1564 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Communications to the Editor
antihypertensive drugs able to selectively antagonize
the pressor effect of ouabain or OLF. More detailed
pharmacological and toxicological results will be de-
scribed in a future paper.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and analytical data for compounds 1, 3, and 4 (5
pages). Ordering information is given on any current mast-
head page.
Refer en ces
(1) (a) de Wardener, H. E.; MacGregor, G. A. Dahl’s Hypothesis that
a Saluretic Substance may be Responsible for a Sustained Rise
in Arterial Pressure: its Possible Role in Essential Hypertension.
Kidney Int. 1980, 18, 1-9. (b) Woolfson, R. G; de Wardener, H.
E. Primary Renal Abnormalities in Hereditary Hypertension.
Kidney Int. 1996, 50, 717-731.
(2) (a) J oergensen, P. L. Structure, Function and Regulation of
Sodium-Potassium ATPase in the Kidney. Kidney Int. 1986, 29,
10-20. (b) Hoffman, B. F.; Bigger, J . T. J r. Digitalis and Allied
Cardiac Glycosides. In The Pharmacological Basis of Therapeu-
tics, 7th ed.; Gilman, A. G., Goodman, L. S., Rall, T. W., Murad,
F., Eds.; Macmillan Publishing Co.: New York, 1985; pp 716-
747.
(3) Blaustein, M. P. Sodium Ions, Calcium Ions and Blood Pressure
Regulation: a Reassessment and a Hypothesis. Am. J . Physiol.
1977, 232, C165-C173.
(4) Goto, A.; Yamada, K.; Yagi, N.; Yoshioka, M.; Sugimoto, T.
Physiology and Pharmacology of Endogenous Digitalis-like Fac-
tors. Pharmacol Rev. 1992, 44, 377-399.
(5) Harris, D. W.; Clark, M. A.; Fisher, J . F.; Hamlyn, J . M.; Kolbasa,
K. P.; Ludens, J . H.; DuCharme, D. W. Development of an
Immunoassay for Endogenous Digitalis-like Factor. Hypertension
1991, 17, 936-943.
(6) (a) Zhao, N.; Lo, L.-C.; Berova, N.; Nakanishi, K.; Tymiak, A.
A.; Ludens, J . H.; Haupert, G. T. Na,K-ATPase Inhibitors from
Bovine Hypothalamus and Human Plasma Are Different from
Ouabain: Nanogram Scale CD Structural Analysis. Biochemistry
1995, 34, 9893-9896. (b) Tymiak, A. A.; Norman, J . A.; Bolgar,
M.; DiDonato, G. C.; Lee, H.; Parker, W. L.; Lo, L.-C.; Berova,
N.; Nakanishi, K.; Haber, E.; Haupert, G. T. J r. Physicochemical
Characterization of a Ouabain Isomer Isolated from Bovine
Hypotalamus. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8189-8193.
(7) Manunta, P.; Rogowski, A. C.; Hamilton, B. P.; Hamlyn, J . M.
Ouabain-Induced Hypertension in the Rat: Relationships Among
Circulating and Tissue Ouabain and Blood Pressure. J . Hyper-
tens. 1994, 12, 549-560.
(8) Saito, Y.; Kanesama, Y.; Okada, M. Preparation of 3-Deoxy and
17-Hydroxy Cardenolide. Chem. Pharm. Bull. 1970, 18, 629-
631.
(9) Minato, H.; Nagasaki, T. A New Method for the Synthesis of
Furan Compounds. J . Chem. Soc. C 1966, 377-379.
(10) Brown, L.; Erdmann, E. Comparison of the Affinity of Human,
Beef and Cat Heart Na+,K+-ATPase for Different Digitalis
Derivatives. Arzneim. Forsh. 1984, 34, 1314-1318.
(11) J ørghensen, P. L. Purification and Characterization of Na+,K+-
ATPase. III. Purification from the Outer Medulla of Mammalian
Kidney after Selective Removal of Membrane Components by
Sodium Dodecylsulphate. Biochim. Biophys. Acta 1974, 356, 36-
52.
(12) Barber, B. R.; Ferrari, P.; Bianchi, G. The Milan Hypertensive
Strain: a Description of the Model. In Handbook of Hyperten-
sion; Ganten, D., de J ong, W., Eds.; Elsevier: Amsterdam, 1994;
pp 316-345.
(13) Hanozet, G. M.; Parenti, P.; Salvati, P. Presence of a Potential
Sensitive Na+ Transport Across Renal Brush Border Membrane
Vesicles from Rats of the Milan Hypertensive Strain. Biochim.
Biophys. Acta 1985, 819, 179-186.
(14) Ferrandi, M.; Salardi, S.; Parenti, P.; Ferrari, P.; Bianchi, G.;
Braw, R.; Karlish, S. J . D. Sodium/Potassium/Chloride-Cotrans-
porter Mediated Rubidium Fluxes in Membrane Vesicles from
Kidneys of Normotensive and Hypertensive Rats. Biochim.
Biophys. Acta 1990, 1021, 13-20.
F igu r e 3. (A) Long-term oral treatment of OS rats with 1.
Four groups of OS rats were orally treated with 1 at different
doses once a day, for 4 weeks, while one group of OS and one
of CS rats (controls) received only vehicle (methocel, 0.5% v/v).
SBP was recorded weekly at the tail, 6 h after the treatment:
OS controls (O); CS controls (4); 1, 0.1 µg/kg (b); 1, 1 µg/kg
(9); 1, 10 µg/kg (2); and 1, 100 mg/kg (0). Data are a mean (
SEM; n ) 7 for each group. Statistical differences from the
OS control group were calculated by two-way ANOVA followed
by Dunnett’s t-test: *p < 0.05; **p < 0.01. (B) Long-term oral
treatment of CS rats with 1. SBP was recorded according to
same schedule as for OS rats: CS controls (4); 1, 100 µg/kg
(2). Data are a mean ( SEM; n ) 7 for each group.
â-blocking or vasodilating activity may be excluded for
1 since it does not affect HR at any tested doses and at
any time. The product seems not to interact with
general and hormonal receptors and to be devoid of
cardiac effects typical of digitalis compounds. Acute and
chronic toxicological studies, both in rat and monkey,
indicate that the ratio between the antihypertensive
dose and that which induces the first observable toxic
effects is higher than 1:10000. Therefore, this product
is under study as a prototype of a new class of potential
(15) Ferrandi, M.; Tripodi, G.; Salardi, S.; Florio, M.; Modica, R.;
Barassi, P.; Parenti, P.; Shainskaya, A.; Karlish, S.; Bianchi, G.;
Ferrari, P. Renal Na+,K+-ATPase in Genetic Hypertension.
Hypertension 1996, 28, 1010-1025.
(16) Ferrandi, M.; Minotti, E.; Salardi, S.; Florio, M.; Bianchi, G.;
Ferrari, P. Ouabainlike Factor in Milan Hypertensive Rats. Am.
J . Physiol. 1992, 263, F739-F748.
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