Effect of Sodium Loading and Depletion on Cyclic Nucleotides in Plasma and Aorta. Interaction between Prostacyclin and Cyclic Nucleotides

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1 Endocrinol. Japon. 1982, 29 (2), Effect of Sodium Loading and Depletion on Cyclic Nucleotides in Plasma and Aorta. Interaction between Prostacyclin and Cyclic Nucleotides MANABU YOSHIMURA, TERUO KITANI, YOSHIHIRO KAJITA, KAZUO TAKEDA, HAKUO TAKAHASHI, TADAYOSHI MIYAZAKI, TAKASHI HACHIYA, YUKIO OCHI* AND HAMAO IJICHI Second Department of Internal Medicine, Kyoto Prefectural University of Medicine. *Second Department of Internal Medicine, Shiga University of Medical Science. The present study evaluated the effect of sodium loading and sodium depletion on camp and cgmp content of rat aorta. Enhanced generation of prostacyclin (PGI2) in aorta was noticed in sodium loading and sodium-depletion. As PGI2 is potent vasoactive agent, the interaction between PGI2 generation in the aorta and cyclic nucleotide accumulation in the aorta was investigated. Sodium depletion of rats induced the elevation of both camp and cgmp in the aorta and of camp in plasma. No change in cyclic nucleotides was noticed following sodium loading. These changes in cyclic nucleotides were felt to reflect the fluctuation of vasoactive agents under various sodium metabolism conditions. These observations may indicate that PGI2 is not a major factor in the regulation of cyclic nucleotide metabolism under sodium loading and sodium depletion. The increased accumulation of camp and cgmp in rat aorta in sodium depletion may be due to the cumulative effects of PGI2, catecholamine and probably angiotension II which are induced by sodium depletion. There is good deal of evidence indicating that cyclic nucleotides may play an important role in blood pressure regulation. In spontaneously hypertensive rats (SHR), several abnormalities of cyclic nucleotides and their regulating enzymes were reported. Amer (1973) demonstrated that aortas from SHR Received May 6, 1981 Abbreviation SHR: spontaneously hypertensive rat camp: adenosine 3', 5'-monophosphate cgmp: guanosine 3', 5'-monophosphate PGI2: prostacyclin PRA: plasma renin activity PAC: plasma aldosterone concentration THI: trihydroxyindole PG: prostaglandin contained a lower concentration of camp, a higher concentration of cgmp and greater camp-phosphodiesterase activity than corresponding controls. On the other hand Triner et al. (1975) and Klenerova et al. (1975) reported different findings of a high camp level and of an increased basal level of adenylate cyclase in SHR. These different results may be due to the different methods used. However, it is postulated that abnormalities in cyclic nucleotides and their regulating enzymes are involved in cardiovascular tissue of hypertensive animals. Previous study in our laboratory indicated that chronic sodium loading to rats induced elevation of blood pressure in association with

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5 Vol.29, No.2 EFFECT OF SALT ON camp, cgmp AND PGI2 249 was more dominant than that of camp, they speculated that the angiotensin induced increase in plasma cgmp might be due to the augmentation of a sympathetic discharge as angiotensin appeared to stimulate the sympathetic nervous system (Severs and Daniels- Severs, 1973). Moreover, angiotensin may directly increase the cyclic nucleotide content in the aorta. In our in vitro assay system, angiotensin II also directly caused a dosedependent increase in camp and cgmp in aortic strips (Yoshimura et al., 1980 b). However, since the opposite result also has been reported (Volicer and Hynie, 1971), further study is recommended. In the present study, the increased amount of urinary norepinephrine excretion was observed in sodium-depleted rats in association with an increase in cyclic nucleotide accumulation in the aorta. It has been accepted that endogenous and exogenous catecholamines produce an increase in camp in plasma in association with the increase in plasma cgmp. It was also speculated that the increase in plasma camp was a beta-adrenergic effect and the increase in plasma cgmp was an alpha-adrenergic response (Ball et al., 1972). Therefore it is suggested that under sodium depletion, enhanced release of norepinephrine may also contribute to the elevation of camp and cgmp in plasma and the aorta. The cumulative effect of angiotensin II, norepinephrine and PGI2 is considered as a possible explanation of the increased cyclic nucleotide under sodium depletion. On the other hand sodium loading did not effect the cyclic nucleotide accumulation in association with suppressed PRA and PAC and reduced urinary excretion of norepinephrine. No definite factors in elevating cyclic nucleotide content in the aorta could be elicited in the present study. From these observations, it is impossible to show that one factor regulates the cyclic nucleotide metabolism under sodium loading and sodium depletion. PGI2 is a potent vasoactive agent, but enhanced generation of PGI2 in the aortic wall was not be associated with the increase in camp and cgmp accumulation under sodium loading. Therefore PGI2 may not be the major factor in increasing camp and cgmp in the aorta. In sodium depletion, the cumulative effect of PGI2, catecholamines and probably angiotensin II is felt to increase cyclic nucleotides in the aorta. References Amer, M. S. (1973. Cyclic adenosine monophosphate and hypertension in rats. Science 179, Armstrong, J. M., G. J. Dusting, S. Moncada and J. R. Vane (1978). Cardiovascular actions of prostacyclin (PGI2), a metabolite of arachidonic acid which is synthesized in blood vessels. Circ. Res. 43 (Suppl. 1), Ball, J. H., N. I. Kaminsky, J. G. Hardman, A. E. Broadus, E. W. Sutherland and G. W. Liddle (1972). Effect of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man. J. Clin. Invest. 51, Dembinska-Kiec, A., W. Rucher and P. S. Schonhofer (1980). Effects of PGI2 and PGI analogues on camp levels in cultured endothelial and smooth muscle cells derived from bovine arteries. Naunyn- Schmiedeberg's Arch Pharmacol. 311, Herman, C. A., T. V. Zenser and B. B. Davis (1979). Comparison of the effects of prostaglandin I2 and prostaglandin E2 stimulation of the rat kidney adenylate cyclase-cyclic AMP system. Biochim. Biophys. Acta 582, Honma, M., T. Satoh., J. Takezawa., and M. Ui (1977). An ultrasensitive method for the simultaneous determination of cyclic AMP and cyclic GMP in small-volume samples from blood and tissues. Biochem. Med. 18, Klenerova, V., I. Albrecht., and S. Hynie (1975). The activity of adenylate cyclase and phesphodiesterase in hearts and aortas of spontaneously hypertensive rats. Pharmacol. Res. Commun. 7, Pace-Asciak, C. R. and M. C. Carrara (1979). Agedependent increase in the formation of prostaglandin developing spontaneously hypertensive rat. Biochim. Biophys. Acta 574, Rosman, P. M., R. Agrawal, A. D. Goodman, and A. L. Steiner (1976). Effect of angiotensin II on cyclic guanosine monophosphate and cyclic adenosine monophosphate in human plasma. J. Clin. Endocrinol. Metab. 42, Schror, K. and P. Rosen (1979). Prostacyclin (PGI2) decreases the cyclic AMP level in coronary arteries.

6 250 YOSHIMURA et al. Endocrinol. April 1982 Japon. Naunyn-Schmiedeberg's Arch. Pharmacol. 306, Severs, W. B., and A. E. Daniels-Severs (1973). Effects of angiotensin on the central nervous system. Pharmacol. Rev. 25, Speranskaya, N. V., V. P. Kulagina and R. I. Sokolova (1980). Effect of indomethacin on cyclic nucleotide metabolism and vascular reactivity in rats. Byull. Eksp. Biol. Med. 90, Triner, L., Y. Vulliemoz., M. Verosky., and W. M. Manger (1975). Cyclic adenosine monophosphate and vascular reactivity in spontaneously hypertensive rats. Biochem. Pharmacol. 24, Volicer, L. and S. Hynie (1971). Effect of catecholamines and angiotensin on cyclic AMP in rat aorta and tail artery. Eur. J. Pharmacol. 15, Yoshimura, M., I. Kaimasu, T., T. Kitani., T. Kawamura., K. Takeda., S. Sasaki., Y. Kajita., M. Nakagawa and H. Ijichi (1980a). Effect of sodium loading and depletion on vascular reactivity and prostacyclin generation. Jpn. Circ. J. 44, Yoshimura, M., Y. Kajita, T. Kawamura, T. Kitani, I. Kaimasu, T. Miyazaki, M. Nakagawa, Y. Ochi and H. Ijichi (1980b). Prostacyclin as circulating hormone, interaction with salt metabolism and renin-angiotensin-aldosterone system (abstract). Folia Endocrinol. Jpn. 56, 381.