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The effect of tolmetin on prostaglandin synthesis by minces of rat renal medulla and on prostaglandin cyclooxygenase of rabbit renal medulla was determined in vitro. The effect of tolmetin was compared to the effects of indomethacin and ibuprofen. Pretreatment of rats in vivo with tolmetin, indmethacin or ibuprofen reduced prostaglandin synthesis by minces of renal medulla. Incubation of medullary tissue in medium containing tolmetin or indomethacin also decreased prostaglandin production. Both drugs reduced O2 consumption by prostaglandin cyclooxygenase from rabbit renal medulla. In addition, the effect of tolmetin, indomethacin and ibuprofen on renal blood flow and the intrarenal distribution of renal blood flow was measured in anesthetized dogs. Tolmetin and ibuprofen resemble indomethacin in reducing renal blood flow and in shifting the distribution of renal cortical flow from the inner cortex toward the outer cortex. It is concluded that tolmetin is an effective inhibitor of prostaglandin synthesis and affects renal function in a fashion similar to other prostaglandin synthesis inhibitors.

The ability of indoprofen or sodium indoprofen to inhibit phenylquinone-writhing and renal prostaglandin synthesis was determined in mice following a single oral dose of either drug. Male mice (4/group) were treated with 1.5 mg/kg indoprofen or sodium indoprofen. Inhibition of phenylquinone-writhing was determined at 2, 4, 8, 16 and 32 hr post treatment. Animals were sacrificed and blood collected for determination of plasma indoprofen concentration. Kidneys were removed and prepared for determination of renal prostaglandin synthesis by an in vitro technique. Phenylquinone-writhing was significantly depressed by both preparations at 2 and 4 hr post treatment. Sodium indoprofen also significantly depressed writhing at 8 hr post treatment. Renal prostaglandin synthesis, like phenylquinone-writhing, was significantly depressed at 2 and 4 hr after drug treatment. Plasma indoprofen concentration was correlated with both inhibition of phenylquinone-wrighing and inhibition of renal prostaglandin synthesis. When writhes were plotted versus prostaglandin synthesis, a positive correlation was observed suggesting a temporal relationship between inhibition of phenylquinone-writhing and inhibition of renal prostaglandin synthesis.

The realtionship between in vitro prostaglandin production by renal medullary tissue and hypertension was investigated in three models of hypertensive rat, i.e., DOCA, Goldblatt and SHR. Medullary minces were incubated for 30 minutes. Following incubation tissue PGE2 concentration was quantified using mass fragmentography. Media PGE2 concentrations were quantified using radioimmunoassay. Concentrations of PGE2 in tissue from Goldblatts and SHRs were significantly less than normotensive controls. The concentration of PGE2 in media after incubating SHR tissue was significantly less than normotensives. The data suggest that alterations in PGE2 metabolism are similar in Goldblatt and SHR hypertension.

A method is described for identifying Ca++ ionophores using the protozoa Actinosphaerium. This organism is a free-floating spherical form with filamentous axopods radiating from the surface. The axopods are composed of microtubules that disaggregate upon exposure to intracellular Ca++. In the presence of an appropriate ionophore, extracellular Ca++ will pass the cell membrane, enter the cell, and disrupt microtubules. The resultant shortening of axopods can be easily quantified under a microscope. This system may prove to be a valuable research tool in the identification of compounds that possess the ability to facilitate transmembrane Ca++ movement.

Increased activity of prostaglandin synthetase in spontaneously hypertensive rats (SHR) during development has previously been reported. The investigations reported herein utilized an immunofluorescent technique to qualitatively assess the activity of the first enzyme in the PGE2 biosynthetic pathway, the prostaglandin-forming cyclooxygenase (PG-C), in SHR kidneys during development. PG-C antigenicity increased from 4 to 15 weeks in both SHRs and Wistar Kyoto normotensive rats. However, in agreement with our previous in vitro data no difference in PG-C was observed between strains at any age.

Many non-steroidal anti-inflammatory, analgesic drugs appear to produce their effects by inhibiting prostaglandin synthesis. These investigations were undertaken to determine whether a new anti-inflammatory compound, indoprofen, inhibited prostaglandin synthesis in vitro when present in incubation medium or following systemic administration. The results indicated that indoprofen effectively inhibited prostaglandin synthesis in kidney and uterus. Indoprofen was equally effective as indomethacin and aspirin in inhibiting prostaglandin synthesis. The relative potency of the drug was intermediate between indomethacin and aspirin.

Synthesis of prostaglandin E2 by renal medulla from SHR and WKY rats was compared during early postnatal development. Although arterial blood pressure was significantly higher in SHR as early as 6 weeks of age, no difference in renal medullary prostaglandin synthesis was observed.