[Inositol trisphosphate, a new "second messenger" for positive inotropic effects on the heart?].
Myocardial alpha 1-adrenoceptors mediate a positive inotropic effect and influence the inositol phosphate cycle. The receptor-stimulated, phospholipase C-mediated hydrolysis of phosphatidylinositol bisphosphate (PIP2) results in the generation of two novel second messengers, inositol trisphosphate (IP3) and diacylglycerol (DG). This effect is concentration-dependent and precedes the increase in force of contraction. Recently, it has been shown that the alpha 1-adrenoceptor-mediated increase in IP3 and force of contraction exists in the human heart as well. Possible mechanisms for an inositol phosphate-mediated positive inotropic effect are: (i) release of Ca2+ from the sarcoplasmic reticulum, elicited by IP3, (ii) increase in Ca2+ sensitivity of the contractile proteins, elicited by IP3, inositol tetrakisphosphate (IP4) and/or DG, (iii) increase in slow Ca2+ inward current, elicited directly by IP4 and/or indirectly by DG through a phosphorylation of the protein kinase C substrate in the sarcolemma. In ventricular cardiac preparations muscarinic agonists have a weak positive inotropic effect, but in cardiac atrial preparations they have a negative inotropic effect. In both preparations, these different effects coincide with a concentration-dependent increase in IP3. Thus, the possible positive inotropic effect in atrial preparations is probably masked by an activation of a K+ outward current. The relationship between the inositol phosphate cycle and the positive inotropic effect is in some points still speculative because not all of the mechanisms discussed are well settled yet. However, the stimulation of myocardial phosphoinositide breakdown resulting in an increased IP3 may be involved in the mechanism(s) whereby alpha1-adrenergic and muscarinic receptor stimulation exert an increase in myocardial force of contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Scholz
J
J
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg.
D000818:Animals; D002118:Calcium / Q000502:physiology; D004075:Diglycerides / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000502:physiology*; D009200:Myocardial Contraction; D011493:Protein Kinase C / Q000502:physiology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D013403:Sugar Phosphates / Q000502:physiology*
D004075:Diglycerides; D007295:Inositol Phosphates; D011942:Receptors, Adrenergic, alpha; D013403:Sugar Phosphates; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D002118:Calcium
Inositoltrisphosphat, ein neuer "Second Messenger" für positiv inotrope Wirkungen am Herzen?