To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic for 12 weeks and treated with vehicle (n = 10), valsartan (ARB; n = 7) or sacubitril/valsartan (ARNI; n = 8) for the final 3 weeks.
Female rats harboring the human angiotensinogen gene [TGR(hAogen)L1623] develop a preeclamptic phenotype with hypertension and albuminuria during pregnancy when mated with male rats bearing the human renin gene [TGR(hRen)L10J] but behave physiologically normal before and after pregnancy.
Chronically elevated Ang II in TGR(hAGT)L1623 hearts leading to increased intracellular calcium through I<sub>Ca-L</sub> suggests that activation of this Ang-(1-12)/chymase-governed cardiac intracrine RAS may contribute to the pathological phenotypes observed in the humanized model of chronic hypertension and cardiac hypertrophy.
Remarkably, in TGR with established hypertension, AAA also decreased SBP (from 187 ± 4 to 158 ± 4 mmHg, <i>P</i><0.05) and exhibited organoprotective effects in addition to marked suppression of kidney ANG II levels.
Animal models of hypertension have ranged from Goldblatt's kidney clip models in which the origin of the disease is clearly renal to animals that spontaneously develop hypertension either through targeted genetic manipulations, such as the TGR(mRen2)27, or selective breeding resulting in more enigmatic origins, as exemplified by the spontaneously hypertensive rat (SHR).
Compared with Sprague-Dawley (SD) control rats (n= 11), male homozygous TGR(hAGT)L1623 (n= 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability.
Spontaneous development of malignant phase hypertension in TGR(mREN2)27 heterozygotes occurs as a consequence of crossing TGR(mREN2)27 homozygotes with Edinburgh Sprague-Dawley rats.