19-norprogesterone and Hypertension

19-nor-progesterone (19-nor-P) has the characteristics of a potent mineralocorticoid in adrenalectomized or salt-loaded rats and is capable of causing hypertension. In human placenta, progesterone is converted to 19-hydroxy-progesterone, a precursor of 19-nor-P. In some states of pregnancy hypertension, 19-nor-P may inhibit renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), thus allowing cortisol to bind to the mineralocorticoid receptor (MR). Therefore, we investigated the ability of 19-nor-P to inhibit human 11beta-HSD2. Fetal kidney cells (HEK 293) were transfected with human 11beta-HSD2 and incubated with increasing concentrations of 19-nor-P, labelled and unlabelled cortisol. Steroids were extracted, separated by TLC, and radioactivity was measured using a TLC scanner. 19-nor-P treatment did not significantly reduce 11beta-HSD2 activity (430 to 300 pmol/mg protein/h) in the range of tested concentrations. In conclusion, 19-nor-P did not inhibit human 11beta-HSD2 and seems not to be involved in human hypertension. Nevertheless, 19-nor-P may be converted by extra-adrenal tissues into 19-nor-deoxycorticosterone (DOC) or 19-nor-corticosterone, which are potent mineralocorticoids and may be involved in the pathogenesis of hypertension during pregnancy.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Hydrocortisone; Hypertension; Kidney; Norprogesterones; Transfection

Recent reports demonstrate that the 19-nor-corticosteroids (19-nor-DOC) are naturally-occurring substances in hypertensive animal models as well as man. Since some 19-nor-corticosteroids are potent mineralocorticoids, they may have a role in regulating systemic arterial pressure and be involved in the pathogenesis of hypertension. This paper reports the probable biosynthetic pathway, factors regulating the secretion or production, and measurement of 19-nor-DOC in man and the spontaneously hypertensive rat (SHR). These studies demonstrate (1) 19-nor-DOC is greatly influenced by ACTH and dexamethasone but less so by high and low salt diets in normotensive subjects; (2) 19-nor-DOC is greatly increased in some but not all hypertensive patients; (3) 19-nor-DOC is increased in prehypertensive SHR compared to WKY rats. The likelihood of metacorticoid hypertension and possible role of other 19-nor-corticosteroids, including 19-nor-progesterone, are discussed. It can be concluded that 19-nor-corticosteroids are synthesized by extra-adrenal tissues in biologically active quantities. They are increased and possibly pathogenetic in certain states of human and experimental hypertension.

Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Animals; Dexamethasone; Disease Models, Animal; Humans; Hyperaldosteronism; Hypertension; Nandrolone; Norprogesterones; Rats; Rats, Inbred Strains; Reference Values

Fifty-day-old unilaterally nephrectomized and 1% saline-drinking Sprague-Dawley CD male rats were divided into three comparable groups on the basis of blood pressure, body weight, and fluid intake. The control group received vehicle only, the second group received 19-nor-progesterone [19-nor-pregn-4-ene-3,20-dione (19-Nor-Prog)] in a dose of 250 micrograms/24 h, and the third group received aldosterone-acetate (Aldo-Ac) in a dose of 125 micrograms/24 h, by means of Alzet osmotic minipumps implanted sc for 21 days. Both the 19-Nor-Prog- and the Aldo-Ac-treated rats became hypertensive to a similar degree in the course of the study. Rats given Aldo-Ac also developed polydipsia, decreased body weight, cardionephromegaly, and hypokalemia. The 19-Nor-Prog-treated rats showed no significant changes in heart and kidney weights. The hypertensinogenicity of 19-Nor-Prog is unrelated to significant changes in heart and kidney weight, as is the case with potent mineralocorticoids.

Topics: Animals; Blood Pressure; Body Weight; Drinking; Heart; Hypertension; Kidney; Male; Nephrectomy; Norprogesterones; Organ Size; Rats; Rats, Inbred Strains

The mineralocorticoid potency of 19-nor-progesterone was evaluated by both its effect on electrolyte excretion in adrenalectomized animals and its ability to cause hypertension and electrolyte changes in mononephrectomized, salt-loaded rats. The mineralocorticoid activity, measured using an adrenalectomized rat bioassay, indicated that 19-nor-progesterone was 2.5% as potent as aldosterone but did not antagonize the effect of aldosterone when both were administered. In mononephrectomized rats, the daily administration of 1 mg/day quickly caused an enhanced consumption of 1% saline and induced severe hypertension within 3-4 weeks. Some severely hypertensive animals had marked anemia, but other did not; as a group they were found to have hypernatremia and hypokalemia. Hypertensive animals were found during life to display a relative hypothermia and, at necropsy, to have heart and kidney enlargement with severe and extensive vascular lesions in both organs, but not adrenal hypertrophy. It is concluded that 19-nor-progesterone has the characteristics of a potent mineralocorticoid and, as such, is capable of causing hypertension. It is not yet clear why this should be accompanied by hypothermia.

Topics: Adrenalectomy; Aldosterone; Animals; Blood Pressure; Body Temperature; Body Weight; Drinking; Female; Hypertension; Kidney; Mineralocorticoids; Norpregnenes; Norprogesterones; Organ Size; Potassium; Rats; Rats, Inbred Strains; Sodium