The time course of the effects of phenylephrine (10 gmol/l) on force of contraction and on inositol phosphates in electrically driven left auricles from rat hearts labeled with [3H] inositol was studied. All experiments were performed in the presence of propranolol (1 ,umol/l) and LiCI (10 mmol/l). Products measured after separation with high-performance liquid chromatography were inositol 1-phosphate (1-IP1), inositol 1,4-bisphosphate (1,4-IP2), inositol 1,3,4trisphosphate (1,3,4-IP3),

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... 1,4,5-trisphosphate (1,4,5-IP3), and inositol 1,3,4,5tetrakisphosphate (1,3,4,5-IP4). All inositol phosphates increased after stimulation with phenylephrine. 1,4,5-IP3 was the first compound to rise maximally within 30 seconds; this rise was followed by an increase in 1,3,4,5-lP4 and 1,4-lP2 beginning within 2 minutes. The increase in 1,3,4-1P3 and 1-I1'was slower and did not reach steady state within 15 minutes. The positive inotropic effect of phenylephrine was maximal after 5 minutes. It is concluded that the increase in the presumed second messengers 1,4,5-iP3 and 1,3,4,5-lP4 coincides with the positive inotropic effect after ael-adrenoceptor stimulation. Since the increase in 1,4,5-lP3 precedes the increase in force of contraction, 1,4,5-lP3 may initiate the positive inotropic effect of ael-adrenoceptor agonists and 1,3,4,5 -lP4 maintains the increase in force of contraction. (Circulation Research 1990;66:580-583) T he phospholipase C-induced hydrolysis of phosphatidylinositol 4,5-bisphosphate produces inositol 1,4,5-trisphosphate (1,4,5-1P3) and diacylglycerol.1 1,4,5-1P3 has been shown to mobilize intracellular calcium,1 although it is still a matter of debate whether 1,4,5-1P3 can release calcium from sarcoplasmic reticulum in the heart.2,3 However, it is well established that a1-adrenoceptormediated positive inotropic effect is accompanied by an increased phosphoinositide turnover in the heart of rats and humans.4-7 We have recently shown that the a1-adrenoceptorinduced increase in 1P3 precedes the positive inotropic effect.58 The time course of 1P3 accumulation after stimulation with phenylephrine had a biphasic shape. Since the 1P3 fraction was not separated further, it remained unclear whether the biphasic time course could be explained by the occurrence of different 1P3 isomers and/or inositol 1,3,4,5-