Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors.

On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta1 and IL-1beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain.

Evidence for, and importance of, cGMP-independent mechanisms with NO and NO donors on blood vessels and platelets.

In the vasculature it is well established that cGMP is involved in the relaxant response to nitric oxide (NO) and NO donors. However, there is an increasing evidence that alternative/additional pathways that are cGMP-independent may also exist. A key criterion for a response to NO or a NO donor drug to be classified as cGMP-independent is lack of (or incomplete) inhibition by the selective inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one).

Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).

1. The aim was to test the hypothesis that nitric oxide (NO) donor drugs can inhibit the 5-hydroxytryptamine (5-HT) transporter, SERT. 2.

Proteinase-activated receptor (PAR)-mediated vasorelaxation in pulmonary arteries from normotensive and hypoxic pulmonary hypertensive rats.

Proteinase-activated receptor (PAR)-mediated vasorelaxant responses were examined in main pulmonary artery preparations from control rats and rats exposed to hypoxia (10% oxygen) for 1 or 4 weeks to induce pulmonary hypertension. Trypsin and the PAR-2 peptide, SLIGRL, relaxed phenylephrine precontracted preparations, with maximum responses the same as the maximum response to acetylcholine. Responses to trypsin and SLIGRL were abolished by endothelium removal or a nitric oxide (NO) synthase inhibitor, and were, therefore, due to release of endothelium-derived NO.

Vascular chymase: pathophysiological role and therapeutic potential of inhibition.

Chymase is a chymotrypsin-like serine protease secreted from mast cells. Mammalian chymases are classified into two subgroups (alpha and beta) according to structure and substrate specificity; human chymase is an alpha-chymase. An important action of chymase is the ACE-independent conversion of Ang I to Ang II, but chymase also degrades the extracellular matrix, activates TGF-beta1 and IL-1beta, forms 31-amino acid endothelins and is involved in lipid metabolism.