First, we will briefly describe how our study on the mechanisms of relaxant effects of nitroglycerin and related compounds (NG) on the vascular smooth muscle developed to a study on the sarcolemmal (SL) Ca2+-ATPase. These compounds were found to have no effects on the voltage-dependent Ca2+ channel and Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR) and Na+-Ca2+ exchange mechanism has been shown not to play an important role in the vascular smooth muscle. Furthermore, when we initiated our study, the idea of receptor-operated Ca2+ channels and Ca2+ release from the SR by inositol triphosphates were not known. A major part of this review is devoted to a description of the characteristic features of SL Ca2+-ATPase and its regulation by various protein kinases. References to SR enzyme are made when necessary. Brief mention is made of the putative molecular structure and its possible variations as envisaged by genetic engineering techniques. However, particular attention is directed to the regulation by cyclic GMP-dependent protein kinase as this seems to be most important as regards the mechanisms of vascular smooth muscle relaxation by NG.
Inositol phosphates have an important role in Ca2+ mobilization and especially inositol 1, 4, 5-trisphosphate (IP3) is now believed to release Ca2+ from the endoplasmic reticulum (ER) . On the other hand, the mechanism of activation of Ca2+ entry is unknown. Non-excitable cells have only receptoroperated Ca2+ channels, lacking voltage-operated Ca2+ channels, and are a useful system for studying signal transduction. In this review, some mechanisms for the regulation of Ca2+ entry in non-excitable cells are discussed and a new hypothesis originally proposed by Putney (1986), the capacitative Ca2+ entry model, is focussed. In this model, Ca2+ influx across the plasma membrane is increased when the IP3-sensitive Ca2+ pools is emptied. Capacitative Ca2+ entry is now confirmed in rat parotid acinar cells by studies on the refilling process for intracellular Ca2+ pools and by using the microsomal Ca2+ATPase inhibitor thapsigargin, which does not increase cellular IP3. Finally, capacitative Ca2+ entry is expected to exist in a variety of cell types including excitable cells.