Characterization of receptors for kinins and neurokinins in the arterial and venous mesenteric vasculatures of the guinea-pig.

1. In the present work, we have studied the microvascular reactivity of the arterial and venous mesenteric beds of the guinea-pig to bradykinin, neurokinins and other agents. 2. The vasoactive properties of three selective agonists for neurokinin receptors, namely [Sar9, Met (O2)11]SP (NK1), [beta-Ala8]NKA(4-10) (NK2) and [MePhe7]NKB (NK3), were evaluated on precontracted arterial and venous mesenteric vasculatures of the guinea-pig. The NK1-selective agonist, [Sar9,Met(O2)11]SP (1 to 1000 pmol), induced an endothelium-dependent and N omega-nitro-L-arginine methyl ester (L-NAME)-sensitive relaxation of the arterial vasculature precontracted with methoxamine, whereas the NK2 and NK3-selective agonists were virtually inactive at high doses (1000 pmol). 3. The three selective neurokinin receptor agonists were inactive in the non-precontracted arterial and venous mesenteric vasculatures as well as in the precontracted venous mesenteric vasculature. 4. Bradykinin (0.1 to 100 pmol) induced a marked dose- and endothelium-dependent vasodilatation of the precontracted arterial and venous vasculatures. ED50 values were 5.5 pmol on the arterial side and 1.9 pmol on the venous side. In contrast, desArg9-bradykinin was inactive at doses up to 1000 pmol. Furthermore, on the arterial and venous sides, a higher dose of bradykinin (1000 pmol), induced a biphasic effect, a transient constriction followed by a marked and sustained vasodilatation. The vasodilator effects of bradykinin were abolished by Hoe 140 (0.1 microM) and CHAPS, markedly reduced by L-NAME and were unaffected by [Leu8]desArg9-bradykinin (0.1 microM) on both sides of the mesenteric vasculature. Hoe 140 also abolished the arterial vasoconstrictions induced by high doses of bradykinin. 5. Noradrenaline, angiotensin II and endothelin-1 produced contractions on both sides of the mesenteric circulation, while acetylcholine (arterial side) and sodium nitroprusside (arterial and venous sides) caused vasodilatation.6. Our study supports the view that NK1 receptors responsible for vasodilatation are present solely in the endothelium of the arterial mesenteric vasculature of the guinea-pig. On the other hand, bradykinin(0.1 to 100 pmol) exerts predominantly vasodilator effects on both sides of the mesenteric vasculature via selective activation of B2 receptors located on the endothelium. The same receptor type located on the smooth muscle appears to be responsible for the arterial and venous constriction with high doses of bradykinin.