Summary1. The effects of some a-and /8-adrenoceptor agonists and antagonists were studied on isolated segments of rabbit intestine in an attempt to characterize the two types of inhibitory response produced by sympathomimetic amines. 2. Phenylephrine, an a-adrenoceptor agonist, produced an inhibition of rapid onset, from which recovery occurred despite the continued presence of the drug. On washout there was an overshoot in contraction height. Isoprenaline, a /3-adrenoceptor agonist, produced an inhibition of slow onset which was maintained throughout the presence of the drug and there was no overshoot on washout.3. Adrenaline resembled phenylephrine more closely than it resembled isoprenaline, in that it showed more affinity for a-adrenoceptors, whereas noradrenaline, and the transmitter released on periarterial nerve stimulation, behaved more like isoprenaline, although both types of receptor were affected. 4. Adenosine-5'-triphosphate produced an inhibition resembling that produced by an a-adrenoceptor agonist, whereas the dibutyryl analogue of cyclic adenosine 3',5'-monophosphate (cyclic 3',5'-AMP) produced an inhibition resembling that produced by a /3-adrenoceptor agonist.
I Acetylcholine-induced contractions of the isolated chronically denervated soleus muscle of the mouse consist of two phases, but both phases are equivalent to the contracture phase seen in vivo.2 Low [Ca2+J0 (0.5-1.5 mM) augmented peak tension, as well as the rate of relaxation, of the first phase, but inhibited the second phase. Ethyleneglycol-bis4p-aminoethyl ether)-N,NM-tetraacetic acid (EGTA) or La3+ (2 mM) also inhibited the second phase, but not the first. 3 It was concluded that the first phase requires Ca2+ release from the sarcoplasmic reticulum, and is terminated by inactivation of the contractile process. The second phase is caused by the entry of activator Ca2+ from the extracellular space.4 Increasing [Ca2+]o to 5 or 10 mm after the addition of acetylcholine caused a contraction, starting after a delay of about 50 seconds. EGTA or La3+ added during the second phase of the acetylcholine contraction caused relaxation after a much shorter lag time. 5 It is concluded that most of the Ca2+ entering from the extracellular fluid is taken up by the sarcoplasmic reticulum. 6 The acetylcholine second phase was augmented in low (25 mM) [Na+I0. It is concluded that Na+ and Ca2+ compete for the acetylcholine controlled ionic channels. 7 Isolated chronically denervated diaphragm muscles were less sensitive to acetylcholine and the contraction usually consisted of a first phase only. 8 It is concluded that sequestration of Ca2+ entering from the extracellular fluid is more complete in the diaphragm.
1 A study was made of desensitization in chronically denervated and in normally innervated mouse soleus muscles. 2 Very high concentrations of acetylcholine produced small contractions of the innervated muscles; these were reduced in size when the addition was repeated 1 min after wash-out. 3 Desensitization in innervated muscles was receptor specific: contractions in response to KCI and caffeine were not reduced following acetylcholine, nor did KCI produce desensitization. 4 In chronically denervated muscles non-specific desensitization was observed if acetylcholine was added in the presence of low concentrations of acetylcholine or carbachol. Contractions to KCI but not to caffeine were reduced. KCl produced a similar kind of desensitization. 5 After washing out moderate or supramaximal concentrations from the chronically denervated muscle no desensitization was observed. However, 1 min after washout of very high concentrations the muscle was non-specifically desensitized. 6 It is concluded that relatively high concentrations of acetylcholine are required to produce specific desensitization in the soleus muscle. Chronically denervated muscles, being supersensitive, show non-specific loss of sensitivity with concentrations of acetylcholine too low to produce specific desensitization.
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