The evolution of our understanding of the actions of ANG II can be described in terms of 3 paradigms that also characterize the development of our knowledge of cardiovascular regulation. The first paradigm, organ physiology, described the variable performance of the heart in terms of length-dependent changes in myocardial contractile function (Starling's Law), and Ang II as a pressor factor that elevated blood pressure. With the shift to the second paradigm, cell biochemistry and biophysics, regulation of cardiac performance came to be explained by altered calcium fluxes and changing myocardial contractility, while the clinical effects of Ang II were understood in terms of changes in the calcium fluxes that control smooth muscle contraction. The third paradigm, gene expression (molecular biology), probably describes the most primitive--and complex--of these regulatory mechanisms. Altered gene expression in response to a variety of chemical and physical forces can explain several aspects of the long-term regulation of cardiac performance in terms of adaptative changes in the architecture and composition of a heterogeneous population of myocardial cells. This third paradigm also describes important effects of Ang II to increase protein synthesis and promote cell growth that appear able both to ameliorate and exacerbate human disease. It is, therefore, probably inappropriate to view Ang II mainly as a vasoconstrictor with secondary effects to induce cell hypertrophy. Instead, Ang II may have been derived from a primitive growth factor that, because it utilized Ca2+ to mediate its effects on gene expression, later in evolution acquired the ability to increase smooth muscle tone and myocardial contractility.(ABSTRACT TRUNCATED AT 250 WORDS)