Transport of [3H]losartan across isolated perfused rabbit proximal tubule.

The transport of the angiotensin II receptor antagonist losartan and its interaction with organic anion transport were examined in the isolated perfused rabbit proximal tubule. Losartan reversibly inhibited the secretion of para-aminohippurate (PAH) in a concentration-dependent manner (IC50 = 15 +/- 0.5 microM). Other angiotensin II receptor antagonists also inhibited PAH secretion with similar potencies: eprosartan, 11 +/- 2.3 microM; irbesartan, 17 +/- 2.2 microM; and valsartan 3 +/- 0.6 microM. [3H]Losartan was secreted by the proximal tubule by a saturable and probenecid-sensitive mechanism. The affinity of losartan for the organic anion transporter (Km = 12.3 +/-1.8 microM) was significantly greater than that of PAH (Km = 88.5 +/- 10.7 microM). [3H]Losartan secretion was stimulated in the presence of alpha-ketoglutarate, suggesting that losartan, like PAH, enters the cell in exchange for a dicarboxylate. These results demonstrate that losartan and probably other nonpeptide angiotensin II receptor antagonists are secreted by an organic anion transporter that is similar to, if not identical with, the classic PAH transporter.

Interaction of L-arginine analogs with L-arginine uptake in rat renal brush border membrane vesicles.

The dibasic amino acid, L-arginine, is a substrate for both nitric oxide synthase (NOS) and arginase and therefore, plays an important role in cell signaling and cell growth. We examined the effects of various NOS inhibitors on L-arginine transport into rat renal brush border membrane (BBM) vesicles. L-Arginine uptake was stimulated in the presence of an inwardly directed Na+ gradient and an imposed inside negative potential in BBM but not basolateral membrane vesicles. In BBM vesicles, the L-arginine analogs, N-iminoethyl-L-orinithine and Nw-monomethyl-L-arginine (L-NMMA) were potent inhibitors of L-arginine uptake (IC50 of 0.48 and 0.82 mM, respectively), while Nw-nitro-L-arginine was less active (IC50 = 10 mM) and Nw-nitro-L-arginine methyl ester (L-NAME) was inactive. The inhibition of L-arginine transport by L-NMMA was competitive in nature. L-NIO, L-NMMA as well as L-arginine and L-lysine but not Nw-nitro-L-arginine methyl ester, trans-stimulated L-arginine uptake when preloaded into BBM vesicles. The L-arginine analogs had no effect on the transport of the neutral amino acid, L-leucine, in the same preparations. The data suggest that in addition to inhibiting NOS, the L-arginine analogs, N-iminoethyl-L-orinithine, L-NMMA and to a lesser extent L-NA, also inhibit L-arginine transport across the BBM of proximal tubules.

[125I]endothelin-1 binding to renal brush border and basolateral membranes.

[125I]Endothelin-1 bound with high affinity to a single site on both brush border membranes (Kd=192+/-26 pM. Bmax=314+/-49 fmol/mg) and basolateral membranes (Kd=94.7+/-3.4 pM, Bmax=612+/-107 fmol/mg) isolated from rat renal cortex. Competition binding experiments using subtype selective ligands revealed that the proportion of ET(B) to ET(A) receptors was 80:20 and 60:40 in the brush border membrane and the basolateral membrane, respectively. The results demonstrate that endothelin-1 binds to brush border membranes, and that endothelin ET(B) receptors may be involved in the previously described effects of endothelin-1 on brush border membrane Na+ transport.

alpha-Ketoglutarate transport in rat renal brush-border and basolateral membrane vesicles.

The dicarboxylate, alpha-ketoglutarate (alphaKG), has been identified as the most likely physiological anion involved in renal proximal tubule basolateral membrane (BLM) dicarboxylate/organic anion exchange. In the present study, we characterized the uptake of alphaKG in BLM and brush-border membrane (BBM) vesicles isolated from rat kidney. In both membrane preparations, alphaKG uptake was Na+-dependent, saturable, electrogenic and inhibited by Li+. The initial rate of alphaKG (5 microM) uptake in BLM vesicles was twice that in BBM vesicles (258 +/- 8.2 vs. 126 +/- 3.9 pmol/mg/5 sec). The BLM transporter had a high affinity for alphaKG (apparent Km = 15.2 microM), but a relatively low transport capacity (Vmax = 386 pmol/mg/5 sec). In contrast, the BBM transporter had characteristics of a low-affinity (Km = 158 microM), high-capacity (Vmax = 1106 pmol/mg/5 sec) system. Other dicarboxylates such as succinate, malate, fumarate and glutarate at a concentration of 1 mM inhibited alphaKG uptake into BLM and BBM vesicles to the same extent (>90%). The tricarboxylate, citrate, also inhibited alphaKG uptake (70-80%). However, of these Krebs' cycle intermediates, only alphaKG and glutarate were able to affect p-aminohippurate (PAH) uptake into BLM vesicles. These results lend further support for a BLM PAH/alphaKG exchanger. Furthermore, if extracellular alphaKG plays a role in the operation of the PAH/alphaKG exchanger, the high-affinity Na+-dependent alphaKG transporter located in the BLM is the likely source of the organic anion.

Adrenomedullin: a new peptide involved in cardiorenal homeostasis?

Adrenomedullin (ADM) was originally discovered in human pheochromocytoma but is now known to be widely distributed in various organs including the kidney. ADM is a potent hypotensive peptide that increases renal blood flow and causes natriuresis and diuresis. While ADM may act in a paracrine manner, circulating levels are increased in hypertension, chronic renal failure and congestive heart failure. Current evidence suggests that ADM may play an important role in cardiorenal homeostasis.

Effect of adrenomedullin on cAMP levels along the rat nephron: comparison with CGRP.

Adrenomedullin (ADM) is a recently discovered hypotensive peptide that has been detected in the kidney. Recent studies have shown that intrarenal administration of ADM produces natriuresis without changes in glomerular filtration rate. Although ADM stimulates adenosine 3',5'-cyclic monophosphate (cAMP) synthesis in some tissues, the site of action and signal transduction pathway in the kidney are unknown. In the present study, we examined the effects of ADM and calcitonin gene-related peptide (CGRP) on cAMP levels in glomeruli and tubules dissected from rat kidney. ADM (1 microM) stimulated cAMP formation in glomeruli (4-fold), cortical thick ascending limb (CTAL, 6-fold), and in the distal convoluted tubule (DCT, 16-fold). In glomeruli, ADM was more potent than CGRP [50% effective concentration (EC50) = 33.7 vs. 156 nM], whereas the opposite was true in the DCT (CGRP, EC50 = 55 vs. 327 nM for ADM). In both glomeruli and DCT, the responses to maximum concentrations of ADM and CGRP were not additive. In glomeruli, the CGRP antagonist, CGRP-(8-37), had no effect on ADM-induced increases in cAMP and inhibited CGRP activity only at concentrations > 1 microM. However, in the DCT and CTAL, CGRP-(8-37) inhibited both ADM- and CGRP-induced increases in cAMP. We conclude that in the kidney, as in other tissues, ADM and CGRP stimulate cAMP accumulation. Our results suggest that ADM and CGRP may be important in the regulation of glomerular and distal tubule function and are consistent with the view that glomeruli have "ADM-like" receptors that have a high affinity for ADM but a low affinity for CGRP and CGRP-(8-37), whereas the DCT has "CGRP-like" receptors with high affinity for CGRP and CGRP-(8-37) but a lower affinity for ADM.

Interaction of nonpeptide angiotensin II receptor antagonists with the urate transporter in rat renal brush-border membranes.

The angiotensin II (AII) antagonist, losartan, increases uric acid excretion when administered to humans. However, the active metabolite of losartan, EXP 3174, and other nonpeptide AII antagonists such as eprosartan and SB 203220 are devoid of uricosuric activity. To investigate the mechanism of losartan-induced uricosuria, we examined the effects of losartan, EXP 3174, eprosartan and SB 203220 on OH- -dependent [14C]urate uptake into rat proximal tubule brush-border membrane vesicles. Losartan (10 microM) inhibited [14C]urate uptake at all time points examined, except at equilibrium (2 hr). Losartan had no effect on urate uptake in the absence of an OH- gradient. The inhibitory effect of losartan on urate uptake was concentration dependent (IC50 = 9.5 +/- 1.4 microM) and competitive in nature. The other AII antagonists also inhibited urate uptake but were 6-8-fold less potent than losartan with IC50 values of EXP 3174 (65 +/- 13 microM), eprosartan (60 +/- 7.0 microM) and SB 203220 (74 +/- 12.5 microM). In contrast to the effects of the nonpeptide AII antagonists, the peptide antagonist, Sar1,Ile8-AII, as well as AII itself had no effect on urate uptake. These results suggest that the uricosuric activity of losartan is, at least in part, due to inhibition of urate reabsorption in the proximal tubule and is unrelated to AII receptor activity. Furthermore, losartan has a greater affinity for the urate/anion exchanger than the other AII antagonists tested. These results are in direct agreement with observations made after administration of these compounds to humans.

Characterization of 125I-endothelin-1 binding to rat and rabbit renal microvasculature.

We characterized 125I-ET-1 binding to renal microvascular membranes isolated from the rat, a species showing ETB receptor-mediated renal vasoconstriction, and the rabbit in which ET-induced renal vasoconstriction is mediated by the ETA receptor. In both species, 125I-ET-1 bound in a manner consistent with a single high-affinity site. Scatchard analysis yielded Kd and Bmax values of 20.1 +/- 0.4 pM and 1343 +/- 64 fmol/mg for the rat and 21.5 +/- 0.9 pM and 810 +/- 64 fmol/mg for the rabbit. Competition binding studies with several selective (sarafotoxin 6c, BQ123) and mixed ETA/ETB (SB 209670) ET receptor ligands showed that the renal microvasculature from both species contain ETA and ETB receptors in a proportion of 40:60. In the rat, the proportion of ETA receptors was higher in the microvasculature than in glomeruli and inner medullary collecting duct cells both of which contained > 80% ETB receptors. In the rabbit, the proportion of ETA/ETB receptors was similar in the microvasculature and inner medullary collecting duct cells (approximately 40:60), whereas glomeruli contained 80% ETB receptors. Although ET-induced renal vasoconstriction in the rat and rabbit is mediated by different ET receptor subtypes, the proportion of ETA to ETB receptors is the same in the renal microvasculature from these species.

SB 203220: a novel angiotensin II receptor antagonist and renoprotective agent.

SB 203220, [(E)-alpha-[[2-butyl-1-[(4-carboxy-1-naphthalenyl)-methyl]-1H- imidazol-5-yl]-methylene]-2-thiophene-propanic acid], is a novel nonpeptide angiotensin II receptor antagonist with significant oral activity. In the present study, we compared the cardiovascular and renal effects of SB 203220 and captopril in rats with chronic renal failure induced by 5/6 nephrectomy. Preliminary studies indicated that SB 203220 (600 ppm in the diet) and captopril (250 mg/l in drinking water) significantly attenuated the pressor activity of exogenous angiotensin II and angiotensin I, respectively. After 5/6 nephrectomy, significant hypertension was observed such that at 6 weeks, systolic blood pressure had reached 176 +/- 9 mm Hg. Both SB 203220 (128 +/- 18 mm Hg) and captopril (131 +/- 7 mm Hg) significantly attenuated the hypertension. Urinary protein excretion increased progressively after renal ablation (from 7 to 124 mg/day), and this was attenuated by both SB 203220 (32 +/- 7 mg/day) and captopril (42 +/- 6 mg/day). Assessment of serum creatinine and urea nitrogen indicated that SB 203220 but not captopril resulted in maintenance of renal function, close to that observed in control rats. Both SB 203220 and captopril attenuated the renal and left ventricular hypertrophy associated with 5/6 nephrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of glomerular arteriolar tone by nitric oxide synthase inhibitors.

The inhibition of nitric oxide production has been shown to reduce RBF. The effects of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine and NG-monomethyl-L-arginine, on afferent and efferent arterioles isolated from rabbit kidneys were examined. Under basal conditions, N omega-nitro-L-arginine (10(-7) to 10(-3) M) had no effect on efferent arteriole lumen diameter but caused a 40% decrease in the lumen diameter of afferent arterioles. In afferent and efferent arterioles precontracted with norepinephrine, N omega-nitro-L-arginine and NG-monomethyl-L-arginine (3 x 10(-4) M) markedly attenuated the vasorelaxant effects of the endothelium-dependent vasodilator acetylcholine. In both arterioles, the inhibitory effect of N omega-nitro-L-arginine on acetylcholine-induced relaxation could be reversed by L- but not D-arginine (10(-3) M). However, N omega-nitro-L-arginine had no effect on the relaxation produced by the endothelium-independent vasodilators prostaglandin E2 (afferent) and dopamine (efferent). These observations demonstrate that under the in vitro conditions used in this study, afferent arterioles but not efferent arterioles synthesize and release nitric oxide in the basal state. However, both arterioles release nitric oxide in response to an endothelium-dependent vasodilator. The results of this study provide further evidence for an important role of nitric oxide in the regulation of renal hemodynamics.

Calcitonin gene-related peptide stimulates adenylate cyclase and relaxes intracerebral arterioles.

The effects of calcitonin gene-related peptide (CGRP) on lumen diameter and adenylate cyclase activity in isolated intracerebral arterioles were examined. CGRP produced a concentration-dependent relaxation of spontaneous tone developed by the arterioles with an EC50 value of 3.9 x 10(-9) M. Calcitonin, as well as substance P, which is frequently colocalized with CGRP, had no effect on arteriolar tone. CGRP also relaxed arterioles contracted with the thromboxane mimetic, U-44619, yielding an EC50 value of 3 x 10(-9) M. The CGRP fragment, human CGRP(8-37), antagonized CGRP-induced relaxation in a noncompetitive manner. Adenylate cyclase activity in single arterioles was stimulated by CGRP, but not by substance P, in a concentration-dependent fashion. Half maximal stimulation occurred at 8 x 10(-9) M, whereas maximum stimulation (2.5-fold over basal) occurred at 10(-7) M. CGRP(8-37) inhibited CGRP-stimulated adenylate cyclase activity over a concentration range of 10(-9) to 10(-5) M. The results demonstrate that CGRP stimulates adenylate cyclase activity and is a potent vasodilator of small parenchymal cerebral arterioles in vitro and may play an important role in the regulation of cerebral blood flow.

Platelet-activating factor (PAF) has no direct effect on rat intracerebral arterioles in vitro.

We examined the effect of platelet activating-factor (PAF) on lumen diameter of penetrating intracerebral arterioles (diameter less than 50 microns) dissected from rat brains. PAF over a concentration range of 10(-12)-10(-6) M had no effect on lumen diameter. However, the arterioles were capable of both vasodilation in response to calcitonin gene-related peptide (EC50 = 4.4 nM) and vasoconstriction in response to the thromboxane mimetic, U44619 (EC50 = 5.8 nM). We conclude that the effects of PAF on the cortical circulation observed in vivo are indirect and may be due to PAF-induced changes in other humoral or cellular mediators.

Relaxation of renal arterioles by parathyroid hormone and parathyroid hormone-related protein.

The effects of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) on renal arteriolar tone and proximal tubule adenylate cyclase were examined. In both afferent and efferent arterioles, PTH produced concentration-dependent relaxation of norepinephrine-induced tone with EC50 values of 8.7 and 9.9 nmol/l, respectively. PTHrP also produced relaxations that were indistinguishable from PTH. In proximal convoluted tubules PTH and PTHrP stimulated adenylate cyclase to the same extent and with similar potencies. The PTH antagonist, bPTH(7-34), totally blocked PTH-induced arteriolar relaxation but had no effect on proximal tubule adenylate cyclase. The results demonstrate that PTH and PTHrP are potent relaxants of glomerular arterioles and that PTH receptors present on the renal microvasculature may differ from those present on proximal tubules.

Renal microvascular effects of endothelin.

The effects of endothelin 1, 2, and 3 (ET-1, -2, -3) on lumen diameter of individual afferent and efferent arterioles dissected from rabbit kidney were examined. ET-1 produced concentration-dependent and long-lasting decreases in lumen diameter in both arterioles. The 50% maximum response (EC50) values were 1.4 +/- 0.41 and 0.9 +/- 0.65 nM for afferent and efferent arterioles, respectively. In afferent arterioles, ET-2 produced decreases in lumen diameter (EC50 = 3.3 +/- 1.75 nM) that were indistinguishable from ET-1. However, ET-3 was considerably less potent (EC50 = 21.9 +/- 6.0 nM, P less than 0.05) than ET-1 or ET-2. Similar results were obtained in the efferent arteriole in which the EC50 for ET-2 (0.25 +/- 0.1 nM) was similar to ET-1, but ET-3 was significantly less potent (EC50 = 2.6 +/- 0.4 nM, P less than 0.05). Nicardipine (0.01-1 microM) produced concentration-dependent shifts in the ET-1 concentration-response curve in afferent arterioles. Verapamil (1 microM) also caused a significant shift in the ET-1 response curve. The contractile response to ET-1 was significantly more sensitive to nicardipine than was the response to norepinephrine. In contrast, the response of efferent arterioles to ET-1 and norepinephrine was unaffected by nicardipine or verapamil. The results demonstrate that ETs are potent vasoconstrictors of both the pre- and postglomerular microvasculature and may play a role in the regulation of renal hemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of enalapril or the thromboxane receptor antagonist, daltroban, in rats with subtotal renal ablation.

There is evidence to suggest that thromboxane synthesis inhibition will attenuate the hypertension and proteinuria associated with subtotal renal ablation. In the present study, the thromboxane receptor antagonist, daltroban, (30 mg/kg/day i.p.) or vehicle was administered to rats for 3 weeks starting 2 weeks after partial renal ablation (right uninephrectomy and ligation of approximately two-thirds of the blood supply to the left kidney). Renal ablation was associated with proteinuria and increased systolic blood pressure. Neither the proteinuria nor the hypertension was affected by daltroban administration. Histological examination of the remaining kidney demonstrated no beneficial effect of daltroban. In a second study, it was determined that, 2 weeks after renal ablation, urinary thromboxane excretion was significantly increased, and subsequent administration of daltroban for 2 weeks resulted in significant blockade of the effects of the thromboxane mimetic, U46619. In a third study, enalapril (50 mg/l in the drinking water) resulted in a significant attenuation of the proteinuria, hypertension and glomerular lesions associated with partial renal ablation. The data indicate that enalapril, but not daltroban, protects against the development of renal disease associated with reduced renal mass.

Response of isolated intracerebral arterioles to endothelins.

The effects of endothelin-1, -2 and -3 (ET-1, -2, -3) on lumen diameter of intracerebral arterioles isolated from rat brain were examined. All three ETs produced concentration-dependent decreases in lumen diameter with EC50 values of 0.7, 1.5 and 58 mmol/l for ET-1, ET-2 and ET-3, respectively. The calcium channel antagonist, nicardipine, had no significant effect on ET-1-induced contractions except at a concentration of 1 mumol/l which attenuated the maximum response to ET-1, but had no effect on the EC50 value. The potent vasoconstrictor action of ET on intracerebral arterioles suggest an important role for this peptide in the regulation of the cerebral microvasculature.

Calcitonin gene-related peptide: effects on renal arteriolar tone and tubular cAMP levels.

The effects of calcitonin gene-related peptide (CGRP) and salmon calcitonin (SCT) on isolated afferent and efferent arteriolar tone and on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in isolated tubules from rabbit kidney were compared. By themselves, CGRP and SCT had no effect on arteriole diameter. In norepinephrine-contracted afferent arterioles, CGRP, but not SCT, produced a concentration-dependent relaxation [50% maximal dose, (EC50) = 1.3 nM]. In contrast, neither CGRP nor SCT had any effect on efferent arterioles precontracted with norepinephrine or angiotensin II. CGRP, but not SCT, stimulated cAMP accumulation in glomeruli (EC50 = 0.5 nM). In tubules, CGRP increased cAMP levels only in SCT-responsive segments, e.g., cortical and medullary thick ascending limbs and distal convoluted tubules. In the medullary thick ascending limb, CGRP was approximately 500-fold less potent than SCT in stimulating cAMP accumulation with EC50s of 0.22 microM and 0.41 nM, respectively. The effect of maximum concentrations (1 microM) of CGRP and SCT on cAMP levels in the medullary thick ascending limb were not additive. The results suggest that there are specific CGRP receptors on afferent arterioles that produce relaxation and in glomeruli that are associated with an increase in cAMP production. In tubules, CGRP appears to be a weak agonist at the SCT receptor. We conclude that CGRP may play a role in the regulation of renal hemodynamics.

Renal microvascular effects of vasopressin and vasopressin antagonists.

The effects of vasopressin (AVP) and vasopressin antagonists on lumen diameters of cortical afferent and efferent arterioles isolated from rabbit kidneys were examined. Over a concentration range of 10(-14) to 10(-7) M, AVP had no effect on lumen diameters of afferent arterioles, although the arterioles were responsive to norepinephrine. Similarly, addition of 10(-8) M AVP to the lumen of afferent arterioles or to the bath of arterioles pretreated with indomethacin had no effect. In contrast, AVP caused a concentration-dependent reduction of lumen diameters of efferent arterioles. AVP was approximately 100-fold more potent than norepinephrine in producing contraction of efferent arterioles. The V1-selective antagonist, [d(CH2)5Tyr(Me)]AVP, and the V1/V2-antagonist, d(CH2)5D-Tyr(Et) desGlyVAVP, inhibited the vasoconstriction produced by AVP in a concentration-dependent but noncompetitive manner. The V2-selective antagonist, [d(CH2)5D-Ile]VAVP, had no significant effect on AVP-induced vasoconstriction. We conclude that, under the in vitro conditions used, AVP selectively contracts efferent arterioles. The results provide direct evidence for a postglomerular vascular effect of AVP in the renal cortex. This activity, together with its previously described effects on the glomerulus, suggests that AVP may produce changes in glomerular function and/or peritubular forces that are involved in tubular reabsorption.

Characterization of alpha-adrenoceptors on isolated rabbit renal arterioles.

Postsynaptic alpha-adrenoceptors were characterized in afferent and efferent arterioles isolated from rabbit renal cortex. In both the afferent and efferent arteriole the selective alpha 1-adrenoceptor agonists phenylephrine and cirazoline produced concentration-dependent vasoconstrictor responses with the maximum responses being equal to that of norepinephrine. The selective alpha 2-receptor agonists B-HT 933 and UK 14304 were examined over a concentration range of 10(-9) to 10(-4) M. At these concentrations, they were either inactive (B-HT 933) or produced maximum contractile responses only 60% (UK 14304) of that produced by norepinephrine or the alpha 1-receptor agonists. Prazosin (10(-7) M), an alpha 1-receptor antagonist, produced a rightward shift in the concentration-response curve to norepinephrine, yielding apparent dissociation constants of 1.7 and 1.2 X 10(-8) M for the afferent and efferent arteriole, respectively. Prazosin also antagonized the contractile effects of UK 14304 (apparent dissociation constants, 0.9 and 1.1 X 10(-8) M for afferent and efferent arterioles, respectively). The selective alpha 2-receptor antagonist, rauwolscine (10(-7) M), had no effect on norepinephrine-mediated vasoconstriction. These results confirm the presence of alpha-adrenoceptors on the glomerular arterioles that mediated vasoconstriction. Furthermore, these receptors appear to be exclusively of the alpha 1-subtype.

Hypertrophy of basolateral Na-K pump activity in the proximal tubule of the remnant kidney.

Reduction of renal mass leads to an increase in the filtration rates of the remaining glomeruli and an increased rate of sodium and water reabsorption by the proximal tubules. To define the basis for this increased tubular reabsorptive capacity, the authors studied the relationship of basolateral sodium pump activity to the process of hypertrophy in the proximal tubule. They wished to determine whether the growth of the cell is associated with an increase in the number of basolateral Na-K pumps and whether basolateral membrane hypertrophy is symmetrical with respect to overall cell growth. Normal and subtotally nephrectomized rabbits (remnant kidneys) were studied. Ouabain-sensitive potassium uptake was measured in a highly purified suspension of cortical proximal tubules using 86Rb as a tracer. In normal kidneys Km was 0.99 +/- 0.30 mM and Vmax 83.1 +/- 13.7 nmoles X mg-1 X minute-1; in remnant kidneys Km was 0.63 +/- 0.10 mM and Vmax 49.2 +/- 10.9 nmoles X mg-1 X minute-1. These values are not significantly different from each other. In a suspension of isolated cortical proximal tubular cells, protein per cell was 172 +/- 23 pg in normal kidney and 450 +/- 56 pg in remnant kidneys, representing a 2.6-fold increase. The extrapolated Vmax for K uptake per cell was thus increased approximately 2.6-fold in the remnant kidney. This was confirmed by measuring the number of specific ouabain-binding sites in proximal tubular cells. This was also found to be approximately 2.5 to 3 times greater in the remnant kidney cells, the increase being proportional to the increase in cell protein. Histomorphometric analysis of S2 proximal convoluted tubules, which comprise the bulk of the cortical tissue, revealed that basolateral membrane area per cross-sectional area of tubule was increased in the remnant kidney. The mean absolute surface area per cross-section of tubule and the surface density (surface/volume ratio) of the basolateral membrane increased by 110 and 26%, respectively, whereas these changes in the luminal membrane were only 38 and -9%, respectively. Thus, the membrane areas of the proximal tubular cell hypertrophy asymmetrically. Although mitochondrial density does not increase in remnant tubules, mitochondrial volume increases significantly, possibly providing a source for the increased ATP required by the hypertrophied basolateral Na-K pump activity. In summary, the cells of the proximal convoluted tubule of the remnant kidney undergo functional and structural hypertrophy.(ABSTRACT TRUNCATED AT 400 WORDS)