Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension

In 1993, Kitamura et al. 1 isolated a new peptide from human pheochromocytoma cells, stimulating cAMP production in human platelets and inducing systemic hypotension in rats. Due to its origin of discovery, i.e. the medulla of the adrenal gland, it was named adrenomedullin 1. Adrenomedullin is a 52-amino acid peptide hormone with structural homology to calcitonin gene-related peptide 2. Together with pro-adrenomedullin N-terminal 20-peptide, adrenomedullin is generated by post-translational splicing from its precursor, pro-adrenomedullin 3. Initially, it was believed that adrenomedullin is only expressed in tumour cells, but subsequent studies revealed that it is a multifunctional peptide, synthesised by a huge variety of mammalian tissues, including myocardium, central nervous system, kidney, and reproductive and digestive organs 2, 4. In addition, adrenomedullin is produced by endothelial and smooth muscle cells of both the systemic and pulmonary circulation 5. Adrenomedullin regulates cardiopulmonary functions and vascular tone as both a circulating hormone and as a local autocrine/paracrine mediator 6. The haemodynamic effects of adrenomedullin are predominantly mediated by cAMP production resulting from activation of two Gs-protein-coupled plasma membrane receptors of the calcitonin peptide family: the calcitonin receptor-like receptor and the receptor activity-modifiying protein-2 or -3 2. Moreover, adrenomedullin mediates smooth muscle cell hyperpolarisation by activating ATP-sensitive K+ channels 7, stimulates the release of vasodilatory prostaglandins 8, and elicits endothelium-dependent vasorelaxation secondary to nitric oxide (NO) formation 8, 9. Inasmuch as adrenomedullin reduces pulmonary vascular tone and improves tissue oxygenation 10, supplementation of exogenous adrenomedullin may be a rationale in the …