Dokument

Summary:
By maintaining the volume and composition of the body fluids within narrow bounds and by producing a set of hormones that affect the blood vessels, the kidneys provide important long-term regulation of the blood pressure. Disturbances of kidney function can cause hypertension, a prevalent disease in modern societies. The kidneys protect their own function against short-term variations in the blood pressure. At the level of the individual functional unit (the nephron), pressure and flow control involves two different mechanisms: the tubuloglomerular feedback, which regulates the incoming blood flow in response to variations of the NaCl concentration of the tubular fluid near the terminal point of the loop of Henle (macula densa), and a myogenic mechanism by which the afferent arteriole regulates its diameter in response to variations in its transmural pressure. Experimentally, both of these mechanisms are found to produce oscillations. In the present study, analysis of experimental data of the tubular pressure and arteriole blood flow in combination with mechanism-based modelling has been used to answer the following questions: (i) How to reveal and characterize interactions between the two mechanisms of renal autoregulation? (ii) To what extend does nephron-to-nephron communication lead to cooperative behaviour? and (iii) How do intra- and inter-nephron interactions differ in normotensive and hypertensive rats? Analysis of experimental data revealed the presence of amplitude and frequency modulation, i.e. the regulation is provided not only by a change in the diameters of the active parts of the vessels, but also by an adjustment of the frequency of the myogenic oscillations. Interaction between the two mechanisms of renal autoregulation was found to be significantly stronger in spontaneously hypertensive rats than in normotensive rats. Synchronization phenomena in neighbouring nephrons were evaluated by measuring both frequency and phase entrainment. Statistical analysis showed that synchronization among mechanisms of renal autoregulation is reduced in hypertensive rats. With a probability exceeding 80%, normotensive rats demonstrated full entrainment in neighbouring nephrons where the oscillatory modes associated with two mechanisms of autoregulation were synchronized. Hypertensive rats displayed about half the probability of full synchronization and about twice the probability of partial synchronization, i.e. a state where neighbouring nephrons synchronize their slow tubuloglomerular feedback dynamics, while the fast myogenic dynamics remain desynchronized, or vice versa. Spontaneously hypertensive rats generally remained in synchrony for only 1/3 to 1/2 as long as the normotensive ones. Numerical simulations with a model of superficial nephrons connected via a flow mediated hemodynamic coupling and a vascular propagated coupling reproduced the experimentally observed patterns of behaviour. Lack of synchronization may be responsible for the development of irregular dynamics in the tubules of rats with experimental hypertension. The model has been extended by including deep nephrons for which it has not yet been possible to perform similar experimental measurements. Using available anatomical and physiological information we constructed a model of an nephron-vascular ensemble including superficial as well as deep nephrons with different length of loop of Henle. The computer simulation suggested that irregular dynamics of nephron ensemble increases at higher arterial pressures and values of the coupling strength. The model showed that, for physiologically reasonable parameter values, the deep nephrons do not synchronize with the superficial nephrons even though they are coupled via the same blood supply.

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