With regard to the present knowledge about o:,-adrenergic influences on heart function and changes seen in some pathophysiological states of the myocardium, as presented above, more detailed knowledge was required on the biochemical mechanism involved in the development of the cardiac a,-adrenergic response. Based on the fact that this mechanism somehow involves changes in the intracellular calcium concentration and on the results of Uchida et al. (1982) and Brown et al. (1985) the possibility that a1- adrenergic receptors are coupled to the PI cycle seemed very likely. A lot of consideration and efforts were given to find and develop the most suitable model in which a,-adrenoceptor mediated PI turnover in myocardial cells could be investigated. The considerations are detailed in Chapter II. The model finally chosen was that of cultured neonatal rat cardiomyocytes. A modified procedure was set up to yield an almost homogenous cardiomyocyte preparation. In this model it was attempted to characterize the biochemical response to a,-adrenoceptor stimulation as enhancement of PI turnover (Chapter III). The development of the a,-adrenoceptor stimulated PI response and the possibility of (feedback) inhibition by PKC activation were studied next (Chapter IV). This study was carried out in view of reports that show an increased number of a,receptors in myocardial ischaemia. Intracellular messengers regulating the receptor activity were not taken into account in those reports [e.g. Carr et al. 1981] The observation of phorbol ester modulation of a,-adrenergic PI( 4,5)P2 hydrolysis brought us to investigate a cell free system, isolated microsomal membranes, in which the PLase C, endogenous PKC and substrate proteins for PKC could be detected and separately activated. The results of this study are described in Chapter V. The phospholipid environment of the a,-adrenergic receptor, the phosphoinositides, PLase C etc, may influence the PI-response. As an example the interactions between phospholipid methylation, a process that slightly changes the phospholipid environment, and the a,-adrenergic receptor stimulated PI( 4,5)P 2 breakdown were investigated (Chapter VI). Furthermore the phospholipid molecular species were changed by inducing incorporation of specific polyunsaturated fatty acids into the phospholipids of the cultured cells. The results of the study of a,-adrenoceptor stimulated PI breakdown in these cells are described in Chapter VII.

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Erasmus University Rotterdam
J.F. Koster (Johan)
hdl.handle.net/1765/50916
Erasmus MC: University Medical Center Rotterdam

Meij, H. (1989, December 6). Myocardial ɑ1-adrenoceptors and phosphoinositide cycle. Retrieved from http://hdl.handle.net/1765/50916