Hyperuricemic nephropathies.

This review explores the relationship between uric acid or urate and the pathogenesis of renal impairment. The following points and conclusions are emphasized: (1) uric acid is an end product of purine degradation in humans and normally depends upon renal excretion for the majority of its elimination from the body; (2) massive urate overproduction - usually occurring acutely because of tumor lysis, rhabdomyolysis, or some other cause of rapid nucleic acid turnover or tissue destruction - tends to cause acute renal failure because of an increase of intratubular uric acid precipitation and obstruction; (3) chronic urate overproduction (with increased urate excretion) is more likely to be associated with stones or gout than with acute renal failure; (4) chronic asymptomatic hyperuricemia is unlikely to cause renal disease, gout, or stones, but is associated with cardiovascular impairment over the long term, and (5) asymptomatic hyperuricemia may serve as an indicator of renal vascular disease, or, to the extent that it may reflect insulin-induced acceleration of renal tubule urate reabsorption, hyperuricemia may serve as an indicator of insulin resistance. Therefore chronic asymptomatic hyperuricemia may predict the adverse cardiovascular consequences of insulin resistance.

Intrarenal angiotensin II inhibition influences the actions of atrial natriuretic peptide.

1. We previously found that kidneys isolated from salt-restricted rats were refractory to atrial natriuretic peptide compared with kidneys from salt-loaded rats. Because the intrarenal tissue renin-angiotensin system may modulate renal responses to atrial natriuretic peptide, we examined the effect of dietary NaCl loading on the responses of isolated perfused kidneys from normal rats to atrial natriuretic peptide, before and after the addition of angiotensin II receptor antagonists or angiotensin I converting enzyme inhibitors to the perfusate. 2. Atrial natriuretic peptide increased the glomerular filtration rate and sodium excretion of kidneys from NaCl-loaded rats. The addition of angiotensin receptor antagonists or converting enzyme inhibitors partially reversed the increments in glomerular filtration rate but not the increments in sodium excretion, leading to an increased fractional sodium excretion. In the absence of atrial natriuretic peptide, these agents did not affect glomerular filtration or sodium excretion. Kidneys from NaCl-restricted rats did not respond to atrial natriuretic peptide or to the inhibitors and antagonists, either separately or in combination. 3. After NaCl loading, the intrarenal renin-angiotensin system may augment the glomerular response to atrial natriuretic peptide while simultaneously inhibiting the natriuretic response to atrial natriuretic peptide. However, activation of the intrarenal renin-angiotensin system is not responsible for the refractoriness of kidneys from salt-restricted rats to atrial natriuretic peptide.

Function of the hypertensive kidney during calcium flux manipulation.

Dihydropyridine calcium channel agonists and antagonists elicit exaggerated glomerular and circulatory responses from kidneys isolated from Dahl rats genetically programmed to develop NaCl-induced hypertension (Dahl S rats). These differential responses are further magnified by NaCl loading. In contrast, "chemical sympathectomy" with 6-hydroxydopamine enhances renal vascular responses to calcium channel agonists in a manner that depends on the antecedent dietary NaCl intake, and is independent of genetic predilection to develop NaCl-induced hypertension. These findings are consistent with the hypothesis that aberrations of vascular and perhaps glomerular calcium entry modulation may be determinants of altered renal hemodynamics in NaCl-sensitive hypertension. The latter may be responsible for the enhanced responsiveness to calcium channel antagonists observed in NaCl-sensitive hypertension in humans.

Genetics and salt modulate renal responses to atrial natriuretic factor.

We examined the consequences of genetic susceptibility or resistance to NaCl-induced hypertension and of prior salt loading (high or low NaCl intake) on the responses of isolated perfused Dahl salt-sensitive (DS) and Dahl salt-resistant rat (DR) kidneys to atriopeptin II. Atriopeptin II increased the glomerular filtration rate only in kidneys from high NaCl-fed rats, irrespective of their DS or DR status. Superimposition of norepinephrine on atriopeptin II further increased the glomerular filtration rate only in kidneys from low NaCl-fed rats (which had not reacted to atriopeptin II alone), irrespective of their DS or DR status, and did not change the glomerular filtration rate of high NaCl-fed rats. Norepinephrine alone, without atriopeptin II, uniformly decreased the glomerular filtration rate by about 80%. Atriopeptin II increased sodium excretion of high NaCl and low NaCl DR kidneys by more than five times as much as in the corresponding DS kidneys. Therefore, the glomerular filtration rate response to atriopeptin II varied globally with dietary NaCl, independently of genetic predisposition or resistance to NaCl-induced hypertension. The natriuretic response to atriopeptin II was blunted in kidneys from rats genetically susceptible to NaCl-induced hypertension, independently of their NaCl consumption. Atriopeptin II also ameliorated or reversed the adverse effect of norepinephrine on the glomerular filtration rate.

Increased vascular response to calcium channel agonist by Dahl S rat kidney.

We examined responses to the calcium channel agonist, BAY-K 8644, of isolated perfused kidneys from Dahl salt-sensitive (DS) and -resistant (DR) rats that had been stabilized on high (HI) and low (LO) NaCl intakes. Mean arterial pressures of DS/HI rats exceeded those of the other three groups. BAY-K 8644 significantly increased the renal vascular resistance (RVR) of DS/HI and DS/LO kidneys, by 38 and 12%, respectively, but did not increase RVR of DR/HI or DR/LO kidneys significantly (6 and 2%, respectively). Increases in RVR and decreases in glomerular filtration rate of DS/HI kidneys exceeded those of DR/HI kidneys. Increases in the RVR of DS/LO kidneys exceeded those of DR/LO kidneys. Experiments utilizing the separate calcium channel agonist and antagonist enantiomers of BAY-K 8644 corroborated these findings, but at lower concentrations. "Chemical sympathectomy" with 6-hydroxydopamine increased the reactivity of kidneys from only high-NaCl animals to BAY-K 8644 without regard to Dahl S or R status. In conclusion, the DS kidney vasculature manifests an increase in responsiveness to this calcium channel agonist, independently of antecedent NaCl loading or high blood pressure. However, a high antecedent salt intake or hypertension enhances vascular responsiveness of the DS kidney to BAY-K 8644.

Response of isolated Dahl rat kidney to calcium antagonists.

We studied the responses of isolated perfused kidneys from prehypertensive, salt-sensitive (DS) and salt-resistant (DR) Dahl rats to nitrendipine or verapamil, after norepinephrine vasoconstriction. The perfusion pressure was kept constant. Superimposition of these calcium antagonists upon norepinephrine increased DS GFR by 155% and DR GFR by 58% (P = 0.03), with verapamil increasing the GFR more than nitrendipine (P = 0.02). Nitrendipine and verapamil also partially reversed norepinephrine induced increases in renal vascular resistance, but did not decrease vascular resistance or increase GFR in the absence of norepinephrine. During the increase in GFR produced by calcium antagonists, DR sodium excretion increased, but DS sodium excretion did not. Therefore, calcium antagonists disproportionately increased DS kidney GFR but did not correct DS kidney sodium retention. These data raise the possibility that the DS rat kidney possesses an abnormality of cell calcium regulation affecting glomerular dynamics, and provide evidence that the renal perfusion pressure is more critical than the GFR in adjusting DS rat sodium-excretion.

Influence of salt on response to nitrendipine by Dahl rat kidney.

We examined the responses to the calcium channel blocker, nitrendipine, of isolated perfused kidneys from Dahl salt-sensitive (DS) and salt-resistant (DR) rats that had been stabilized on high- and low-NaCl diets. Blood pressures of high-salt DS rats exceeded those of the other three groups. After norepinephrine vasoconstriction sufficient to increase renal vascular resistance (RVR) by 50%, the superimposition of 10(-5) M nitrendipine increased the glomerular filtration rate (GFR) of high-salt DS rat kidneys by 125% over control values but returned the GFR of high-salt DR kidneys only to control. Nitrendipine superimposition increased the GFR of low-salt DS and DR rat kidneys by 124 and 40% over control values, respectively, and partially restored the RVR toward control. Nitrendipine alone, without norepinephrine, did not affect the GFR or RVR. The persistence within the DS kidney of an exaggerated glomerular circulatory "rebound" response to nitrendipine following the development of hypertension suggests the possibility of a maladaptation of DS kidney cell calcium regulation. The DR kidney manifests a similar response during salt restriction, but this disappears on a high-NaCl diet.

Dihydropyridine calcium antagonists and agonists in the isolated perfused Dahl rat kidney.

Isolated perfused kidneys from prehypertensive Dahl salt-sensitive (DS) rats demonstrated marginally increased glomerular responsiveness when nitrendipine or verapamil was superimposed upon norepinephrine vasoconstriction. This was manifested by a greater increase in the glomerular filtration rate of DS rat kidneys, as compared to kidneys from Dahl salt-resistant (DR) rats. This glomerular response to nitrendipine by isolated kidneys was not affected by the development of salt-induced hypertension in DS rats, but was eliminated by antecedent salt loading in DR rats. In further experiments designed to assess more directly the reactivity of renal vascular calcium channels in DS and DR rats, the calcium channel agonist BAY-K-8644 and its pure agonist isomer elicited greater increases in renal vascular resistance in kidneys from prehypertensive DS rats than in kidneys from similarly prepared DR rats. Renal vascular reactivity to both BAY-K-8644 and its agonist isomer were greatly magnified following salt-induced DS rat hypertension. These results suggest that a genetically conferred abnormality of calcium channel function may contribute to the renal functional characteristics of the DS rat kidney.

Calcium entry modulation and renal hemodynamics in the hypertensive kidney.

In the isolated perfused rat kidney, the superimposition of a number of calcium entry blockers (CEB) upon norepinephrine vasoconstriction prompts an increase in the glomerular filtration rate (GFR) to a level substantially greater than the original value. A similar acute GFR response to CEB is manifested in the intact anesthetized rat with the renal perfusion pressure remaining constant. This glomerular response to CEB is accentuated in isolated perfused kidneys from Dahl salt-sensitive (DS) rats as compared with kidneys from Dahl salt-resistant (DR) rats. The disparities between DS and DR kidney responses are further amplified in the DS rat kidney after a high NaCl intake and the development of hypertension by the DS rat. In addition, vasoconstrictor responses to BAY-K 8644, a calcium entry facilitator, are accentuated in DS rat kidneys, and even more so following a high NaCl intake or 'chemical sympathectomy' with 6-hydroxydopamine. These results suggest that subtle changes in vascular and glomerular calcium entry modulation may be the key determinants of altered renal hemodynamics in salt-dependent hypertension.

Exaggerated Dahl salt-sensitive kidney response to calcium channel agonist isomer of Bay k 8644, but not to calcium channel antagonist isomer of Bay k 8644.

We examined the influence of calcium channel agonist and antagonist optical isomers of BAY-K-8644 on the renal vascular resistance, glomerular filtration rate and sodium excretion of isolated perfused kidneys from Dahl salt-sensitive (DS) and salt-resistance (DR) rats previously stabilized on high- and low-NaCl regimens. The agonist isomer affected these parameters at a lower concentration and to a greater degree in the high-salt DS rat kidneys than in the other three groups. The antagonist isomer also reversed agonist-induced changes to the greatest degree in the high-salt DS rat kidneys. However, the low-salt DS and high-salt DR rat kidneys appeared to be slightly more reactive to these isomers than the low-salt DR rat kidneys, suggesting that hereditary predisposition and dietary NaCl may contribute independently to renal responsiveness to calcium channel-active agents.

Glomerular response to verapamil by isolated spontaneously hypertensive rat kidney.

We investigated the possibility that altered cell calcium regulation may affect function of isolated Kyoto spontaneously hypertensive rat (SHR) kidneys as compared with kidneys from Wistar-Kyoto control (WKY) rats. The kidneys were perfused at 120 and 160 mmHg. At 120 mmHg, SHR glomerular filtration rate (GFR) was 0.24 +/- 0.04 compared with WKY GFR of 0.70 +/- 0.10 ml/min (P = 0.001). At 160 mmHg, SHR GFR was 0.48 +/- 0.05 compared with WKY GFR of 1.09 +/- 0.05 ml/min (P less than 0.001). At 120 mmHg, addition of norepinephrine increased renal vascular resistance (RVR) by 50% and decreased SHR GFR by 27% and WKY GFR by 57% (P = 0.04). At 160 mmHg, norepinephrine elicited similar changes. Addition of verapamil, 5-10 microM, in the presence of norepinephrine returned RVR to 100-110% of control. With verapamil at 120 mmHg, SHR GFR increased to 0.84 +/- 0.23 ml/min, a value 3.5 times that of control (P = 0.03). In contrast, WKY GFR in the presence of norepinephrine and verapamil was 0.97 +/- 0.07 ml/min, unchanged from control (P = 0.07). At 160 mmHg, norepinephrine and verapamil also failed to increase WKY GFR above control (P = 0.4) but increased SHR GFR to 52% above control (P = 0.03). Isolated SHR kidneys exhibited exaggerated GFR responses to verapamil but not to norepinephrine. Abnormal cell calcium regulation may underlie the marked decrease in GFR when SHR kidneys are perfused acutely at normotensive perfusion pressures.

Function of the isolated spontaneously hypertensive rat kidney after blood pressure reduction.

We treated 20-week-old spontaneously hypertensive rats (SHR) with either placebo or hydralazine, reserpine and hydrochlorothiazide for 1 month. Mean arterial pressure in treated SHR averaged 113 +/- 7 mm Hg (mean +/- SE), compared to 162 +/- 12 mm Hg in animals receiving placebo (p less than 0.01). Glomerular filtration rate (GFR) and sodium excretion were similar in both groups. In isolated perfused kidneys, the GFR and sodium excretion were significantly greater in the treatment group than in the placebo group at a perfusion pressure of 140 mm Hg (p less than 0.01). Renal vascular resistance (RVR) of kidney from treated SHR was no different from RVR of kidney from placebo SHR. Hydralazine (6 mM) and diazoxide (4 mM) increased the GFR and sodium excretion of isolated SHR kidney perfused at 140 mm Hg (p less than 0.05), but decreased RVR significantly (p less than 0.05). We conclude that prolonged antihypertensive treatment renders higher GFR values to isolated SHR kidneys perfused at 140 mm Hg, with sodium excretion varying in proportion to the GFR. The addition of vasodilators to the perfusate of isolated SHR kidneys partially reproduced these changes, but only at extremely high concentrations unlike to be attained in vivo.

Muzolimine modification of renal vasoconstriction.

Utilizing an isolated perfused rat kidney preparation, we studied the modification by muzolimine of changes in glomerular filtration rate (GFR) and renal vascular resistance (RVR). Superimposition of muzolimine upon norepinephrine-induced vasoconstriction revealed that muzolimine returned RVR nearly to control values and increased GFR to supracontrol values. Muzolimine reversed norepinephrine-induced decreases in GFR at concentrations as low as 1 microM, but reduced RVR only at concentrations of 500 microM or greater. Muzolimine also reversed, at least partially, the increased RVR and depressed GFR secondary to potassium-induced depolarization. Although muzolimine has not been shown to possess calcium antagonist activity, our data inicate that it elicits renal actions similar to calcium channel blockers at high concentrations. It also elicits a specific increase in GFR during intense norepinephrine-induced vasoconstriction.

Calcium in neural control of renal circulation.

We assessed the role of calcium in neurogenically mediated alterations of the renal circulation in the isolated perfused rat kidney. The transarterial application of high-frequency renal nerve stimulation (RNS) increased renal vascular resistance (RVR) by 50% (P less than 0.001). Concomitantly, glomerular filtration rate (GFR), urine flow (V), and sodium excretion (UNaV) decreased by 83, 82, and 78%, respectively (P less than 0.006 for all). Kidneys obtained from rats that had undergone prior chemical sympathectomy by 6-hydroxydopamine treatment did not respond to RNS. Addition of the calcium channel-blocking agents, verapamil or diltiazem (5 microM), during RNS of normal kidneys completely reversed the changes in GFR, V, and UNaV and returned RVR nearly to control. Aside from a small decrease in RVR and an increase in V produced by verapamil, diltiazem or verapamil alone did not affect kidney function. Norepinephrine (5-8 microM) increased RVR 50% and decreased GFR, V, and UNaV similarly to RNS. When added to perfusate in the presence of norepinephrine, verapamil reversed all these changes. With a low-calcium perfusate (0.4 mM total calcium), RNS did not increase RVR and did not decrease GFR, V, or UNaV. These results indicate that the circulatory changes produced in the isolated rat kidney by high-frequency RNS depend critically upon the extracellular calcium, are closely reproduced by norepinephrine, and are largely reversed by calcium channel blockers.

Renal interactions between norepinephrine and calcium antagonists.

The combined action of norepinephrine and calcium antagonists on the glomerular filtration rate (GFR) of isolated rat kidneys perfused at a constant pressure of 105 mm Hg was studied. Norepinephrine, 74 +/- 9 ng/ml (mean +/- SEM), increased the renal vascular resistance (RVR) by 50% and GFR declined by 88% (P less than 0.001). The subsequent addition of either diltiazem or verapamil (5 microM) returned RVR nearly to control and increased the GFR by an average of 86% over control (P = 0.007). Diltiazem or verapamil alone had little effect on RVR or GFR. Norepinephrine (20 ng/ml) did not affect RVR or GFR. In the presence of diltiazem, norepinephrine (20 ng/ml) again did not affect RVR but increased GFR by 58% (P = 0.003). With a low-calcium perfusate containing 0.4 mM total calcium, norepinephrine (90 ng/ml) did not affect RVR or GFR. Increasing perfusate norepinephrine to 236 +/- 8 ng/ml elicited a 50% increase in RVR, and GFR decreased by 95% (P less than 0.001). The subsequent addition of verapamil increased GFR to 2.8 times the original baseline value (P = 0.011) and restored RVR to control levels. These data suggest that diltiazem and verapamil block the vasoconstrictor action of norepinephrine on afferent arterioles selectively. Renal vascular sensitivity to norepinephrine decreases markedly either when the extracellular calcium concentration is reduced or in the presence of a calcium antagonist. However, a low-calcium perfusate does not mimic the property of calcium antagonists to facilitate an increase in GFR in the presence of norepinephrine.

Function of the arachidonate-deficient spontaneously hypertensive rat kidney.

In order to assess the effect of renal prostaglandins on the glomerular filtration rate (GFR) and electrolyte excretion in the spontaneously hypertensive rat (SHR), we perfused isolated SHR and normotensive Wistar-Kyoto (WKY) kidneys after pretreatment with either a control diet or a diet deficient in arachidonate, the precursor of prostaglandins. When perfusion pressures were increased from 100 to 160 mm Hg, renal vascular resistances (RVR) increased by 32-41%. RVR of SHR kidneys always exceeded that of WKY kidneys by a nearly constant amount, and arachidonate deficiency had little effect on this relationship. In contrast to RVR, the GFR increased severalfold. GFR and urine flow were greater in WKY than in SHR kidneys, a relationship unaffected by arachidonate deficiency. Changes in sodium and chloride excretion occurred in parallel with GFR. Although arachidonate-deficient SHR and WKY kidneys manifested potassium wastage compared to controls, arachidonate deficiency did not result in altered sodium or chloride excretion. The results suggest that direct actions of arachidonate or renal prostaglandins are not responsible for most functional differences between SHR and WKY kidneys.

Pressure-dependent action of angiotensin II on glomerular filtration in the isolated rat kidney.

We examined the action of angiotensin II (AII) on isolated rat kidney perfused with a recirculating cell-free solution at either 12 pKa (90 mmHg) or 17 kPa (128 mmHg). The renal perfusion pressure was maintained constant while sufficient AII was added to increase the renal vascular resistance by 50%. In the low-pressure kidneys. AII increased the glomerular filtration rate (GFR) by 155%, increased sodium reabsorption by 157%, and decreased the urine sodium concentration by 34% without affecting sodium excretion. In the high-pressure kidneys, GFR initially was significantly greater but was not affected by AII. In these experiments, AII had no effect on sodium reabsorption or excretion and decreased the urine sodium concentration by 7%. The data suggest that AII could be involved in autoregulation of the GFR without producing large changes in sodium excretion.

Actions of angiotensin II on the isolated spontaneously hypertensive rat kidney.

We studied the effects of angiotensin II (AII) on isolated spontaneously hypertensive rat (SHR) and Wistar-Kyoto control (WKY) kidneys utilizing a recirculating cell-free perfusate. Sufficient AII was infused to increase renal vascular resistance (RVR) by approximately 50%. When the perfusion pressure was allowed to increase with RVR during AII infusion, significant increases in the glomerular filtration rate (GFR), urine flow, and electrolyte excretion occurred in both the SHR and the WKY kidneys. However, when the increase in perfusion pressure was prevented, AII increased the GFR of SHR kidneys but had no effect on the GFR of WKY. In contrast to WKY, AII increased the GFR, urine flow, and sodium excretion of SHR kidneys as much at "normotensive" perfusion pressures as at "hypertensive" pressures. However, the "normotensive" perfusion pressures utilized in these studies were less than the blood pressure of the SHR in vivo. Accordingly, the response of SHR kidneys to AII was assessed when perfusion pressure was maintained constant at 160 torr. Under these conditions, AII did not elicit any further increases in GFR or changes in the electrolyte excretion. Results indicate that the renal perfusion pressure is a critical determinant of the renal responsiveness to AII and suggests that AII enhances renal function at perfusion pressures less than those customarily encountered in vivo.

Interactions of starvation and selective phosphorus depletion on renal phosphate reabsorption.

Renal phosphate (Pi) wastage following 7 days of starvation was investigated in normal rats (HI-P) and others previously stabilized on a low phosphorus (LO-P)diet. In LO-P animals, Pi excretion increased after starvation, but was significantly less than in starved HI-P rats. After thyroparathyroidectomy, the increase in Pi excretion after parathyroid hormone (PTH) was significantly greater in nonacidotic starved HI-P rats than in LO-P animals. However, PTH elicited a 31-fold increase in Pi excretion in both of these groups. Starved LO-P and HI-P rats responded equivalently to dibutyryl cyclic AMP. The renal response to phosphate depletion normally promotes Pi conservation, but is attenuated markedly by 7 days of subsequent starvation. This results from at least partial restoration of phosphaturic responsiveness to PTH during starvation.