Neuropeptide Y (NPY) is a powerful stimulant of food intake and is proposed to activate a hypothalamic 'feeding' receptor distinct from previously cloned Y-type receptors. This receptor was first suggested to explain a feeding response to NPY and related peptides, including NPY2-36, that differed from their activities at the Y1 receptor. Here we report the expression cloning of a novel Y-type receptor from rat hypothalamus, which we name Y5. The complementary DNA encodes a 456-amino-acid protein with less than 35% overall identity to known Y-type receptors. The messenger RNA is found primarily in the central nervous system, including the paraventricular nucleus of the hypothalamus. The extent to which selected peptides can inhibit adenylate cyclase through the Y5 receptor and stimulate food intake in rats correspond well. Our data support the idea that the Y5 receptor is the postulated 'feeding' receptor, and may provide a new method for the study and treatment of obesity and eating disorders.

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1 The pharmacological profile of valsartan, (S)-N-valeryl-N-([2'-(lH-tetrazol-5-yl) (p.o.). The antihypertensive effect lasted for at least 24 h after either route of administration. After repeated oral administration for 4 days (3 and 10 mg kg-' daily), in 2K1C renal hypertensive rats, systolic blood pressure was consistently decreased, but heart rate was not significantly affected. 7 In conscious, normotensive, sodium-depleted marmosets, valsartan decreased mean arterial pressure, measured by telemetry, after oral doses of 1-30 mg kg'. The hypotensive effect persisted up to 12 h after 3 and l0mgkg-' and up to 24h after 30mgkg-'.8 In sodium-depleted marmosets, the hypotensive effect of valsartan lasted longer than that of losartan (DuP 753). In renal hypertensive rats, both agents had a similar duration (24 h), but a different onset of action (valsartan at 1 h, losartan between 2 h and 24 h). 9 These results demonstrate that valsartan is a potent, specific, highly selective antagonist of AII at the AT,-receptor subtype and does not possess agonistic activity. Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats and in conscious normotensive, sodium-depleted primates.

Angiotensin I1 (Ang II), an octapeptide formed from the decapeptide angiotensin I by the proteolytic action of angiotensin-converting enzyme (ACE), plays a key role in the regulation of blood pressure and fluid and electrolyte homeostasis (for review see ref. 16). Inhibitors of ACE are used for the treatment of hypertension and congestive heart failure and in patients with left-ventricular dysfunction after myocardial infarction (22,26,27). In the past, attempts to develop Ang I1 receptor antagonists failed because they lack oral activity (25) and have unwanted agonistic properties (24). More recently specific, nonpeptide, orally active Ang 11-receptor antagonists have been developed (1,12,15,20,33,37,41,44) from imidazole derivatives first described by Furukawa et al. ( 1 3). This new class of agents provides selective blockade of the AT,-Ang I1 receptor subtype without interfering with the AT2-receptor subtype. The AT,-receptor subtype is responsible for the well-known effects of Ang 11, such as vasoconstriction, aldosterone and epinephrine release, water intake, and cellular proliferation (6,32,36), whereas the pathophysiological role of the AT2-receptor subtype is not yet well understood (63).Losartan (originally known as DuP 753) was the first orally active antagonist of the AT,-receptor subtype (1 2,32,44,46). The blood pressure-lowering effect of losartan is enhanced by its conversion to the active, hepatically-generated carboxylic acid metabolite, EXP3174 or E3174, which is about 20 times more potent than the parent compound as an AT,-receptor antagonist (47). By contrast, valsartan (originally CGP 48933) is a novel and orally active Ang I1 antagonist that does not require hepatic metabolism (5,lO). It is a highly selective antagonist of Ang 11 at the AT,-receptor subtype and does not possess agonistic properties (5). Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats ( 5 ) , conscious normotensive,

In rat coronary arteries, NO is synthesized via the endothelial L-arginine pathway and released after stimulation with acetylcholine. In SHR, chronic antihypertensive therapy with either angiotensin receptor antagonists, an angiotensin-converting enzyme inhibitor, or a calcium antagonist specifically increased the normal endothelium-dependent relaxations to acetylcholine, probably because of their blood pressure-lowering effects, whereas the responsiveness of vascular smooth muscle to NO remained unaffected.