Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findings, it was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hypertrophy and renal glomerular sclerosis by inhibiting RAS.

To investigate the aldosterone responsiveness of genetically hypertensive rats, we compared characteristics of renal cytosolic aldosterone receptors from the M strain of stroke-prone, spontaneously hypertensive rats (M-SHRSP) with normotensive Wistar-Kyoto rats (WKY). In M-SHRSP, blood pressure was elevated significantly at 6 wk of age, when their plasma aldosterone concentrations were similar to those in WKY. Decreases in urine volume and sodium excretion were also observed in M-SHRSP. At 10 wk of age, M-SHRSP plasma aldosterone concentrations became significantly higher than those in WKY. On the other hand, the concentration of renal cytosolic aldosterone receptors (type I, aldosterone specific) had already increased at 6 wk of age in M-SHRSP, with no difference in affinity, and levels remained increased thereafter. There were no significant differences in molecular weights or ionic charges of either "activated" or "non-activated" aldosterone-receptor complexes between M-SHRSP and WKY, indicating that the molecular properties were similar in both groups. These results suggest that the increased concentration of aldosterone receptors in the kidneys of M-SHRSP might increase their aldosterone responsiveness and contribute to the development of high blood pressure in these animals.

Tsukuba hypertensive mice (THMs) are transgenic mice carrying human renin and angiotensinogen genes. The aim of this study was to evaluate the role of the renin-angiotensin system (RAS) in cardiac hypertrophy and renal disorders in THMs. After a 2-wk control period, 10-wk-old THMs were treated with lisinopril (ACEI group) or hydralazine (hydralazine group) or left untreated (control group) for 8 wk. C57BL16 mice of similar age (wild group) were used as normal controls . Systolic blood pressure and urinary albumin excretion were measured once a week. All mice were sacrificed at 20 wk of age , and h eart to body weight ratio, cardiac myocyte diameter, renal glomerular sclerosis index , and glomerular size were measured. Fibronectin expression was also evaluated. At 20 wk of age, systolic blood pressure and urinary albumin excretion in the control group were significantly higher than those in the wild group and significantly lower than those in the ACEI and hydralazine groups. Heart to body weight ratio and cardiac myocyte diameter were significantly higher in the hydralazine and control groups than in the other groups. Renal glomerular sclerosis index and glomerular size were also significantly higher in the control group than in the other groups, and there were significant differences between the ACEI and hydralazine groups in these variables. Fibronectin expression was marked in the control and hydralazine groups. These findings suggest that the RAS plays an important role in cardiac hypertrophy in THMs, but that both the RAS and elevation of blood pressure contribute to the pathogenesis of renal glomerular sclerosis. (Hypertens Res 1998; 21: 39-46) Key Words: cardiac hypertrophy, glomerular sclerosis, renin-angiotensin systemHypertension is a multifactorial disease. The reninangiotensin system (RAS) is one of the most important factors. Recently, the RAS has been reported to exist not only in circulating blood but also in local tissues, such as the brain, heart, and vascular endothelium. The relationship between the tissuelocalized RAS and many diseases, including hypertension, has therefore become a focus of study. Angiotensin II (Ang II), the final physiological activator of the RAS, is known to accelerate hypertrophy of cardiac muscles and renal glomerular sclerosis when administrated alone (1-3). Mechanical stress such as high blood pressure has also been reported to produce the same effects (4-6). Tsukuba hypertensive mice (THMs), into which both a human renin gene and a human angiotensinogen gene have been introduced, are a model of hypertension (7). THMs were established by crossbreeding a mouse into which a 15-kb full length human renin gene, including its 3-kb native promoter, had been introduced with a mouse into which a 14-kb human angiotensinogen gene, including its 1.3-kb native promoter, had been introduced (Fig . 1).The increase in blood pressure in this model is caused only by increased RAS activity. The Ang II concentrations in this mouse are about four to five times higher in serum, heart,...

1. In the present study, we examined the effect of a novel angiotensin I1 type I receptor antagonist, TCV-116, on carotid neointimal formation after balloon injury in SHR and WKY rats.2. Oral administration of TCV-116 at a dose of 10mg/kg per day reduced not only systolic blood pressure but also neointimal formation after carotid balloon injury. TCV-116 also suppressed cardiac hypertrophy. An angiotensin-converting enzyme inhibitor, lisinopril (20 mg/kg per day), had a similar effect to that of 3. In the WKY experiment, both TCV-116 and lisinopril suppressed neointimal formation as well as systolic blood pressure, but did not suppress cardiac hypertrophy. 4.Although SHR showed markedly enhanced neointimal formation after balloon injury compared with age-matched WKY rat, both TCV-116 and lisinopril showed similar suppressive effects on neointimal formation in both SHR and WKY rats.5. These results confirm the important role of angiotensin I1 in neointimal formation following balloon injury. Further studies are needed to clarify the mechanism of the difference between SHR and WKY rats in the response of vascular smooth muscle cells.

The effects of beta-blocker treatment on hemodynamics were studied in relation to plasma atrial natriuretic peptide (ANP) levels in 17 outpatients with essential hypertension. Administration of propranolol for twelve weeks to untreated subjects resulted in a significant (P < 0.001) rise in plasma ANP levels (from 37.9 +/- 21.2 to 66.7 +/- 46.2 pg/mL, mean +/- SD). Systolic and diastolic blood pressures were significantly decreased (P < 0.05 and P < 0.01, respectively). Heart rate was also significantly decreased (P < 0.001). On the other hand, a significant reduction of cardiac index was detected (from 4.12 +/- 1.34 to 2.96 +/- 0.75 L/min/m2, P < 0.01) with chronic administration of propranolol, suggesting a reflection of decreased cardiac function. A significant negative correlation was observed between %changes in systolic blood pressure and %changes in plasma ANP (r = -0.594, P < 0.05). These results suggest that the increased plasma ANP levels may contribute to the antihypertensive effect with propranolol.