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We have demonstrated previously that deoxycorticosterone acetate (DOCA)/salt induces cardiac hypertrophy and left ventricular dysfunction independent of blood pressure (BP) in 1-renin gene mice. Because these mice also develop hypokalemia and metabolic alkalosis caused by mineralocorticoid excess, we investigated whether correcting hypokalemia by dietary potassium supplementation would prevent the DOCA/salt-induced cardiac hypertrophy, cardiac dysfunction, and electrocardiographic changes in normotensive, 1-renin gene and hypertensive, 2-renin gene mice. All mice were studied after 5 weeks of DOCA and salt administration. Potassium was given by adding 0.4 or 0.6% KCl to the drinking water. Our results show that correction of hypokalemia and metabolic alkalosis prevents cardiac hypertrophy and normalizes cardiac function without affecting BP in normotensive, 1-renin gene mice. In hypertensive, 2-renin gene mice, potassium supplementation induces a significant decrease in BP. The decrease in BP and correction of kalemia are associated with a significant but partial correction of cardiac hypertrophy. In both group of mice, electrocardiographic alterations were measured after administration of DOCA/salt, which could be corrected by potassium supplementation. Thus, these results show that correction of hypokalemia and metabolic alkalosis does prevent the development of cardiac hypertrophy and normalizes cardiac function independent of BP in normotensive, 1-renin gene mice that receive excess mineralocorticoid and salt. In 2-renin gene, hypertensive mice, potassium supplementation also prevents the development of cardiac hypertrophy, but the effect cannot be separated from the decrease in BP.

Chronic elevation of plasma angiotensin II (Ang II) is detrimental to the heart. In addition to its hemodynamic effects, Ang II exerts cardiotrophic actions that contribute to cardiomyocyte remodeling. However, it remains to be clarified whether these direct actions of Ang II are sufficient to cause contractile dysfunction and heart failure in the absence of altered hemodynamic conditions. In this study, we used TG1306/1R (TG) mice that develop Ang II-mediated cardiac hypertrophy in absence of elevated blood pressure to investigate the phenotypic changes in cardiomyocytes during the adaptive response to chronic cardiac-specific endogenous Ang II stimulation. A 94-week longitudinal study demonstrated that TG mice develop dilated cardiomyopathy with aging and exhibit a significant increase in mortality compared with wild-type (WT) mice. Cardiac hypertrophy in TG mice is associated with cardiomyocyte hypertrophy (15 to 20 weeks: length +20%; 35 to 40 weeks: length +10%, width +15%) but not collagen deposition. In vivo analysis of cardiac function revealed age-dependent systolic and diastolic dysfunction in TG mice (approximately 45% reduction in dP/dtmax and dP/dtmin at 50 to 60 weeks of age compared with WT). Analysis of isolated cardiomyocyte isotonic shortening showed impaired contractility in TG cardiomyocytes (30% to 40% decrease in rates of shortening and lengthening). In TG hearts, chronic Ang II exposure induced downregulation of the sarcoplasmic reticulum calcium pump (SERCA2) and diminution of Ca2+ transients, indicative of an underlying disturbance in calcium homeostasis. In conclusion, chronic Ang II myocardial stimulation without hemodynamic overload is sufficient to produce cardiomyocyte and cardiac dysfunction culminating in heart failure.

Angiotensin II is a potent arterial vasoconstrictor and induces hypertension. Angiotensin II also exerts a trophic effect on cardiomyocytes in vitro. The goals of the present study were to document an in vivo increase in cardiac angiotensins in the absence of elevated plasma levels or hypertension and to investigate prevention or regression of ventricular hypertrophy by renin-angiotensin system blockade. We demonstrate that high cardiac angiotensin II is directly responsible for right and left ventricular hypertrophy. We used transgenic mice overexpressing angiotensinogen in cardiomyocytes characterized by cardiac hypertrophy without fibrosis and normal blood pressure. Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent or normalize ventricular hypertrophy. Surprisingly, in control mice, receptor blockade decreases tissue angiotensin II despite increased plasma levels. This suggests that angiotensin II may be protected from metabolization by binding to its receptor. Blocking of the angiotensin II type 1 receptor rather than enhanced stimulation of the angiotensin II type 2 receptor may prevent remodeling and account for the beneficial effects of angiotensin antagonists.

Cardiac hypertrophy is frequent in chronic hypertension. The renin-angiotensin system, via its effector angiotensin II (Ang II), regulates blood pressure and participates in sustaining hypertension. In addition, a growing body of evidence indicates that Ang II acts also as a growth factor. However, it is still a matter of debate whether the trophic effect of Ang II can trigger cardiac hypertrophy in the absence of elevated blood pressure. To address this question, transgenic mice overexpressing the rat angiotensinogen gene, specifically in the heart, were generated to increase the local activity of the renin-angiotensin system and therefore Ang II production. These mice develop myocardial hypertrophy without signs of fibrosis independently from the presence of hypertension, demonstrating that local Ang II production is important in mediating the hypertrophic response in vivo.

The mouse remains the animal of choice in transgenic experiments, creating a need for methods of evaluating the physiology of genetically modified animals. We have established and characterized two murine models of renovascular hypertension known as the two-kidney, one clip and one-kidney, one clip models. The appropriate size of the clip lumen needed to induce high blood pressure was determined to be 0.12 mm. Clips with a lumen of 0.11 mm induced a high percentage of renal infarction, and clips with a 0.13-mm opening did not produce hypertension. Four weeks after clipping, two-kidney, one clip hypertensive mice exhibited blood pressure approximately 20 mm Hg higher than their sham-operated controls. After a similar period, this increase reached almost 35 mm Hg in the one-kidney, one clip model. Depending on the model, mice develop either renin-dependent or renin-independent hypertension. Both models are characterized by the development of cardiovascular hypertrophy.