Of rat and man

In this issue of the journal, the thorough and well-documented study by Wollard et al. 1 contributes to the body of studies in hypertensive rats, all confirming that a short period of blood pressure lowering has a prolonged effect after treatment has been discontinued. Whereas the earlier literature suggested that this effect might be specific for drugs that interfere with the renin–angiotensin system, Wollard et al. 1 suggest that treatment with other antihypertensive agents might also be efficacious. Their study also demonstrates that a relatively short period of treatment has the same effect on attenuation of post-treatment hypertension as a longer period. The final novelty is that, whereas other investigators chose to treat the animals very early, including intra utero 2, Wollard et al. 1 demonstrate a prolonged after-treatment blood pressure lowering also in adult rats. They suggest that ‘drug holidays’ might be appropriate in the treatment of hypertension. Together with the result from other studies of experimental hypertension, Wollard and colleagues provide the proof of the principle that, under some circumstances, intermittent treatment might have beneficial long-term effects. However, extrapolation from animals to humans is extremely difficult. Starting with the obvious, it is impossible to say what is ‘young’ or ‘old’ age, as well as ‘long’ versus ‘short’ treatment, in humans compared to animals. Furthermore, the pathophysiology of human and spontaneously hypertensive rat (SHR) hypertension is not similar. SHR do not develop the metabolic syndrome, which exists very early in human hypertension 3 and, unless specially treated, they do not develop atherosclerosis. Thus, the vascular changes in humans and in rats cannot be compared. However, the paper by Wollard et al. 1 warrants a systematic re-examination of our attitudes towards the treatment of hypertension for several reasons. The first reason concerns learning how the practice of continuous treatment of hypertension evolved. After the VA Cooperative trial of moderate to severe hypertension in the USA 4 had been completed, blood pressure tended to rebound to pretreatment levels very soon after drug discontinuation. Subsequent trials of milder forms of hypertension 5–8 showed that patients with mild hypertension are more likely to remain normotensive (from 50 to 75% in the first year and 45 to 52% in the second year) and that, if hypertension reoccurs, blood pressure is likely to rebound in the first 4 months after treatment. Whereas this held out some hope for intermittent treatment of the early phases of hypertension, an undocumented consensus evolved which assumed that patients who remained normotensive never had ‘real’ hypertension. The issue was not investigated further and the clinical recommendation focused on repeated blood pressure monitoring before treatment in order to identify ‘true’ hypertension. Thus, at present, we have no information whether intermittent treatment of hypertension is feasible. The second reason is in the dismal rates of blood pressure control with the present ‘for life treatment’ approach to every patient with hypertension. Most asymptomatic patients fail to persevere in taking drugs. If it were proven that intermittent treament is feasible, investigations of whether this approach would improve patient compliance would be in order. The third related issue is the practical failure of non-pharmacological treatment measures to control blood pressure. Whereas physical exercise, weight loss, mental relaxation and salt restriction can decrease blood pressure under artificially controlled conditions, their practical real-life application is fraught with difficulties. There is no evidence that public education and the advice of the physician for non-pharmacological treatment have a positive effect on long-term blood pressure control in the general population. Approximately 70% of all patients with hypertension have stage I hypertension and, if we wish to improve public health, some new approaches to this large group of patients need to be developed. At present, only two clinical trials have evaluated whether a period of treatment of very mild hypertension might have long-term beneficial effects after treatment had been discontinued 9. Hopefully studies such as that of Woolard et al. 1 will give a new impetus to human studies with regard to new modalities of usage of antihypertensive drugs in patients with hypertension.