Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Abstract

We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.