PROSTAGLANDINS
INHIBITIONOF PROSTAGLANDINFgo-INDUCEDRBFLEX BRADYCARDIA AND BYPOTBNSIONBY MRCLOFRNAMICACID
Michael C. Koss, Jiro Nakano and Joseph A. Rieger
Department of Pharmacology University of Oklahoma College of Medicine P.O. Box 26901 Oklahoma City, Oklahoma 73190
ABSTRACT Intravenousinjection of prostaglandinF (4-15 ug/kg, i.v.) produces an increase in pulmonary arterial pr&sure in conjunctionwith reflex bradycardia and hypotension in the anesthetizedcat. Meclofenamic acid ( 30 mg/kg, i.v.) inhibited the bradycardia and the reflex contribution to the systemic hypotension. Neither the PGF -induced pulmonary vasoconstrictionnor the direct systemic vasodil&or actions of PGF were blocked by meclofenamate. In addition, the reflex responses ca&d by i.v. veratrine and 5-HT were not inhibitedby meclofenamate. These results suggest that meclofenamic acid selectivelyblocks the afferent mechanism by which PGF20 induces reflex bradycardia and hypotension in the cat.
Acknowledgements: This work was supported by research grants from the Oklahoma Heart Association, and the Tulsa Chapter of the American Heart Association.
4-22-76
APRIL
1976
VOL. 11 NO. 4
691
PROSTAGLANDINS
INTEODUCTION In the cat, the cardiovascularresponses to prostaglandinF2 (PGF2,) appear to be composed of a variety of direct and reflex effects. Although a direct vasodilator action has been demonstrated (l), this effect is highly variable between preparationsand more transient than the overall hypotensive response following systemic injection. A decrease in cardiac output related to pulmonary arterial constrictionand reflex bradycardia and hypotension contribute greatly to the overall systemic hypotensive response to PGF2o (2,3). Both the afferent and efferent componentsof the reflex are carried in the vagal nerves. We have found that PGF activates this reflex by acting on "receptors" located either in t& left heart or on structuresreceiving their blood supply via the coronary arteries (4). Although meclofenamicacid is usually regarded as a potent inhibitor of prostaglandinsynthesis (5,6) it has also been reported to block the actions of PGF on several smooth muscle systems (7,8). Levy and Lindner (9) found th& meclofenamicacid selectivelyblocked the systemic vasodepressoreffects of PGF2o in the rabbit while having no effect on the responsesto PGE . The present investigationwas undertaken to determine if meclofena,ate would also inhibit the overall in the cat, and if so, to determinewhich involved. METHODS Adult cats of either sex were anesthetizedwith alpha-chloralose (60-80 mg/kg) given intraperitoneally. In the majority of the preparations a femoral artery and vein were cannulatedin order to measure systemic arterial blood pressure and for the intravenousadministration of drugs. Following cannulationof the trachea, positive pressure respirationwas initiated using a Harvard respirator. The animals were placed on their right side and the left hemithoraxwas opened, usually between the fourth and ninth ribs. A branch of the pulmonary artery supplying either the left cardiac or left apical lobe was cannulated for direct measurement of pulmonary arterial pressure. Pulmonary and systemic arterial pressureswere recorded continuouslyby means of Statham pressure transducers. Heart rate was measured with a Grass tachograph (7P4D) and all responseswere recorded on a Grass polygraph (7B). In one series of experimentsthe right subclavian artery and vein were cannulated for measuring systemic arterial pressure and i.v. injection of drugs. The abdominal aorta was cannulatedboth distally and proximally and the hindlimbs were perfused at a constant rate by means of a Sigmamotorpump. Systemic arterial and perfusion pressures were continuouslyrecorded. In four cats, aortic blood flow (utilizedas an index of cardiac output) was measured by means of a Statham electromagnetic flowmeter (M-4001) and Statham flow probe (Q-2050). The probe was positioned around the descending aorta distal to the exit of the left subclavian artery in order to avoid damage to the vagal fibres near the heart.
692
APRIL
1976
VOL. 11 NO. 4
PROSTAGLANDINS
Several criteria were establishedwith regard to the effects of t.v. that were qualitativePGF : 1) at least two control responses to PGF nitial baseline values ly &d quantitativelysimilar with 2) return to 1" after subsequent injections of PGF and 3) a bradycardia of at least 30 beats/min following the maximally gpfectiva dose of PGF2o. Only about 60% of the preparationstested met these requirements. (tromethaminesalt) used in these experiCrystalline powder PGF ments was supplied by Dr. .l?oLE. Pike, Upjohn Company, Kalamazoo,Michigan. A stock solution (1 mg/ml) was prepared with distilledwater and stored at -1OOC. Fresh solutions (10 or 100 pg/ml) were prepared shortly before the experimentsby diluting the stock solution with 0.9% NaCl solution. Meclofenamic acid (Parke-Davis)was dissolved in O.lN sodium hydroxide and infused over a 15-25 min interval. The majority of animals exhibited slight clonic jerking movements following the infusion of meclofenamate. In 3 cases these were severe enough to result in termination of the experiment.
Figure 1. Effect of PGF (10 pg/kg, i.v.) on pulmonary arterial pressure, heart ra 2?e and systemic arterial blood pressure before and after infusion of meclofenamicacid (30 mg/kg, i.v.). Note that both the reflex bradycardia and hypotension induced by PGF20 are attenuated following treatmentwith meclofenamate.
APRIL
1976 VOL. 11 NO. 4
693
PROSTAGLANDINS
RESULTS AND DISCUSSION The effects of i.v. administrationof PGF before and after treatment with meclofenamicacid were studied in 142gats. At the onset of each experiment, the dose of PGF2, producing the maximal change in all parameterswas determined. This maximally effective dose was within the range of 4-15 ug/kg. As shown in figure 1, PGF20 caused an increase in pulmonary arterial pressure and a decrease in systemic arterial pressure associatedwith apronauncedbradycardia. These responseswere qualitatively and quantitativelysimilar to those reported previously (l-4, 10). Following infusion of meclofenamicacid (30 mg/kg, i.v.), PGF produced about the same increase in pulmonary arterial pressure, howe& the PGF induced changes in heart rate and systemic arterial pressure were great?! ly attenuated. Figure 2 summarizes these responses in the 14 preparations Levy and Lindner have previously reported a similar observation in the rabbit (9). They found that meclofenamicselectivelyblocked the vasodepressorresponse to i.v. PGF2, but not that due to administration of PGE . The effects of these two prostaglandinson uterine and oviduct motilit y were not reduced by meclofenamicacid. They concluded that meclofenamicacid selectivelyblocks vascular smooth muscle receptors sensitive to PGF 2a'
1
0
3
6 mm
9
;2
i,--
6
0
12
Fig 2. Composite representationof the effects of PGF (4-15 up/kg, i.v.) on pulmonary arterial pressure (PAP) hea?f rate (HR) and mean systemic arterial pressure (MSAP)before (left) and after infusion of meclofenamicacid (30 mg/kg, i.v.) in 14 preparations. Vertical lines are + S.E.M.
694
APRIL 1976
VOL. 11 NO. 4
PROSTAGLANDINS
2
min
PWUSION PRESSURf mm Hs
MECLORNMIC
ACID
)(I Wks 60 min
PERFUSION PRESSURE MM
h=
Figure 3. Effect of PGF2o (0.5 ug/kg, i.a.) on the constantlyperfused hindliab pressure in the cat (smaller arrows). After infusion of meclofenamicacid (30 mg/kg, i.a.) the vasodilatoreffect of PGF2o remains. Panel b is 20 min after completionof the meclofenamateinfusion. Panel c is after one hour. To test the hypothesis that meclofenamicacid may act on vascular receptors,we observed its effects on i.a. administrationof PGF to the hindlimb of the cat perfused at a constant rate (1). PGF2u i&31.0 pg/kg i.a.) resulted in a consistentand reproduciblereduction in perfusion pressure in this preparation. Meclofenamicacid (30 mg/kg, i.a.) produced no alteration in the vasodepressoractivity of PGF for periods of up to one hour (figure 3). Similar results were seen 2::four other preparations.These findings are not in agreementwith the concept proposed by Levy and Lindner (9) and suggest that some other mechanism is responsiblefor the blocking actions of meclofenamicacid. The PGF2uinduced increase in pulmonary arterial pressure (figures 1 and 2) and the concommitantdecrease in aortic blood flow (measureddirectly in 4 experiments)were also not reduced by treatmentwith meclofenamicacid.
APRIL
1976
VOL. 11 NO. 4
695
PROSTAGLANDINS
Figure 4. Upper panels representheart rate and systemic arterial blood pressure responses induced following i.v. administrationof PGF2,, veratrine and 5-HT in the anesthetizedcat (A-D). Responses E-H are to these same agents after treatmentwith meclofenamic acid (30 mg/kg, i.v.). The dose of veratrine in panel F is less than the dose given in panel B. Note that giving 2X the dose of PGF20 (panel H) did not produce any appreciable effect on these parameters after blockade with meclofenamate. In previous studies we found that PGF and hypotensionby activating"receptors"l~C~~~~e~,‘~~~er,“f~~~~~d~~ on structuresperfused by means of the coronary arteries (4). As the cardiovasculareffects of PGF followingmeclofenamicacid r,esemblethe responses seen after atropine28rvagotomy (2,4) it is possible that the blockade occurs at some point in this reflex arc. The final series of experimentswere designed to determinewhether the afferent,central, or efferent componentsof this reflex are blocked by meclofenamate. As shown in figure 4 only the bradycardia and hypotension caused by PGF are blocked by meclofenamicacid. The reflex responses due to verat?&e and 5-HT were not significantlyaltered by this agent in 6 experiments (figure 4) nor was there any significantblockade of the reflex tachycardia or bradycardia resulting from i.v. administrationof acetylcholine (5 up/kg) or nonepinephrine(3 pg/kg) in four additional cats.
696
APRIL
1976
VOL. 11 NO. 4
PROSTAGLANDINS
The most plausable explanation for the present observationsis that meclofenamicacid competes with PGF2, for the mechanisms involved in the generation of the afferent component of this vagal reflex. Although meclofenamicacid is generally classifiedas a prostaglandin synthesis inhibitor (5,6), several studies have demonstrated that it also has direct blocking actions (7,8,9). It is possible that the fenamateshave both antisyntheticactivity as well as an antagonistic effect on the direct action of some prostaglandins. Villanueva et al. (11) reported that polyphloretinphosphate (PPP) selectivelyblocked the vasodepressoreffect of PGF2o in the cat. The vasodepressoreffect of PGEl was not altered in these experiments. A selective blockade of the depressor action of PGF was also observed by Math6 et al. in this species (12). It is pos&le that PPP is also demonstratingits selectivitynot by acting on receptors in the peripheral vasculaturebut upon those hemodynamic factors (reflexbradycardia and hypotension) that are unique to PGF2c(.
APRIL
1976 VOL. 11 NO. 4
697
PROSTAGLANDINS
REFERENCES 1. Koss, M. C. and J. Nakano. Effects of prostaglandinsEl and F on the peripheral circulationin the cat. Proc. Sot. Exp. Bioia . Med. 142: 383, 1973. M. C., J. W. Gray, M. Davison and J. Nakano. Cardiovascular actions of prostaglandinsEl and P2crin the cat. Europ. J. Pharmacol. 24: 151, 1973.
2.
Koss,
3.
KOSS, M. C. and J. Nakano. Cardiac arrhythmiasinduced by prostaglandin P20 in cats. Prostaglandins10: 179, 1974.
4.
Koss, M. C. and J. Nakano. Reflex bradycardia and hypotension produced by prostaglandinF20 in the cat. Brit. J. Pharmacol. 56: 245, 1976.
5.
Flower, R. J. Drugs which inhibit prostaglandinbiosynthesis. Pharmacol.Rev. 26: 33, 1974.
6.
Ferreira, S. I-I. and J. R. Vane. New aspects of the mode of action on nonsteroid anti-inflammatorydrugs. Ann. Rev. Pharmacol. 14: 57, 1974.
7.
Collier, ?I.0. J. and W. J. F. Sweatman. Antagonism by fenamates and slow reacting substance on human bronchial of prostaglandinF muscle. Nature 21@ 864, 1968.
8.
Tolman, E. L. and R. Partridge. Multiple sites of interaction between prostaglandinsand non-steroidalanti-inflammatoryagents. Prostaglandins9: 349, 1975.
Levy, B. and H. R. Lindner. Selective blockade of the vasodepressor response to prostaglandinF20 in the anaesthetizedrabbit. Brit. J. Pharmacol. 43: 236, 1971. .. .. 10. Angggrd, E. and S. Bergstrom. Biological effects of an unsaturated trihydroxyacid (PGF2,) from normal swine lung. Acta. Physiol. Stand. 58: 1, 1963. 9.
11. Villanueva,R., L. Hinds, R. L. Katz and K. E. Eakins. The effect of polyphloretinphosphate on some smooth muscle actions of prostaglandins in the cat. J. Pharmacol. Exp. Ther. 180: 78, 1972. 12.
698
Mathe; A. A., Strandberg,K. and B. Fredholm. Antagonism of prostainduced bronchoconstrictionand blood pressure changes glandin F by polyph%retin phosphate in the guinea-pigand cat. J. Pharm. Pharmacol. 24: 378, 1972.
APRIL
1976
VOL. 11 NO. 4
INHIBITIONOF PROSTAGLANDINFgo-INDUCEDRBFLEX BRADYCARDIA AND BYPOTBNSIONBY MRCLOFRNAMICACID
Michael C. Koss, Jiro Nakano and Joseph A. Rieger
Department of Pharmacology University of Oklahoma College of Medicine P.O. Box 26901 Oklahoma City, Oklahoma 73190
ABSTRACT Intravenousinjection of prostaglandinF (4-15 ug/kg, i.v.) produces an increase in pulmonary arterial pr&sure in conjunctionwith reflex bradycardia and hypotension in the anesthetizedcat. Meclofenamic acid ( 30 mg/kg, i.v.) inhibited the bradycardia and the reflex contribution to the systemic hypotension. Neither the PGF -induced pulmonary vasoconstrictionnor the direct systemic vasodil&or actions of PGF were blocked by meclofenamate. In addition, the reflex responses ca&d by i.v. veratrine and 5-HT were not inhibitedby meclofenamate. These results suggest that meclofenamic acid selectivelyblocks the afferent mechanism by which PGF20 induces reflex bradycardia and hypotension in the cat.
Acknowledgements: This work was supported by research grants from the Oklahoma Heart Association, and the Tulsa Chapter of the American Heart Association.
4-22-76
APRIL
1976
VOL. 11 NO. 4
691
PROSTAGLANDINS
INTEODUCTION In the cat, the cardiovascularresponses to prostaglandinF2 (PGF2,) appear to be composed of a variety of direct and reflex effects. Although a direct vasodilator action has been demonstrated (l), this effect is highly variable between preparationsand more transient than the overall hypotensive response following systemic injection. A decrease in cardiac output related to pulmonary arterial constrictionand reflex bradycardia and hypotension contribute greatly to the overall systemic hypotensive response to PGF2o (2,3). Both the afferent and efferent componentsof the reflex are carried in the vagal nerves. We have found that PGF activates this reflex by acting on "receptors" located either in t& left heart or on structuresreceiving their blood supply via the coronary arteries (4). Although meclofenamicacid is usually regarded as a potent inhibitor of prostaglandinsynthesis (5,6) it has also been reported to block the actions of PGF on several smooth muscle systems (7,8). Levy and Lindner (9) found th& meclofenamicacid selectivelyblocked the systemic vasodepressoreffects of PGF2o in the rabbit while having no effect on the responsesto PGE . The present investigationwas undertaken to determine if meclofena,ate would also inhibit the overall in the cat, and if so, to determinewhich involved. METHODS Adult cats of either sex were anesthetizedwith alpha-chloralose (60-80 mg/kg) given intraperitoneally. In the majority of the preparations a femoral artery and vein were cannulatedin order to measure systemic arterial blood pressure and for the intravenousadministration of drugs. Following cannulationof the trachea, positive pressure respirationwas initiated using a Harvard respirator. The animals were placed on their right side and the left hemithoraxwas opened, usually between the fourth and ninth ribs. A branch of the pulmonary artery supplying either the left cardiac or left apical lobe was cannulated for direct measurement of pulmonary arterial pressure. Pulmonary and systemic arterial pressureswere recorded continuouslyby means of Statham pressure transducers. Heart rate was measured with a Grass tachograph (7P4D) and all responseswere recorded on a Grass polygraph (7B). In one series of experimentsthe right subclavian artery and vein were cannulated for measuring systemic arterial pressure and i.v. injection of drugs. The abdominal aorta was cannulatedboth distally and proximally and the hindlimbs were perfused at a constant rate by means of a Sigmamotorpump. Systemic arterial and perfusion pressures were continuouslyrecorded. In four cats, aortic blood flow (utilizedas an index of cardiac output) was measured by means of a Statham electromagnetic flowmeter (M-4001) and Statham flow probe (Q-2050). The probe was positioned around the descending aorta distal to the exit of the left subclavian artery in order to avoid damage to the vagal fibres near the heart.
692
APRIL
1976
VOL. 11 NO. 4
PROSTAGLANDINS
Several criteria were establishedwith regard to the effects of t.v. that were qualitativePGF : 1) at least two control responses to PGF nitial baseline values ly &d quantitativelysimilar with 2) return to 1" after subsequent injections of PGF and 3) a bradycardia of at least 30 beats/min following the maximally gpfectiva dose of PGF2o. Only about 60% of the preparationstested met these requirements. (tromethaminesalt) used in these experiCrystalline powder PGF ments was supplied by Dr. .l?oLE. Pike, Upjohn Company, Kalamazoo,Michigan. A stock solution (1 mg/ml) was prepared with distilledwater and stored at -1OOC. Fresh solutions (10 or 100 pg/ml) were prepared shortly before the experimentsby diluting the stock solution with 0.9% NaCl solution. Meclofenamic acid (Parke-Davis)was dissolved in O.lN sodium hydroxide and infused over a 15-25 min interval. The majority of animals exhibited slight clonic jerking movements following the infusion of meclofenamate. In 3 cases these were severe enough to result in termination of the experiment.
Figure 1. Effect of PGF (10 pg/kg, i.v.) on pulmonary arterial pressure, heart ra 2?e and systemic arterial blood pressure before and after infusion of meclofenamicacid (30 mg/kg, i.v.). Note that both the reflex bradycardia and hypotension induced by PGF20 are attenuated following treatmentwith meclofenamate.
APRIL
1976 VOL. 11 NO. 4
693
PROSTAGLANDINS
RESULTS AND DISCUSSION The effects of i.v. administrationof PGF before and after treatment with meclofenamicacid were studied in 142gats. At the onset of each experiment, the dose of PGF2, producing the maximal change in all parameterswas determined. This maximally effective dose was within the range of 4-15 ug/kg. As shown in figure 1, PGF20 caused an increase in pulmonary arterial pressure and a decrease in systemic arterial pressure associatedwith apronauncedbradycardia. These responseswere qualitatively and quantitativelysimilar to those reported previously (l-4, 10). Following infusion of meclofenamicacid (30 mg/kg, i.v.), PGF produced about the same increase in pulmonary arterial pressure, howe& the PGF induced changes in heart rate and systemic arterial pressure were great?! ly attenuated. Figure 2 summarizes these responses in the 14 preparations Levy and Lindner have previously reported a similar observation in the rabbit (9). They found that meclofenamicselectivelyblocked the vasodepressorresponse to i.v. PGF2, but not that due to administration of PGE . The effects of these two prostaglandinson uterine and oviduct motilit y were not reduced by meclofenamicacid. They concluded that meclofenamicacid selectivelyblocks vascular smooth muscle receptors sensitive to PGF 2a'
1
0
3
6 mm
9
;2
i,--
6
0
12
Fig 2. Composite representationof the effects of PGF (4-15 up/kg, i.v.) on pulmonary arterial pressure (PAP) hea?f rate (HR) and mean systemic arterial pressure (MSAP)before (left) and after infusion of meclofenamicacid (30 mg/kg, i.v.) in 14 preparations. Vertical lines are + S.E.M.
694
APRIL 1976
VOL. 11 NO. 4
PROSTAGLANDINS
2
min
PWUSION PRESSURf mm Hs
MECLORNMIC
ACID
)(I Wks 60 min
PERFUSION PRESSURE MM
h=
Figure 3. Effect of PGF2o (0.5 ug/kg, i.a.) on the constantlyperfused hindliab pressure in the cat (smaller arrows). After infusion of meclofenamicacid (30 mg/kg, i.a.) the vasodilatoreffect of PGF2o remains. Panel b is 20 min after completionof the meclofenamateinfusion. Panel c is after one hour. To test the hypothesis that meclofenamicacid may act on vascular receptors,we observed its effects on i.a. administrationof PGF to the hindlimb of the cat perfused at a constant rate (1). PGF2u i&31.0 pg/kg i.a.) resulted in a consistentand reproduciblereduction in perfusion pressure in this preparation. Meclofenamicacid (30 mg/kg, i.a.) produced no alteration in the vasodepressoractivity of PGF for periods of up to one hour (figure 3). Similar results were seen 2::four other preparations.These findings are not in agreementwith the concept proposed by Levy and Lindner (9) and suggest that some other mechanism is responsiblefor the blocking actions of meclofenamicacid. The PGF2uinduced increase in pulmonary arterial pressure (figures 1 and 2) and the concommitantdecrease in aortic blood flow (measureddirectly in 4 experiments)were also not reduced by treatmentwith meclofenamicacid.
APRIL
1976
VOL. 11 NO. 4
695
PROSTAGLANDINS
Figure 4. Upper panels representheart rate and systemic arterial blood pressure responses induced following i.v. administrationof PGF2,, veratrine and 5-HT in the anesthetizedcat (A-D). Responses E-H are to these same agents after treatmentwith meclofenamic acid (30 mg/kg, i.v.). The dose of veratrine in panel F is less than the dose given in panel B. Note that giving 2X the dose of PGF20 (panel H) did not produce any appreciable effect on these parameters after blockade with meclofenamate. In previous studies we found that PGF and hypotensionby activating"receptors"l~C~~~~e~,‘~~~er,“f~~~~~d~~ on structuresperfused by means of the coronary arteries (4). As the cardiovasculareffects of PGF followingmeclofenamicacid r,esemblethe responses seen after atropine28rvagotomy (2,4) it is possible that the blockade occurs at some point in this reflex arc. The final series of experimentswere designed to determinewhether the afferent,central, or efferent componentsof this reflex are blocked by meclofenamate. As shown in figure 4 only the bradycardia and hypotension caused by PGF are blocked by meclofenamicacid. The reflex responses due to verat?&e and 5-HT were not significantlyaltered by this agent in 6 experiments (figure 4) nor was there any significantblockade of the reflex tachycardia or bradycardia resulting from i.v. administrationof acetylcholine (5 up/kg) or nonepinephrine(3 pg/kg) in four additional cats.
696
APRIL
1976
VOL. 11 NO. 4
PROSTAGLANDINS
The most plausable explanation for the present observationsis that meclofenamicacid competes with PGF2, for the mechanisms involved in the generation of the afferent component of this vagal reflex. Although meclofenamicacid is generally classifiedas a prostaglandin synthesis inhibitor (5,6), several studies have demonstrated that it also has direct blocking actions (7,8,9). It is possible that the fenamateshave both antisyntheticactivity as well as an antagonistic effect on the direct action of some prostaglandins. Villanueva et al. (11) reported that polyphloretinphosphate (PPP) selectivelyblocked the vasodepressoreffect of PGF2o in the cat. The vasodepressoreffect of PGEl was not altered in these experiments. A selective blockade of the depressor action of PGF was also observed by Math6 et al. in this species (12). It is pos&le that PPP is also demonstratingits selectivitynot by acting on receptors in the peripheral vasculaturebut upon those hemodynamic factors (reflexbradycardia and hypotension) that are unique to PGF2c(.
APRIL
1976 VOL. 11 NO. 4
697
PROSTAGLANDINS
REFERENCES 1. Koss, M. C. and J. Nakano. Effects of prostaglandinsEl and F on the peripheral circulationin the cat. Proc. Sot. Exp. Bioia . Med. 142: 383, 1973. M. C., J. W. Gray, M. Davison and J. Nakano. Cardiovascular actions of prostaglandinsEl and P2crin the cat. Europ. J. Pharmacol. 24: 151, 1973.
2.
Koss,
3.
KOSS, M. C. and J. Nakano. Cardiac arrhythmiasinduced by prostaglandin P20 in cats. Prostaglandins10: 179, 1974.
4.
Koss, M. C. and J. Nakano. Reflex bradycardia and hypotension produced by prostaglandinF20 in the cat. Brit. J. Pharmacol. 56: 245, 1976.
5.
Flower, R. J. Drugs which inhibit prostaglandinbiosynthesis. Pharmacol.Rev. 26: 33, 1974.
6.
Ferreira, S. I-I. and J. R. Vane. New aspects of the mode of action on nonsteroid anti-inflammatorydrugs. Ann. Rev. Pharmacol. 14: 57, 1974.
7.
Collier, ?I.0. J. and W. J. F. Sweatman. Antagonism by fenamates and slow reacting substance on human bronchial of prostaglandinF muscle. Nature 21@ 864, 1968.
8.
Tolman, E. L. and R. Partridge. Multiple sites of interaction between prostaglandinsand non-steroidalanti-inflammatoryagents. Prostaglandins9: 349, 1975.
Levy, B. and H. R. Lindner. Selective blockade of the vasodepressor response to prostaglandinF20 in the anaesthetizedrabbit. Brit. J. Pharmacol. 43: 236, 1971. .. .. 10. Angggrd, E. and S. Bergstrom. Biological effects of an unsaturated trihydroxyacid (PGF2,) from normal swine lung. Acta. Physiol. Stand. 58: 1, 1963. 9.
11. Villanueva,R., L. Hinds, R. L. Katz and K. E. Eakins. The effect of polyphloretinphosphate on some smooth muscle actions of prostaglandins in the cat. J. Pharmacol. Exp. Ther. 180: 78, 1972. 12.
698
Mathe; A. A., Strandberg,K. and B. Fredholm. Antagonism of prostainduced bronchoconstrictionand blood pressure changes glandin F by polyph%retin phosphate in the guinea-pigand cat. J. Pharm. Pharmacol. 24: 378, 1972.
APRIL
1976
VOL. 11 NO. 4
