HYPOTHALAMIC ANGIOTENSIN RECEPTOR SUBTYPES IN NORMOTENSIVE AND HYPERTENSIVE RATS

The binding of I-125-labeled [Sar(1),Ile(8)]angiotensin II to the hypo thalamic membranes of the normotensive Wistar-Kyoto rat (WKY) and the spontaneously hypertensive rat (SHR) was studied. Displacement experim ents with four centrally active angiotensins, losartan, and PD-123319 confirm the known existence of angiotensin AT(1) and AT(2) receptors i n the rat hypothalamus. The values of the inhibitory constants for ang iotensin II and PD-123319 in the SHR were significantly lower than the corresponding values in the WKY, indicating the possible existence of high-affinity hypothalamic AT1 and AT2 receptors for the two ligands in the SHR. The angiotensin AT1 receptor was further separated into a 5'-guanylyl imidodiphosphate-sensitive and -nonsensitive subtype, indi cating that one of the subtypes is G protein coupled. The SHR has sign ificantly higher numbers of measurable AT(1)-receptor subtypes as well as AT2 receptor subtypes. The former data support the findings of oth er investigators showing that the hypothalamus of the SHR expressed mo re AT(1A) and AT(1B) mRNAs than that of the normotensive rat. Des-Asp( 1)-angiotensin I, which is known to attenuate the central presser acti on of angiotensin II and angiotensin III, acts on both the AT1 and AT2 receptors, although it has a higher affinity for the AT1 receptors. T he overall increase in the number of AT(1) and AT(2) receptors in the SHR is in line with the contention that the brain of the hypertensive rat, compared with that of the WKY, has a hyperactive rein-angiotensin system.