During the decade between 1955 and 1965 major new conceptual milestones were introduced in the field of cell biology through electron microscopic investigations. During this time, investigations on both, cardiac and skeletal muscle, made it possible to visualize the subcellular basis of the processes of muscle contraction and excitation-contraction coupling. Similar studies carried out on mammalian atrial muscle posed questions that remained unanswered through the span of the above mentioned decade. Namely, cardiac muscle cells (cardiocytes) in the mammalian atria differ morphologically from ventricular muscle cells in several ways. Most notably, these cells display secretory-like features similar to those found in polypeptide-hormone producing cells such as the cells of the endocrine pancreas or the pituitary gland. These morphological features (phenotype) did not fit the view of classical cell biology of the heart muscle cell that associated these cells with contraction, excitation and conduction but not with secretion.

It is now well established that the atria of the heart in mammals including man, produce two polypeptide hormones:atrial natriuretic factor (ANF) (13) and brain natriuretic peptide (BNP) so named because it was first detected in brain) (8). Thus these cells are involved in both the mechanical activity of the atria and the endocrine function of the heart.

Each NP is encoded by a specific gene. Both ANF and BNP are synthesized by cardiocytes as preprohormones that are enzymatically processed to yield prohormones and, ultimately, hormones that are released into the circulation.

ANF and BNP are released from the heart at a basal rate that increases following appropriate mechanical (hemodynamic) or neuroendocrine stimuli. The many biological properties of ANF and BNP allow these hormones to interact with fast responding as well as slow onset mechanisms involved in cardiovascular homeostasis. In many ways, the endocrine heart appears as a modulator of systems such as the sympathetic nervous system, the renin-angiotensin-aldosterone system and other determinants of vascular tone and renal function . Three receptors have been described for NPs. Types A and B are guanylyl cyclases, that is, enzymes through which the ligands induce the production of cyclic guanosine monophosphate (cGMP).The properties of ANF and BNP are predominantly mediated through increases of cGMP in target cells. Intracellular cGMP targets include cGMP-dependant protein kinases, cGMP-gated ion channels and cGMP-regulated phosphodiesterases.

The importance of the function of the endocrine heart is reflected in experiments showing that blockade of guanylyl cyclase-coupled NP receptors results in impairment of cardiorenal regulation of homeostasis (6,9). In pathophysiological states such as in chronic congestive heart failure the activation of the renin-angiotensin-aldosterone (RAAS) and adrenergic systems fulfils the role of compensating for pump failure by increasing extracellular fluid volume and inducing vasoconstriction. Early during the development of this and other pathophysiologies, cardiac ANF and BNP are activated to modulate these compensatory responses. For this reason, measurement of different fragments of ANF and BNP in plasma have unique clinical prognostic and diagnostic value (5). In decompensated cardiac failure, the endocrine heart is not able to moderate the predominant and deleterious role of the RAAS system or the sympathetic nervous system hyperactivity despite the strong inhibitory properties of ANF and BNP on these systems. Interestingly, exogenously administered these hormones does improve cardiovascular function in an acute setting in patients in heart failure. These findings indicate that the NP receptors are responsive to additional circulating peptides.

The modulatory function of ANF and BNP are so many that they are truly remarkable. For example, they inhibit renin release, increase glomerular filtration rate, decrease tubular sodium reabsorption, increase renal blood flow, inhibit aldosterone synthesis and release, relax vascular smooth muscle, inhibit salt and water appetite, decrease baroreflex activity and even regulate vascular smooth muscle cell proliferation. Other biological effects are still being discovered and some are not clear as is, for example, the association of these peptides with the immunological and reproductive systems. All of these properties make ANF and BNP target for pharmaceutical development in the field of hypertension and heart failure: a multi billion dollar market. Efforts are ongoing to produce an orally active product that would bind to the ANF biological receptors. Still, ANF and BNP as such are being used in the treatment of intrinsic renal failure and in chronic congestive heart failure. This field of research has grown from just one article describing the discovery of ANF in 1981 to more than 10,000 articles in today's biomedical literature.

Our laboratory was also the first to isolate, purify and sequence ANF but despite the insight that this pioneer work gives us, we are still trying to clarify how the production of ANF and BNP iscontrolled. A particularly puzzling fact is that both ANF and BNP share all known biological properties. It is not clear then why the heart produces two hormones with virtually the same properties. We are beginning to see that often, neither the synthesis nor the release of these two peptides are coordinated. For example, recent studies looking at the production of ANF and BNP in hypertensive rats treated with the ACE inhibitor Ramipril (7), shows that hemodynamic load and the hypertrophic process contribute differently to the production of these peptides. From this and other studies(4), it looks as if the two peptides are activated differentially depending upon the challenge.

Naturally, the effect of any hormone does not only depend upon its rate of synthesis or release but it is also dependent upon its effective levels in the circulation as determined by a number of factors including its rate of clearance. In addition, the level of expression of receptor genes in different tissues should be expected to contribute to determine overall effect. In the case of ANF and BNP it is known that their receptors' tissue distribution varies within and between species for reasons that are still unknown.