932; Kjellmer, 1965; Mellander & Lundvall, 1971) since they all develop following muscular work. However, the extent to which these factors change in the venous blood in conjunction with exercise does not seem to offer a sufficient explanation for the hyperaemia either. Recently inorganic phosphate has been demonstrated as a possible mediator of functional hyperaemia in working muscles (Hilton & Vrbova', 1970). Since the factors mentioned do not afford a complete explanation for the mechanism behind functional or reactive hyperaemia, others must be considered too. Among the most potent known mediators of vasodilation are the prostaglandins of the E series (PGE) (cf. Karim & Somers, 1972), which on intra-arterial infusion have been shown to cause extensive vasodilatation in man even at very low concentrations (BevegArd & Or6, 1969). In the present study we have investigated the possibility that endogenous PGEs contribute to the functional and reactive hyperaemia in man. Forearm blood flow, recorded with and without inhibition of PG synthesis, has been studied after isometric and dynamic muscle activity as well as ischaemia, and the concentration of prostaglandin E-like substances (PLS) has been assayed in the forearm venous effluent. Part of this work has been published in abstract form (Kilbom & Wennmalm, 1974).
PROSTAGLANDINS AND FOREARM BLOOD FLOW
111
METHODS
Healthy subjects, aged 23-39, five women and five men, participated in the study. Forearm blood flow and venous PLS activity were measured at rest and during hyperaemia, induced by muscular activity or ischaemia. Venous occlusion plethysmography was used for estimating forearm blood flow. All experiments were performed twice, in the absence as well as in the presence of indomethacin (Indomee, 1-25 mg/kg body weight rectally).
Estimation of forearm blood flow The changes in forearm volume during proximal venous occlusion were measured with an air-filled rubber cuff placed around the thickest part of the forearm (Dohn, 1956; Graf & Westersten 1959). The pressure in the cuff was about 3 mmHg and the venous occlusion pressure was 60 mmHg. The pressure changes in the rubber cuff induced by venous occlusion were measured with a pressure transducer (EMT 31, Siemens-Elema) and recorded on a Mingograf 34. The recordings were calibrated with known amounts of air, inflated into the cuff. The circulation to the hand was occluded during measurements in connexion with ischaemia, but not those with muscular activity. Three series of experiments were performed, separated by an interval of at least 1 week. Some of the subjects took part in all three. The series were: Effect of indomethacin on reactive hyperaemia. After 5 min of supine rest, blood flow was measured five or six times; arterial occlusion was then applied proximally on the upper arm for 5 min, after which the post-ischaemic blood flow was measured every 15th sec for 150 sec. The subjects were given indomethacin and the procedure was repeated 1 hr later. Effect of indomethacin on functional hyperaemia following dynamic work. After repeated blood flow measurements at rest, dynamic forearm work (handgrip) was performed on a hand ergometer (Fiab, Sweden) for 5 min (Wahren, 1966). The contraction frequency was 1 Hz and the work load was 0-83 W (5 kp.m/min) for the female and 1-67 W (10 kp.m/min) for the male subjects. Immediately after this work, forearm blood flow was measured repeatedly, every 15 sec, during the first 5 min of recovery and then every 30 sec for a further 5 min. Indomethacin was then given and the procedure was repeated 1 hr later. Effect of indomethacin on functional hyperaemia induced by stained isometric contraction. After repeated flow measurements at rest, maximal isometric forearm strength (handgrip) was measured (see below). The subjects then performed a sustained isometric contraction for 5 min with an intensity corresponding to 15 % of the maximal isometric strength. During this contraction, blood flow measurements were made every 30 sec, and after the contraction every 15 sec for 2 min and then every 30 see for another 8 min. Indomethacin was administered and 1 hr later the blood flow measurements were repeated during and after isometric contraction of the same intensity. The isometric strength was measured on a strain gauge connected to a measuring bridge (Philips PT 1200/01) (Wahren, 1966). The maximal isometric strength and the intensity of the submaximal isometric contraction were monitored on a scale connected to the measuring bridge. The subjects could easily follow the deflexion on the scale and adjust the contraction to the individual intensity. The measurements in the three procedures, were also obtained twice in five subjects each, with an interval of 1 hr but without the administration of indomethacin between the measurements.
112
A. KILBOM AND A. WENNMALM
Analy8i8 of forearm venous prostaglandin E-like substances (PLS) In order to avoid the release of PG from the platelets during the sampling of blood, all subjects were pre-treated with 3 g aspirin 3 days before the investigation. This treatment, while not affecting the general PG synthesis in the tissues at the time of blood sampling (see Hamberg, 1972), inhibits the release of PG from the platelets for 3-4 days after administration of the drug (Kocsis, Hernandovich, Silver, Smith & Ingerman, 1973). Forearm venous blood wvas sampled via a 1-7 mm Teflon catheter, inserted 50 mm in the retrograde direction from the medial cubital vein on the side to be investigated. Care was taken to ensure that the tip of the catheter was positioned deep in the forearm muscle. This catheter position yields blood representative of the forearm venous effluent (Wahren, 1966). Blood samples (20 ml.) were taken at rest and during the 2 min immediately after the end of the ischaemia or work period. During sampling the blood was allowed to flow spontaneously into the test-tube, containing 0-5 ml. 0-1 M-EDTA (ethylenediaminetetra-acetate). The plasma was immediately separated by centrifuging at 2500 g for 10 min at a temperature of + 40 C. The plasma was subsequently passed over columns of Amberlite XAD-2 and PGs were elated with ethanol (Keirse & Turnbull, 1973). The eluate was purified with petrol at neutral pH and subsequently acidified and extracted twice with equal amounts of ethyl acetate. After evaporation to dryness, the residue was dissolved in 250 1L. distilled water. Quantitative estimation of PLS was performed on isolated superfused rat stomach muscle strip (Vane, 1957), mounted in a 4 ml. organ bath containing aerated Tyrode solution. The contractions of the assay organ were transferred to a Watana be Multicorder via a Harvard 0386 Heart/Smooth muscle transducer. Phentolamine (7 x 10-7 M), propranolol (7 x 10-7 m), atropine (10-6 M), methysergide (6 x 10-7 M) and diphenylhydramine (7 x 10-7 M) were added to the Tyrode solution to prevent activity in the assay organ due to the presence of noradrenaline, adrenaline, acetylcholine, serotonin or histamine in the lipid extracts of the plasma samples. Indomethacin (10-5 M) was also added to the medium in order to increase the sensitivity to PGE (Eckenfels & Vane, 1972). All samples were tested against known amounts of PGE1. The sensitivity of the assay organ was accepted when 1 ng PGE, evoked a distinct contraction. Usually 200 #sl. sample to be tested was added to the organ bath. Since each sample derived from 10-12 ml. plasma, the method permitted the accurate estimation of PLS levels equivalents to 100 pg/ml. plasma. The recovery of added PGE1 or PGE2 during the purification described was regularly checked, and was found to average 60 %. The figures given have not been corrected for losses during the purification procedure.
Calculations The total hyperaemia was estimated in each individual as the area between the blood flow curve during recovery and the preceding basal flow. The hyperaemia during isometric contraction was estimated in analogy with that during recovery and was added to the hyperaemia during recovery to give the total hyperaemia in connexion with isometric contraction. The figures given are expressed in ml./ 100 ml. tissue. Student's t-test for paired observations was used for statistical analysis. Values for resting blood flow, hyperaemia and PLS-concentration were compared in the absence and presence of indomethacin and are given as the mean + S.E. of the mean.
PROSTAGLANDINS AND FOREARM BLOOD FLOW
113
RESULTS
Reactive hyperaemia Mfter ischaemia there was a pronounced but relatively brief vasodilatation, increasing the mean forearm blood flow from 3-7 + 0'5 to a maximum of 42-0 + 4-3 ml. min-' 100 ml. tissue-' (Fig. 1). Blood flow had returned to the resting level after 150 sec. After indomethacin, the resting blood flow did not differ significantly from the pre-indomethacin value but the reactive hyperaemia was significantly decreased, the peak value being 25 % lower and blood flow being back on the resting level after only 75 sec (Fig. 1). 50 ,- rest---
ischaemiaW-
4,
recovery
~~~~~T
-
40
30 H.0J
E C> C>
0I
.20 ~-
T-
10
[-
OL
L 0
50
100
150
Time (sec)
Fig. 1. Forearm blood flow at rest and during the recovery period after 5 mini of arterial ischaemia. Mean values and S.E. of mean for ten subjects before, 0, and after indomethacin, *.
Functional hyperaemia (dynamic work) After dynamic work there was a more prolonged vasodilatation and blood flow had still not returned to the resting level after 10 min. The peak flow occurred 0-60 sec after dynamic work and the maximal values were almost as high as after ischaemia (Fig. 2). Following indomethacin, the functional hyperaemnia after dynamic work was significantly reduced but blood flow
114 A. KILBOM AND A. WENNMALM had still not returned to the resting level by the end of the 1 0 min observation period. Blood flow at rest before work was not significantly affected
by indomethacin (Fig. 2). s0
-dynamic work-'--
recovery
rest
~40 IC 30E
o 20 0 0 .0
E
E10
0 U..
01 0 5
10
15
Time (min) Fig. 2. Forearm blood flow at rest and during recovery after dynamic work. Mean values and s.E. of mean for ten subjects before, 0 and after ,
indomethacin,@0. Functional hyperaemia (isometric contraction) During isometric forearm contraction at 15 % of maximal strength, blood flow increased slowly and was about three times the resting value after 5 min. During the recovery period the blood flow went on rising at first, reaching peak values 0-60 sec after the muscular activity. These peak values, however, were lower than those after ischaemnia and after dynamic work. Blood flow had nearly returned to the resting level 10 min after -the isometric contraction (Fig. 3). After indomethacin, resting blood flow was unaffected but the hyperaemia during and after isometric work was significantly reduced and blood flow had returned to the resting level about 5 min after the contraction (Fig. 3). Total hyperaemia after ischaemia, after dynamic work or in connexion with isometric contraction was significantly higher when the PG synthesis was intact than when it was inhibited (Table 1). The duration of the hyperaemia was shorter after ischaemia than after muscular activity (Fig. 1-3). The indomethacin-induced reduction of blood flow also differed
PROSTAGLANDINS AND FOREARM BLOOD FLOW
115
TABLE 1. Reactive and functional hyperaemia in ten subjects with PG-synthesis inhibited (with indomethacin) and intact. Total reactive hyperaemia following ischaemia and functional hyperaemia after dynamic work were measured during the recovery periods of 150 sec and 10 min respectively. Functional hyperaemia at isometric contraction was measured during 5 min of contraction and during the subsequent 10 min recovery period
After ischemia After dynamic work During and following isometric contraction
PG synthesis inhibited 13±2 120 + 25
PG synthesis intact 25±4(P < 0.01) 206± 35 (P < 0.01)
% increase
77 ± 12
113±14 (P
