CAN. J. PHYSHOL. PHARMACOL. VOL, TO, 1992
716
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 11/11/14 For personal use only.
factor and potentiates its action in coronary arteries of the pig. Br. P. Phamacol. 95: 1197-1203. Siegel, G., Carl, A., Adler, A., and Stock, G. 1989. Effect of the prostacyclin analogue iloprost on K + permeability in the smooth muscle cells of the canine carotid artery. Eicosanoids, 2: 213222. Stanworth, P. A., Dutton, P., Paul, K. S., eta!. 1988. hostacyclin: a new treatment for vasospasm associated with subarachnoid hemorrhage. Acta Neurockir. Suppl. mien), 42: $5 -87. Vemue, N. A., Hertog, A. D., and Zaagsrna, J. 1987. Desensitiza-
tion of PGE, and PG12 induced contractions in different smooth muscles of guinea-pig unmasking relaxing properties of prostanoids. Eur. J. Pharmcol. 644: 399 -403. Whalley, E. T., Schilling, L., and Wakl, M. 1989. Cerebrovascular effects of prostanoids: in-vitro studies in feline middle cerebral and basilar artery. Prostaglandins, 38: 625 -634. Zhang, H.,Stockbridge, N., Weir, B., et al. 1991. Glibenclamide relaxes vascular smooth muscle constriction pduced by prostaglandin F,,. Eur. I. Pharmacol. 695: 27 -35.
Competitive antagonism of pressor responses to angiotensin II and angiotensin 111 by the angiotensin n-1 receptor ligand losartan ALY ABDELRAHMAN AND CATHERINE C. Y PANG^ Depament of Phamcslogy & ~ e r q e u t i c sFaculty , of Medicine, 7%e University of British Co/umbia, 9%76 H ~ a / f Sciences h Mail, Vancouver, B. C., Canada V6T d B Received September 25, 1991 ABDELWAHMAN, A., and PANG,C. C. .$r. 1992. Competitive antagonism of pressor responses to angiotensin I1 and angiotensin I11 by the angiotensin 11-1 receptor ligand losartan. Can. J. Physiol. Pharmacol. 70: 716-719. Losartan (DuP 753) and PD123177 are nonpeptide angiotensin (ANG) receptor ligands for subtypes of ANG I1 receptors ANG 11-1 and ANG 11-2, respectively. We examined the effects of losamn and PI3123177 on dose - mean arterial pressure (MAP) response curves for ANG I1 and ANG 111in eight groups (n = 6 each) of conscious rats. Sdine (0.9 % NaCl), losarfam (1 x and 9 x 10-hollkg), and PD123177 (2 x BOs%olIkg) were i.v. bolus injected 1.5 min before the construction of ANG II dose-response curves in groups 1, 11, 111, and IV, respectively. Groups V-VIII were treated similarly to I-IV except that ANG I11 was given in place of ANG 11. Losartan dose dependently shifted the dose-response curves of ANG I1 and ANG I11 to the right with similar dissociation constants (-log Kl of 6.6 f 0.7 and 6.6 B 0.B mollkg, respectively) and no change in the maxima. PD123177 affected neither maximum MAP nor ED,, values for ANG I1 or ANG 111. Our results show that losarfan but not BD123177 is a competitive antagonist of the MAP effects of ANG I1 and ANG 111. Key words: nonpeptide angiotensin receptor antagonist, angiotensin gZ, angiotensin 111, blood pressure, losartan. -
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ABDELRAHMAN, A., et PANG,C. C. Y. 1992. Competitive antagonism of pressor responses to angiotensin I1 and angiotensin 111 by the angiotensin 11-1 receptor ligand losartan. Can. I. Physiol. Phamacol. 70 : 716-719. Le losartan (DuP 753) et le BD123177 sont des ligands cles rCcepteurs d'angiotensine (ANG) non peptidique pour les soustypes de rkcepteurs d'ANG 11, wit I'ANG 11-1 et I'ANG 11-2. Nous avons examin6 les effets du losartan et du PD123177 sur les courbes dose - rkpnse moyenne a la pressisn artkrielle (PAM) pour 1'ANG I1 et 19ANG111 chez huit groupes (re = 6 chacun) de rats conscients. Une solution saline (0,9% de NaCI), le losartan (1 x lomget 9 x 1W6 mollkg) et le PI3123177 (2 x l W 5 mllkg) ont CtC inject& i.v. sous forme de bolus, 15 min avant 1'6ta8Pliswment des courbes dose-rCponse chez les groupes 1, 11, I11 et IV, respectivement. k s groupes V-VIII ont bt6 trait& similairement i I-IV, sauf que I'ANG I11 a CtC substituke Zi I'ANG 11. Le lssartan a dCplacC, en fonction de la dose, les courbes dose-rCpnse de I'ANG H I et de B'ANG I11 vers la droite avec des constantes de dissociation similaires (-Bog KI de 6,6 f 0,7 et 6,6 f 0 , l mollkg, respwtivement), sans variation au niveau des maximums. HR PI9123177 n'a affect6 ni Ia PAM maximale, ni les vdeurs de ED,, pour 1'ANG I1 ou 1'ANG 111. Nos rCsultats montrent que le losartan, mais non pas le PD123177, est un antagoniste comHtitif des effets sur I'ANG I1 et 1'ANG 111 sur la PAM. Mots cl& : antagoniste des rbcepteurs d'angiotensine non peptidique, angiotensine 11, angiotensine 111, pression sanguine, losartan. [Traduit par la rkdaction]
Introduction It has been shown that angiotensin 11 (ANG II) binds to two subtypes of ANG 11 binding sites in the rat adrenal gland, namely, the ANG 11-1 site which is inhibited by DuP 753 (losarhn) and ANG 11-2 site which is inhibited by PD123177 (Chiu et a&.1989). However, in rat aortic smooth muscle cells, lassastan, but not PD123177, inhibits the specific binding 'Author to whom correspondence should be addressed. Printed in Canada i Imprid au Canada
sf ANG %I9 suggesting the existence of only ANG 11-1 sites in these cells (Criscione et a&. 1990). Although ANG II has similar affinities for both subtypes of ANG %I receptors (Timermans et a&. 1991), ANG II has been known to produce biological effects only via the activation of ANG 11-1 receptors. Eosartan, but not PD123177, inhibits ANG I1 induced ddosterone release, catecholamine secretion, water drinking, in vitrs arterial contractile response, and in vivo pressor response Wong et a&.199861). The inhibition by losar-
BREF RBPOR'RiFL4PPORTS BREFS
TABLE1. M a n arterial pressure (means f SE) 5 min prior to and 15 min following i.v. bolus of losartan, PD123 177, or vehicle in eight groups of conscious rats
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 11/11/14 For personal use only.
Mean arterial pressure Groups
n
Control
+ Antagonist
I (vehicle) I1 (losartan, 1 x mol/kg) I11 (losartan, 9 x los6 mol/kg) IV (PD123177, 2 x mol/kg) V (vehicle) VI (losartan, 1 x lose molkg) VII (losamn, 9 x 1W6 mol/kg) VIII (PD123177, 2 x 1W5 mol/kg)
6 5 6 4 6 6 5 4
110f 3 105f 5 108f 3 108 f 2 181f 2 113+ 2 loo* 2 109f 1
110k3 105 f 6 108 f 3 lllf 1 161 f 2 112+2 99+2 %12*3
tan on ANG I1 induced contraction in the rabbit aorta is competitive (Wiest et al. 199%).The oral administrations of losartan to spontaneously hypertensive rats (Wong et ak. 19906) and rend hypertensive rats (Wong et al. 1990~)dose dependently reduce blood pressure. It is h o w n that ANG 11 and ANG I11 (des-Asp1-Ang 11) act on different ANG receptors in vascular smooth muscles (Carey et a&.1978; Ackerly et al. 1977; Trachte and Beach 1983; Tabrizchi and Bang 1987). The ANG 11 analogue [Sara,Ile"Ang I1 selectively antagonizes the pressor responses to ANG 11 but not ANG I11 (Tabrizchi and Bang 1987), while the ANG LII analogue [Sar
716
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 11/11/14 For personal use only.
factor and potentiates its action in coronary arteries of the pig. Br. P. Phamacol. 95: 1197-1203. Siegel, G., Carl, A., Adler, A., and Stock, G. 1989. Effect of the prostacyclin analogue iloprost on K + permeability in the smooth muscle cells of the canine carotid artery. Eicosanoids, 2: 213222. Stanworth, P. A., Dutton, P., Paul, K. S., eta!. 1988. hostacyclin: a new treatment for vasospasm associated with subarachnoid hemorrhage. Acta Neurockir. Suppl. mien), 42: $5 -87. Vemue, N. A., Hertog, A. D., and Zaagsrna, J. 1987. Desensitiza-
tion of PGE, and PG12 induced contractions in different smooth muscles of guinea-pig unmasking relaxing properties of prostanoids. Eur. J. Pharmcol. 644: 399 -403. Whalley, E. T., Schilling, L., and Wakl, M. 1989. Cerebrovascular effects of prostanoids: in-vitro studies in feline middle cerebral and basilar artery. Prostaglandins, 38: 625 -634. Zhang, H.,Stockbridge, N., Weir, B., et al. 1991. Glibenclamide relaxes vascular smooth muscle constriction pduced by prostaglandin F,,. Eur. I. Pharmacol. 695: 27 -35.
Competitive antagonism of pressor responses to angiotensin II and angiotensin 111 by the angiotensin n-1 receptor ligand losartan ALY ABDELRAHMAN AND CATHERINE C. Y PANG^ Depament of Phamcslogy & ~ e r q e u t i c sFaculty , of Medicine, 7%e University of British Co/umbia, 9%76 H ~ a / f Sciences h Mail, Vancouver, B. C., Canada V6T d B Received September 25, 1991 ABDELWAHMAN, A., and PANG,C. C. .$r. 1992. Competitive antagonism of pressor responses to angiotensin I1 and angiotensin I11 by the angiotensin 11-1 receptor ligand losartan. Can. J. Physiol. Pharmacol. 70: 716-719. Losartan (DuP 753) and PD123177 are nonpeptide angiotensin (ANG) receptor ligands for subtypes of ANG I1 receptors ANG 11-1 and ANG 11-2, respectively. We examined the effects of losamn and PI3123177 on dose - mean arterial pressure (MAP) response curves for ANG I1 and ANG 111in eight groups (n = 6 each) of conscious rats. Sdine (0.9 % NaCl), losarfam (1 x and 9 x 10-hollkg), and PD123177 (2 x BOs%olIkg) were i.v. bolus injected 1.5 min before the construction of ANG II dose-response curves in groups 1, 11, 111, and IV, respectively. Groups V-VIII were treated similarly to I-IV except that ANG I11 was given in place of ANG 11. Losartan dose dependently shifted the dose-response curves of ANG I1 and ANG I11 to the right with similar dissociation constants (-log Kl of 6.6 f 0.7 and 6.6 B 0.B mollkg, respectively) and no change in the maxima. PD123177 affected neither maximum MAP nor ED,, values for ANG I1 or ANG 111. Our results show that losarfan but not BD123177 is a competitive antagonist of the MAP effects of ANG I1 and ANG 111. Key words: nonpeptide angiotensin receptor antagonist, angiotensin gZ, angiotensin 111, blood pressure, losartan. -
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ABDELRAHMAN, A., et PANG,C. C. Y. 1992. Competitive antagonism of pressor responses to angiotensin I1 and angiotensin 111 by the angiotensin 11-1 receptor ligand losartan. Can. I. Physiol. Phamacol. 70 : 716-719. Le losartan (DuP 753) et le BD123177 sont des ligands cles rCcepteurs d'angiotensine (ANG) non peptidique pour les soustypes de rkcepteurs d'ANG 11, wit I'ANG 11-1 et I'ANG 11-2. Nous avons examin6 les effets du losartan et du PD123177 sur les courbes dose - rkpnse moyenne a la pressisn artkrielle (PAM) pour 1'ANG I1 et 19ANG111 chez huit groupes (re = 6 chacun) de rats conscients. Une solution saline (0,9% de NaCI), le losartan (1 x lomget 9 x 1W6 mollkg) et le PI3123177 (2 x l W 5 mllkg) ont CtC inject& i.v. sous forme de bolus, 15 min avant 1'6ta8Pliswment des courbes dose-rCponse chez les groupes 1, 11, I11 et IV, respectivement. k s groupes V-VIII ont bt6 trait& similairement i I-IV, sauf que I'ANG I11 a CtC substituke Zi I'ANG 11. Le lssartan a dCplacC, en fonction de la dose, les courbes dose-rCpnse de I'ANG H I et de B'ANG I11 vers la droite avec des constantes de dissociation similaires (-Bog KI de 6,6 f 0,7 et 6,6 f 0 , l mollkg, respwtivement), sans variation au niveau des maximums. HR PI9123177 n'a affect6 ni Ia PAM maximale, ni les vdeurs de ED,, pour 1'ANG I1 ou 1'ANG 111. Nos rCsultats montrent que le losartan, mais non pas le PD123177, est un antagoniste comHtitif des effets sur I'ANG I1 et 1'ANG 111 sur la PAM. Mots cl& : antagoniste des rbcepteurs d'angiotensine non peptidique, angiotensine 11, angiotensine 111, pression sanguine, losartan. [Traduit par la rkdaction]
Introduction It has been shown that angiotensin 11 (ANG II) binds to two subtypes of ANG 11 binding sites in the rat adrenal gland, namely, the ANG 11-1 site which is inhibited by DuP 753 (losarhn) and ANG 11-2 site which is inhibited by PD123177 (Chiu et a&.1989). However, in rat aortic smooth muscle cells, lassastan, but not PD123177, inhibits the specific binding 'Author to whom correspondence should be addressed. Printed in Canada i Imprid au Canada
sf ANG %I9 suggesting the existence of only ANG 11-1 sites in these cells (Criscione et a&. 1990). Although ANG II has similar affinities for both subtypes of ANG %I receptors (Timermans et a&. 1991), ANG II has been known to produce biological effects only via the activation of ANG 11-1 receptors. Eosartan, but not PD123177, inhibits ANG I1 induced ddosterone release, catecholamine secretion, water drinking, in vitrs arterial contractile response, and in vivo pressor response Wong et a&.199861). The inhibition by losar-
BREF RBPOR'RiFL4PPORTS BREFS
TABLE1. M a n arterial pressure (means f SE) 5 min prior to and 15 min following i.v. bolus of losartan, PD123 177, or vehicle in eight groups of conscious rats
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by UNIV CHICAGO on 11/11/14 For personal use only.
Mean arterial pressure Groups
n
Control
+ Antagonist
I (vehicle) I1 (losartan, 1 x mol/kg) I11 (losartan, 9 x los6 mol/kg) IV (PD123177, 2 x mol/kg) V (vehicle) VI (losartan, 1 x lose molkg) VII (losamn, 9 x 1W6 mol/kg) VIII (PD123177, 2 x 1W5 mol/kg)
6 5 6 4 6 6 5 4
110f 3 105f 5 108f 3 108 f 2 181f 2 113+ 2 loo* 2 109f 1
110k3 105 f 6 108 f 3 lllf 1 161 f 2 112+2 99+2 %12*3
tan on ANG I1 induced contraction in the rabbit aorta is competitive (Wiest et al. 199%).The oral administrations of losartan to spontaneously hypertensive rats (Wong et ak. 19906) and rend hypertensive rats (Wong et al. 1990~)dose dependently reduce blood pressure. It is h o w n that ANG 11 and ANG I11 (des-Asp1-Ang 11) act on different ANG receptors in vascular smooth muscles (Carey et a&.1978; Ackerly et al. 1977; Trachte and Beach 1983; Tabrizchi and Bang 1987). The ANG 11 analogue [Sara,Ile"Ang I1 selectively antagonizes the pressor responses to ANG 11 but not ANG I11 (Tabrizchi and Bang 1987), while the ANG LII analogue [Sar
