Functional interaction between losartan and central tachykinin NK 3 receptors in the conscious rat

1 The cardiovascular and behavioural effects elicted by the intracerebroventricular (i.c.v.) injection of substance P (SP), neurokinin A (NKA), [MePhe 7 ]neurokinin B ([MePhe 7 ]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 AT 1 (losartan and its active metabolite EXP 3174), angiotensin AT 2 (PD 123,319) or tachykinin NK 3 (R 486) receptors. 2 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 [MePhe 7 ]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 [MePhe 7 ]NKB in increasing MAP and HR, but did not produce water intake or wet dog shake behaviours. 3 Losartan (650 pmol, i.c.v.) reduced significantly the cardiovascular and behavioural responses to All or [MePhe 7 ]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 [MePhe 7 ]NKB‐mediated responses, the dose of 650 pmol blocked only the responses to AII. 4 The central responses to All and [MePhe 7 ]NKB were not affected by PD 123,319 (650 pmol). On the other hand, the [MePhe 7 ]NKB‐induced central effects were significantly reduced by R 486 (650 pmol). The NK 3 ‐selective antagonist had no effect against AII. 5 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 NK 3 receptor in rat brain. However, the cardiovascular and behavioural responses induced by central tachykinin agonists (SP, NKA and [MePhe 7 ]NKB) and All are mediated by unrelated mechanisms.