Study on the mechanisms of glucocorticoid-induced hypertension: Glucocorticoids increase transmembrane Ca²⁺influx in vascular smooth muscle in vivo

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.

Profiling transcript levels for steroidogenic enzymes in fetal tissues

“…The aorta expresses all the steroidogenic enzymes needed to produce cortisol and to convert androgens into estrogens. Previously, several authors have demonstrated that glucocorticoids and mineralocorticoids both modulate vascular smooth muscle cell permeability to electrolyte ions, resulting in increased smooth muscle tone and responsiveness to various humoral and neurogenic vasoconstrictive agents [37][38][39][40]. The fetal aorta production of glucocorticoids could act through this mechanism, however, further studies are necessary to understand the role of aorta-produced steroid.…”

Cardiovascular and endocrine responses to acute hypoxaemia during and following dexamethasone infusion in the ovine fetus

“…Glucocorticoid treatment may induce structural and functional changes at the level of vascular smooth muscle and connective tissue, thereby modifying basal vascular tone and the gain of superimposed vasoconstrictor stimuli (Altura & Altura, 1974; Leitman et al 1984; Pierce et al 1995). Treatment of adult rabbits with dexamethasone increases transmembrane Ca 2+ flux in aortic smooth muscle cells (Kornel et al 1995) and induces expression of transport proteins for transmembrane sodium and calcium influx (Kornel et al 1993), augmenting the intracellular signal for vascular smooth muscle cell contraction. In addition, treatment of cultured rat vascular smooth muscle cells with dexamethasone (10 −7 m ) for 48 h enhances the production of inositol trisphosphate in response to α‐adrenoceptor stimulation with noradrenaline (Liu et al 1992), and fetal treatment with betamethasone for 48 h has been shown to enhance the maximum vasoconstrictor tension generated by fetal femoral arterial segments in response to depolarizing potassium solutions (Anwar et al 1999).…”

Inhibitory effect of glucocorticoid on coronary artery endothelial function

“…Similarly, elevation of intracellular Ca 2ϩ decreases endothelial synthesis of the vasoconstrictor endothelin (38). Interestingly, glucocorticoid stimulates an increase in peak [Ca 2ϩ ] i response to various vasoconstrictors in vascular smooth muscle in vitro and in vivo (2,29). While this may or may not represent a separate mechanism of Ca 2ϩ modulation, it is clear that glucocorticoid acts in multiple tissues in a concerted fashion to decrease vasodilation and increase vasoconstriction.…”