Metastin stimulates aldosterone synthesis in human …
Although synthesis of aldosterone is the final step in the RAAS cascade, the intermediate component Angiotensin II also has potent physiological effects as discussed in the next section.
Antimineralocorticoid - Wikipedia
In search of a mechanism other than 11β-HSD2 that would allow aldosterone to compete successfully with corticosterone for MR in target cells of the brain, we studied the possibility of the extra-adrenal synthesis of aldosterone in or near aldosterone target neurons. The requisite enzymes for aldosterone synthesis from cholesterol are expressed in the normal human and rat brains (; ; , ; ; ), and low levels of aldosterone are synthesized in normal rat brain in vitro and in vivo (, , ). However, the amounts of extra-adrenal synthesis of aldosterone are so low in comparison with adrenal production that it has been impossible to measure reliably in the adrenal-intact subject and its physiological relevance is difficult to ascertain.
As expected from the literature (; , ), total 24 h aldosterone synthesis in SS rats was lower than that of SD rats. Aldosterone levels in blood increase with activity producing orthostatic changes that stimulate angiotensin II, the most important regulator of aldosterone synthesis, and are influenced by the circadian rhythm of adrenocorticotrophic hormone and increased by acute stress. Therefore, measurement of aldosterone excreted in the urine over 24 h in properly acclimated animals is a more accurate indication of basal aldosterone synthesis than momentary blood levels. Concordant with significantly less adrenal AS mRNA, 24 h aldosterone excretion in the urine, normalized to creatinine excretion, was significantly less in SS compared with SD rats, but aldosterone concentration in their brains was greater. Most of the aldosterone in the brains of normotensive rats (SD and Wistar rats) is derived from the circulation (, ). The only known mechanism to sequester aldosterone is by binding by the MR (, ), and expression of MR mRNA is not increased in the brains of SS compared with SD rats. The distribution and relative amounts of MR mRNA in the different brain parts in our studies correlate well with autoradiographic studies (; ). If the increase in aldosterone content were due to binding of circulating steroid to MR, one would expect that the hippocampus would have a greater concentration than the hypothalamus. In a comparison of SS and SR rats consuming a normal-salt diet, aldosterone concentrations in the hippocampus and hypothalamus of were similar, and slightly lower than the plasma levels, in the 500 pg ml−1 range (). Leenen and Huang's laboratories have reported significant increments in the aldosterone content of the hypothalamus, but not hippocampus, in a rat model hypertension due to the intracerebroventricular infusion of hypernatraemic artificial CSF () and that aldosterone increases in the hippocampus to a greater extent than in the hypothalamus in a model of myocardial infarction (). The aldosterone concentration in the plasma and brains in these reports were in the 300–400 pg ml−1 and 300–700 pg g−1 ranges, respectively; values that indicate considerable acute stress, increasing circulating aldosterone levels by at least an order of magnitude at the time of sample collection (). Similar studies of brains at basal non-stressed aldosterone levels will be of great interest because circulating stress levels of aldosterone may mask basal levels in the different brain parts ().