Many laboratories have shown that Ang II has trophic effects on cultured cardiomyocytes, and these studies have led to important insights into the mechanisms of intracellular signaling by this hormone (reviewed in Reference 20). Nevertheless, because these studies are by necessity carried out in highly defined conditions that often include the lack of serum proteins and the absence of parallel stimulation by other hormones, the biological relevance of the hypertrophic effects of Ang II on cardiomyocytes in vitro has to be tested in whole animals. Making this leap has been difficult because of the compound effects of Ang II on vasoconstriction, aldosterone secretion, sodium reabsorption, and fluid volume, all of which can raise blood pressure and confound the differentiation of primary and secondary effects of Ang II on the heart. The various molecular strategies used by investigators to address this question in whole animals represent the epitome of experimental physiological sleuthing. Nevertheless, because of the pleiotropic effects of Ang II, they also require careful critical analysis.

One approach used by several groups is to treat animals with so-called “subpressor” doses of Ang II, and such studies have often reported a stimulation of cardiac hypertrophy and fibrosis that did not ensue from a detected increase in blood pressure. However, this approach cannot rule out systemic effects, and there is some debate as to whether they are truly subpressor, particularly during the night when rodents are most active. For this reason, they will not be dealt with further in this review. As an alternative, several groups have resorted to the unique ability to modify the genome of mice to inactivate genes by homologous recombination (knockout mice) and to target the tissue-specific overproduction of proteins using transgenesis.