Mechanisms underlying ACh induced modulation of neurogenic and applied ATPconstrictions in the submucosal arterioles of the guinea-pig small intestine

1 Role of the vascular endothelium in acetylcholine (ACh) induced modulatio n of neurogenic and applied ATP (adenosine 5'-triphosphate) constrictions o f intestinal submucosal arterioles was investigated. 2 Arteriole constrictions, induced either by exogenous ATP or evoked by per ivascular nerve stimulation, were attenuated in the presence of ACh. 100 nM ACh almost completely abolished neurogenic constrictions whereas up to 10 mu M ACh reduced constrictions to exogenous ATP by only about 60%. 3 Treatment of the arterioles with 100 mu M N omega-nitro-L-arginine (NOLA) and 5 mu M indomethacin, to block respectively nitric oxide (NO) and prost anoid release from the endothelium, had no effect on the ACh induced inhibi tion of neurogenic constrictions but significantly attenuated the inhibitor y effects of ACh on constrictions to exogenous ATP. 4 Disruption of the vascular endothelium had no effect on the ACh induced i nhibition of neurogenic constrictions but attenuated the inhibitory effects of ACh on applied ATP constrictions to the same extent as after treatment with NOLA and indomethacin. In comparison, endothelial disruption completel y abolished the inhibitory effect of substance P (SP) on exogenously applie d ATP constrictions. 5 50 nM ACh significantly attenuated the amplitude of neurally evoked excit atory junction potentials (ejps) recorded from the vascular smooth muscle w ithout altering the time constant of decay (tau(decay)) Of the ejps. 6 It is concluded that ACh inhibits neurogenic constrictions by prejunction al modulation of transmitter release from the perivascular sympathetic nerv es with no major role for endothelial paracrine factors. 7 Endothelial NO and/or prostanoids mediate some of the ACh induced inhibit ion of constrictions to exogenous ATP whereas the endothelium independent i nhibitory effects of ACh are attributed to a direct action of ACh on the va scular smooth muscle. However, an indirect effect resulting from activation of vasodilator nerves cannot be ruled out.