Simply removing pressure doesn't work, but youthful drug-taking prevents hereditary mid-life failure

The original logic of therapy that suppresses the effects of angiotensin II [angiotensin-converting enzyme inhibitor or AT1-receptor (AT1-R) antagonism] was to produce structural and functional cardiovascular benefit by reducing elevated blood pressure [1]. However, such treatment can reduce cardiovascular events regardless of whether or not patients are hypertensive [2], implying that AT1-R mediate the deleterious effects of angiotensin II that are independent of vasoconstriction [3,4]. In hypertensive animal models, short-term treatment with anti-angiotensin therapy can also produce a long-lasting cardiovascular benefit that was originally attributed to lowering blood pressure [5,6] (i.e. a finite treatment can produce a ‘correction’ that prevents the subsequent development of cardiovascular morbidity). In this issue of the journal, Baumann et al. [7] show that short-term AT1-R antagonism (losartan) of young genetically hypertensive rats resulted in prolonged alleviation of hypertension and a reduced cardiovascular pathology at what is, for a rat, the advanced age of 72 weeks. By contrast, treatment with another class of blood pressure-lowering agent, hydralazine, had no persistent effect on blood pressure or protective effect at older age. This suggests that the protective effect is not due to the temporary lowering of blood pressure at a young age but due to some further action of AT1-R antagonism at a key point in post-natal development. The ‘correction’ of a pathological situation that is set in train in the young may be related to the general hypothesis of Barker [8], who proposed that events in early life determine subsequent cardiovascular disease. In the case of spontaneously hypertensive rats (SHR), a combination of genetic programming and early events produces a key metabolic state, such as an imbalance amongst reactive oxygen species, that determines subsequent development of cardiovascular morbidity [9,10]. Baumann et al. [7] suggest that this remarkable effect could translate into interesting therapeutic possibilities if it were to apply to appropriate human subjects who would otherwise develop hypertension. Essentially, by giving prophylactic treatment to individuals in their youth, to block the effects of angiotensin II, cardiovascular morbidity in later life might be avoided. This raises many interesting ethical and scientific issues. However, consideration of the former can await the outcome of the latter. The possibilities for translation of this phenomenon from SHR to humans depend on the alignment of a number of aspects between the two species. First is the aetiology of clinical hypertension versus the SHR model. Despite considerable effort, the primary cause of hypertension in the SHR remains unknown, although several secondary phenomena very closely identified with the onset of hypertension have been identified [10,11]. The prospects for translation to humans depend on whether anti-AT1-R action targets a primary defect in SHR that may be of no human relevance, or a secondary consequence that may be common to early origin hypertension in both rats and humans. A new aspect introduced by Baumann et al. [7] is the dissociation of the protective effect from a simple ‘hypotensive’ effect at the early age. The authors argue that this dissociates the protection at old age from the effect on hypertension. However, their treatment regime does delay the onset of morbid hypertension and, although hypertension is eventually established, it may also have delayed other effects that might eventually show up at even older ages. Thus, the benefits of treatment should be seen, generally, in terms of delay rather than prevention, and thus time-scale becomes important. This leads on to the issue of timing of the treatment versus the onset of hypertension during ontogenetic development in each species. The SHR has a very rigidly programmed sequence of events, where the origin of hypertension can be traced to the post-natal period. There is debate over whether SHR are ever normotensive after birth, although many recent investigations, including the current one [7,11], proceed on the basis that they are normotensive at 8 weeks and hypertensive by 6 months, and this is the critical time window in which most investigations of the underlying mechanisms have concentrated. Interventions to prevent the onset of hypertension are therefore concentrated at the start of this period, around 2–3 months, partly due to the lower practicality of studying blood pressure at even younger ages. Nevertheless, a number of studies have shown that very early nutrition, such as suckling dams of different rat strains, can influence the onset of hypertension [12], and thus the first 3 months post-natal are crucial. The sequence of cardiovascular morbidity associated with the model is: (i) ‘causal’ events very early in life; (ii) elevated blood pressure, starting at around 3 months and well established by 6 months of age; and (iii) further damage to other organs, including the kidneys and heart, that shows up in the period up to 72 weeks (14 months) of age. A simplistic extrapolation of this to the human lifespan might suggest that causal events occur in childhood, treatment is given during puberty (rats are sexually mature at 6 weeks; treatment was given from 4–8 weeks) and the benefits would be seen in terms of preventing hypertension that starts in early adulthood and further morbidity that extends to middle age (‘normal’ rats start to show morbidity at around 18 months but can live much longer). This is, of course, a progression that occurs during ad libitum nutrition and a sedentary lifestyle for these rats. There is no shortage of material for debate as to how this may differ, or not, from humans who are susceptible to hypertension. Another viewpoint might be that the effect lasts for approximately 1 year in rats, and so perhaps might last for 1 year in humans. This depends on whether the programming of the sequence of development of morbid responses is related to ontogenetic development and is therefore slower in humans, or is a straightforward series of metabolic events that may have the same chronology in any species. Whatever the relationship to the lifespan, the mechanism involved is intriguing. What key processes at a key stage in the development of hypertension in the SHR can be blunted by a short-term prevention of activation of AT1-R? Are free radicals a key? Does this occur in the kidneys? Is there an equivalent process taking place in normal development whose suppression does subsequent harm? This fascinating paper certainly gives us much food for thought.