Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 3. Pyridinylalkyl-substituted 8-[(arylsulfonyl)amino]octanoic acids.

A series of 8-[(arylsulfonyl)amino]octanoic acids substituted with a pyridinylalkyl group along the chain were synthesized and tested in vitro for their ability to both antagonize the binding of thromboxane A2 to its receptors and to inhibit the thromboxane synthase enzyme. This series of compounds were found to inhibit the U 46619-induced aggregation of human platelets and the U 46619-induced contraction of dog saphenous vein. The compounds also inhibited TxA2 biosynthesis in a human microsomal platelet preparation. The relative position of the pyridinylalkyl and arylsulfonamide groups had significant effects on the thromboxane receptor antagonist (TxRA) activity and thromboxane synthase inhibitor (TxSI) activity. Compounds with the pyridine ring at the 7- or 8-position of the octanoic acid side chain were weakly active as TxSI but behaved as potent TxRA at the platelet receptor for TxA2. However, these compounds were agonists at the vascular receptor. Substitution of the pyridinylalkyl group at the 2- or 3-position resulted in compounds with potent TxSI activity and weak TxRA activity. The activity profile of the compounds with the pyridinylalkyl substitution at the 4-, 5-, or 6-position was very desirable. Compound 22 with a pyridinylpropyl substituent at the 4-position was found to display extremely potent TxRA and TxSI properties.

K+ alters cytochrome P-450-dependent arachidonate metabolism by rabbit renomedullary cells.

We studied the effects of K+ on cytochrome P-450-dependent arachidonic acid (P450-AA) metabolism by cells isolated from the rabbit medullary thick ascending limb of Henle's loop (MTAL) by varying K+ from 0 to 7.5 mM in the incubating medium because of the known effects of K+ on AA metabolism. Rabbit MTAL cells convert AA to metabolites that segregate into two peaks (P1 and P2) on reverse-phase high-performance liquid chromatography; P1 contains vasodilator material and P2 an inhibitor(s) of Na(+)-K(+)-ATPase activity. Formation of P450-AA metabolites by MTAL was enhanced by reducing external K+ (P less than 0.01) and was not affected by changes in external Cl- but was dependent on the presence of intact MTAL cells, suggesting that P450-AA metabolism was related to altering ion fluxes and/or cell volume changes. The effects of altered external K+ on MTAL P450-AA metabolism could be nullified by increasing K+ intake before killing the rabbits. Evidence for the absence of a direct effect of zero K+ on Na(+)-K(+)-ATPase was provided by the demonstration that ouabain failed to affect AA metabolism in MTAL cells. We conclude that P450-AA metabolism by MTAL cells can be influenced either directly by altering external K+ in the incubate or indirectly by changing dietary K+ before killing the rabbits. Furthermore, MTAL P450-AA metabolism was independent of changes in external Cl- and Na(+)-K(+)-ATPase activity.

Drug and environmentally induced manipulations of the opiate and serotonergic systems alter nociception in neonatal rat pups.

The influence of drug- and environmentally induced alterations in serotonergic and opiate activity on pain sensitivity was assessed in 6-day-old Sprague-Dawley-derived rat pups using tail flick-testing procedures. The opiate agonist morphine was observed to induce tail flick analgesia that was blocked by concurrent administration of the opiate antagonist naloxone. Similarly, the serotonergic agonist quipazine induced analgesia that was blocked by pretreatment with the serotonergic antagonist metergoline. Naloxone alone did not alter tail flick responsivity in non-isolated, nondeprived neonates, suggesting that the opiate system may not exert a significant tonic inhibition of pain sensitivity in neonates. In contrast, the serotonergic system may exert some tonic analgesic influence at this age, given that metergoline was observed to induce slight hyperalgesia in nondeprived, non-isolated neonates. Twenty four hours of food and maternal deprivation, shown previously to increase brain serotonin and 5-hydroxyindole acetic acid and their ratio in neonates (L. P. Spear & F. M. Scalzo, 1984, Developmental Brain Research, in press) was observed to induce tail flick analgesia, an effect blocked by metergoline. Isolation from siblings and the dam and nest for 30 min also induced tail flick analgesia; this analgesia was blocked by treatment with naloxone prior to testing. Together, these experiments support the suggestion that the serotonergic and opiate systems may regulate pain sensitivity even in neonatal rat pups, with agonist- or environmentally precipitated increases in serotonergic or opiate activity inducing significant analgesia during the early postnatal period.