DOSE EFFECTS OF HUMAN RENIN IN RATS TRANSGENIC FOR HUMAN ANGIOTENSINOGEN

We examined the effect of chronic human renin infusion and human renin inhibition on blood pressure in a unique transgenic rat model. We inf used incremental doses of human renin (1 to 500 ng/h) with minipumps f or 10 days into rats harboring the human angiotensinogen gene [TGR (hA OGEN)1623]. We measured blood pressure and heart rate continuously by telemetry. We found that human renin at 5 ng/h was necessary to increa se blood pressure, whereas 10 ng/h caused systolic blood pressure to i ncrease to 215 +/- 13 mm Hg. Heart rate decreased initially but then i ncreased by 100 beats per minute compared with basal values. Drinking behavior also increased. Doses as high as 500 ngih did not increase bl ood 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 i nfluenced by human renin infusion. Human angiotensinogen levels remain ed stable until 500 ng/h human renin was infused, at which time they d ecreased by 50% at 9 days. Rat renin gene expression (RNase protection assay) was decreased by human renin infusion, whereas rat and human a ngiotensinogen gene expressions in liver and kidney as well as angiote nsin-converting enzyme gene expression in kidney were not affected. Th e human renin inhibitor Ro 42-5892 was given by gavage repeatedly to r ats receiving human renin at 40 ng/h. Ro 42-5892 lowered blood pressur e promptly to basal values. High human renin hypertension in this mode l is dose dependent, features a steeper relationship between blood pre ssure and plasma renin activity over time, and is associated with tach ycardia and increased drinking. We conclude that the human angiotensin ogen transgenic rat offers new perspectives in the study of human reni n-induced hypertension.