Peter G. Werness

EQUIL2: a BASIC computer program for the calculation of urinary saturation.

A BASIC computer program for the calculation of urinary supersaturation with respect to the common kidney stone components is described. In vitro and in vivo tests show that the program described accurately calculates supersaturation. The application of this computer program to urolithiasis research is discussed.

Inhibitors of crystal growth of hydroxyapatite: a constant composition approach.

Pyrophosphate, citrate and magnesium, inhibitors of hydroxyapatite crystal growth, were studied using a seeded crystal growth system of constant composition at pH 5.80, 6.60 and 7.40. With this technique, crystal growth was studied at constant supersaturation at different pH values without the induction of other calcium phosphate phases. One inhibitor unit (that concentration of material that results in a reduction of 50 per cent in the growth rate from control) was calculated using the Langmuir adsorption isotherm. Pyrophosphate and citrate increased inhibitor activity with decreasing pH, whereas magnesium increased inhibitor activity with increasing pH. These data suggest that, at the urinary concentrations of these inhibitors, pyrophosphate is the most potent inhibitor, citrate less, and magnesium least. Pooled urine collections were studied using the same system and were found to have decreased inhibitor activity as pH decreased. This suggests that other modulators of hydroxyapatite, either promoters or inhibitors, are active in this system at the pH values studied.

Pentosan Polysulfate As An Inhibitor of Calcium Oxalate Crystal Growth

Pentosan polysulfate was studied as a calcium oxalate crystal growth inhibitor. The inhibition from pentosan polysulfate at concentrations ranging from 3.5 to 110 mg./l. was measured in simple inorganic calcium oxalate solutions at pH 5, 6 and 7. Pentosan polysulfate also was mixed with urine at concentrations from 10 to 350 mg./l. and inhibition determined. Measurement of calcium oxalate crystal growth inhibition was performed in a seeded crystal growth system. One inhibitory unit (concentration of pentosan polysulfate necessary to give a 50 per cent reduction in the rate of crystal growth) was 5.7 +/- 2 mg./l. at pH 5, 7.2 +/- 1.1 mg./l. at pH 6 and 6.0 +/- 2.1 mg./l. at pH 7. Urine-pentosan polysulfate mixtures showed more inhibitory activity than the predicted inhibition present. Addition of pentosan polysulfate to urine at a concentration of 10 mg./l. increased the inhibitory activity from 45 +/- 3 to 59 +/- 3 IU/l. Pentosan polysulfate is a potent calcium oxalate crystal growth inhibitor in urine at physiologic pH levels. If the urinary concentration of pentosan polysulfate after oral administration reaches 10 mg./l., the increase in inhibitory activity in urine that may occur might be important in the treatment of patients who form calcium oxalate calculi within the urinary tract.

Sulfate and methyldopa metabolism: metabolite patterns and platelet phenol sulfotransferase activity.

Sulfate conjugation catalyzed by phenol sulfotransferase (PST) is the major metabolic pathway for methyldopa. Methyldopa is also O‐methylated in a reaction catalyzed by catechol‐O‐methyltransferase (COMT). Our studies were performed to determine whether sodium sulfate alters methyldopa metabolism. Methyldopa powder, 3.5 mg/kg, was taken with and without sodium sulfate, 13.25 mg/kg, by 24 subjects in a randomized, crossover design. Compared with results obtained when only methyldopa was taken, sodium sulfate taken with methyldopa increased the proportion of drug excreted as methyldopa sulfate expressed as the percentage of all urinary metabolites (66.0% ± 5.3% and 50.1% ± 7.5%; X̄ ± SD). The percentage of free methyldopa excreted also decreased (17.1% ± 3.7% and 27.3% ± 5.5%). Platelet PST and red blood cell COMT activities were measured in blood samples from these subjects. When sodium sulfate was taken with methyldopa, there was a significant correlation between platelet PST activities and percentages of metabolites excreted as methyldopa sulfate (r = 0.545; P < 0.01). This correlation was not significant when methyldopa was taken alone (r = −0.340; P > 0.10). There was a significant correlation between red blood cell COMT activities and the proportion of urinary metabolites excreted as 3‐O‐methyl‐α‐methyldopa when methyldopa was taken alone (r = 0.532; P < 0.01) but not when it was taken with sodium sulfate (r = 0.153; P > 0.20). Our data support the conclusion that variation in sulfate availability may be one factor responsible for individual differences in the metabolism of clinically used doses of methyldopa. Platelet PST activity correlates with individual variations in the sulfate conjugation of methyldopa taken by mouth with sodium sulfate.

Is Hydroxyapatite Important in Calcium Urolithiasis

Calculi formed within the urinary tract are commonly of mixed crystalline composition (1–3). This observation led Modlin in an address to the Royal College of Surgeons in England to suggest that heterogenous nucleation may be an important etiologic factor in the initiation of stone formation in the urinary tract (4). The crystalline mixture of calcium oxalate and hydroxyapatite is especially common. Boyce has shown that at least some hydroxyapatite was present in all the stones he examined, including “pure” calcium oxalate stones. He found that this hydroxyapatite was often located in close association with stone matrix (5). Meyer et al. demonstrated the ability of hydroxyapatite to induce the heterogenous nucleation of calcium oxalate monohydrate in vitro (6). They found that the addition of hydroxyapatite seed crystals to a solution that was supersaturated in terms of calcium oxalate and saturated in terms of hydroxyapatite induced the nucleation of calcium oxalate. Calcium oxalate did not precipitate within the time allowed by the study if no seed crystals were added. The rate of heterogenous nucleation of calcium oxalate was dependent upon the surface area of the seed crystals added.

Low Phosphate Diet in Rats: A Model for Calcium Oxalate Urolithiasis

Rats fed low phosphate diet show a marked hypercalciuria. We have shown previously that one week of low phosphate diet in rats results in urine highly supersaturated with respect to calcium oxalate with large amounts of calcium oxalate crystalluria, predominantly calcium oxalate dihydrate1. We have extended these studies to ten months and examined kidney tissue to evaluate the suitability of rats fed low phosphate diet as a long-term model for calcium oxalate urolithiasis.

Effect of Orthophosphate Treatment on Urine Composition in Idiopathic Calcium Urolithiasis

Oral neutral orthophosphate (OP) has been shown to be effective in the treatment of patients with idiopathic calcium urolithiasis (ICU)1,2.

Specificity of angiotensin antagonists in the mesenteric vasculature of dogs.

Abstract Experiments were conducted to assess whether the octapeptide antagonist Sar1-Ile8-angiotensin II or the heptapeptide antagonist Ile7-angiotensin III demonstrates specificity for antagonizing the mesenteric vasoconstrictor properties of angiotensin II or angiotensin III. Experiments were performed on 12 dogs anesthetized with sodium pen-tobarbital. In all dogs, the effects of five graded doses (10, 20, 40, 80, and 160 pmole, bolus injections) of angiotensin II and angiotensin III on superior mesenteric artery blood flow were tested. At all doses tested, angiotensin II was more potent than angiotensin III. Administration of the middle dose (40 pmole) of angiotensin II and angiotensin III was repeated during the infusion of either Ile7-angiotensin III (N = 6) or Sar1-Ile8-angiotensin II (N = 6) at five different dosages into the superior mesenteric artery, Sar1-Ele8-angiotensin II antagonized equally the mesenteric vasoconstrictor effects of both angiotensin II and angiotensin III. Ile7-angiotensin III was not absolutely specific as an antagonist of the mesenteric vasoconstrictor effects of angiotensin III.