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Selective antagonism of the systemic vasodepressor response to PGE1 by d,1–11, 15-bisdeoxy PGE1
PROSTAGLANDINS
SELECTIVE ANTAGONISM OF THE SYSTEMIC VASODEPRESSOR RESPONSE TO PGEl BY d,l-11, 15-BISDEOXY PGEl Robert B. Stinger, Thomas M. Fitzpatrick, Jacques Van Dam, Peter W. Ramwell and Peter A. Kot Georgetown University Medical Center Department of Physiology and Biophysics 3900 Reservoir Road, N.W. Washington, D.C. 20007 ABSTRACT Several bisdeoxy PGEl analogs are potent, competitive antagonists of PGEl -induced colonic contractions in the gerbil. The efficacy of these analogs in antagonizing PGE -mediated systemic vasodepression has not been previously d Bmonstrated. In this study, serial doses of PGs were administered before, during and after infusion of d,l-11, 15-bisdeoxy PGEl. Bolus injections of PGE (3.0 pk/kg), PGE (3.0 ug/kg) and PGI (0.3 ug/kg) were a dministered via t i2i e right external jug 4 lar vein to male Wistar rats. PGE PGE and PGI decreased systemic arterial pressure 41%, 38% and'j8%, gespectivgly. The PGE analog was infused (200 ug/kg/min) through the right commo?i aarotid artery. The analog itself had no effect on mean systemic arterial pressure, but maximum reversible inhibition (51%) of PGE -mediated vasodepression occurred following a 50 minute in $usion. No significant effect of the PGEl analog was observed on PGE or PG12-mediated vasodepression. These data demonstrate thz ability to antagonize PGE -mediated vasodepression, and to differentiate the vascular lesponses to PGEl and PGE2 or PG12. INTRODUCTION Prostaglandins (PGs) are involved in several physiologic and pathologic mammalian systems. Salicylates and other nonsteroidal anti-inflammatory agents block the formation of all prostaglandins. Antagonists specific for each PG would aid in differentiating individual mechanisms of action (1). Antagonists have been identified which differentiate the PGE and PGF2, vascular responses in vivo (2), but separation of &he PGEl and PGE2 vascular responses is unique. From a pharmacologic standpoint, the optimal antagonist should be specific, potent, reversible and possess no agonist activity. Removal of the hydroxy function from either carbon 11 or carbon 15 reduces the agonist potency of certain prostaglandin analogs (3).
FEBRUARY 1980 VOL. 19 NO. 2
213
PROSTAGLANDINS
Several bisdeoxy PGEl analogs are potent, competitive antagonists to PGEl -induced colonic contractions in the gerbil (4). However, the efficacy of these analogs in antagonizing PGEl-mediated systemic vasodepression has not previously been examined. The objective of this study was to test d,l-11, 15-bisdeoxy PGE for -in vivo antagonism of the systemic vascular response 8 o several vasodepressor prostaglandins in the rat. METHODS Male Wistar rats (300-400 g) of comparable age were anesthetized with sodium pentobarbital (50 mg/kg) I.P. A tracheotomy was performed to maintain airway patency during the experiment. Systemic arterial pressure was continuously monitored through an indwelling catheter (PE 50) placed in the left common carotid artery. Bolus injections of prostaglandin were administered through an indwelling catheter (PE 20) placed in the left external jugular vein. is structurally similar to PGEl d,l-11, 15-bisdeoxy PGE except for the absence of hy A roxyl groups on carbons 11 and 15 (5). The analog was supplied by Lederle Laboratories (Pearl River, N.Y.) as an oil, and was prepared by dissolving in ethanol, evaporating to dryness under nitrogen and dissolving The resulting solution, used in normal saline (0.15 m NaCl). only when clear, was infused through an indwelling catheter (PE.50) in the right common carotid artery at a constant flow Normal rate (0.10 ml/min) and concentration (200 hg/kg/min). saline was infused at an identical flow rate and duration in control experiments. PGEl, PGE2 and PG12 were supplied by the Upjohn Company Stock solutions (1 mg/ml in ethanol) (Kalamazoo, Michigan). or PGE were evaporated to dryness over nitrogen and of PGE The sodium salt of PGI was dissolted in n 2 rmal saline. prepared daily in 1 mg/ml ethanol solution and dilu 2 ed with 0.1 M tris buffer at pH 9. Serial doses of prostaglandin were administered in volumes not exceeding 0.1 ml at 10 minute intervals, before, during and after a 50 minute infusion of d,l-11, 15-bisdeoxy PGEl, and were flushed through the catheter with 0.1 ml saline. These volumes were selected to ensure accurate dosing and to minimize volume artifacts in systemic arterial pressure. Results are expressed as means + standard error of mean (SEM). Student's t-test was used for the statistical analysis of data and significance was set at Pc.01.
214
FEBRUARY
1980 VOL. 19 NO. 2
PROSTAGLANDINS
RESULTS Since the vascular response from a single dose of prostaglandin was to be compared before, during and after infusion of the analog, dose-response curves to each PG were constructed (Figure 1) to determine a submaximal dose for further experiments.
I6(
50-
40
30
20
10
0
1.0
0.1 Log
Dose
3.0
5.0
10.0
(Bg i kgl
Figure 1. Regression lines for % decrease in mean systemic ;r_te;i;; pressure for PGEl (open circles; y = 37.2 x + 11.5, . , n = 9), PGE2 (solid circles; y = 47.3 x + 11.1, r = 0.99, n = 12) and PGI2 (open triangles; y = 24.0 x + 44.2, r = 0.99, n = 13). is about one order of magnitude more potent than PGI PGEl or 3 GE2. We therefore chose approximately equipotent and 3.0 ug/kg for PGE doses of (0.3 ug/kg for PGI . 3 er of the 3.0 ug/kg for PGE1) as Stan 3' ards for the remain study, which gave responses of approximately 50% of maximum.
FEBRUARY
1980 VOL. 19 NO. 2
215
PROSTAGLANDINS
Control
After 50 min. of Antagonist infusion at 200 pgIkq/min
20 min. after Cessation of Infusion
Figure 2. Summary of changes in systemic arterial pressure following administration of PGI 0.3 vg/kg (N = 6) (open bars), PGE 3.0 vg/kg (N = 4) ?Ltriped bars) and PGE 3.0 vg/kg ?A = 6) (solid bars) before, during and aft.&; infusion of d,l-11, 15-bisdeoxy PGE (200 ug/kg/min). Means expressed + S.E. (*) signifies P<.bl.
216
FEBRUARY
1980 VOL. 19 NO. 2
PROSTAGLANDINS
In a second group of animals, standard doses of PGI2, PGE, and PGE, decreased mean systemic arterial pressure 37.4 + 2.4%,l37.6 + 2.8%, and 41.2 + 1.8% (N = 11, 9 and administered-10 minutes prior to 30), respectively,Ghen infusion of the analog (Figure 2). Only the systemic vasodepressor response to PGE was attenuated by the infusion of d,l-11, 15'bisdeoxy P&E . After a fifty minute infusion of the analog (N = 6) th&re was a 51% reduction of the vasodepressor response to the same dose of PGE (Figure 2). The analog had no significant effect on systemiclvasodepression induced by PGE2 (N = 4) or PG12 (N = 6). Infusion of the analog alone did not affect mean systemic arterial pressure. Normal saline, infused at an equal flow rate and duration of time as the analog, did not alter the PGEl-mediated systemic vasodepression. Effects of the analog on the PGE -mediated systemic vasodepression were reversible. Twen &y minutes following termination of the analog infusion, the vascular responses of PGE 1 had returned to control values (Figure 2). DISCUSSION At least four intrinsic properties are desirable for compound to be considered an efficacious, competitive pharmacologic antagonist: specificity, potency, reversibility and lack of agonist activity. Three well-known compounds that have been evaluated for prostaglandin antagonist activity have posed several practical problems: 7-oxaprostaglandin analogs (6), SC-19220, a dibenzoxazopine derivative (7) and PPP, a polyphloretin phosphate (8). a
In this study, d,lrll, 15-bisdeoxy PGE has fulfilled our requirements for an efficacious prostag 1 andin antagonist better than any -in vivo antagonist evaluated thus far. The specificity of d,l-11, 15-bisdeoxy PGE for the PGEl vascular response was demonstrated by the signi+ icant attenuation of PGEl-mediated systemic vasodepression and the lack of effect on vascular responses to PGE2 and PG12. While inter-class soecificitv of urostaalandin antaaonist druas has been demonstrated both -in viva (9) and in-vitro (4); the differentiation of PGE, and PGE,-mediated sGt=vasod,l-fl, 15-bisdeoxy PGE demondepression is unique (r) . strated dose-dependent, competitive antagonism to & GE1 in the gerbil colon, yet had no effect on colonic contractions induced by PGF2e or acetylcholine (4). Thus, different
FEBRUARY 1980VOL.19NO.2
217
PROSTAGLANDINS
receptors may be involved prostaglandins (1).
in the activities
of -E and -FZa
The potency of thjs analog appears to be greater than other in vivo -E antagonists tested thus far. While the nature .-of this study makes it difficult for an accurate determination of potency, a relative estimation can be made. If all of the infused analog were confined to the vascular compartment and none were biotransformed, an unlikely circumstance, a concentration of 10 mg/kg analog was present following fifty minutes of continuous infusion. This was effective in inhibiting the PGEl vascular response by 51%. A concentration of 100 mg/kg PPP was required to achieve an IC50 for PGE and PGE mediated systemic vasodepression in vivo (16 ). Sims.1ar doses of SC-19220 were required toinhibit PGE, activity in uivo (1). Even such high doses of SC-19220: following stra-arterial infusion in the canine, were ineffective in inhibiting the vasodepressor effects of PGE and PGE (11). However, moderate concentrations of a carboA 1 N-dimzthylamide derivative of PGF2c competitively inhibited the pulmonary vasoconstrictor response to PGF2a, -_I in situ (12). The attenuating action of the PGE analog was reversible as demonstrated by the return of the vascular response to Tolman et al. PGEl following termination of the infusion. (4) demonstrated that this analog competes with or displaces 3H-PGE from binding to a broken cell preparation of rat adipo&es. Thus, although the nature of antagonism has not been fully investigated, these two observations suggest that d,l-11, 15-bisdeoxy PGEl may be a competitive antagonist of PGEl. The lack of agonist activity shown with this analog is consonant with in vitro findings (4). Removal of the hydroxy T-function from either carbon 11 or carbon 15 reduces the agonigt potency of other prostaglandin'analogs (3). In contrast, polyphloretin phosphate (PPP) decreased systemic arterial pressure lo-35% in the chicken (lo), and had similar effects in the rabbit (13) and in the guinea-pig and cat (14). There appear to be species differences in the agonist properties of PPP (14), and it would be of importance to know whether PPP is exerting this agonistic effect at the target tissue level, as has been shown for 7-oxa-13-prostanoic acid (15), or by inhibiting the biotransformation of prostaglandins by competing for 15-hydroxy prostaglandin dehydrogenase (16), as has been suggested (17). The specificity, potency, reversibility and lack of analog on agonist activity suggested by this bisdeoxy PGE rat vascular smooth muscle may prove useful in Burther
218
FEBRUARY
1980 VOL. 19 NO. 2
PROSTAGLANDINS
differentiating putative E-prostaglandin other tissue preparations.
receptors
in various
ACKNOWLEDGEMENTS This work was supported by Grant HL-18718. We would also like to thank Dr. Ed Tolman of Lederle Laboratories for making this new analog available to us, and Dr. John Pike for kindly supplying the standard prostaglandins. REFERENCES 1.
Eakins, K.E. and J.H. Sanner. Prostaglandin antagonists. In The Prostaglandins, Progress in Research. (S.M.M. KariK ea.), Medical and Technical Pub. Co. Ltd., Oxford and London, 1972, pp. 261-292.
2.
B. and H.R. Lindner. Selective blockade of the Levy, vasodepressor response to prostaglandin F in the 432c' 236-241. anesthetized rabbit. Br. J. Pharmac. -*
3.
Fried, J., T.S. Santhanakrishan! J. Mimizu, C.H. Lin, S.H. Ford, R. Rubin and E.O. Grigas. Prostaglandin antagonists: Synthesis and smooth muscle activity. Nature 223: 208-210. 1969.
4.
ProstaglanTolman, E.L., R. Partridge and E.T. Barris. din E antagonist activity of 11, 15-bisdeoxy prostaglandin El and congeners. Prostaglandins -14: 11-19. 1977.
5.
Prostaglandins and Bernady, K.F. and J.J. Weiss. congeners. I. The synthesis of 11, 15-bisdeoxyprostag,;;;",i~;",$,aE1 and Fl - The stereospecific conjugate ithium grans-l-alkenylalanate. Tetrahedron 4083-4086. 1972. Letters -40:
6.
Fried, J., S. Heim, S.J. Etheredge, P. Sunder-Plassman, Synthesis of 15T.S. Santhanakrishan and J. Himizu. deoxy-7-oxaprostaglandin Flc and related substances. In Prostaglandin Symposium of the Worcester Foundation (P.W. Ramwell and J.E. Shaw, for Experimental Biology. pp. 351-363. zds.), John Wiley and Son, New York, 1968.
7.
Sanner, action.
FEBRUARY
Substances that inhibit prostaglandin J.H. 133: 133-146. 1974. Arch. Intern. Med.
1980 VOL. 19 NO. 2
219
PROSTAGLANDINS
8.
Eakins, K.E. and S.M.M. Karim. Polyphloretin phosphate A selective antagonist of prostaglandins Fla and FZa. Life Sci. 9: l-5. 1970. -
9.
Eakins, K. Prostaglandin antagonism by polymeric phosphates of phloretin and related compounds. Ann. 386-395. 1971. N.Y. Acad. Sci. 180: -
10.
Chand, N. and P. Eyre. Effects of prostaglandins El, and F and polyphloretin phosphate on carotid :?ood pr&sure of domestic fowl. Arch. Int. Pharmacodyn. 221: 261-265. 1976. -
11.
Nakano, J., A.V. Prancan and S. Moore. Effect of prostaglandin antagonists on the vasoactivities of (PGAl), and prostaglandins El (PGEl), E (PGE ), A 14: 71% 19+1. Clan. Res. F2a (PGF2a). -
12.
Fitzpatrick, T.M., I. Alter, E.J. Corey, P.W. Ramwell, Antagonism of the pulmonary J.C. Rose and P.A. Kot. by N-dimethylamino vasoconstrictor response to PGF substitution of PGF2a. J . Pharz? Exp. Ther. 206: 139-142. 1978.
13.
Antagonism Eakins, K.E., S.M.M. Karim and J.D. Miller. of some smooth muscle actions of prostaglandins by 556polyphloretin phosphate. Br. J. Pharmac. 2: 563. 1970.
14.
Antagonism Mathe, A.A., K. Strandberg and B. Fredholm. and of prostaglandin F2cr-induced bronchoconstriction blood pressure changes by polyphloretin phosphate in J. Pharm. Pharmacol. the guinea-pig and cat. -24: 378-382 1972.
15.
Ozaki, N., J.D. Kohli, L.E. Goldberg and J. Fried. Vascular smooth muscle activity of 7-oxa-13-prostanoic Blood Vessels acid. -16: 52-57. 1979.
16.
Polyphloretin phosphate Karim. Ganesan, P.A. and S.M.M. temporarily potentiates prostaglandin E on the rat fundus, probably by inhibiting PG 15_hy?iroxydehydrogenase. J. Pharm. Pharmacol. -25: 229-233. 1973.
17.
Prostaglandin antagonists. Sanner, J.H. and K.E. Eakins. Chemicals and Biological Agent.s. In Prostaglandins: (S.M.M. Karred.), University Press, Baltimore, 1976. pp. 139-189.
-
Editor: Alan Bennett Received Dec. 15, 1979 Accepted Jan. 15, 1980
220
FEBRUARY 1980VOL.19N0.2
SELECTIVE ANTAGONISM OF THE SYSTEMIC VASODEPRESSOR RESPONSE TO PGEl BY d,l-11, 15-BISDEOXY PGEl Robert B. Stinger, Thomas M. Fitzpatrick, Jacques Van Dam, Peter W. Ramwell and Peter A. Kot Georgetown University Medical Center Department of Physiology and Biophysics 3900 Reservoir Road, N.W. Washington, D.C. 20007 ABSTRACT Several bisdeoxy PGEl analogs are potent, competitive antagonists of PGEl -induced colonic contractions in the gerbil. The efficacy of these analogs in antagonizing PGE -mediated systemic vasodepression has not been previously d Bmonstrated. In this study, serial doses of PGs were administered before, during and after infusion of d,l-11, 15-bisdeoxy PGEl. Bolus injections of PGE (3.0 pk/kg), PGE (3.0 ug/kg) and PGI (0.3 ug/kg) were a dministered via t i2i e right external jug 4 lar vein to male Wistar rats. PGE PGE and PGI decreased systemic arterial pressure 41%, 38% and'j8%, gespectivgly. The PGE analog was infused (200 ug/kg/min) through the right commo?i aarotid artery. The analog itself had no effect on mean systemic arterial pressure, but maximum reversible inhibition (51%) of PGE -mediated vasodepression occurred following a 50 minute in $usion. No significant effect of the PGEl analog was observed on PGE or PG12-mediated vasodepression. These data demonstrate thz ability to antagonize PGE -mediated vasodepression, and to differentiate the vascular lesponses to PGEl and PGE2 or PG12. INTRODUCTION Prostaglandins (PGs) are involved in several physiologic and pathologic mammalian systems. Salicylates and other nonsteroidal anti-inflammatory agents block the formation of all prostaglandins. Antagonists specific for each PG would aid in differentiating individual mechanisms of action (1). Antagonists have been identified which differentiate the PGE and PGF2, vascular responses in vivo (2), but separation of &he PGEl and PGE2 vascular responses is unique. From a pharmacologic standpoint, the optimal antagonist should be specific, potent, reversible and possess no agonist activity. Removal of the hydroxy function from either carbon 11 or carbon 15 reduces the agonist potency of certain prostaglandin analogs (3).
FEBRUARY 1980 VOL. 19 NO. 2
213
PROSTAGLANDINS
Several bisdeoxy PGEl analogs are potent, competitive antagonists to PGEl -induced colonic contractions in the gerbil (4). However, the efficacy of these analogs in antagonizing PGEl-mediated systemic vasodepression has not previously been examined. The objective of this study was to test d,l-11, 15-bisdeoxy PGE for -in vivo antagonism of the systemic vascular response 8 o several vasodepressor prostaglandins in the rat. METHODS Male Wistar rats (300-400 g) of comparable age were anesthetized with sodium pentobarbital (50 mg/kg) I.P. A tracheotomy was performed to maintain airway patency during the experiment. Systemic arterial pressure was continuously monitored through an indwelling catheter (PE 50) placed in the left common carotid artery. Bolus injections of prostaglandin were administered through an indwelling catheter (PE 20) placed in the left external jugular vein. is structurally similar to PGEl d,l-11, 15-bisdeoxy PGE except for the absence of hy A roxyl groups on carbons 11 and 15 (5). The analog was supplied by Lederle Laboratories (Pearl River, N.Y.) as an oil, and was prepared by dissolving in ethanol, evaporating to dryness under nitrogen and dissolving The resulting solution, used in normal saline (0.15 m NaCl). only when clear, was infused through an indwelling catheter (PE.50) in the right common carotid artery at a constant flow Normal rate (0.10 ml/min) and concentration (200 hg/kg/min). saline was infused at an identical flow rate and duration in control experiments. PGEl, PGE2 and PG12 were supplied by the Upjohn Company Stock solutions (1 mg/ml in ethanol) (Kalamazoo, Michigan). or PGE were evaporated to dryness over nitrogen and of PGE The sodium salt of PGI was dissolted in n 2 rmal saline. prepared daily in 1 mg/ml ethanol solution and dilu 2 ed with 0.1 M tris buffer at pH 9. Serial doses of prostaglandin were administered in volumes not exceeding 0.1 ml at 10 minute intervals, before, during and after a 50 minute infusion of d,l-11, 15-bisdeoxy PGEl, and were flushed through the catheter with 0.1 ml saline. These volumes were selected to ensure accurate dosing and to minimize volume artifacts in systemic arterial pressure. Results are expressed as means + standard error of mean (SEM). Student's t-test was used for the statistical analysis of data and significance was set at Pc.01.
214
FEBRUARY
1980 VOL. 19 NO. 2
PROSTAGLANDINS
RESULTS Since the vascular response from a single dose of prostaglandin was to be compared before, during and after infusion of the analog, dose-response curves to each PG were constructed (Figure 1) to determine a submaximal dose for further experiments.
I6(
50-
40
30
20
10
0
1.0
0.1 Log
Dose
3.0
5.0
10.0
(Bg i kgl
Figure 1. Regression lines for % decrease in mean systemic ;r_te;i;; pressure for PGEl (open circles; y = 37.2 x + 11.5, . , n = 9), PGE2 (solid circles; y = 47.3 x + 11.1, r = 0.99, n = 12) and PGI2 (open triangles; y = 24.0 x + 44.2, r = 0.99, n = 13). is about one order of magnitude more potent than PGI PGEl or 3 GE2. We therefore chose approximately equipotent and 3.0 ug/kg for PGE doses of (0.3 ug/kg for PGI . 3 er of the 3.0 ug/kg for PGE1) as Stan 3' ards for the remain study, which gave responses of approximately 50% of maximum.
FEBRUARY
1980 VOL. 19 NO. 2
215
PROSTAGLANDINS
Control
After 50 min. of Antagonist infusion at 200 pgIkq/min
20 min. after Cessation of Infusion
Figure 2. Summary of changes in systemic arterial pressure following administration of PGI 0.3 vg/kg (N = 6) (open bars), PGE 3.0 vg/kg (N = 4) ?Ltriped bars) and PGE 3.0 vg/kg ?A = 6) (solid bars) before, during and aft.&; infusion of d,l-11, 15-bisdeoxy PGE (200 ug/kg/min). Means expressed + S.E. (*) signifies P<.bl.
216
FEBRUARY
1980 VOL. 19 NO. 2
PROSTAGLANDINS
In a second group of animals, standard doses of PGI2, PGE, and PGE, decreased mean systemic arterial pressure 37.4 + 2.4%,l37.6 + 2.8%, and 41.2 + 1.8% (N = 11, 9 and administered-10 minutes prior to 30), respectively,Ghen infusion of the analog (Figure 2). Only the systemic vasodepressor response to PGE was attenuated by the infusion of d,l-11, 15'bisdeoxy P&E . After a fifty minute infusion of the analog (N = 6) th&re was a 51% reduction of the vasodepressor response to the same dose of PGE (Figure 2). The analog had no significant effect on systemiclvasodepression induced by PGE2 (N = 4) or PG12 (N = 6). Infusion of the analog alone did not affect mean systemic arterial pressure. Normal saline, infused at an equal flow rate and duration of time as the analog, did not alter the PGEl-mediated systemic vasodepression. Effects of the analog on the PGE -mediated systemic vasodepression were reversible. Twen &y minutes following termination of the analog infusion, the vascular responses of PGE 1 had returned to control values (Figure 2). DISCUSSION At least four intrinsic properties are desirable for compound to be considered an efficacious, competitive pharmacologic antagonist: specificity, potency, reversibility and lack of agonist activity. Three well-known compounds that have been evaluated for prostaglandin antagonist activity have posed several practical problems: 7-oxaprostaglandin analogs (6), SC-19220, a dibenzoxazopine derivative (7) and PPP, a polyphloretin phosphate (8). a
In this study, d,lrll, 15-bisdeoxy PGE has fulfilled our requirements for an efficacious prostag 1 andin antagonist better than any -in vivo antagonist evaluated thus far. The specificity of d,l-11, 15-bisdeoxy PGE for the PGEl vascular response was demonstrated by the signi+ icant attenuation of PGEl-mediated systemic vasodepression and the lack of effect on vascular responses to PGE2 and PG12. While inter-class soecificitv of urostaalandin antaaonist druas has been demonstrated both -in viva (9) and in-vitro (4); the differentiation of PGE, and PGE,-mediated sGt=vasod,l-fl, 15-bisdeoxy PGE demondepression is unique (r) . strated dose-dependent, competitive antagonism to & GE1 in the gerbil colon, yet had no effect on colonic contractions induced by PGF2e or acetylcholine (4). Thus, different
FEBRUARY 1980VOL.19NO.2
217
PROSTAGLANDINS
receptors may be involved prostaglandins (1).
in the activities
of -E and -FZa
The potency of thjs analog appears to be greater than other in vivo -E antagonists tested thus far. While the nature .-of this study makes it difficult for an accurate determination of potency, a relative estimation can be made. If all of the infused analog were confined to the vascular compartment and none were biotransformed, an unlikely circumstance, a concentration of 10 mg/kg analog was present following fifty minutes of continuous infusion. This was effective in inhibiting the PGEl vascular response by 51%. A concentration of 100 mg/kg PPP was required to achieve an IC50 for PGE and PGE mediated systemic vasodepression in vivo (16 ). Sims.1ar doses of SC-19220 were required toinhibit PGE, activity in uivo (1). Even such high doses of SC-19220: following stra-arterial infusion in the canine, were ineffective in inhibiting the vasodepressor effects of PGE and PGE (11). However, moderate concentrations of a carboA 1 N-dimzthylamide derivative of PGF2c competitively inhibited the pulmonary vasoconstrictor response to PGF2a, -_I in situ (12). The attenuating action of the PGE analog was reversible as demonstrated by the return of the vascular response to Tolman et al. PGEl following termination of the infusion. (4) demonstrated that this analog competes with or displaces 3H-PGE from binding to a broken cell preparation of rat adipo&es. Thus, although the nature of antagonism has not been fully investigated, these two observations suggest that d,l-11, 15-bisdeoxy PGEl may be a competitive antagonist of PGEl. The lack of agonist activity shown with this analog is consonant with in vitro findings (4). Removal of the hydroxy T-function from either carbon 11 or carbon 15 reduces the agonigt potency of other prostaglandin'analogs (3). In contrast, polyphloretin phosphate (PPP) decreased systemic arterial pressure lo-35% in the chicken (lo), and had similar effects in the rabbit (13) and in the guinea-pig and cat (14). There appear to be species differences in the agonist properties of PPP (14), and it would be of importance to know whether PPP is exerting this agonistic effect at the target tissue level, as has been shown for 7-oxa-13-prostanoic acid (15), or by inhibiting the biotransformation of prostaglandins by competing for 15-hydroxy prostaglandin dehydrogenase (16), as has been suggested (17). The specificity, potency, reversibility and lack of analog on agonist activity suggested by this bisdeoxy PGE rat vascular smooth muscle may prove useful in Burther
218
FEBRUARY
1980 VOL. 19 NO. 2
PROSTAGLANDINS
differentiating putative E-prostaglandin other tissue preparations.
receptors
in various
ACKNOWLEDGEMENTS This work was supported by Grant HL-18718. We would also like to thank Dr. Ed Tolman of Lederle Laboratories for making this new analog available to us, and Dr. John Pike for kindly supplying the standard prostaglandins. REFERENCES 1.
Eakins, K.E. and J.H. Sanner. Prostaglandin antagonists. In The Prostaglandins, Progress in Research. (S.M.M. KariK ea.), Medical and Technical Pub. Co. Ltd., Oxford and London, 1972, pp. 261-292.
2.
B. and H.R. Lindner. Selective blockade of the Levy, vasodepressor response to prostaglandin F in the 432c' 236-241. anesthetized rabbit. Br. J. Pharmac. -*
3.
Fried, J., T.S. Santhanakrishan! J. Mimizu, C.H. Lin, S.H. Ford, R. Rubin and E.O. Grigas. Prostaglandin antagonists: Synthesis and smooth muscle activity. Nature 223: 208-210. 1969.
4.
ProstaglanTolman, E.L., R. Partridge and E.T. Barris. din E antagonist activity of 11, 15-bisdeoxy prostaglandin El and congeners. Prostaglandins -14: 11-19. 1977.
5.
Prostaglandins and Bernady, K.F. and J.J. Weiss. congeners. I. The synthesis of 11, 15-bisdeoxyprostag,;;;",i~;",$,aE1 and Fl - The stereospecific conjugate ithium grans-l-alkenylalanate. Tetrahedron 4083-4086. 1972. Letters -40:
6.
Fried, J., S. Heim, S.J. Etheredge, P. Sunder-Plassman, Synthesis of 15T.S. Santhanakrishan and J. Himizu. deoxy-7-oxaprostaglandin Flc and related substances. In Prostaglandin Symposium of the Worcester Foundation (P.W. Ramwell and J.E. Shaw, for Experimental Biology. pp. 351-363. zds.), John Wiley and Son, New York, 1968.
7.
Sanner, action.
FEBRUARY
Substances that inhibit prostaglandin J.H. 133: 133-146. 1974. Arch. Intern. Med.
1980 VOL. 19 NO. 2
219
PROSTAGLANDINS
8.
Eakins, K.E. and S.M.M. Karim. Polyphloretin phosphate A selective antagonist of prostaglandins Fla and FZa. Life Sci. 9: l-5. 1970. -
9.
Eakins, K. Prostaglandin antagonism by polymeric phosphates of phloretin and related compounds. Ann. 386-395. 1971. N.Y. Acad. Sci. 180: -
10.
Chand, N. and P. Eyre. Effects of prostaglandins El, and F and polyphloretin phosphate on carotid :?ood pr&sure of domestic fowl. Arch. Int. Pharmacodyn. 221: 261-265. 1976. -
11.
Nakano, J., A.V. Prancan and S. Moore. Effect of prostaglandin antagonists on the vasoactivities of (PGAl), and prostaglandins El (PGEl), E (PGE ), A 14: 71% 19+1. Clan. Res. F2a (PGF2a). -
12.
Fitzpatrick, T.M., I. Alter, E.J. Corey, P.W. Ramwell, Antagonism of the pulmonary J.C. Rose and P.A. Kot. by N-dimethylamino vasoconstrictor response to PGF substitution of PGF2a. J . Pharz? Exp. Ther. 206: 139-142. 1978.
13.
Antagonism Eakins, K.E., S.M.M. Karim and J.D. Miller. of some smooth muscle actions of prostaglandins by 556polyphloretin phosphate. Br. J. Pharmac. 2: 563. 1970.
14.
Antagonism Mathe, A.A., K. Strandberg and B. Fredholm. and of prostaglandin F2cr-induced bronchoconstriction blood pressure changes by polyphloretin phosphate in J. Pharm. Pharmacol. the guinea-pig and cat. -24: 378-382 1972.
15.
Ozaki, N., J.D. Kohli, L.E. Goldberg and J. Fried. Vascular smooth muscle activity of 7-oxa-13-prostanoic Blood Vessels acid. -16: 52-57. 1979.
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Editor: Alan Bennett Received Dec. 15, 1979 Accepted Jan. 15, 1980
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