Functional interaction between losartan and central tachykinin NK3 receptors in the conscious rat

Abstract

The cardiovascular and behavioural effects elicted by the intracerebroventricular (i.c.v.) injection of substance P (SP), neurokinin A (NKA), [MePhe7]neurokinin B ([MePhe7]NKB) or angiotensin II (All) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for angiotensin AT1 (losartan and its active metabolite EXP 3174), angiotensin AT2 (PD 123,319) or tachykinin NK3 (R 486) receptors. I.c.v. administration of 25 pmol All evoked an increase in mean arterial blood pressure (MAP) and water intake behaviour, accompanied by a transient bradycardia, whereas 25 pmol [MePhe7]NKB caused a transient increase in MAP and heart rate (HR) concurrently with marked wet dog shake behaviour. At the same dose, SP and NKA were more potent than [MePhe7]NKB in increasing MAP and HR, but did not produce water intake or wet dog shake behaviours. Losartan (650 pmol, i.c.v.) reduced significantly the cardiovascular and behavioural responses to All or [MePhe7]NKB, but not to SP or NKA. While 65 pmol losartan was inactive, 260 pmol inhibited selectively the central effects of AII Whereas EXP 3174 (6.5 nmol) blocked both All and [MePhe7]NKB‐mediated responses, the dose of 650 pmol blocked only the responses to AII. The central responses to All and [MePhe7]NKB were not affected by PD 123,319 (650 pmol). On the other hand, the [MePhe7]NKB‐induced central effects were significantly reduced by R 486 (650 pmol). The NK3‐selective antagonist had no effect against AII. This study provides functional evidence, to support earlier binding data, that losartan (and to some extent its active metabolite EXP 3174) interact with the tachykinin NK3 receptor in rat brain. However, the cardiovascular and behavioural responses induced by central tachykinin agonists (SP, NKA and [MePhe7]NKB) and All are mediated by unrelated mechanisms. 1995 British Pharmacological Society