Reduced lung endothelial angiotensin-converting enzyme activity in Watanabe hyperlipidemic rabbits in vivo

Abstract

We investigated pulmonary endothelial function in vivo in 12- to 18-mo-old male Watanabe heritable hyperlipidemic (WHHL; n = 7) and age- and sex-matched New Zealand White (n = 8) rabbits. The animals were anesthetized and artificially ventilated, and the chest was opened and put in total heart bypass. The single-pass transpulmonary utilizations of the angiotensin-converting enzyme (ACE) substrate [(3)H]benzoyl-Phe-Ala-Pro (BPAP) and the 5'-nucleotidase (NCT) substrate [(14)C]AMP were estimated, and the first-order reaction parameter A(max)/K(m), where A(max) is the product of enzyme mass and the catalytic rate constant and K(m) is the Michaelis-Menten constant, was calculated. BPAP transpulmonary utilization and A(max)/K(m) were reduced in WHHL (1.69 +/- 0.16 vs. 2.9 +/- 0.44 and 599 +/- 69 vs. 987 +/- 153 ml/min in WHHL and control rabbits, respectively; P < 0.05 for both). No differences were observed in the AMP parameters. BPAP K(m) and A(max) values were estimated separately under mixed-order reaction conditions. No differences in K(m) values were found (9.79 +/- 1 vs. 9.9 +/- 1.31microM), whereas WHHL rabbit A(max) was significantly decreased (5.29 +/- 0.88 vs. 7. 93 +/- 0.8 micromol/min in WHHL and control rabbits, respectively; P < 0.05). We conclude that the observed pulmonary endothelial ACE activity reduction in WHHL rabbits appears related to a decrease in enzyme mass rather than to alterations in enzyme affinity.

Pulmonary capillary endothelial dysfunction in early systemic sclerosis

“…Animal studies have shown that PCEB‐ACE dysfunction is an early and sensitive index of several types of acute vascular lung injury (9, 16–18). In addition, PCEB‐ACE activity is reduced in an animal model of chronic hyperlipidemia (37). In humans without lung disease, there is evidence for homogeneous PCEB‐ACE concentrations and capillary transit times in both lungs, as well as similar capillary transit times among subjects (19), while PCEB‐ACE activity is reduced in critically ill patients with acute lung injury, at an early disease stage (20).…”

Increased circulatory RAS activity can be inhibited by statins in patients with hypercholesterolemia

“…3 However, Orfanos et al found that pulmonary endothelial ACE activity was significantly lower in Watanabe heritable hyperlipidemic rabbits than in age- and sex-matched New Zealand White rabbits. 2 This difference indicates that the relationship between HC and RAS activity may vary among animal species and organs.…”

“…Activation of the renin-angiotensin system (RAS) has been considered an independent mechanism in the development of atherosclerotic diseases. 1 Apart from a study performed in Watanabe heritable hyperlipidemic rabbits that did not find a significant correlation between blood lipids and angiotensin-converting enzyme (ACE) levels in lung tissue, 2 most data from animal models of atherosclerosis have shown consistently that HC increases significantly the activity of RAS. 3–6 This association is also found in human beings.…”