Renal function and tubular transport effects of sulindac and naproxen in chronic heart failure.

Renal function and excretion of water, salt, and the prostacyclin hydration product (6-keto-PGF1 alpha) were evaluated in 10 furosemide-treated patients with well-controlled congestive heart failure. Four doses of sulindac (200 mg b.i.d.) and naproxen (500 mg b.i.d.) were given every 12 hours in a double-blind crossover design. Naproxen significantly decreased the urinary excretion of water (19%), sodium (26%), chloride (26%), and 6-keto PGF1 alpha (76%) and decreased osmolal clearance (18%). No significant changes in these functions were observed in the patients receiving sulindac. Plasma renin activity, plasma aldosterone, freewater clearance, or clearance of furosemide did not change significantly with either treatment. Although the basal glomerular filtration rate (GFR) and renal plasma flow (RPF) were reduced, these patients with cardiac disease, with normal serum sodium concentration, did not have any further reduction of GFR or RPF despite naproxen-induced inhibition of renal prostacyclin synthesis. It is concluded that renal prostaglandins contribute to the natriuretic effect of oral furosemide in patients with compensated congestive heart failure. In this clinical setting, GFR and RPF are not critically dependent on intact renal PGI2 synthesis. The lack of effect on renal prostaglandin synthesis and the renal response to oral furosemide supports the concept of a renal sparing effect of sulindac.

A double blind comparison of naproxen and sulindac in female patients with heart failure.

The objective of this investigation was to study the effects of the two NSAIDs sulindac and naproxen on renal hemodynamics and excretion of water, salt and the prostacyclin metabolite 6-keto-PGF1 alpha in patients with well controlled congestive heart failure. Ten elderly females with congestive heart failure treated with oral furosemide were given four doses of sulindac and naproxen every twelve hours after a control day in a double-blind cross-over fashion. Naproxen significantly decreased the urinary excretion of water (19%), sodium (26%), chloride (26%), 6-keto-PGF1 alpha (76%) and decreased osmolal clearance by 18%. Sulindac had no significant effect on those parameters. There were no significant changes in glomerular filtration rate, renal blood flow, plasma renin activity, plasma aldosterone, free-water clearance or clearance of furosemide with either treatment. We conclude that renal prostaglandins are involved in the control of sodium excretion and urinary volume in patients with congestive heart failure even if renal hemodynamics are unaffected. Sulindac seems to be a selective inhibitor of extrarenal cyclooxygenase and consequently an appropriate drug for patients who require both diuretics and anti-inflammatory therapy.

Aspects of the effects of NSAID's on renal function in congestive heart failure.

In summary the present study shows that sulindac does not interfere with the action of furosemide in contrast to naproxen. Therefore, treatment of arthritic disorders with sulindac might be of advantage in elderly patients with cardiac failure.

Elimination of cholesterol in hyperlipoproteinaemia.

1. Cholesterol intake (about 0-25 mmol/day) and the faecal excretion of cholesterol, coprostanol and coprostanone were determined in normolipidaemic control subjects and hyperlipidaemic patients, whose bile acid kinetics had been previously studied. 2. The combined excretion of the neutral steroids (excluding plant sterol and plant sterol metabolites) averaged 1-07 +/- 0-13 (+/-SEM)mmol/day in the control subjects (n=14). The corresponding values in patients with hyperlipoproteinaemia type IIa (n=19), IIb (n=12) and IV (n=23) were 0-86 +/- 0-10, 0-93 +/- 0-11 and 1-48 +/- 0-17 mmol/day respectively. 3. The mean values for the net steroid "balance", defined as the combined amount of bile acid synthesized (determined by an isotope-dilution technique) and the faecal excretion of neutral steroids minus cholesterol intake, were 1-83 +/- 0-22 mmol/day in the control subjects and 1-60 +/- 0-15, 1-81 +/- 0-19 and 3-53 +/- 0-23 mmol/day in patients with type IIa, IIb and IV lipoprotein patterns respectively. 4. No significant correlations between net steroid "balance" and sex, age, serum lipid concentrations, body weight or body surface area were found in any of the groups of subjects. 5. It is concluded that patients with type II hyperlipoproteinaemia eliminate cholesterol as bile acids and neutral faecal steroids normally. The type IV lipoprotein pattern is associated with increased bile acid synthesis and/or elevated faecal excretion of neutral steroids, so that the net steroid "balance" is usually above the normal limit.

The effect of chenodeoxycholic acid feeding on bile acid kinetics and fecal neutral steroid excretion in patients with hyperlipoproteinemia types II and IV.

The kinetics of 24-14C-cholic acid and 3H-chenodeoxycholic acid and the elimination of cholesterol as fecal neutral steroids were studied in 6 patients with Type II and 7 patients with Type IV lipoprotein pattern before and during the ingestion of 0.8 to 1.0 Gm. of chenodeoxycholic acid per day. During treatment, the pool size of chenodeoxycholic acid increased in all subjects (not studied in one Type IV patient). In Type II patients, this effect was associated with a decrease of the cholic acid pool size from 868 +/- 141 to 213 +/- 51 mg. and of the cholic acid synthesis from 204 +/- 36 to 54 +/- 20 mg. per day. In the patients with hyperlopoproteinemia Type IV, the cholic acid pool size diminished in 6 of the 7 subjects all of whom showed a decrease in the cholic acid synthesis on the average from 607 +/- 155 to 202 +/- 44 mg. per day. It is suggested that the feedback control of cholic acid synthesis is less sensitive in the Type IV than in the Type II patients. Chenodeoxycholic acid feeding did not influence the fecal excretion of cholesterol, coprostanol, and coprostanone in a consistent way.

Gallbladder disease in hyperlipoproteinaemia.

The occurrence of gallbladder disease (G.B.D.) (cholelithiasis, cholecystitis, cholecystectomy) was examined in patients consecutively admitted beccause of hyperlipoproteinaemia types IIa and IV. Altogether 37 of the 52 patients with the type IIa pattern were women, whereas 56 of the 75 subjects with hyperlipoproteinaemia type IV were men. The overall incidence of G.B.D. in the group with the type IIa was 13 per cent in the males and 22 per cent in the females; the corresponding figures in type IV were 41 per cent and 68 per cent, respectively. The findings in the major age-group (40-59 years) were compared with those from three necropsy series covering subjects of the same age. The incidence of G.B.D. was then found to be normal in type IIa but abnormally high in type IV. Patients with and without G.B.D. did not differ with regard to body-weight or glucose tolerance.

Bile acid kinetics in relation to sex, serum lipids, body weights, and gallbladder disease in patients with various types of hyperlipoproteinemia;.

Bile acid kinetics were determined in 15 normolipidemic and 61 hyperlipidemic subjects with the aid of [(14)C]cholic acid and [(3)H]chenodeoxycholic acid. The diet was standardized and of natural type. The total bile acid formation was within normal limits in patients with hyperlipoproteinemia types IIa and IIb. On the average the production of cholic acid (C) represented less than 50% of the total bile acid synthesis in both groups. The corresponding value recorded for the controls was 64+/-2% (mean+/-SEM). The synthesis of C in hyperlipoproteinemia type IIa was significantly below normal. Of the 27 patients with the type IV pattern, 18 had a synthesis of C and C + chenodeoxycholic acid (CD) that exceeded the upper range recorded for the controls. In these subjects the C formation represented 73+/-3% of the total bile acid synthesis. Similar findings were also encountered in the five patients with the type V lipoprotein pattern studied. The bile acid pool size of the 11 patients with hyperlipoproteinemia type IV, who had been cholecystectomized or suffered from cholelithiasis, was 900 mg smaller on the average than that of the other subjects with the same type of hyperlipoproteinemia. However, the pool size in the former subjects still tended to be higher than that of the control subjects without evidence of gallbladder "disease". In all groups of subjects the formation of bile acids tended to be higher in the male than in the female subjects. Bile acid synthesis showed no linear correlation to actual body weight, relative body weight, or body surface area. A moderate weight reduction in five patients (one with type IIb and four with type IV pattern) was followed by a 50% reduction of the C and CD synthesis.