Myeloperoxidase evokes substantial vasomotor responses in isolated skeletal muscle arterioles of the rat.

AIMS: Myeloperoxidase (MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid (HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses. METHODS: Following exposure to MPO (1.92 mU mL(-1)) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles (SMAs) and coronary arterioles (CAs) and in the isometric force in basilar arteries (BAs) of the rat were monitored. RESULTS: Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 µM), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 µM), the thromboxane A2 (TXA2) antagonist SQ-29548 (1 µM) or the non-specific cyclooxygenase (COX) antagonist indomethacin (1 µM) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca(2+)] levels in SMAs. CONCLUSION: These data showed that H2O2 -derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca(2+) sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2 O2 -evoked vasoconstrictions. Nevertheless, inhibition of the HOCl-COX-TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs.

Insertion/deletion polymorphism of the angiotensin-converting enzyme predicts left ventricular hypertrophy after renal transplantation.

BACKGROUND: Kidney transplant recipients show a higher risk for cardiovascular complications, such as left ventricular hypertrophy and heart failure, leading to the premature death in many cases. METHODS: We investigated the contribution of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism to the development of left ventricular hypertrophy (LVH), an indicator of heart disease progression among kidney transplant recipients. RESULTS: We observed a significant correlation between graft function and left ventricular mass index. The occurrence of LVH or severe LVH was significantly greater among patients with at least one D-allele (ID or DD). CONCLUSION: The use of ACE inhibitors or angiotensin receptor blockers seemed to be advantageous for patients with the ID and especially, the DD genotype.

Insertion/Deletion polymorphism of Angiotensin-converting enzyme as a risk factor for chronic allograft nephropathy.

Angiotensin-converting enzyme (ACE) inhibitor therapy is widely used to treat chronic allograft nephropathy (CAN), which suggests a possible role of the renin-angiotensin system in the pathologic mechanism of the disease. The objective of this study was to investigate the possible link between CAN and ACE. The ACE insertion/deletion polymorphism and the amount and activity of ACE were determined in cadaver kidney recipients with CAN (n = 38) or normal renal function (n = 34). The DD genotype was observed significantly more frequently in the CAN group compared with the group with normal renal function. Moreover, the DD genotype was associated with a higher serum ACE concentration and greater serum ACE activity, compared with II genotype homozygotes. The insertion/deletion polymorphism of ACE affects ACE expression and activity in serum, and, therefore, may have an important role in the pathogenesis of CAN. These findings suggest that determination of the ACE genotype may be useful in identifying patients at high risk. In particular, the DD genotype may be considered an indication for ACE inhibitor therapy.