SR 121463A, a potent and selective, orally active, nonpep-tide vasopressin V 2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V 2 receptors in rat, bovine and human kidney (0.6 K i [nM] 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (K i 0.26 0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [ 3 H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V 2 receptors. In comparison, the nonpeptide V 2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V 2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (K i in the 10 nanomolar range). Moreover , OPC-31260 exhibited a poor V 2 selectivity profile and can be considered as a V 2 /V 1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na and K excretions unlike that of known diuretic agents such as furosemide or hydrochloro-thiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattle-boro rats. Thus, SR 121463A is the most potent and selective , orally active V 2 antagonist yet described and could be a powerful tool for exploring V 2 receptors and the therapeutical usefulness of V 2 blocker aquaretic agents in water-retaining diseases. (J. Clin. Invest. 1996. 98:2729-2738.) Key words: SR 121463A • vasopressin • nonpeptide antagonist • V 2 receptor • aquaretic

Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) are marketed as racemic mixtures, composed of (R)- and (S)- enantiomers. Racemic NSAIDs are potent cyclooxygenase (COX) inhibitors only through the action of the (S)- enantiomers, as the (R)- enantiomers do not exhibit COX inhibition. However, the (R)- enantiomer of ketoprofen exhibits potent analgesic activity and minimal ulcerogenic potential. To extend these observations, we examined the (R)- and (S)- enantiomers of RS- ketorolac, (S)- ketorolac exhibited potent COX1 and COX2 enzyme inhibition, whereas (R)- ketorolac was > 100-fold less active on both COX subtypes. Both enantiomers did not affect norepinephrine or serotonin uptake sites, and nitric oxidase or lipoxygenase activities, nor did they demonstrate any affinity for opioid receptors (mu, delta, or kappa). In experimental models, (S)- ketorolac exhibited about 10-fold greater activity than (R)- ketorolac in the murine phenylquinone writhing model. In this model, morphine sulfate was effective at much lower doses, however, and neither (R)- nor (S)- ketorolac showed any morphine-sparing effect. In the rat gait test for analgesia in the foot paw after injection of brewers yeast suspension, neither (R)- nor (S)- ketorolac affected paw volume. However, both provoked changes in gait scores, the (S)- enantiomer being 30-fold more potent than the (R)- enantiomer. A similar reduction was observed with respect to ulcerogenic potential, measured by direct microscopic changes after test conclusion. These findings suggest that (R)- ketorolac may possess analgesic activity that is independent of COX inhibition and may be associated with reduced ulcerogenic potential compared to effects exhibited by (S)- ketorolac.

Adipocyte blood flow in four distinct adipose tissue depots has been measured in conscious, unrestrained, male Sprague-Dawley rats by using the microsphere technique together with cellularity determinations. Blood flow was determined in young rats (90 days old, 387 g mean body wt), spontaneously obese rats (450 days old, 713 g mean body wt), and long-term calorically restricted rats (450 days old, 390 g mean body wt), therefore allowing the comparison of the relative effects of age and fat mass on adipose tissue blood flow. Results of these experiments indicate that while cardiac index remained constant, cardiac output increased in only the obese group, concomitant with increased body fat mass. Spontaneously obese rats exhibited increased adipose tissue depot weight, fat cell lipid, and fat cell size compared with young and restricted groups. Despite significant differences in cell volume, blood flow per cell was remarkably similar between young and obese rats. Long-term caloric restriction, however, was associated with decreased flow per cell. Interdepot comparisons of flow per unit surface area (mm2) or per unit volume (pl) indicate that mesenteric cells receive significantly more blood than cells of the other depots. Our results suggest that adipocyte blood flow is dependent in part on anatomic location, may be further influenced by age or dietary manipulation, and is not a limiting factor in the enlargement of adipocytes during the development of spontaneous obesity.

Chan, P.S., and P. Cervoni: Prostaglandins, prostacyclin, and thromboxane in cardiovascular diseases. Drug Dev. Res. 7:341-359, 1986. Prostaglandins appear to play an important role in or to be found therapeutically useful in various cardiovascular diseases, such as hypertension, arrhythmias, ventricular fibrillation, arterial thrombosis, myocardial ischemia, myocardial infarction, certain types of angina pectoris, atherosclerosis, circulatory shock, and peripheral arterial diseases, etc. Prostacyclin and prostaglandins El, E2, and D2 are considered beneficial, while thromboxane A2 and prostaglandin FpU are considered harmful and their formations should be inhibited. Inhibition of the formation of the vasodepressor prostaglandins, such as prostacyclin and prostaglandin E2, in humans and animals leads to increase in arterial blood pressure and total peripheral resistance as well as to decrease the efficacy of most antihypertensive drugs, which suggests that these vasodepressor prostaglandins play an important role in hypertension. Most prostaglandins exert antiarrhythmic activity. Prostacyclin and thromboxane synthetase inhibitors are particularly effective in myocardial infarctionlreperfusioninduced arrhythmias and ventricular fibrillation (sudden cardiac death) where the classical antiarrhythmic agents are not very effective. Prostacyclin and thromboxane synthetase inhibitors are effective in reducing myocardial infarct size, increasing coronary blood flow, and inhibiting arterial thrombosis. Atheroclerosis may result from decrease in prostacyclin formation in the blood vessel wall due to inhibition by the high concentration of lipid peroxides in the blood. Prostacyclin stimulates cholesterol ester hydrolase, the enzyme that converts cholesterol ester to free cholesterol for mobilization out of the cells. PGE2 inhibits acyl CoA cholesterol-0-acyltransferase (ACAT), the enzyme that catalyzes the reesterification of free cholesterol. Therefore, prostacyclin, PGE2, and their stable analogs may be useful for the prevention and induction of regression of atherosclerosis. Prostacyclin, PGE1, and other stable prostaglandin analogs, such as iloprost and viprostol, have Received final version December 20, 1985; accepted February 20, 1986 342Chan and Cervoni been reported to be beneficial for the treatment of peripheral arterial diseases. It is very likely that new drugs that affect the prostaglandin systems will be introduced for the prevention and treatment of various cardiovascular diseases in the very near future.

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