Tachykinin receptors in smooth muscles: a study with agonists (substance P, neurokinin A) and antagonists

Four preparations, sensitive to tachykinins, the guinea-pig urinary bladder, the rat duodenum, the hamster and dog urinary bladders have been investigated and compared with four other preparations described before: the guinea-pig ileum and trachea, the dog carotid artery and the rabbit mesenteric vein. On the basis of the order of potency of agonists, evaluated with substance P, physalaemin, eledoisin, kassinin and neurokinin A, the preparations can be separated into three groups, the guinea-pig urinary bladder and the dog carotid artery, in which substance P is the most potent and neurokinin A the weakest tachykinin, the rabbit mesenteric vein, the guinea-pig trachea and the rat duodenum, in which the opposite order is observed and the hamster and dog urinary bladders, in which kassinin is the most potent agonist. The guinea-pig ileum shows similar sensitivity to the five tachykinins. C-terminal partial sequences appear to be weaker than SP-(1-11) in three of the four new preparations, SP-(6-11) being first in the rat duodenum and slightly weaker than SP-(1-11) in the hamster and dog urinary bladders. Studies performed with antagonists or inhibitors of endogenous agents suggest that substance P and neurokinin A act directly on specific receptors. The effects of the two peptides are reduced by antagonists analogues of the sequence SP-(4-11). One of the antagonists, [D-Pro4,Lys6,D-Trp7,9,10, Phe11]SP-(4-11) has been shown to be competitive against substance P and neurokinin A in the guinea-pig ileum, the guinea-pig urinary bladder and the rat duodenum. This compound, shows definitely higher activity against neurokinin A and kassinin, compared to substance P in various preparations. [D-Tyr4,D-Trp7,9,Nle11]SP-(4-11) is the most potent tachykinin antagonist in the hamster and dog urinary bladders. In these preparations, the antagonists act also against substance P, but with lower affinity. These findings with antagonists support the indication, emerged from the order of potency of agonists, that tachykinins may act on two and possibly three different receptor types.