A series of disubstituted ureas containing amide or amine groups was prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyl transferase in vitro and to lower plasma total cholesterol in a variety of cholesterol-fed rat models in vivo. The presence of polar or ionizable functionalities within this class of compounds may impart greater aqueous solubility to those compounds and thus allow improved transport to the enzyme location within the intestinal enterocyte. Compounds from this class exhibit good cholesterol lowering in a chronic cholesterol-fed rat model of hypercholesterolemia even when dosed in an aqueous vehicle. In general, the amine-containing compounds were more potent and efficacious than the amides in the acute rat model of hypercholesterolemia. Further structure-activity relationship studies showed that the preferred position of the amide/amine group was beta to the urea moiety and not alpha, and that in this series, the presence of a secondary amine (or amide) proton is required for good in vitro potency. One of these compounds, 9n(-), lowered plasma total cholesterol (-47%) and elevated high-density lipoprotein cholesterol (+256%) when dosed in an aqueous vehicle to rats with preestablished hypercholesterolemia.
1. The effects of angiotensin II infusion without and with simultaneous infusion of prostaglandin E2 were studied in 25 women in second trimester pregnancy. Twenty received one infusion of angiotensin II alone, followed by its infusion simultaneously with prostaglandin E2; five received two identical infusions of angiotensin II alone as controls.
2. Angiotensin II infusion alone was associated with suppression of plasma renin concentration to levels inversely proportional to the evoked change in diastolic blood pressure. Plasma renin substrate concentration was unchanged, but plasma aldosterone concentration rose markedly. This rise was inversely proportional to the threshold for pressor effect of angiotensin II.
3. Prostaglandin E2 administration alone was associated with increased plasma renin concentrations.
4. The pressor effect of angiotensin II was blunted when given together with prostaglandin E2 and plasma concentrations of angiotensin II reached were lower.
5. Plasma renin concentration was again suppressed during the joint infusion regimen; the degree of suppression was inversely proportional to the change in diastolic pressure. Plasma aldosterone concentration rose, but did not differ in the control and experimental groups.
6. Thus although the renin-angiotensin system is stimulated in normal pregnancy, the normal control mechanisms are still functional, and the capacity for further increases in activity exists.
Measurement of angiotensin II binding in the second trimester has no value as a screening test for nonproteinuric or proteinuric pregnancy-induced hypertension.
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