Sulindac is not renal sparing in man.

We investigated the claimed renal-sparing effect of the cyclooxygenase inhibitor sulindac. Fifteen normal women following a diet of 50 mEq salt a day were randomly assigned to 5 days of either placebo, sulindac, 200 mg b.i.d., or indomethacin, 25 mg q.i.d., after first serving as their own controls. Renal effects were assessed by the excretion rate of prostaglandin (PG) E2 (an index of renal PG synthesis), sodium balance, plasma renin activity (PRA), and the response to furosemide. Systemic effects were assessed by collagen-induced platelet aggregation and thromboxane B2 formation and by the urinary excretion of a systemically formed metabolite of PGF2 alpha (PGF-M). Both sulindac and indomethacin resulted in a positive sodium balance and a reduction in 24-hour urinary PGE2 excretion (range -49% to -86%). Basal PRA was decreased by indomethacin only, but the increases in PRA and in urinary PGE2 excretion in response to furosemide were inhibited by both sulindac and indomethacin. Sulindac reduced the natriuresis induced by furosemide, and indomethacin reduced the rise in inulin clearance after furosemide. Thus the two nonsteroidal anti-inflammatory drugs had similar effects on the kidney. Indomethacin had a greater effect than sulindac on the inhibition of collagen-induced platelet aggregation and thromboxane synthesis and the two drugs had equivalent effects on the reduction of PGF-M excretion. Peak plasma drug concentration of indomethacin (1.9 +/- 0.4 microgram/ml) and sulindac sulfide (7.7 +/- 1.9 microgram/ml) were those associated with clinical efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of interaction between tricyclic antidepressants and clonidine at the alpha 2-adrenoceptor on human platelets.

The pharmacologic interaction between tricyclic antidepressants and clonidine at the alpha 2-adrenoceptor was examined in human platelets by quantifying the ability of tricyclic antidepressant drugs to inhibit clonidine-stimulated platelet aggregation in vitro. Platelet aggregation induced by increasing concentrations of clonidine (0.3 to 3 microM) was not altered by pretreatment of the platelets with 10 microM imipramine. Imipramine at concentrations above 100 microM attenuated clonidine-induced platelet aggregation, but this was a nonspecific drug effect because the high concentrations of imipramine inhibited adenosine diphosphate-induced platelet aggregation as well. Desmethyldoxepin and nortriptyline also inhibited platelet aggregation nonspecifically at higher concentrations (greater than 10 microM). We were also not able to establish a specific interaction between alpha-methlnorepinephrine (the active metabolite of methyldopa) and the tricyclic antidepressants at the platelet alpha 2-adrenoceptor. Our data suggest that if there is an adverse dynamic interaction between tricyclic antidepressants and clonidine, the interaction occurs at a site other than the alpha 2-adrenoceptor.

Is it better to avoid urethral catheterization at hysterectomy and caesarean section?

This study involved 329 patients who had either a Caesarean section or a hysterectomy. A comparison has been made between 70 patients who were never catheterized and 251 who had a urethral catheter perioperatively. The absence of recognized urinary tract infections in those without a catheter was significant when compared with the 21 urinary infections identified in the catheterized group (p<0.05). The absence of urinary tract infections in the uncatheterized group clearly demonstrates the benefit of avoiding catheterization when possible.

Histamine release in vivo by pentagastrin from the canine stomach.

The effect of intragastric arterial infusion of pentagastrin on gastric histamine release was evaluated in mongrel dogs in vivo. Histamine secretory rates were evaluated by measuring the arterial and gastric venous plasma histamine concentrations at 0, 5, 10, 15 and 20 min into pentagastrin infusions, and gastric blood flow was continuously monitored. Histamine secretory rates were calculated by subtracting the arterial from the venous histamine concentrations and multiplying the difference by gastric plasma flow. Two separate 20-min infusions of pentagastrin, separated by 60 min, resulted in a peak of histamine release in 5 to 10 min that returned to base line within 20 min. During the first infusion, histamine release peaked at 179 ng/min, whereas, during the second infusion, histamine peaked at 125 ng/ml. The increase in gastric blood flow to pentagastrin correlated with the increases in histamine release. Somatostatin infused into the gastric artery to attain a concentration of 10 nM, a concentration that results in the inhibition of gastric acid secretion, abolished the gastric histamine release to pentagastrin. In addition, somatostatin also attenuated the gastric vasodilation to pentagastrin. Our data indicate that, in the in vivo dog model, pentagastrin can cause a pulsed release of gastric histamine, and somatostatin inhibits this release of histamine.

Measurement of arachidonic acid in the plasma by gas-liquid chromatography-flame ionization using dihomo-gamma-linolenic acid as an internal standard.

A gas-liquid chromatography-flame ionization method is described for measuring arachidonic acid in plasma using dihomo-gamma-linolenic acid as an internal standard. We found this technique to -e reproducible, and quicker and superior to previously described techniques because of the similar physico-chemical properties of the unsaturated fatty acid internal standard and arachidonic acid. In addition, we observed that the use of the saturated fatty acid, n-tricosanoic acid, was unsatisfactory as an internal standard because of its poor extractability from plasma as compared to arachidonic acid.

Combination contraceptive effects on monthly cycle of plasma aldosterone, renin activity and renin substrate.

A post-ovulatory peak of fasting supine plasma aldosterone (PA) preceded or accompanied by an increase in plasma renin activity (PRA) was previously reported. These studies have now been extended in 4 additional normal menstruating women and 4 women taking oestrogen-progestogen oral contraceptive pills (OCP), all studied daily for an entire cycle. Distinct luteal phase increases in PRA were seen in the 4 normals, with 2 also demonstrating a rise in PA. Plasma renin substrate (PRS) was usually unvarying throughout the control cycles. The women taking OCP, on the other hand, all had PA and PRA peaks that were apparent by the fourth or fifth day of taking "the pill". All 4 of the treated women had elevated PRS levels but only one woman showed an increase which preceded the elevation of PRA and PA. Plasma cortisol levels were usually above the normal range in the women taking OCP. This study thus indicates that factors other than oestrogen-induced increased substrate production may be responsible for the PRA and PA rise during OCP treatment. Such factors might be the natri-uretic effects of oestrogens and progestogens or a direct effect on renin secretion by one of these steroids.

Increased PGE2 excretion by dDAVP in humans depends on state of hydration.

The relationship of renal prostaglandin E2 (PGE2) excretion (UPGEV) to water deprivation, water diuresis, and subsequent antidiuresis by 1-desamino-8-D-arginine vasopressin (dDAVP) was studied in female volunteers. After 16 h of water deprivation, the subjects began a sustained water diuresis for 8 h. This diuresis caused a transient twofold rise in UPGEV at 2 h (P less than 0.05), which then fell back to or below baseline levels. dDAVP given during the water diuresis caused a transient rise of UPGEV as urine volume decreased and plasma osmolality fell from 277 +/- 1.5 to 271 +/- 2 mosmol/kg (P less than 0.01). Another group of subjects had the water diuresis discontinued after 4 h with dDAVP given at the 5th h when urine volume was decreasing and urine osmolality was increasing. In this setting dDAVP did not produce as great a fall in plasma osmolality nor did it increase UPGEV. These data indicate that renal prostaglandin synthesis (as determined by UPGEV) is increased transiently by an acute water load; dDAVP given during continued water ingestion results in a fall in plasma osmolality and increased PGE excretion; however, dDAVP does not increase UPGEV during normal hydration; and UPGEV is independent of changes in urine flow. These findings imply that renal prostaglandins may have a functional role in humans to inhibit the hydroosmotic actions of antidiuretic hormone, and thus hasten the excretion of a water load, and to prevent overhydration when inappropriate antidiuresis occurs. However, there is no evidence that the stimulus for prostaglandin production is dDAVP per se.

A dual effect of nonsteroidal anti-inflammatory drugs on renal water handling in humans.

The role of renal prostaglandins (PGs) in the induction and maintenance of a sustained water diuresis was studied by using two different nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and meclofenamate given either before or during the diuresis. Urinary PGE2 excretion increased with the initiation of a water diuresis (from 2.5 +/- 0.7 to 6.1 +/- 1 pg/kg/min during the 2nd hr, P less than .01) but then fell back to control levels when water diuresis was established. Pretreatment with NSAIDs abolished the initial increase in PGE excretion and delayed the onset of the water diuresis so that 1 hr after the initiation of the diuresis, the urine osmolality in the control subjects was 205 +/- 50 mosm/kg as compared with 440 +/- 55 mosm/kg (P less than .05) for the NSAID-treated subjects. In contrast, the urine osmolality did not change when subjects were given the NSAIDs 5 hr after the onset of the water diuresis. However, the NSAIDs did decrease urine volume and free water clearance for as long as the urinary PG excretion was suppressed, regardless of when the drugs were given. This action of the NSAIDs to decrease the urine volume and free water clearance was due to a decrease in delivery of water and solute to the diluting segments of the nephron. These data imply that the transient increase in urinary PGE excretion occurring at the onset of a water diuresis has functional significance, as NSAIDs block the increase in PG synthesis and also interfere with the onset of a water diuresis by delaying the attainment of a maximally dilute urine.(ABSTRACT TRUNCATED AT 250 WORDS)