Inhibition of tubuloglomerular feedback by the D1 agonist fenoldopam in chronically salt-loaded rats.

1. Chronic dietary NaCl loading in rats is paralleled by an increase of the dopamine concentration in the tubular fluid and humorally mediated inhibition of the tubuloglomerular feedback mechanism at the macula densa. Since these two phenomena are causally linked, the alterations in the tubuloglomerular feedback response by the luminal application of dopamine, the D1 agonist fenoldopam, the D2 agonist bromocriptine and the D1 and D2 antagonists SCH 23390 and metoclopramide were further investigated using the micropuncture technique. 2. Very similar, concentration-dependent inhibition of the tubuloglomerular feedback response was observed for dopamine and fenoldopam. Half-maximal inhibition was achieved at 10(-11) M and the slope factors of the sigmoid concentration-response curves were comparable. Bromocriptine was ineffective. 3. The inhibition of TGF by both agonists could be antagonized very similarly and concentration dependently by the D1 antagonist SCH 23390. At equimolar concentrations of 10(-9) M the inhibition was reduced by approximately 50%. Raising the SCH 23390 concentration to 10(-6) M completely abolished the TGF inhibition. In contrast, TGF inhibition by 10(-9) M-fenoldopam or dopamine was not significantly affected by an equimolar concentration of the D2 antagonist metoclopramide. Increasing metoclopramide concentration to 10(-6) M attenuated tubuloglomerular feedback inhibition by approximately 55%. 4. It is concluded that the inhibition of tubuloglomerular feedback seen during chronic dietary salt loading can be ascribed to the binding of endogenous dopamine to luminal D1 receptors on the macula densa cells.

Renal blood flow control by tubuloglomerular feedback (TGF) in normal and spontaneously hypertensive rats--a role for dopamine and adenosine.

Following the elementary laws of hemodynamics and the functional characteristics of the renal myogenic and macula densa-mediated (TGF) vascular resistance control mechanisms, TGF-mediated changes of renal vascular resistance are amplified by cooperative changes of the myogenic mechanism. Myogenically induced changes, on the other hand, would be antagonized by TGF. Resetting of renal vascular flow resistance by alterations to the TGF mechanisms might thus be more effective than alterations to the myogenic mechanism. Dopamine and adenosine, two autacoids occurring normally in the tubular fluid, may play a key role in operating such a resetting mechanism. Dopamine and adenosine were found in proximal tubular fluid at concentrations of 10(-8) and 0.5 10(-6) M respectively. Dopamine inhibits the tubuloglomerular feedback mechanism, this inhibition is antagonized concentration-dependently by adenosine. These effects most likely occur via D1 and A1 receptors and hence by regulation of the adenyl cyclase activity in the macula densa cells. The balance between adenosine and dopamine in tubular fluid appears to be under the control of extrarenal parameters. In normal rats, high dietary salt intake, by influencing the secretion of an unknown adrenal hormone, and inhibition of Na-K-ATPase might be of importance. In spontaneously hypertensive rats unknown genetic parameters may also play a role.

Chronic dietary salt loading: resetting of tubuloglomerular feedback control of renal hemodynamics by an adrenal hormone.

Experiments were performed in chronically salt loaded rats (4 g% NaCl diet for 2 weeks) to determine whether the resetting of tubuloglomerular feedback (TGF) by a humoral inhibitor in tubular fluid is caused by a humoral factor from the adrenal glands. TGF response was assessed by measuring NGFR in the absence of loop of Henle perfusion and during perfusion at 40 nl/min with tubular fluid from normal or salt loaded rats and expressed as NGFR40/NGFR0. (1) Loop of Henle perfusion with tubular fluid from normal rats elicited a TGF response of 50.3% +/- 7.9% (mean +/- SEM) in normal rats and 57.2% +/- 7.9% in salt loaded rats. With tubular fluid from high salt rats, TGF response in normal rats was 97.4% +/- 6.3% and in salt loaded rats 98.0% +/- 1.6%. Participation of adrenal steroids in the inhibition is suggested by the following results: (2) Acute adrenalectomy (ADX) in high salt rats abolished the TGF inhibitory potency of high salt tubular fluid. TGF response in salt loaded rats with high salt tubular fluid from high salt ADX rats was 62.3% +/- 3.0%. Substitution of high salt ADX rats with matching adrenal venous blood from high salt rats restored TGF inhibition. (3) With cross over experiments the effect of heterologous adrenal venous blood substitution on TGF inhibitory activity was studied. The TGF response in high salt rats with high salt tubular fluid and tubular fluid from normal ADX rats substituted with adrenal venous blood collected from high salt rats was 88.9% +/- 5.5% and 91.7% +/- 6.0%.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoregulation of the glomerular filtration rate and the single-nephron glomerular filtration rate despite inhibition of tubuloglomerular feedback in rats chronically volume-expanded by deoxycorticosterone acetate.

Tubuloglomerular feedback (TGF) function and autoregulation (renal blood flow RBF; glomerular filtration rate, GFR; single-nephron glomerular filtration rate, SNGFR) were examined in rats chronically treated with deoxycorticosterone acetate (DOCA) and given isotonic saline to drink. DOCA treatment depressed arterial plasma renin activity, expanded plasma volume by 25% and increased arterial blood pressure. Autoregulation of RBF and GFR was maintained in the DOCA animals above 90 mm Hg and 110 mm Hg respectively, whereby both GFR and RBF were lower than in controls. Micropuncture experiments demonstrated the absence of TGF in the DOCA animals. There was no difference between SNGFR values measured in the distal and proximal tubules, nor was there a significant response of SNGFR when loops of Henle were perfused with Ringer's solution at 20 nl/min. Loop perfusion in control rats with tubular fluid collected in DOCA rats elicited a normal TGF response, showing that TGF inhibition in the DOCA animals is due to changes in the function of the juxtaglomerular apparatus. In contrast to control rats, proximal SNGFR was perfectly autoregulated. These results suggest that TGF is not primarily responsible for autoregulation and that the vasodilatation normally resulting from acute TGF interruption is therefore compensated by some other mechanism such that RBF and GFR are lower than in controls.