Our long-term goal is to explain interactions among renal blood flow control, pressure natriuresis, and blood pressure regulation. Autoregulation of renal blood flow and glomerular filtration rate, and increased NaCl excretion are two of the kidney's chief responses to acute changes in blood pressure. We suggest that the two mechanisms interact; autoregulation serving to minimize the increase in NaCl excretion that occurs with acute blood pressure rise, pressure natriuresis increasing the delivery of NaCl to the macula densa, a sensing site for tubuloglomerular feedback(TGF), an important component of autoregulation. The NaCl concentration in tubular fluid is the signal for the macula densa. We will test the significance of this proposed interaction by examining hypotheses about vascular components of TGF, and about the mechanism of the effect of blood pressure change on fluid and solute reabsorption by the proximal tubule, and other renal segments. Using a perfused isolated juxtamedullary nephron preparation, and image processing methods, we will test the hypothesis that TGF and pressure dependent myogenic reactions interact to provide effective blood flow control at the single nephron level, and that the interaction allows a high frequency oscillation in contraction, initiated by the myogenic sensor, to provide a dither frequency to the lower frequency autonomous oscillation in TGF that we observed. We will use the same preparation to test the hypothesis that whole kidney blood flow control arises from the cooperative interaction of an ensemble of nephrons, coupled by TGF initiated signals that propagate to nephrons derived from a common interlobular artery. Using in situ tubular microperfusion, we will test the hypothesis that acute pressure changes inhibit the action of the apical Na/H antiport in the proximal tubule, and that specific second messengers signal this change. Other experiments will be used to test the role of inhibition of local angiotensin II production in the continuation of pressure natriuresis, and the participation of more distal segments. The response to acute blood pressure change is important because the blood pressure of conscious animals fluctuates spontaneously. The power spectrum of the blood pressure has a characteristic 1/f pattern. Virtually nothing is known about the mechanisms that cause this variation, and experiments are proposed to test hypotheses about the role of known components of blood pressure, using telemetering in conscious rats and osmotic minipumps to deliver antagonists. An interesting preliminary result indicates that animals with experimental hypertension, both genetic and renovascular, have increased blood pressure variability at high frequency. Experiments are proposed to test hypotheses about the origin of this change.
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