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-1 c allele or in mice containing one copy each of Ren-1 c , Ren-1 d , 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-renindependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system. ( J. Clin. Invest. 1996. 97:1047-1055.)

Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II

“…We previously generated double transgenic mice carrying both the hREN and hAGT genes (25). These mice exhibited a marked elevation in BP and a resetting of the baroreflex control of HR to a higher pressure without significantly changing the gain of the reflex (25).…”

“…In the first, the baroreflex curve is shifted or reset to a higher pressure, whereas in the second there is a decreased sensitivity of the reflex as measured by a decreased slope (or attenuated gain) of the baroreflex curve. These mechanisms have been documented in many experimental animal models of hypertension (10,17,25,26).…”

“…In the first, the baroreflex curve is shifted or reset to a higher pressure, whereas in the second there is a decreased sensitivity of the reflex as measured by a decreased slope (or attenuated gain) of the baroreflex curve. These mechanisms have been documented in many experimental animal models of hypertension (10,17,25,26).There is considerable evidence that circulating ANG II plays a critical role in the baroreflex control of HR by modulating either the set point or sensitivity of the reflex (7,24,25,34). For example, chronic intracerebroventricular (ICV) infusion of ANG II decreased baroreflex gain and blockade of ANG II AT 1 receptors with losartan increased baroreflex gain in conscious rabbits (9).…”

“…There is considerable evidence that circulating ANG II plays a critical role in the baroreflex control of HR by modulating either the set point or sensitivity of the reflex (7,24,25,34). For example, chronic intracerebroventricular (ICV) infusion of ANG II decreased baroreflex gain and blockade of ANG II AT 1 receptors with losartan increased baroreflex gain in conscious rabbits (9).…”

Oxidative Stress through Activation of NAD(P)H Oxidase in Hypertensive Mice with Spontaneous Intracranial Hemorrhage

“…Nontransgenic (RÀ/AÀ) and single transgenic littermate mice (R + /AÀ or RÀ/A + ) were used as controls for R + /A + mice, because strict specificity in the enzymatic reaction exists between the mouse and human renin-angiotensinogen system (Merrill et al, 1996). Breeding and genotyping of R + /A + mice and their control mice were performed in the transgenic animal facility located in a virus-and pathogen-free animal-care facility.…”