Human primary aldosteronism: from clinical observations to in-vivo and ex-vivo studies on the pressor effects of Urotensin II

In a patient affected by primary aldosteronism we have identified the presence of a pheochromocytoma not secreting catecholamines. The analysis of the transcriptome in the pheochromocytoma revealed a high expression of Urotensin II (UII). UII is a somatostatin-like cyclic 11-aminoacid vasoconstrictor peptide, first identified in the teleost fish caudal-neuro-secretory system and then in humans, that has been demonstrated to be a potent vasoactive peptide involved in the physiology and pathophysiology of the cardiovascular system through mechanisms still largely unknown. Its action is now the subject of intensive studies on the effects it produces in different animal models and in different vascular beds. The direct effects on the myocardium such as ventricular hypertrophy, increased extracellular matrix and reduction of myocardial contractility suggest a role of UII in cardiac remodelling after myocardial infarction and heart failure. Even if the effects on cardiovascular system are still controversial UII has attracted considerable scientific interest aimed to investigate on its pathophysiology and on its the mechanism of action. We investigated among the expression of UII and its receptor in human adrenal glands and in different adrenal tumors. The opposite trend of expression of UII receptor obtained between aldosterone-producing adenoma and pheocromocitoma, along with the differences of genes implicated in UII signaling, supported a role of UII in the paracrine interactions between the adrenal medulla and cortex. Being relevant for the regulation of adrenal gland function and for the pathophysiology of pheocromocitoma and aldosterone-producing adenomas, these interactions might provide a mechanistic explanation for the pheocromocitomas that presented clinically as aldosteronism. We tested the “in vivo” effects of UII on blood pressure in rats, showing a delayed transient hypertensive effect that resembles the pressure trend in chronic infusion of aldosterone. Thus further supporting the hypothesis of a close interaction between UII and the renin-angiotensin-aldosterone system or even that UII acts through production of aldosterone as well as assess its hypertensive activity, its effect of cardiac hypertrophy and fibrosis and its role in regulating the growth of adrenocortical cells in rats. Considering that the mechanisms involved in the so called “escape phenomenon” seem responsible of the peculiar blood pressure trend in hyperaldosteronism we tested the blood pressure modifications in chronic infusion of UII counteracting the “escape phenomenon” through unilateral nephrectomy, high salt diet and concomitant infusion of spironolactone. The results obtained were promising: for the first time was shown an in-vivo not transient but continuous hypertensive effect of UII. The evidences obtained in blood pressure modification during chronic infusion of UII combined with the ones regarding UII and development of cortical tumors, has taken a step forward in identifying the mechanism of action of UII supporting the hypothesis of a possible close communication between medulla and adrenal cortex and a possible action of UII mediated by aldosterone. Additional investigations on the transgenic rat overexpressing UII in adrenal medulla will certainly contribute to verify our hypothesis