*4.1. Effects on SBP*

The present results showed that treatment effects on SBP were greater in ySHRs than in oSHRs, thus confirming the experience from earlier studies [24,25]. Early treatment of SHR with RAS antagonists is able to reduce SBP even to normotensive values [24,28]. However, in their studies, the treatment started in the prehypertensive stage of life, that is, at or before the age of 4 weeks, and lasted 6–8 weeks. At 7 weeks of age, SBP of untreated SHRs ranged between 154 and 187 mmHg [26] and increased to 210–220 mmHg by week 12–15 [29]. For comparison, at that age, SBP of normotensive WKY ranges between 115 and 137 mmHg [24,26]. With further aging up to senescence, SBP increases only slightly; in untreated SHRs aged 60–82 weeks, it was about 240 mmHg (see Table 1). In contrast, SBP of old WKY remained in the range of young WKY [24]. The present results show that the treatment effect significantly depends on age; despite a much shorter interval of therapy (3 weeks only) treatment with C+N between the 7th and 10th week of life reduced SBP even more than a 22-week therapy with the same medication between the 60th and 82nd week of life.

Antihypertensive treatment started early in life has not only stronger but also more persistent effects on SBP. In young SHRs aged 4–6 weeks, transient antihypertensive therapy over 4–6 weeks resulted in a significant SBP reduction, which remained until age 24–30 weeks. In contrast, if such a treatment was initiated during adulthood (between week 20 and 24), the effect on SBP was significantly lower or even completely abolished [25,30–32]. Antagonists of the RAS not only exert vasodilatory effects, thus directly decreasing BP. In addition, they prevent or attenuate structural changes of resistance vessels. This effect, however, is only present in adolescent and young adult SHRs up to about 20 weeks of age, and is most pronounced at

4–10 weeks of age [33]. Of note, vascular antihypertrophic effects of RAS antagonists were also demonstrated in both young and old WKY [24]. Nifedipine is also able to reduce vascular hypertrophy in SHRs [34]. Prevention of vascular hypertrophy may explain the more potent antihypertensive effect of early-onset treatment and the long-term maintenance of BP reduction even after withdrawal of the therapy.

The effect of age found in our study cannot be differentiated from an effect of SBP at treatment onset; while SBP of all ySHRs presented here was lower than 200 mmHg at baseline, all of the oSHRs had a baseline SBP above 200 mmHg [26,27]. There was a significant positive correlation between age and SBP at baseline (r = 0.83; *p* < 0.001). These results strongly suggest that greater treatment effects and even normotension might be achieved the earlier in life the treatment is started.
