Summary1. Effects of inhibitors of DOPA decarboxylase, dopamine 8-hydroxylase and monoamine oxidase, and haloperidol on the secretion of pancreatic juice induced by L-DOPA and dopamine were studied in preparations of the isolated blood-perfused canine pancreas. 2. The increased secretion induced by the infusion of L-DOPA (100 ,ug/min) was completely antagonized by Ro 4-4602 (300 ug), a DOPA decarboxylase inhibitor. 3. The secretogogue effect of dopamine (1-10 ug) intra-arterially was not affected by Ro 4-4602, but was enhanced by the infusion of fusaric acid (100
#-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...
In two models of hypertension in rats, it was shown that collagen synthesis and deposition are increased in arteries where blood pressure is elevated. By contrast, there were no alterations in any of the markers of collagen synthesis in veins, where blood pressure was only slightly elevated. It would appear that the stimulus for vascular collagen synthesis is provided by a direct effect of the increased pressure on the arterial cells rather than by a humoral factor released into the general circulation.
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