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Effect of acute oral administration of captopril and MK-421 on vascular angiotensis converting enzyme activity in the spontaneously hypertensive rat
Life Sciences, Vol. 32, pp. 565-569 Printed in the U.S.A.
Pergamon Press
EFFECT OF ACUTE ORAL ADMINISTRATION OF CAPTOPRIL AND MK-421 ON VASCULARANGIOTENSIN CONVERTING ENZYMEACTIVITY IN THE SPONTANEOUSLYHYPERTENSIVERAT Marlene L. Cohen, Kathryn S. Wiley and Ken D. Kurz L i l l y Research Laboratories Eli L i l l y and Company Indianapolis, Indiana 46285 (Received in final form October 14, 1982)
Summary Vascular angiotensin converting enzyme (ACE) may be important as a potential site of action for the antihypertensive effect of ACE inhibitors. ACE a c t i v i t y , estimated by hydrolysis of [JH] HipGlyGly, was similar in the aorta, mesenteric and carotid arteries of SHR. ACE a c t i v i t y in veins was not as consistent and was significantly lower in the jugular veins and vena cava of SHR than in the arteries. Nevertheless, ACE a c t i v i t y in all the blood vessels examined, although less than lung ACE a c t i v i t y , was higher than ACE a c t i v i t y found in other tissues such as brain, heart and kidney. Equieffective antihypertensive doses of captopril (10 mg/kg p.o.) and MK-421 (1.0 mg/kg p.o.) dramatically inhibited ACE a c t i v i t y in all the arteries and veins examined. Maximal ACE inhibition occurred within 15 minutes after the oral administration of captopril. In contrast, maximal ACE inhibition was slower in onset and of longer duration after MK-421 than after captopril for all the vessels. Thus, r e l a t i v e l y high ACE a c t i v i t y can be measured in both arteries and veins from the spontaneously hypertensive rat (SHR) and ACE was dramatically inhibited after antihypertensive oral doses of captopril or MK-421. Furthermore, vascular ACE inhibition can be used to compare the onset and duration of a c t i v i t y of ACE inhibitors; MK-421 has a longer onset and duration in SHR than captopril based on inhibition of ACE in blood vessels. Previous studies have demonstrated that blood pressure reduction produced by angiotensin converting enzyme (ACE) inhibitors did not correlate with inhibition of serum ACE a c t i v i t y (I-3). This observation has led to the proposal that the localized inhibition of ACE in vascular tissue may provide a better predictive index of antihypertensive efficacy. In this regard, renin has been found in vascular tissue and is elevated in arteries from spontaneously hypertensive rats (SHR) (4). ACE a c t i v i t y has been demonstrated in vascular tissue based on contractile responses to angiotensin I (5-8) and biochemical assay of ACE a c t i v i t y in aorta of SHR (3). Furthermore, the renin-angiotensin system in vascular tissue is independent of changes in serum renin levels (4,9). Thus the possibility exists that vascular ACE may be inhibited independently of serum ACE a c t i v i t y . Using MK-421 and captopril, we demonstrated dramatic inhibition of aortic 0024-3205/83/060565-05503.00/0 Copyright (c) 1983 Pergamon Press Ltd.
566
Captopril and MK-421 on Vascular ACE
Vol. 32, No. 6, 1983
ACE a c t i v i t y at a time when blood pressure was reduced, but serum ACE a c t i v i t y was uninhibited (3). Because of the well documented heterogeneity of vascular tissue, and questions regarding the s u i t a b i l i t y of aortic ACE as an index of other vascular beds, we have extended our i n i t i a l stuides to several smaller peripheral vessels. Furthermore, since the antihypertensive effect of ACE inhibitors does not appear to be associated with pronounced postural hypotension, we questioned the extent of ACE a c t i v i t y in veins and the extent to which venous ACE was inhibited after oral administration of ACE inhibitors. The aim of these studies was twofold: 1) to compare control ACE a c t i v i t y between arteries and veins and, 2) to compare the disposition of captopril and MK-421 between such smaller arteries and veins. Methods Tissue preparation: Male SHR ranging from 20-24 weeks of age (325-375 gms) (Taconic Farms, Germantown, NY) were treated orally with equal volumes of captopril (10 mg/kg), MK-421 (1.0 mg/kg) or saline. These doses of captopril and MK-421 resulted in an approximately 15 to 20 mmHg f a l l in blood pressure that had not returned to control pressure by 24 hours (3). At the times indicated in Results, rats were k i l l e d by cervical dislocation. Vessels were removed, cleaned and a 5 or 10 percent homogenate of each tissue was prepared in ground glass homogenizers using Hepes (O.05M) buffer containing NaCl(O.15M), NapSO4 (O.6M) and NaN3(O.I percent) at pH 8.0 for optimal enzyme a c t i v i t y (I0). One mesenteric artery and vena cava, two carotid arteries and mesenteric veins and 4 jugular veins were assayed per sample. ACE assay: ACE a c t i v i t y was assayed using a radiometric assay method (Ventrex Laboratories, Inc., Portland, Maine) with [3H] Hippuryl-glycyl-glycine as substrate (800 nmoles) in a final volume of 100~I. Samples were preincubated for 5-10 minutes and then incubated with substrate for 60 minutes at 37°C. The reaction was stopped by the addition of 1.0 ml of O.1N HCI. Ethyl acetate (1.0 ml) was added and the samples were vortexed and centrifuged at lO00g for 10 min. Three hundred ~l of the ethyl acetate layer was added to 10 ml of s c i n t i l l a t i o n cocktail (Aquasol) and radiolabeled hippuric acid was counted by liquid s c i n t i l l a t i o n spectrometry. ACE a c t i v i t y was expressed as nmoles of [JH] hippuric acid formed/min/mg tissue. All assays were performed in duplicate and tissue samples from captopril-treated rats were processed and assayed within three hours since storage can influence the enzyme inhibition measured after captopril (11-13). Mean values were s t a t i s t i c a l l y compared by one-way analysis of variance followed by the Student's t - t e s t for unpaired data. Statistical significance between means was assumed when P
Vol. 32, No. 6, 1983
Captopril and MK-421 on Vascular ACE
567
vessels within 15 min after the oral administration of captopril. Within 15 min after MK-421, ACE inhibition was apparent in the mesenteric artery, vena cava and mesenteric vein, but not in the carotid artery or jugular vein. In all tissues, inhibition was less at this early time point after MK-421 than after captopril suggesting a slower onset of action after MK-421 r e l a t i v e to captopril. By one hour after MK-421, greater than 85 percent inhibition of ACE a c t i v i t y occurred in all the vessels examined. T h i s inhibition was comparable to that which occurred 15 min after captopril. TABLE I Control ACE A c t i v i t y in Peripheral Arteries and Veins from the SHR
Blood Vessel
n
ACE A c t i v i t y a nmol/mg/min
Arteries: Aorta
8
0.99 * 0.14
10
0.90 • 0.10
8
1.05 • 0.08
Vena Cava
8
0.23 * 0.2 b
Mesenteric Vein
7
0.87 • 0.12
Jugular Vein
5
0.45 * 0.06 b
Mesenteric Artery Carotid Artery Veins:
a) ACE a c t i v i t y was determined radiometrically as indicated under Methods. Enzymea c t i v i t y was expressed as nanomoles of [3H] hippuric acid formed per minute per milligram of tissue. Values are means * S. E. and n represents the number of samples. b) Significantly (p<.05) different from all other tissues as determined by one-way analysis of variance and subsequent Student's t - t e s t . Twenty four hours after oral administration of captopril, ACE a c t i v i t y in the vena cava and mesenteric veins was back to control values, although greater than 50 percent inhibition remained in the carotid and mesenteric arteries and jugular vein. Relative to captopril, ACE inhibition 24 hours after MK-421 was greater in all the vessels examined consistent with the longer duration of a c t i v i t y reported for MK-421 (1). Discussion In the present report, we have extended our information on tissue ACE a c t i v i t y to several peripheral arteries and veins from the SHR. ACE a c t i v i t y in a l l the blood vessels examined, while lower than that found in lung (3), was higher than ACE a c t i v i t y in heart, brain or kidney (3). All the arteries examined had similar ACE a c t i v i t y whereas ACE a c t i v i t y in veins was more variable ranging from a low of 0.23 nmol hippuric acid formedlmg tissue/min in the vena cava to 0.87 n ~ l hippuric acid formed/mg tissuelmin in the mesenteric vein.
568
Captopril and MK-421 on Vascular ACE
Vol. 32, No. 6, 1983
CAROTID ARTERY SHR m CAPTOPIIL (iDmg/k9 p.o.)
>. : 1 . 2 ~,~JMK421( l ~ / k g p.a.) I - "~ !.o
~..c. 1.2 ;" ~1.Oi
r ,! $
.2 0
,&, •
B
.25
,~ E .41
~
,
1
24
.25 1 24 TIME (hours)
TIME (hours)
i
1.2
_~
i.o
¢AVA I VENA SHR
MESENTERIC VEIN SHR J~CAPTOPRIL(iDml;/kg p.o.) ~'~JMK 421 ( 1.Omg/kg p.o.)
JJ~J CAPTOI~IL (1Omti/ks p.o.)
I JUGULAR VEIN SHR U CAPTOPRfL{IOmg/k s p.o.) )mE 0 . 6 i ~ MK421(l~nlm/Ica P.o.)
0.4 .6 I
.2 0
.25 1 24 TIME (hours)
0.2 v
.25 I TiME (hours)
0
.25 ! 24 TiME (hours)
FIG. 1 Effect of captopril (10.0 mg/kg) and MK-421 (1.0 mg/kg) on vascular ACE activity in SHR at various times (15 min, 60 min and 24 hrs.) after oral administration of each inhibitor. Shadedarea represents control ACE activity in each vascular bed determined after administration of saline to SHR. Bars are means * S.E. for the number of samples indicated above each bar. Tissues from captopril treated rats were not evaluated at one hr, since samples could not be stored (11-13). Since vascular tissue has been proposed as a target site for the antihypertensive activity of ACE inhibitors (1,3,4) and since prolonged ACE inhibition occurred in the aorta from SHR (3) after ACE inhibitors, i t became necessary to determine i f aortic ACE inhibition reflected the inhibition occurring in other smaller peripheral arteries Equieffective antihyertensive doses (3) of both captopril (10 mg/kg p.o.) and MK-421 (1.0 mglkg p.o.) inhibited ACE activity in the mesenteric and carotid artery. The time course of ACE inhibition in these smaller arteries by both captopril and MK-421 qualitatively paralleled the time course demonstrated in the aorta (3). However, ACE inhibition 24 hours after captopril (65 percent) or MK-421 (80 percent) in the mesenteric and carotid arteries was less than found in the aorta (>90 percent). With regard to venous ACE inhibition, both captopril and MK-421 inhibited ACE activity in all three veins. With the exception of the jugular vein where only 2 tissue samples were evaluated at 24 hours after oral administration of captopril or MK-421, the duration of ACE inhibition was less in the vena cava
Vol. 32, No. 6, 1983
Captoprll and MK-421 on Vascular ACE
569
and mesenteric vein than in the arteries. Thus, while captopril and MK-421 can inhibit venous ACE, the inhibition may not be as long lasting as arterial ACE inhibition. We might speculate that this observation is consistent with the minimal postural hypotension observed after clinical use of ACE inhibitors. For all the peripheral blood vessels, ACE inhibition by maximal within 15 mins after its oral administration to SHR. maximal ACE inhibition was slower in onset after MK-421, and duration than after captopril. These results are similar to ACE inhibition in other tissues from the SHR (3).
captopril was In contrast, of a longer that reported for
In summary, the prototype ACE inhibitors, captopril and MK-421 effectively inhibited ACE activity in small peripheral arteries and veins of the SHR. Relative to captopril, MK-421 had a longer onset to peak inhibition and a longer duration of inhibition of vascular ACE. Acknowledgements The authors express their appreciation to Mr. Richard Moore for his excellent technical assistance and to Mrs. Jessie Tomlin for the preparation of this manuscript. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
C.S. Sweet, D.M. Gross, P.T. Arbegast, S.L. Gaul, P.M. B r i t t , C.T. Ludden, D. Weitz and C.A. Stone, J. Pharmacol. Exp. Ther. 216 558-566 (1981). B. Waeber, H.R. Brunner, D.B. Brunner, A.L. Curtet, G.A. Turini and H. Gavras, Hypertension 2 236-242 (1980). M.L. Cohen, and K.D. Kurz, J. Pharmacol. Exp. Ther. 220 63-69 (1982). M . J . Antonaccio, M. Asaad, B. Rubin, and Z.P. Horovitz, An~iotensin Convertin 9 Enzyme Inhibitors, ed. by Horovitz ZP. Urban ana Schwarzenberg, Baltimore-Munich. pp 161-180 (1981). J.W. Aiken, and J.R. Vane, Nature 228 30-34 (1970). J. Di Salvo, and C.B. Montefusco, Am. J. Physiol. 221(6) 1576-1579 (1971). S. Britton, and J. Di Salvo, Am. J. Physiol. 225(5) 1226-1231 (1973). B. Ljung, B. Jandhyala, A. Kjellstedt, Acta. Physiol. Scand. 111 409-416 (1981). H. Thurston, and J.D., Clinical Science and Molecular Medicine 52 299-304 (1977). F.E. Dorer, J.R. Kahn, K.E. Lentz, M. Levine and L.J. Skeggs, Biochem. et Biophys. Acta 429 220-228 (1976). F.M. Lai, T. Tanikella, H. Herzlinger and P. Cervoni, Eur. J. Pharmacol. 67 97-99 (1980). J.E. Roulston, G.A. MacGregor and R. Bird, New Eng. J. Med. 303 397 (1980). T. Anderson, K. Kurz and M.L. Cohen, N. Eng. J. Med. 304 1550 (1981).
Pergamon Press
EFFECT OF ACUTE ORAL ADMINISTRATION OF CAPTOPRIL AND MK-421 ON VASCULARANGIOTENSIN CONVERTING ENZYMEACTIVITY IN THE SPONTANEOUSLYHYPERTENSIVERAT Marlene L. Cohen, Kathryn S. Wiley and Ken D. Kurz L i l l y Research Laboratories Eli L i l l y and Company Indianapolis, Indiana 46285 (Received in final form October 14, 1982)
Summary Vascular angiotensin converting enzyme (ACE) may be important as a potential site of action for the antihypertensive effect of ACE inhibitors. ACE a c t i v i t y , estimated by hydrolysis of [JH] HipGlyGly, was similar in the aorta, mesenteric and carotid arteries of SHR. ACE a c t i v i t y in veins was not as consistent and was significantly lower in the jugular veins and vena cava of SHR than in the arteries. Nevertheless, ACE a c t i v i t y in all the blood vessels examined, although less than lung ACE a c t i v i t y , was higher than ACE a c t i v i t y found in other tissues such as brain, heart and kidney. Equieffective antihypertensive doses of captopril (10 mg/kg p.o.) and MK-421 (1.0 mg/kg p.o.) dramatically inhibited ACE a c t i v i t y in all the arteries and veins examined. Maximal ACE inhibition occurred within 15 minutes after the oral administration of captopril. In contrast, maximal ACE inhibition was slower in onset and of longer duration after MK-421 than after captopril for all the vessels. Thus, r e l a t i v e l y high ACE a c t i v i t y can be measured in both arteries and veins from the spontaneously hypertensive rat (SHR) and ACE was dramatically inhibited after antihypertensive oral doses of captopril or MK-421. Furthermore, vascular ACE inhibition can be used to compare the onset and duration of a c t i v i t y of ACE inhibitors; MK-421 has a longer onset and duration in SHR than captopril based on inhibition of ACE in blood vessels. Previous studies have demonstrated that blood pressure reduction produced by angiotensin converting enzyme (ACE) inhibitors did not correlate with inhibition of serum ACE a c t i v i t y (I-3). This observation has led to the proposal that the localized inhibition of ACE in vascular tissue may provide a better predictive index of antihypertensive efficacy. In this regard, renin has been found in vascular tissue and is elevated in arteries from spontaneously hypertensive rats (SHR) (4). ACE a c t i v i t y has been demonstrated in vascular tissue based on contractile responses to angiotensin I (5-8) and biochemical assay of ACE a c t i v i t y in aorta of SHR (3). Furthermore, the renin-angiotensin system in vascular tissue is independent of changes in serum renin levels (4,9). Thus the possibility exists that vascular ACE may be inhibited independently of serum ACE a c t i v i t y . Using MK-421 and captopril, we demonstrated dramatic inhibition of aortic 0024-3205/83/060565-05503.00/0 Copyright (c) 1983 Pergamon Press Ltd.
566
Captopril and MK-421 on Vascular ACE
Vol. 32, No. 6, 1983
ACE a c t i v i t y at a time when blood pressure was reduced, but serum ACE a c t i v i t y was uninhibited (3). Because of the well documented heterogeneity of vascular tissue, and questions regarding the s u i t a b i l i t y of aortic ACE as an index of other vascular beds, we have extended our i n i t i a l stuides to several smaller peripheral vessels. Furthermore, since the antihypertensive effect of ACE inhibitors does not appear to be associated with pronounced postural hypotension, we questioned the extent of ACE a c t i v i t y in veins and the extent to which venous ACE was inhibited after oral administration of ACE inhibitors. The aim of these studies was twofold: 1) to compare control ACE a c t i v i t y between arteries and veins and, 2) to compare the disposition of captopril and MK-421 between such smaller arteries and veins. Methods Tissue preparation: Male SHR ranging from 20-24 weeks of age (325-375 gms) (Taconic Farms, Germantown, NY) were treated orally with equal volumes of captopril (10 mg/kg), MK-421 (1.0 mg/kg) or saline. These doses of captopril and MK-421 resulted in an approximately 15 to 20 mmHg f a l l in blood pressure that had not returned to control pressure by 24 hours (3). At the times indicated in Results, rats were k i l l e d by cervical dislocation. Vessels were removed, cleaned and a 5 or 10 percent homogenate of each tissue was prepared in ground glass homogenizers using Hepes (O.05M) buffer containing NaCl(O.15M), NapSO4 (O.6M) and NaN3(O.I percent) at pH 8.0 for optimal enzyme a c t i v i t y (I0). One mesenteric artery and vena cava, two carotid arteries and mesenteric veins and 4 jugular veins were assayed per sample. ACE assay: ACE a c t i v i t y was assayed using a radiometric assay method (Ventrex Laboratories, Inc., Portland, Maine) with [3H] Hippuryl-glycyl-glycine as substrate (800 nmoles) in a final volume of 100~I. Samples were preincubated for 5-10 minutes and then incubated with substrate for 60 minutes at 37°C. The reaction was stopped by the addition of 1.0 ml of O.1N HCI. Ethyl acetate (1.0 ml) was added and the samples were vortexed and centrifuged at lO00g for 10 min. Three hundred ~l of the ethyl acetate layer was added to 10 ml of s c i n t i l l a t i o n cocktail (Aquasol) and radiolabeled hippuric acid was counted by liquid s c i n t i l l a t i o n spectrometry. ACE a c t i v i t y was expressed as nmoles of [JH] hippuric acid formed/min/mg tissue. All assays were performed in duplicate and tissue samples from captopril-treated rats were processed and assayed within three hours since storage can influence the enzyme inhibition measured after captopril (11-13). Mean values were s t a t i s t i c a l l y compared by one-way analysis of variance followed by the Student's t - t e s t for unpaired data. Statistical significance between means was assumed when P
Vol. 32, No. 6, 1983
Captopril and MK-421 on Vascular ACE
567
vessels within 15 min after the oral administration of captopril. Within 15 min after MK-421, ACE inhibition was apparent in the mesenteric artery, vena cava and mesenteric vein, but not in the carotid artery or jugular vein. In all tissues, inhibition was less at this early time point after MK-421 than after captopril suggesting a slower onset of action after MK-421 r e l a t i v e to captopril. By one hour after MK-421, greater than 85 percent inhibition of ACE a c t i v i t y occurred in all the vessels examined. T h i s inhibition was comparable to that which occurred 15 min after captopril. TABLE I Control ACE A c t i v i t y in Peripheral Arteries and Veins from the SHR
Blood Vessel
n
ACE A c t i v i t y a nmol/mg/min
Arteries: Aorta
8
0.99 * 0.14
10
0.90 • 0.10
8
1.05 • 0.08
Vena Cava
8
0.23 * 0.2 b
Mesenteric Vein
7
0.87 • 0.12
Jugular Vein
5
0.45 * 0.06 b
Mesenteric Artery Carotid Artery Veins:
a) ACE a c t i v i t y was determined radiometrically as indicated under Methods. Enzymea c t i v i t y was expressed as nanomoles of [3H] hippuric acid formed per minute per milligram of tissue. Values are means * S. E. and n represents the number of samples. b) Significantly (p<.05) different from all other tissues as determined by one-way analysis of variance and subsequent Student's t - t e s t . Twenty four hours after oral administration of captopril, ACE a c t i v i t y in the vena cava and mesenteric veins was back to control values, although greater than 50 percent inhibition remained in the carotid and mesenteric arteries and jugular vein. Relative to captopril, ACE inhibition 24 hours after MK-421 was greater in all the vessels examined consistent with the longer duration of a c t i v i t y reported for MK-421 (1). Discussion In the present report, we have extended our information on tissue ACE a c t i v i t y to several peripheral arteries and veins from the SHR. ACE a c t i v i t y in a l l the blood vessels examined, while lower than that found in lung (3), was higher than ACE a c t i v i t y in heart, brain or kidney (3). All the arteries examined had similar ACE a c t i v i t y whereas ACE a c t i v i t y in veins was more variable ranging from a low of 0.23 nmol hippuric acid formedlmg tissue/min in the vena cava to 0.87 n ~ l hippuric acid formed/mg tissuelmin in the mesenteric vein.
568
Captopril and MK-421 on Vascular ACE
Vol. 32, No. 6, 1983
CAROTID ARTERY SHR m CAPTOPIIL (iDmg/k9 p.o.)
>. : 1 . 2 ~,~JMK421( l ~ / k g p.a.) I - "~ !.o
~..c. 1.2 ;" ~1.Oi
r ,! $
.2 0
,&, •
B
.25
,~ E .41
~
,
1
24
.25 1 24 TIME (hours)
TIME (hours)
i
1.2
_~
i.o
¢AVA I VENA SHR
MESENTERIC VEIN SHR J~CAPTOPRIL(iDml;/kg p.o.) ~'~JMK 421 ( 1.Omg/kg p.o.)
JJ~J CAPTOI~IL (1Omti/ks p.o.)
I JUGULAR VEIN SHR U CAPTOPRfL{IOmg/k s p.o.) )mE 0 . 6 i ~ MK421(l~nlm/Ica P.o.)
0.4 .6 I
.2 0
.25 1 24 TIME (hours)
0.2 v
.25 I TiME (hours)
0
.25 ! 24 TiME (hours)
FIG. 1 Effect of captopril (10.0 mg/kg) and MK-421 (1.0 mg/kg) on vascular ACE activity in SHR at various times (15 min, 60 min and 24 hrs.) after oral administration of each inhibitor. Shadedarea represents control ACE activity in each vascular bed determined after administration of saline to SHR. Bars are means * S.E. for the number of samples indicated above each bar. Tissues from captopril treated rats were not evaluated at one hr, since samples could not be stored (11-13). Since vascular tissue has been proposed as a target site for the antihypertensive activity of ACE inhibitors (1,3,4) and since prolonged ACE inhibition occurred in the aorta from SHR (3) after ACE inhibitors, i t became necessary to determine i f aortic ACE inhibition reflected the inhibition occurring in other smaller peripheral arteries Equieffective antihyertensive doses (3) of both captopril (10 mg/kg p.o.) and MK-421 (1.0 mglkg p.o.) inhibited ACE activity in the mesenteric and carotid artery. The time course of ACE inhibition in these smaller arteries by both captopril and MK-421 qualitatively paralleled the time course demonstrated in the aorta (3). However, ACE inhibition 24 hours after captopril (65 percent) or MK-421 (80 percent) in the mesenteric and carotid arteries was less than found in the aorta (>90 percent). With regard to venous ACE inhibition, both captopril and MK-421 inhibited ACE activity in all three veins. With the exception of the jugular vein where only 2 tissue samples were evaluated at 24 hours after oral administration of captopril or MK-421, the duration of ACE inhibition was less in the vena cava
Vol. 32, No. 6, 1983
Captoprll and MK-421 on Vascular ACE
569
and mesenteric vein than in the arteries. Thus, while captopril and MK-421 can inhibit venous ACE, the inhibition may not be as long lasting as arterial ACE inhibition. We might speculate that this observation is consistent with the minimal postural hypotension observed after clinical use of ACE inhibitors. For all the peripheral blood vessels, ACE inhibition by maximal within 15 mins after its oral administration to SHR. maximal ACE inhibition was slower in onset after MK-421, and duration than after captopril. These results are similar to ACE inhibition in other tissues from the SHR (3).
captopril was In contrast, of a longer that reported for
In summary, the prototype ACE inhibitors, captopril and MK-421 effectively inhibited ACE activity in small peripheral arteries and veins of the SHR. Relative to captopril, MK-421 had a longer onset to peak inhibition and a longer duration of inhibition of vascular ACE. Acknowledgements The authors express their appreciation to Mr. Richard Moore for his excellent technical assistance and to Mrs. Jessie Tomlin for the preparation of this manuscript. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
C.S. Sweet, D.M. Gross, P.T. Arbegast, S.L. Gaul, P.M. B r i t t , C.T. Ludden, D. Weitz and C.A. Stone, J. Pharmacol. Exp. Ther. 216 558-566 (1981). B. Waeber, H.R. Brunner, D.B. Brunner, A.L. Curtet, G.A. Turini and H. Gavras, Hypertension 2 236-242 (1980). M.L. Cohen, and K.D. Kurz, J. Pharmacol. Exp. Ther. 220 63-69 (1982). M . J . Antonaccio, M. Asaad, B. Rubin, and Z.P. Horovitz, An~iotensin Convertin 9 Enzyme Inhibitors, ed. by Horovitz ZP. Urban ana Schwarzenberg, Baltimore-Munich. pp 161-180 (1981). J.W. Aiken, and J.R. Vane, Nature 228 30-34 (1970). J. Di Salvo, and C.B. Montefusco, Am. J. Physiol. 221(6) 1576-1579 (1971). S. Britton, and J. Di Salvo, Am. J. Physiol. 225(5) 1226-1231 (1973). B. Ljung, B. Jandhyala, A. Kjellstedt, Acta. Physiol. Scand. 111 409-416 (1981). H. Thurston, and J.D., Clinical Science and Molecular Medicine 52 299-304 (1977). F.E. Dorer, J.R. Kahn, K.E. Lentz, M. Levine and L.J. Skeggs, Biochem. et Biophys. Acta 429 220-228 (1976). F.M. Lai, T. Tanikella, H. Herzlinger and P. Cervoni, Eur. J. Pharmacol. 67 97-99 (1980). J.E. Roulston, G.A. MacGregor and R. Bird, New Eng. J. Med. 303 397 (1980). T. Anderson, K. Kurz and M.L. Cohen, N. Eng. J. Med. 304 1550 (1981).