ABSTRACT
Although by definition arterial hypertension is a hemodynamic disease, the primary cause of the disorder in young and middle-aged individuals usually does not involve structural abnormalities in the arteries themselves. Rather the increased pressure found in the early hypertensive patient results from impaired pressure natriuresis associated with functional vasoconstriction, volume overload, or both, with fixed architectural changes in the vessels usually occurring later in the history of the disorder. Moreover, the causes of vasoconstriction and impaired natriuresis are multiple so that idiopathic (essential) hypertension can be considered a multifaceted disease process resulting from the abnormal elaboration of vasoconstricting and/or fluid-retaining physiological signals, be they neurotransmitters at nerve terminals abutting vascular smooth muscle cells in arteries, vasoconstricting peptides such as angiotensin (Ang), or sodium-retaining hormones such as aldosterone. Moreover, some heritable forms of hypertension have been shown to be associated with disorders of hormone-associated receptors and intracellular signaling cascades leading to abnormal signaling and hypertension. This formulation of the causation of hypertension has been extremely productive and has led to the understanding of the roles of signaling proteins like renin in the genesis and treatment of hypertension.1,2
Yet for all its success, the above schema may be incomplete in an important way because it is, in part, based on the tacit assumption that all peptide hormone signaling is mediated by cell surface receptors and that knowledge of the status of these hormones and their cognate receptors is sufficient to predict their effect on the physiologic state of a tissue. While this may be true in the example of dynamic vasoconstriction, there is reason to believe that it is not the case for
longer-term growth abnormalities that are produced by hypertensinogenic hormones which lead to the sequelae of hypertension. The idea that some peptide/ protein hormones can act within cells after internalization and even in cells which synthesize them (i.e. without benefit of secretion) is old but remains little appreciated.1,3-6 Two decades ago we introduced the term intracrine for the intracellular action of a peptide hormone either after internalization or retention in the cell that synthesized it.7,8 Thereafter, evidence was developed to support the association of intracrine functionality with many hormones and growth factors, as well as with some transcription factors and enzymes. For example, there are enzymes (such as phospholipase A2-I, acetyl cholinesterase R, and phosphoglucose isomerase) which, in addition to serving catalytic functions, can also be secreted whereupon they act as signaling molecules; and these intracrine enzymes act in the intracellular space either after internalization or retention in their cells of synthesis.9-11 As is evident from Box 11.1,6,9-22 the number of known intracrines is large. Thus intracrine action, although not widely appreciated, is not uncommon. Over time, the term intracrine has also been applied by others to steroid hormones which either directly or following intracellular modification act within the cells that synthesized them. While these mechanisms undoubtedly occur and while they are physiologically relevant, the principal focus of this chapter will be peptide intracrines because their role in hypertension has been studied in more detail. Indeed, one of the earliest studied intracrines was Ang II. In 1971, it was reported that the infusion of labeled Ang II into rats led to the detection of tracer in the nuclei and mitochondria of cardiac myocytes within seconds.23 Although these early experiments could be challenged on methodological grounds, the basic finding has been reproduced over the years with ever more sophisticated imaging techniques.
