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

Abstract

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 (37.4Ϯ3.8 to 19.3Ϯ5.2 mL/100 g/min; PϽ0.05), along with decreases in fractional shortening (FS) (8.4Ϯ0.7 to 5.4Ϯ0.4%; PϽ0.05) and lactate extraction rate (LER) (Ϫ31.7Ϯ2.9 to Ϫ41.4Ϯ3.7%; PϽ0.05). 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 PKCdependent 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 Ⅲ ischemia Ⅲ protein kinases A ldosterone modulates cardiovascular function in addition to the crucial role in sodium and potassium homeostasis through binding to the intracellular mineralocorticoid receptors (MRs). 1 These receptor-mediated effects with transcriptional modulation of target genes are termed genomic effects. 2 Recently, another pathway possibly mediated by the specific membrane receptors through which aldosterone acts, ie, nongenomic effects of aldosterone, has been investigated. [2][3][4] Although this nongenomic action of aldosterone was shown in a variety of tissues such as vascular smooth muscle cells or cardiomyocytes, the effects of aldosterone on vascular tone are divergent. 4 -9 Aldosterone increased systemic vascular resistance in humans, as shown in the first report on the nongenomic effects of aldosterone, whereas aldosterone inhibits vasoconstriction in renal afferent arterioles. 7-9 Until now, the rapid nongenomic effects of aldosterone on vascular tone of coronary artery and cardiac functions in vivo under ischemia are not still fully estimated. Moreover, several rapid aldosterone-induced changes of the concentration of intracellular second messengers have been described. 6,10,11 Aldosterone is reported to activate pro...

Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts

“…Moreover, its effect was greater in DSHF-E 100 than in DSHF-E 10 and E 30 . In contrast, the levels of TGF-␤1 and type I collagen mRNA and protein expression were significantly higher in DSHF-V than in DR-C.…”

“…29 PKC is implicated in the nongenomic effects of aldosterone. 30 In addition, Src also induces activation of MAP kinases associated with cell growth, apoptosis, and collagen deposition, as well as activation of other downstream proteins involved in cell adhesion processes. 29 Recently, Callera et al 9 suggested that nongenomic signaling pathway by aldosterone occurred through c-Src-regulated activation of MAP kinase, and these responses were abrogated by eplerenone.…”

“…Chronic eplerenone therapy in DS rats significantly increased expression of eNOS mRNA and protein, phosphorylation of eNOS and Akt, and nitrite production. Moreover, these indexes were significantly higher in DSHF-E 100 than in DSHF-E 10 and E 30 ( Figure 2A and 2B).…”

A Comparison of the Aldosterone‐blocking Agents Eplerenone and Spironolactone

“…6,7 Effects of aldosterone that have been proven to occur via a nongenomic mechanism include coronary vasoconstriction leading to worsening contractile and metabolic functions in the ischemic heart, increased systemic vascular resistance, negative inotropic response in human trabeculae, and potentiation of the vasoconstrictor effect of angiotensin II in coronary arteries. 5,6,8 That these nongenomic effects of aldosterone are sometimes mediated by MR is supported by the ability of MR blockers to inhibit many of these actions. Overall, eplerenone appears to produce more consistent inhibition of some of the nongenomic effects of aldosterone 7,9 than spironolactone.…”

Aldosterone Does Not Predict Cardiovascular Events Following Acute Coronary Syndrome in Patients Initially Without Heart Failure

“…In heart failure, secretion of aldosterone may become maladaptive, promoting excessive sodium retention and blood volume. In addition, sustained high levels of aldosterone may exert direct adverse effects on the arterial wall by promoting vascular remodeling with fibrosis and calcification1, 2, 3 and in myocardium by decreasing contractility and promoting coronary vasoconstriction4, 5 and fibrosis that may provide the substrate for arrhythmias 6, 7, 8. Acting in the central nervous system, aldosterone may stimulate neural pathways that promote hypertension and sodium retention 9, 10, 11…”