Dose Effects of Human Renin in Rats Transgenic for Human Angiotensinogen

Abstract

Abstract We examined the effect of chronic human renin infusion and human renin inhibition on blood pressure in a unique transgenic rat model. We infused incremental doses of human renin (1 to 500 ng/h) with minipumps for 10 days into rats harboring the human angiotensinogen gene [TGR(hAOGEN)1623]. We measured blood pressure and heart rate continuously by telemetry. We found that human renin at 5 ng/h was necessary to increase blood pressure, whereas 10 ng/h caused systolic blood pressure to increase to 215±13 mm Hg. Heart rate decreased initially but then increased by 100 beats per minute compared with basal values. Drinking behavior also increased. Doses as high as 500 ng/h did not increase blood pressure further. A linear relationship was found between the log of plasma renin activity and systolic blood pressure that increased in slope from days 2 to 9. Rat angiotensinogen levels were low and not influenced by human renin infusion. Human angiotensinogen levels remained stable until 500 ng/h human renin was infused, at which time they decreased by 50% at 9 days. Rat renin gene expression (RNase protection assay) was decreased by human renin infusion, whereas rat and human angiotensinogen gene expressions in liver and kidney as well as angiotensin-converting enzyme gene expression in kidney were not affected. The human renin inhibitor Ro 42-5892 was given by gavage repeatedly to rats receiving human renin at 40 ng/h. Ro 42-5892 lowered blood pressure promptly to basal values. High human renin hypertension in this model is dose dependent, features a steeper relationship between blood pressure and plasma renin activity over time, and is associated with tachycardia and increased drinking. We conclude that the human angiotensinogen transgenic rat offers new perspectives in the study of human renin–induced hypertension.