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Modification of angiotensin II-induced relaxation by dipyridamole, phthalazinol and aspirin in isolated dog renal arteries.

Angiotensin (ANG) II-induced relaxations in isolated dog renal and cerebral arteries are postulated to be mediated by the release of prostaglandin (PG) I2 from the arterial wall. In helical strips of dog renal arteries treated with dipyridamole, relaxations induced by ANG II (10(-7) M) and exogenously applied PGI2 (10(-8) M) were potentiated; the potentiation was appreciably greater in the ANG-induced relaxation. Treatment with phthalazinol did not alter the response to ANG II, but significantly potentiated the relaxation induced by PGI2. The ANG-induced relaxations were suppressed or reversed to contractions by aspirin or indomethacin. Combined treatment of dipyridamole with aspirin or indomethacin restored the relaxant response to ANG II, while phthalazinol in combination with aspirin did not restore the response. It may be concluded that the potentiation of responses to ANG II by dipyridamole is associated with increments in the release of PGI2 from the arterial wall and potentiations of the response of arterial smooth muscle to PGI2. Dipyridamole appears to increase the production of PGI2 even in the presence of PG synthesis inhibition by aspirin or indomethacin.

Aspirin inhibits the aggregation of platelets induced by collagen, adrenaline and ADP due to inactivation of cyclooxygenase which transforms platelet arachidonic acid to pro staglandin (PG) endoperoxides (1,2). Results of the efficacy of aspirin in prevention of ischemic cerebral and myocardial diseases are not yet conclusive (3,4). The inhibition by aspirin of PGI2 biosynthesis in the vascular wall may reduce its effectiveness on the diseases (5). Combined treatment with dipyridamole and aspirin reduced coronary mortality (6). These antithrombotic agents have different and additive modes of action (7). However, attention has not been paid to the action of dipyridamole on an aspirin induced inhibition of the PGI2 synthesis.
Angiotensin (ANG) II produces a relaxation of isolated dog renal and cerebral arteries contracted with PGF20, PGE2 or norepine phrine (8)(9)(10). This relaxation is abolished by ANG II antagonists, reversed to a con traction by aspirin or indomethacin, and suppressed by PGI2 synthesis inhibitors, 15 hydroperoxy arachidonic acid and tranylcy promine. In the superfusate of isolated renal arteries in response to ANG II, PGI2-like substance is detected by the bioassay system with rat stomach and dog coronary artery strips (9). It is thus postulated that ANG II stimulates ANG receptors in the vascular wall, resulting in an increment of the synthesis and the release of PGI2 which relaxes the arterial strip (9,10). The ANG-induced release of PGI2-like substance from blood vessels has also been demonstrated (11,12). The present study was thus undertaken to   determine the alteration by dipyridamole and  phthalazinol  of the relaxant response  of  isolated dog renal arteries to ANG II, possibly  mediated  via endogenous  PG12, and the  response  to exogenously  applied  PGI2.  Dipyridamole  and phthalazinol  inhibit the  aggregation  of platelets,  possibly  by an  accumulation of cyclic AMP in the platelets (13,14). Interaction between dipyridamole and aspirin or indomethacin in the ANG induced relaxations was also studied.

Materials and Methods
Mongrel dogs of either sex, weighing 7 to 15 kg, were anesthetized with intraperitoneal injections of sodium thiopental (50 mg/kg) and sacrificed by bleeding from the common carotid arteries. The kidney was rapidly removed. Intrarenal, interlobar branches of the renal artery (0.5 to 0.8 mm outside diameter) were isolated. The arteries were helically cut into strips, approx. 20 mm long. The strips were vertically fixed between hooks in a muscle bath containing the nutrient solution, which was aerated with a mixture of 95% 02 and 5% C02 and main tained at 37+0.3°C. The hook anchoring the upper end of the strips was connected to the lever of a force-displacement transducer (Nihon Kohden Kogyo Co., Tokyo, Japan

Results
Effects of dipyridamole and phthalazinol on the response to ANG II and PGI2: In helical strips of dog renal arteries contracted with PGF2a, the addition of ANG II in a concen tration of 10-7 M caused a transient con traction followed by a moderate relaxation. Exogenously applied PGI2 (10-8 M) mode rately relaxed the renal arterial strips. Treat ment with 10-5 M dipyridamole potentiated the relaxant response to ANG II by 100% ( Fig. 1)  ). The PGI2-induced relaxation was also potentiated by dipyridamole; however, the potentiation was less than that seen in the response to ANG II (22% vs. 100%, Fig. 1). In paired comparison, dipyridamole always potentiated the ANG-induced relaxation to a greater extent. The potentiating effect was reversed by repeated washing of preparations. Typical responses to ANG II and PGI2 before and after treatment with dipyridamole are shown in the upper tracings of Fig. 2. The solvent of dipyridamole in the same concen tration as that obtained when 10-5 M dipyridamole was applied did not alter the relaxant response to ANG II (Table 1) and PGI2 (43.5±8.4% in the control and 42.0±8.0% in strips treated with solvent, N=6). On the other hand, phthalazinol (10-5 M) did not alter the relaxation induced by ANG II, but significantly potentiated the PGI2-induced relaxation (Fig. 2, lower tracings, and Fig. 3). The contractile response to ANG II tended to be attenuated (from 149±47 mg to 104±35 mg, N=16). The concentration-response curve for PGI2 was shifted to the left following treatment with 10-5 M phthalazinol. Treatment for 60 min with polyphloretin phosphate (3x10-5 g/ml), an antagonist of vasoconstrictor PG's (16), did not significantly affect the relaxation induced by ANG II (Table 1)    reversed to contractions following treatment of renal arterial strips with aspirin in concen trations higher than 10-5 M or with in domethacin in concentrations higher than 3X10-8 M (Table 1). Dipyridamole (10-5 M) applied in combination with 10-5 M aspirin markedly attenuated the inhibitory effect of aspirin (Fig. 4); responses to ANG II in arteries treated with aspirin alone and with aspirin plus dipyridamole differed signifi cantly (12.5% contraction vs. 24.2% relaxation, respectively, P<0.02) ( Table 1). Combined treatment with dipyridamole and aspirin potentiated the relaxation induced by PGI2. However, the inhibitory effect of 5 X 10-5 M aspirin was not prevented by dipyridamole in concentrations of 10-5 (Table  1)    thacin alone (P<0.02, Fig. 5). The inhibitory effect of 10-7 M indomethacin on ANG induced relaxations was not prevented by 10-5 M dipyridamole. Phthalazinol (10-5 M) failed to alter the aspirin-induced inhibition in the respnses to ANG II ( Table 1). Recordings of a renal arterial strip treated with indomethacin alone or with in domethacin plus dipyridamole are demon strated in Fig. 6. The significant relaxation was induced in the dipyridamole-treated strip, despite the presence of an effective concen tration of indomethacin.

Discussion
Treatment of renal arterial strips with dipyridamole potentiated the relaxant response to ANG II, which is postulated to result mainly from PGI2 released from the arterial wall (9,10). In preparations in response to ANG II in which only a slight or no contraction preceded the relaxation, di pyridamole potentiated the relaxation to a similar extent to that seen when the con traction was evident. When the contractile response to ANG II was inhibited by phthal azinol, the relaxation was not potentiated (Fig. 2, lower tracings). Polyphloretin phos phate did not potentiate the relaxation. ANG II has been demonstrated to release PGI2 as well as vasoconstrictor PG's such as PG F2,,, and E2 (9); the contractile response to these PG's is specifically attenuated by poly phloretin in the concentration used here (16). This antagonist, however, does not reduce the relaxant response to PGI2 (Toda, unpublished data). These results indicate that the potentiation of relaxant responses to ANG II by dipyridamole is not due to an inhibition of the contraction. The arterial relaxation induced by PGI2 was also poten tiated by dipyridamole as was the anti aggregating action of PGI2 (7); however, the potentiation in the arteries was appreciably less than that seen in the response to ANG II. Therefore, it appears that the increased biosynthesis and release of PGI2 as well as the augmented responsiveness of arterial smooth muscle to PGI2 are involved in the potentiation of ANG-induced relaxations. The biosynthesis of PGI2 from tritiated arachidonic acid in rat stomach fundus homogenates and from PGH2 in pig aorta microsomes is reportedly increased by dipyridamole (17).
Dipyridamole produced an arterial relax ation, which was unaffected by treatment with aspirin, indicating that vasodilator PG's are not involved in the dipyridamole-induced relaxation. It may be concluded that di pyridamole does not release precursor fatty acid, but increases the biosynthesis of PGI2 when the precursor is released by chemical stimuli such as ANG II or when arachidonic acid or PGH2 is applied (17).
Treatment with phthalazinol potentiated the relaxation induced by PGI2, but not the relaxant response to ANG II. Similar poten tiation of the effect of exogenously applied PG12 has been seen in rabbit platelets (18). Therefore, phthalazinol may interfere either with the biosynthesis or the release of PGI2 stimulated by ANG II in dog renal arteries or may inhibit the action of ANG II on receptors.
Dipyridamole and phthalazinol inhibit cyclic AMP phosphodiesterase (13,19) aril accumulate cyclic AMP in platelets, being possibly involved in the inhibition of platelet aggregation (13). PGI2 increases the pro duction of cyclic AMP in arteries (20) and has antiaggregating (21) and vasodilator activities (22). Therefore, potentiating effects of dipyridamole and phthalazinol may be explained by a greater accumulation of cyclic AMP in dog renal arterial smooth muscle. However, effects of these antiaggregating agents on the arterial relaxation induced by ANG II were quite different. Therefore, it seems unlikely that changes in the synthesis of PGI2 and its release from the arterial wall are related to the phosphodiesterase inhibition and the cyclic AMP accumulation.
ANG 11-induced relaxations were abolished or reversed to contractions following treat ment with aspirin or indomethacin, which is expected to suppress the production of PGI2 following the inhibition of cyclooxygenase activity. Dipyridamole prevented the inhibitory effect of aspirin and indomethacin in concen trations sufficient to partially inactivate the enzyme. The prevention could be associated mainly with the increased biosynthesis and release of PGI2 and to a lesser extent with the augmented responsiveness of arteries to PG12.