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CARDIOVASCULAR

Angiotensin I-Converting Enzyme Inhibitors Block Protein Kinase C by Activating Bradykinin B₁ Receptors in Human Endothelial Cells

Departments of Pharmacology (S.S., T.I., P.A.D., V.B., K.Z., E.G.E., R.A.S.) and Anesthesiology (E.G.E., R.A.S.), University of Illinois College of Medicine, Chicago, Illinois

Angiotensin I-converting enzyme (ACE) inhibitors are widely used to treat patients with cardiovascular and kidney diseases, but inhibition of ACE alone does not fully explain the beneficial effects. We reported that ACE inhibitors directly activate bradykinin B₁ receptor at the canonical Zn²⁺ binding site, leading to prolonged nitric oxide (NO) production in endothelial cells. Protein kinase C (PKC) , a novel PKC isoform, is up-regulated in myocardium after infarction, suggesting a role in the development of cardiac dysfunction. In cytokine-treated human lung microvascular endothelial cells, B₁ receptor activation by ACE inhibitors (enalaprilat, quinaprilat) or peptide ligands (des-Arg¹⁰-Lys¹-bradykinin, des-Arg⁹-bradykinin) inhibited PKC with an IC₅₀ = 7 x 10^–9 M. Despite the reported differences in binding affinity to receptor, the two peptide ligands were equally active, even when inhibitor blocked the cleavage of Lys¹, thus the conversion by aminopeptidase. The synthetic undecapeptide (LLPHEAWHFAR) representing the binding site for ACE inhibitors on human B₁ receptors reduced PKC inhibition by enalaprilat but not by peptide agonist. A combination of inducible and endothelial NO synthase inhibitors, 1400W [N-(3(aminomethyl) benzyl) acetamidine dihydrochloride] and N-nitro-L-arginine (2 µM), significantly reduced inhibition by enalaprilat (100 nM), whereas the NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) amino]diazen-1-ium-1,2-diolate (100 µM) inhibited PKC activity just as the B₁ ligands did. In conclusion, NO generated by B₁ receptor activation inhibits PKC.

Address correspondence to: Dr. E. G. Erdös, Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue (MC 868), Chicago, IL 60612. E-mail: egerdos{at}uic.edu

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