1The action of substance P (SP) on the release of y-aminobutyric acid (GABA) and acetylcholine (ACh) and on contraction were studied in strips of the guinea-pig urinary bladder. Substance P induced a dose-dependent contraction of strips of guinea-pig urinary bladder (EC50 = 1.2 X 1O-9M). This contraction was not altered by tetrodotoxin, but with a dose of 1O-9M and less, there was a complete inhibition by 10-6 M atropine. Contractions initiated by 3 x 1O-9M SP or more were partly inhibited by atropine. The EC50 value of substance P in the presence of atropine was7.0x 10-9M. 5 Therefore, substance P appears to exert excitatory effects on the contractility of urinary bladder predominantly by stimulating its own receptor located on the cholinergic nerve terminals. GABA released by substance P inhibits stimulation of the cholinergic neurone. However, the direct action of substance P on the cholinergic neurone is more potent that the indirect action via GABA release.
A calcium- and phospholipid-dependent protein kinase C subspecies purified from rat brain was inhibited by thiamylal, thiopentone, pentobarbitone, mepivacaine and bupivacaine. This was attributed to the inhibition of the activation process rather than to direct interaction with the active site of the enzyme. It is well established that unsaturated diacylglycerol markedly increases the affinity of protein kinase C for calcium ions. Kinetic analysis suggested that pentobarbitone brought about the inhibition by competing with the diacylglycerol diolein and that mepivacaine and bupivacaine competed with the phospholipid phosphatidylserine used in the assay. The possibility exists that the effects of local anaesthetics on the function of various tissues are due, in part, to an inhibitory action on protein kinase C.
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