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The recently discovered rat neuropeptide Y (NPY) receptor, the Y5 subtype, has been proposed to mediate the NPY-induced feeding response and therefore plays a central role in the regulation of food intake. These conclusions were based on studies with peptidic agonists. We now report studies in which phosphothioate end-protected antisense oligodeoxynucleotides (ODNs) targeted to prepro NPY (prepro NPY antisense ODNs) or to the Y5 receptor (Y5 antisense ODNs) were used to assess the functional importance of this novel receptor subtype in vivo. NPY antisense ODNs given intracerebroventricularly to rats prevented the increase in hypothalamic NPY levels during food deprivation and inhibited fasting-induced food intake. Likewise, repeated intracerebroventricular injections of Y5 antisense ODNs prevented fasting-induced food intake in rats. Moreover, two Y5 antisense ODNs, targeted to different sequences of the receptor, significantly decreased basal food intake and inhibited the increase in food intake after intracerebroventricular injection of NPY. These effects proved to be selective, since the feeding response to galanin was not affected. Analysis of the structure of feeding behavior revealed that prepro NPY and Y5 receptor antisense ODNs reduced food intake by inducing decreases in meal size and meal duration analogous to the orexigenic effects of NPY that are mediated by increases in these parameters. Although changes in Y5 receptor density could not be measured, the results with Y5 antisense ODNs strongly suggest that this receptor subtype mediates the feeding response to exogenous and endogenous NPY. Selective Y5 antagonists may therefore be of therapeutic value for the treatment of obesity and eating disorders.

OBJECTIVE: These studies were designed to test the hypothesis that endogenous leptin, acting within the brain plays a physiologically important role in the control of food intake in lean rats. DESIGN: Antibodies directed against mouse leptin were raised in rabbits. The puri®ed IgG fractions prepared from pre-immune and immune sera were injected into the right lateral ventricle of lean Sprague-Dawley rats and obese Zucker fatty faafa rats. Changes in food intake were measured over the following 20 h period. RESULTS: The anti-leptin antibodies recognized a major epitope in the C-terminal region of the leptin molecule. The antibodies bound both mouse and rat leptin with high af®nity, but did not bind human leptin, or a selected range of other hormones and neurotransmitters known to affect food intake. In competition studies, the binding of mouse, but not human leptin to the human Ob-Rb receptor was prevented by the antibodies. This indicates that the antibodies can block the action of leptin by preventing its binding to the Ob-Rb receptor. Injection of the anti-leptin antibodies into the brain of lean rats led to an increase in food intake during the ®rst hour after injection which was not compensated during the following 19 h period. Injection of the anti-leptin antibodies did not affect food intake in Zucker fatty faafa rats which express an abnormal Ob-Rb receptor. CONCLUSION: Endogenous leptin acting within the brain plays a physiologically important role in the control of food intake in lean rats.

Oxprenolol, 40, 80 and 160 mg, was administered orally to seven healthy volunteers. Over the following eight hours repeated measurements were made of the plasma concentrations and effects on heart rate, myocardial contractility (PEPc) and systolic and diastolic blood pressure in recumbency, in the upright position and during physical effort at a work load of 120 watts on a bicycle ergometer. The maximum plasma levels and the area beneath the plasma concentration curves increased roughly in proportion to the dosage increment. No evidence of first-pass inactivation in the liver was found. The half-life of the drug in plasma was approximately 80 minutes, irrespective of the dose administered. Oxprenolol slowed heart rate, prolonged PEPc and lowered systolic blood pressure, by comparison with values recorded after a placebo. The effects were generally least marked in the recumbent position and most marked during effort, when a clear-cut dose-response relation was found. The pharmacodynamic effects of oxprenolol were compared with its concentration in plasma. Marked beta-receptor blockade still persisted eight hours after dosing, although at this time, after doses of 40 and 80 mg, the drug could not be detected in plasma.

OBJECTIVE: The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator of food intake, using the human leptin mutant R128Q leptin. DESIGN: In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agonistic activity and to competitively inhibit the proliferative effects of leptin. To determine whether R128Q leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) into rats in the absence and presence of leptin. R128Q was also injected intraperitoneally (i.p.) into oba aob and into dba adb mice expressing, respectively, either normal or defective ObRb receptors. RESULTS: R128Q was shown to be a competitive antagonist of leptin induced cellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly less potent than leptin itself. In fasted rats, the inhibitory effects of leptin and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R128Q leptin produced the same inhibition of food intake as leptin when injected i.p. in oba aob mice and, like leptin, was inactive after i.p. injection to dba adb mice. CONCLUSION: R128Q leptin is a leptin agonist in vivo, but behaves as an antagonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for investigating the physiological actions of leptin.

In the Anturan Reinfarction Trial (ART 1978). reinfarctions and, expecially, sudden cardiac deaths were less frequent among patients treated with sulphinpyrazone than among those receiving placebo medication. There is wide, general interest in elucidating the mechanism by which sulphinpyrazone brings about these protective effects. Although they are presumed to be in some way related to its platelet-stabilizing action, conclusive evidence is lacking and exactly how the two phenomena are linked is still very much a matter of conjecture. Various research groups have therefore investigated the effects of sulphinpyrazone on the course of events following acute experimental myocardial infarction in animals. In their initial studies, Kelliher et al and Povalski et al (in press) and Moschos et al (1979) found that the early arrhythmias (ventricular fibrillation, ventricular tachycardia and ventricular extrasystoles) occurring subsequent to coronary occlusions in cats and dogs were less frequent if the animals had been pretreated with sulphinpyrazone. We have studied the effects of the drug on mortality after ligation of the left anterior descending coronary artery (LAD) in the rat.The operation was performed according to Selye et al (1960) in male rats (Tierfarm Sisseln), 222 f 2 g, anaesthetized with ether. Essentially, this technique consists in ligating the LAD between the left auricle and the pulmonary cone. If the operation is completed within 30 s, spontaneous respiration recommences after air has been expelled from the thorax by gentle lateral pressure and the wound closed.A few animals died as a result of haemorrhage during or short!y after the operation. In the present series of experiments, there were four deaths in the sulphinpyrazone group and two among the controls. These animals were not included in the evaluation of the results.* Correspondence.Sulphinpyrazone was administered for three days in a dose of 30 mg kg-' S.C. twice daily, mornings and evenings. The controls received 0.90,; NaCl (saline). LAD ligature was performed on the second day of treatment, that is between 1-6 h after the third sulphin. pyrazone dose. N o attempt was made to relate subsequent mortality with the exact time, after the last dose, of coronary artery ligation. After surgery, i.e. excluding the animals that died during the operation, the sulphin. pyrazone group numbered 91 rats and the control group 103. These were composed of 12 separate control and sulphinpyrazone-treated groups with 5-1 1 rats in each.The post operative mortality was followed up in both groups over a period of 21 days. In computing the mortality rates, a distinction was drawn between deaths within 30 min of the operation and later deaths. This was done because, according to previous findings (Kane et a1 1979;Kenedi & Losonci 1973), deaths occurring in the first half hour are predominantly due to arrhythmias, whereas, in our own experience, the main causes of subsequent deaths are pulmonary oedema, hydrothorax or massive infarctions with dilatation of the he...