Published Online
on June 13, 2005

A more recent version of this article appeared on July 1, 2005

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Submitted on December 26, 2004
Revised on January 12, 2005

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

Masashi Fujita; Tetsuo Minamino^*; Hiroshi Asanuma; Shoji Sanada; Akio Hirata; Masakatsu Wakeno; Masafumi Myoishi; Hiroko Okuda; Akiko Ogai; Ken-ichiro Okada; Osamu Tsukamoto; Hidekazu Koyama; Masatsugu Hori; and Masafumi Kitakaze

From the Departments of Internal Medicine and Therapeutics (M.F., T.M., H.A., S.S., A.H., H.O., K.O., O.T., H.K, M.H.), and Bioregulatory Medicine (M.W., M.M.), Osaka University Graduate School of Medicine, Suita, Osaka; Cardiovascular Division of Medicine (A.O., M.K.), National Cardiovascular Center of Japan, Suita, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: minamino{at}medone.med.osaka-u.ac.jp.

Abstract--Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4±3.8 to 19.3±5.2 mL/100 g/min; P<0.05), along with decreases in fractional shortening (FS) (8.4±0.7 to 5.4±0.4%; P<0.05) and lactate extraction rate (LER) (-31.7±2.9 to -41.4±3.7%; P<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.

Key words: aldosterone • ischemia • protein kinases

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