To be or not to be … hypertensive: That is the question

Abstract

‘Measure what is measurable and make measurable what is not so’. Galileo's dictum may easily be applied to the history of the measurement of blood pressure – the force at the point of measurement (usually in mmHg) within the cardiovascular system (i.e. the pressure exerted by the blood on the wall of the blood vessel). Blood pressure (BP) is created through the opposing forces generated by the pumping of the heart – within a closed circulatory system – against the resistance offered by the peripheral vasculature. The first recorded measurement of BP in an animal (a horse in 1733) required a brass pipe being directly inserted into a major artery (by the Rev Stephen Hales). Thankfully, techniques for blood pressure measurement have been refined but invasive cannulation remains the gold standard (e.g. radiotelemetry). Non-invasive sphygmomanometry (developed ∼1881) had much greater clinical application and very soon it was clear that the blood pressure distribution in a given population was normal (Gaussian), where a defined rightward shift identified individuals as being ‘hypertensive’, i.e. a statistical term denoting a significant shift away from the median for the population from which the individual was drawn. For man, this shift is ∼20 mmHg (from an optimal systolic blood pressure of 120 mmHg to stage I hypertensive of > 140 mmHg; Verdecchia & Angeli, 2003). Sphygmomanometry was readily applied to animals from rodents (Pfeffer et al. 1971) to horses (Giussani et al. 2003), but has always attracted criticism (Gross & Luft, 2003), due mainly to experimental error or being ‘stressful’ and therefore representing ‘resting’ BP (Tonkiss et al. 1998). Consequently, a number of studies have sought to validate the procedure (e.g. Pfeffer et al. 1971; Bunag, 1973). The paradigm of the developmental origins of health and disease is an active area of research that has brought the methods for measurement of BP into focus and stimulated much related debate. Fourteen years ago it was shown that a maternal low protein (MLP) diet fed to young Wistar rats (i.e. 90 versus 180 g kg−1) increased the systolic blood pressure of their adult offspring (Langley & Jackson, 1994), as assessed by tail-cuff sphygmomanometry. To my knowledge, and surprisingly, no further study since has sought to corroborate these data with radiotelemetry and with some groups reporting similar increases in BP (Woods et al. 2001), no change (Martin et al. 2004) or reduced BP (after global nutrient restriction; Brennan et al. 2008), the field appears confusing, in part, because of the different methods used for measurement of BP. Does a maternal low protein diet lead to hypertensive offspring or alternatively, offspring more ‘stressed’ by the tail-cuff procedure (Tonkiss et al. 1998)? Rodford et al. (2008) in the current issue of The Journal of Physiology, revisit the MLP paradigm and report no change in tail-cuff measured systolic blood pressure in the offspring from 4 to 16 weeks of age, in contrast to much of the published literature. Rather, they observe marked effects on the structure and function of the endothelium that is, in part, sex specific. They interpret the data as an adaptation to the less than optimal prenatal environment that may mark ‘prehypertensives' (rats after all may live > 100 weeks). An optimal functioning endothelium is crucial to stable blood pressure control (e.g. through tonic generation of nitric-oxide and endothelins) and has one of the largest active surface areas of any organ in the body. The authors rightly argue that the lack of effect on resting (or stimulated) blood pressure measured by tail-cuff sphygmomanometry is perhaps not important; rather, demonstration of hypertension (relative to a contemporaneous control population) is a useful tool for demonstrating proof-of-principle (i.e. that the prenatal environment has delayed effects) but may not be symptomatic of clinical disease. Indeed, rats rarely, if ever, suffer cardiovascular disease. As the authors point out, in robust epidemiological studies the inverse relationship between low birth weight (an outcome often observed after MLP) and adult blood pressure is less clear cut than with clinical cardiovascular outcomes (Curhan et al. 1996). While the study of Rodford et al. focuses attention on the endothelium as a potentially important marker of prehypertension, many questions remain. How does MLP in utero affect endothelial remodelling? Is the adaptive response prenatal or postnatal (unresolved in the current study as the offspring were not cross-fostered)? Why the sex specificity? Fetal growth is supply driven; cut the supply (e.g. of nutrients) and growth slows, the available blood volume may redistribute to provide substrate for growth in essential organ beds (e.g. the brain and heart) leaving the peripheral cardiovascular network susceptible at a developmentally sensitive time (Berry, 1978; Folkow, 1993). In another 14 years perhaps these will be answered and the data can be translated into clinical practice.