A specific substance P antagonist blocks smooth muscle contractions induced by non-cholinergic, non-adrenergic nerve stimulation

Abstract

Nerve fibres containing substance P (SP) are widely distributed in the body^1–3 and seem to innervate autonomic ganglia, blood vessels, epithelial structures and smooth muscle. SP stimulates secretion from exocrine glands, causes vasodilation and contracts non-vascular smooth muscle⁴. The presence of SP in primary sensory neurones has lent support to the view that it is associated with sensory nerve conduction, conceivably as a transmitter⁵, and that it is a causative factor in the ‘irritative’ response to antidromic stimulation of sensory nerves⁶. Gut smooth muscle contracts in response to non-cholinergic, non-adrenergic nervous stimulation^7,8, and it has been suggested that SP acts as an excitatory transmitter in intramural neurones in the gut wall^2,3,9,10. Recently, a series of synthetic analogues of SP with antagonist activity to SP has been developed^11,12. We report here that a new analogue, (D-Pro², D-Trp^7,9)-SP, exercises a specific, possibly competitive antagonism to SP. While being a partial agonist it antagonized the contractile response to applied SP and to non-cholinergic, non-adrenergic nerve stimulation in the isolated guinea pig taenia coli and rabbit iris sphincter pupillae muscle, suggesting that SP, or a closely related peptide, is indeed a motor excitatory transmitter. In contrast, (D-Pro², D-Trp^7,9)-SP did not inhibit the contractile response to non-cholinergic, non-adrenergic nerve stimulation of smooth muscle from the guinea pig urinary bladder.