These studies explored the hypothesis that angiotensin II increases bicarbonate absorption in the proximal convoluted tubule (PCT) by decreasing intracellular cAMP. In vivo microperfusion was performed in rat PCT with measurements of bicarbonate absorption and of tubular fluid cAMP delivery, as a reflection of intracellular cAMP. Intravenous angiotensin II potently increased S1 PCIT bicarbonate absorption (348±11 to 588±8 peq/mm. min, P < 0.001) and decreased tubular fluid cAMP (18±2 to 12±2 fmol/mm. min, P < 0.05). Parathyroid hormone had the expected opposite effects, which were additive to those of angiotensin II. Over a wide range of hormonal activities, there was an excellent inverse relationship between hormonally modulated bicarbonate absorption and cAMP delivery. Pertussis toxin pretreatment significantly attenuated (by 35-45%) the angiotensin-induced increase in bicarbonate absorption and decrease in cAMP delivery, indicating G1-protein intermediation. Luminal dibutyryl cAMP abolished the transport response to angiotensin II. In conclusion, these in vivo results suggest angiotensin II stimulates bicarbonate absorption in the SI PCIC by a G1-mediated depression in intracellular cAMP.

A B S T R A C T The effects of systemic bicarbonate concentration and extracellular fluid volume status on proximal tubular bicarbonate absorption, independent of changes in luminal composition and flow rate, were examined with in vivo luminal microperfusion of rat superficial proximal convoluted tubules. Net bicarbonate absorption and bicarbonate permeability were measured using microcalorimetry. From these data, net bicarbonate absorption was divided into two parallel components: proton secretion and passive bicarbonate diffusion.The rate of net bicarbonate absorption was similar in hydropenic and volume-expanded rats when tubules were perfused with 24 mM bicarbonate, but was inhibited in volume-expanded rats when tubules were perfused with 5 mM bicarbonate. Volume expansion caused a 50% increase in bicarbonate permeability, which totally accounted for the above inhibition. The rate of proton secretion was unaffected by volume expansion in both studies.The rate of net bicarbonate absorption was markedly inhibited in alkalotic expansion as compared with isohydric expansion. Bicarbonate permeabilities were not different in these two conditions, and the calculated rates of proton secretion were decreased by >50% in alkalosis. Net bicarbonate absorption was stimulated in acidotic rats compared to hydropenic rats. This stimulation was attributable to a 25% increase in the rate of proton secretion.We conclude that (a) proton secretion is stimulatedPortions of this study were presented at the 13th, 14th, and 15th Annual Meetings of the American Society of Nephrology and were published in abstract

The effects of renal impairment and age on the pharmacokinetics of metformin were evaluated. The subjects, including 6 young, 12 elderly, and 3 middle-age healthy adults and 15 adults with various degrees of chronic renal impairment (CRI) each were given a single, 850-mg metformin HCl tablet. Multiple whole blood, plasma, and urine samples were collected and analyzed for metformin levels using a high-performance liquid chromatography (HPLC) method. In healthy elderly individuals, the plasma and whole blood clearance/absolute bioavailability values [CL/F and (CL/F)b], and corresponding renal clearance values (CLR and CLR,b) of metformin were 35-40% lower than the respective values in healthy young individuals. These two groups did not differ significantly with respect to volume of distribution (Vd), time to peak concentration (tmax), and parameters related to metformin's appearance in the urine. In the moderate and severe CRI groups, all clearance values were 74-78% lower than in the healthy young/middle-age group, and all other evaluable pharmacokinetic parameters (with the exception of tmax) differed significantly in this group. In the mild CRI group, clearance values of metformin, which were 23-33% lower than in the young/middle-age group, were the only parameters that differed significantly. Based on a regression analysis of the combined data, both creatinine clearance (CL*cr; corrected for body surface area) and age are predictors of metformin clearance, with the following model best fitting the data: CL/F [or (CL/F)b, CLR, CLR,b] = alpha + beta.CL*cr + gamma.CL*cr.age. Metformin should not be used in patients with moderate and severe CRI, or in patients with mild, but not absolutely stable, renal impairment. The initial and maximum doses in elderly patients and patients with stable mild CRI should be lowered to approximately one third that given to the general (i.e., patients without non-insulin-dependent diabetes) population.

Angiotensin II has recently been shown to exert potent control over sodium and water absorption in the proximal convoluted tubule. This transport stimulation is effected by receptors on both the luminal and basolateral membranes of cells located predominantly in the early, S, proximal tubule. Angiotensin II increases transport primarily by a G f proteinmediated reduction in intracellular cyclic adenosine monophosphate, which enhances the affinity of the Na + -H + antiporter. Change in early proximal acidification ultimately causes alteration in the amount of sodium chloride leaving the proximal tubule and entering the urine. et al 4 was very small. The maximal response was only 16% above the baseline value and was trivial (0.1 nl/mm • min) compared with the normal amount of fluid reabsorbed by the PCT in vivo (18 nl/min). 5The studies described above were performed in the late (S 2 ) subsegment of the PCT. With recent adaptation in micropuncture techniques, it is now recognized that the early (S^ PCT subsegment of the rat has a far more robust capacity for both active and passive transport than the S 2 PCT, or for that matter, any other nephron segment.56 Indeed, although the S, PCT is only a little over 1 mm in length in the rat, it is normally responsible for reabsorbing fully 20% of the solute and water that is filtered by the kidney. 5Were angiotensin II to control this powerful Si PCT transport system, it would obviously have substantial potential for regulating renal sodium and water reabsorption.As shown in Figure 1, angiotensin II does indeed have a potent effect on Si PCT sodium and water transport in the Munich-Wistar rat.7 -9 Angiotensin II infusion (20 ng/kg • min i.v.), which achieves a subpressor, systemic concentration within the physiological range (10~1 2 to 10~n M), augmented S, PCT water absorption by 2.5 nl/mm • min (closed squares) when measured by in vivo microperfusion.

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After restoring plasma volume to conscious levels, glomerular pressures and flows governing single nephron glomerular filtration rate (SNGFR) were measured in Munich-Wistar rats possessing surface glomeruli accessible to micropuncture. Although the mean glomerular transcapillary hydraulic pressure difference in these euvolemic rats was similar to that observed in hydropenic animals, initial glomerular plasma flow rate and SNGFR were at least 50% higher than in hydropenic rats. Nevertheless, filtration pressure equilibrium was generally achieved in euvolemic rats, as in hydropenic rats. Afferent and efferent arteriolar resistances were found to be lower in euvolemic than hydropenic rats, suggesting more potent vasoconstrictor forces in the latter group.

There has been conflict as to whether crude extracts of atrial natriuretic factor increase renal solute excretion by a hemodynamic mechanism or by direct inhibition of tubular transport. To investigate this issue, seven rats were studied during a euvolemic control period and following continuous administration of pure, synthetic 24 amino acid atrial natriuretic factor. A 10-25-fold increase in urinary sodium and chloride excretion occurred with a brisk kaliuresis but little bicarbonaturia. Atrial natriuretic factor caused whole kidney glomerular filtration rate to increase from 1.17±0.04 to 1.52±0.07 ml/min (P < 0.005). A parallel increase in single nephron glomerular filtration rate, from 34±1 to 44±2 nl/min (P < 0.001), and from 26±1 to 37±2 nl/min (P < 0.005) was measured at the end-proximal and early distal nephron sites, respectively. Appropriate for the higher flows were an increase in absolute proximal and loop reabsorptive rates for bicarbonate, chloride, and water, with a slight decrease in fractional solute and volume reabsorption in proximal and loop segments. To exclude the possibility that atrial natriuretic factor increased filtration rate only in anesthetized animals, eight unanesthetized rats were studied. Glomerular filtration rate increased by 45%, from 2.04±0.17 to 2.97±0.27 ml/min (P < 0.005) without significant change in renal plasma flow, as reflected by 14C-para-aminohippurate clearance (5.4±0.5-5.6±0.9 ml/min). The clearance and micropuncture data did not preclude changes in relative blood flow distribution to or in transport by deep nephron segments. In conclusion, atrial natriuretic factor appears to increase renal solute excretion predominantly by a hemodynamic mechanism without directly inhibiting superficial tubular transport.

The early proximal convoluted tubule (PCI)