| First Author | Smithies O | Year | 1997 |
| Journal | Hypertension | Volume | 30 |
| Issue | 6 | Pages | 1318-24 |
| PubMed ID | 9403547 | Mgi Jnum | J:45365 |
| Mgi Id | MGI:1195244 | Doi | 10.1161/01.hyp.30.6.1318 |
| Citation | Smithies O (1997) Theodore Cooper Memorial Lecture. A mouse view of hypertension. Hypertension 30(6):1318-24 |
| abstractText | Essential hypertension probably results from combinations of genetic variations, not necessarily the same in all afflicted persons, which individually may not cause sufficient deviation from normality to be significantly harmful. We have used gene targeting to vary the amounts of angiotensinogen and angiotensin-converting enzyme (ACE) synthesized from their genes (Agt and Ace). These ''gene titration'' experiments establish that changes in Agt gene expression cause changes in the blood pressures of mice. Surprisingly, quantitative changes in Ace gene expression over a threefold range do not affect blood pressures. Computer simulations with a simple version of the renin- angistensin system predict that changes in Agt function alter the steady state levels of both angiotensin I (Ang I) and angiotensin II (Ang II). In contrast, modest changes in Ace function alter Ang I levels considerably but scarcely affect Ang II levels. Simulations over the ranges of ACE levels that can be achieved with ACE inhibitors predict that Ang II levels will decrease only when Ang I levels have plateaued. Comparisons of the computer simulations with our genetic experiments and with prior work of others using wide dose ranges of ACE inhibitor show a satisfactory agreement and help reconcile the apparent contradictions between the genetic and pharmacological experiments. |
