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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK015968-25
Application #
2136970
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1976-05-01
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
25
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Brown University
Department
Physiology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Sosnovtseva, Olga V; Pavlov, Alexey N; Mosekilde, Erik et al. (2007) Synchronization among mechanisms of renal autoregulation is reduced in hypertensive rats. Am J Physiol Renal Physiol 293:F1545-55
Chon, Ki H; Raghavan, Ramakrishna; Chen, Yu-Ming et al. (2005) Interactions of TGF-dependent and myogenic oscillations in tubular pressure. Am J Physiol Renal Physiol 288:F298-307
Marsh, Donald J; Sosnovtseva, Olga V; Pavlov, Alexey N et al. (2005) Frequency encoding in renal blood flow regulation. Am J Physiol Regul Integr Comp Physiol 288:R1160-7
Walstead, Christopher; Yip, Kay-Pong (2004) Acute arterial hypertension inhibits proximal tubular fluid reabsorption in normotensive rat but not in SHR. Am J Physiol Regul Integr Comp Physiol 286:R726-33
Yip, Kay-Pong (2002) Coupling of vasopressin-induced intracellular Ca2+ mobilization and apical exocytosis in perfused rat kidney collecting duct. J Physiol 538:891-9
Chan, W L; Holstein-Rathlou, N H; Yip, K P (2001) Integrin mobilizes intracellular Ca(2+) in renal vascular smooth muscle cells. Am J Physiol Cell Physiol 280:C593-603
Yip, K P; Wagner, A J; Marsh, D J (2000) Detection of apical Na(+)/H(+) exchanger activity inhibition in proximal tubules induced by acute hypertension. Am J Physiol Regul Integr Comp Physiol 279:R1412-8
Chon, K H; Hoyer, D; Armoundas, A A et al. (1999) Robust nonlinear autoregressive moving average model parameter estimation using stochastic recurrent artificial neural networks. Ann Biomed Eng 27:538-47
Chon, K H; Chen, Y M; Holstein-Rathlou, N H et al. (1998) Nonlinear system analysis of renal autoregulation in normotensive and hypertensive rats. IEEE Trans Biomed Eng 45:342-53
Yip, K P; Tse, C M; McDonough, A A et al. (1998) Redistribution of Na+/H+ exchanger isoform NHE3 in proximal tubules induced by acute and chronic hypertension. Am J Physiol 275:F565-75

Showing the most recent 10 out of 40 publications