Data from clinical and experimental studies indicate that mechanism(s) for action of mineralocorticoids, other than renal, must be involved in the overall effect of mineralocorticoids on circulation--increased peripheral resistance and hypertension. We have postulated existence of such a mechanism in the arterial wall and have looked for the evidence for its presence. We have found high affinity, specific binders for mineralocorticoids, and glucocorticoids, with characteristics of steroid receptors, in the cytosol of rabbit aorta and femoral and carotid arteries. These binders possess physicochemical properties of steroid receptors and, moreover, they translocate to cell nuclei (as steroid-receptor complexes) and bind to relatively specific "acceptor-sites" on nuclear chromatin. This provides evidence for the existence of an intracellular-molecular mechanism for a direct in situ action of mineralocorticoids, and also glucocorticoids, in the arterial wall. We postulate that the demonstrated previously effect of mineralocorticoids on arterial smooth muscle cell-membrane permeability to electrolytes, leading presumably to increased peripheral resistance and hypertension, is elicited through the receptor-mediated mechanism for action of mineralocorticoids in the arterial wall.

No abstract

Blood pressure (BP) and ex vivo influx rate of Ca2+ in excised aortae were measured in rabbits implanted with silastic rubber strips impregnated with glucocorticoids (GC) [dexamethasone (DEX) or cortisol (FK)], or carbenoxolone (CX) [inhibitor of 11 beta-hydroxysteroid dehydrogenase (11-HSD), in a large (lg) or a small (sm) (10 times smaller) concentration], or FK plus CX (sm), or DEX plus RU 38486 (a specific GC-receptor blocker). After 4-6 weeks rabbits implanted with DEX, CX (lg), and FK+CK (sm) developed hypertension. Those implanted with FK alone (yielding physiological serum concentration of FK), CX (sm), and DEX+RU 38486 did not develop hypertension. Rates of unidirectional influx of Ca2+ measured in rings of excised aortae were in all hypertensive rabbits more than twice those in the control rabbits (implanted with silastic strips not containing any steroids). In all normotensive rabbits, Ca2+ influx rates remained normal. We conclude that, in analogy with the in vitro findings in cultured vascular smooth muscle (VSM) cells treated with GC, also in vivo, the elevation of tissue levels of GC causes an increase in the influx rate of Ca2+ in VSM. We propose that this may be the main pathogenic mechanism of GC-induced hypertension.