ABSTRACT
In order to maintain homeostasis, the body has developed multiple vasoconstrictor and vasodilator systems. The balance between vasoconstrictor and vasodilator systems assures adequate perfusion pressure to essential organs without excessive hypo-or hypertension. The endogenous vasoconstrictor substances that are most prominent include angiotensin II, the adrenergic system, endothelin-1, vasopressin and aldosterone. The endogenous vasodilator systems that are most prominent include nitric oxide, endothelial-derived hyperpolarizing factor (EDHF), prostaglandins, adrenomedullin and natriuretic peptides. In cardiovascular diseases, whether it be hypertension, heart failure or atherosclerosis, there is an imbalance which favors vasoconstriction.1-3
Endogenous vasoconstrictor systems not only increase blood pressure2
and cause sodium and water retention,4 but also stimulate growth and fibrosis.5 In addition, they promote coagulation,6 increase oxygen free radical formation,7 increase adhesive molecules and monocyte adhesion to vessels and stimulate inflammation,8 thereby promoting atherosclerosis.9 Conversely, the parallel endogenous vasodilator systems not only reduce blood pressure10 and improve sodium and water excretion,11 but also reduce growth and fibrosis.12 They inhibit coagulation13 and decrease adhesive molecules14 and monocyte adhesion to vasculature,15
as well as reducing inflammation.16,17
Angiotensin converting enzyme (ACE), (EC3.415.1) is a widely distributed zinc metallopeptidase, located principally in the vascular endothelium of the lung. It is generally located on the endothelium with the bulk of its mass and its two catalytic sites (N-and C-domains) exposed on the
extracellular surface of the cell. Initially, it was thought that ACE was limited in its tissular localization; however, it has now been shown to be present in a large number of tissues including the heart and the kidney.18,19 ACE not only converts angiotensin I to II, but also metabolizes kinins such as bradykinin (BK). The vascular wall, blood, skeletal muscle, heart muscle, and endothelial tissue all contain both the precursors of kinins (the kininogens) and kininogenases capable of releasing vasoactive kinins, virtually in all tissues. In humans, BK is the principal member of this class of autocoids. In a single passage through the pulmonary vascular bed, about 80-90% of the kinins might be destroyed and as many as five peptide bonds might be cleaved. The affinity (enzyme substrate affinity or Michaelis-Menton) constant (Km) of ACE for BK is greater (Km = 0.18 uM) than for angiotensin I (Km = 16 uM) prompting some to consider it a kininase rather than an angiotensinase.20
