Reduction of blood pressure and vascular collagen in hypertensive rats by beta-aminopropionitrile.

Abstract

#-Aminopropionitrile, a specific inhibitor of lysyl oxidase preventedthe rise in blood pressure induced by deoxycorticosterone-salt in rats. In addition, after the onset of hypertension, administration of P-aminopropionitrile lowered the blood pressure. Concomitant with the lowering of blood pressure, there was a reduction in the more highly crosslinked form of vascular collagen. These findings would indicate that increases in vascular connective tissue are not only sequelae of hyprtension, but may also contribute to the maintenance of eevated blood pressure. We have previously reported that vascular collagen biosynthesis and deposition is increased in hypertensive rats and that these effects are reversed when blood pressure is lowered by antihypertensive drugs (1, 2). Those findings suggested that the deposition of vascular connective tissue is one of the sequelae of hypertension. The availability of agents that selectively inhibit collagen formation and deposition make it possible to determine whether the increased amounts of collagen also contribute to the maintained hypertension. One of these agents, fl-aminopropionitrile, is a fairly specific inhibitor of lysyl oxidase, the enzyme which catalyzes the oxidative deamination of the e-amino groups of lysine and hydroxylysine in collagen and elastin (3-5). In the absence of lysyl oxidase activity, the formation of crosslinked collagen is blocked. This can be demonstrated by a diminution of insoluble collagen (6).In the present study we have shown that administration of f3-aminopropionitrile to rats receiving deoxycorticosterone-salt markedly diminishes the hypertension produced by the steroid. Rats were killed by decapitation. The entire aorta and the mesenteric artery were excised from each animal and perivascular adipose tissue was carefully removed from them. Each vascular tissue was homogenized in 30 volumes of 0.5 M acetic acid in a ground-glass homogenizer, and the soluble collagen was extracted for 24 hr at 40 (10). The extracts were centrifuged at 11,500 X g for 30 min and the supernatants were dialyzed against 10 mM acetic acid. The precipitates, containing the insoluble collagen, were then lyophilized. After this, the supernatants and precipitates were hydrolyzed in 6 M HCl for 20 hr at 105°. Hydroxyproline was measured by the method of Kivirikko et al. (11). These values yield collagen content when multiplied by 6.98 (12).Tissue sections from each experiment were prepared for histological examination. RESULTSChanges in blood pressure and body weight As shown in Fig. 1, the blood pressures of the rats treated with deoxycorticosterone-salt were markedly increased over those of the controls. Administration of (3-aminopropionitrile to rats treated with deoxycorticosterone-salt largely prevented the increase in blood pressure for 5 weeks. After this time, the blood pressure gradually increased to about 170 mm of Hg by the fifteenth week of treatment. At this point, however, the blood pressure was still much lower than in the rats treated with de-o...

Differential renal gene expression in prehypertensive and hypertensive spontaneously hypertensive rats

“…In addition, the lower expression of elastase and cathespin L observed in SHR suggests a difference in the regulation of the vascular extracellular matrix system (20,42). The reduction in expression of elastase in the current study is consistent with a reported reduction in blood pressure observed in SHR after injection of elastase (18). The altered expression of matrix genes appears to begin early in the SHR animals, since the differences between strains were apparent at 3 wk of age.…”

“…Aging is associated with many vascular changes, such as a rise in arterial stiffness, smooth muscle cell hypertrophy, and fibrosis (22). The regulation of expression of extracellular matrix proteins is important in the elastic properties of the vascular system, and an age-related increase in aortic stiffness has been observed in SHR (2,14,18,26,47,49). Interestingly, we observed significant changes in the expression of several connective tissue genes from 3 to 9 wk of age in both WKY and SHR; however, the levels of procollagen (type I and II) and collagen (type I) were higher in SHR at both 3 and 9 wk of age.…”

Effects of hypertension and its reversal on aortic metabolism in the rat.

“…27 /3-Aminopropionitrile, an inhibitor of lysyl oxidase, an enzyme necessary for crossUnking in collagen and elastin, also reduced aortic collagen biosynthesis in hypertensive rats and lowered the blood pressure as well. 7 Our studies on the SHR with well-established hypertension indicated that changes in the vascular connective tissue composition did not occur following antihypertensive drug therapy.…”

“…5 The spontaneously hypertensive rat (SHR) appears to be a useful animal model to study human essential hypertension as judged by several physiological and pathological criteria. 6 Comparative studies on aortic tissue between the SHR and normotensive control rats have shown differences in several biochemical processes including connective tissue metabolism, 7 cyclic nucleotide metabolism, 8 ' 9 glycolytic and lysosomal enzyme activity, 10 ' n norepinephrine metabolism, 12 and calcium uptake. 13 ' 14 The present study was conducted to determine whether biochemical differences in aortic tissue between the SHR and the normotensive WistarKyoto (WKY) rats were affected by the reversal of hypertension.…”

Collagen deposition and the reversal of coronary reserve in cardiac hypertrophy.

“…To inhibit collagen deposition in the vascular and extravascular myocardial tissue, we superimposed /3-aminopropionitrile (/3-APN) treatment on ascending aortic banding for 10 weeks in rats. In experimental models of systemic 13 and pulmonary 14 " 16 hypertension, inhibition of collagen deposition by /3-APN lowered the blood pressure. Collagen deposition in the vascular wall plays a key role in sustaining the high blood pressure of the systemic or pulmonary circulation.…”