TY - JOUR T1 - R SMOOTH MUSCLE JF - Pharmacological Reviews JO - Pharmacol Rev SP - 249 LP - 353 VL - 22 IS - 2 AU - A. P. SOMLYO AU - A. V. SOMLYO Y1 - 1970/06/01 UR - http://pharmrev.aspetjournals.org/content/22/2/249.abstract N2 - Regional and species differences in the responsiveness of vascular smooth muscle to drugs have been conclusively established during the period covered by this review. Differences among the membrane properties of different vascular smooth muscles have also been recognized, although in this area our knowledge is still limited. Several forms of spike electrogenesis, probably analogous to those produced by other excitable membranes, have been observed in certain types of vascular smooth muscle. The contractile mechanism of smooth muscle appears to be based on the sliding of two types of filaments in a manner fundamentally similar to that of striated muscles. Graded membrane-potential changes elicited by drugs and the increasing evidence of contractile regulation by mechanisms other than the membrane potential, however, clearly indicate that smooth muscles cannot be considered as reduced scale models of the frog sartorius fiber. What may we anticipate to occur in this field within the next 15 years? The structural identification of receptors would be assigned high priority by most pharmacologists. The variable distribution of receptors in smooth muscle could be used, as was done with transport-negative and transport-positive mutants (708), for the specific labelling of receptors in a drug-sensitive population of cells. The nature of the physicochemical changes of the membrane that bring about an increase in ion-permeability and active transport is equally important and probably related to receptor-identification. It is our impression that the investigation of slow, graded potential changes common to smooth muscles, certain synaptic membranes, and epithelial cells will elucidate new aspects of membrane physiology. Because of their slow time course, these graded potential changes would be expected to reveal more readily the underlying physicochemical transients, that might also be qualitatively different from the rapid, regenerative permeability change that characterizes the action potential. It is commonly assumed that conformational changes of specific polar groups determine the permeability of the membrane, but a plausible hypothesis of synaptic electrogenesis based on the hydrolysis of membrane phospholipids has also been proposed (263) and may be relevant to the generation of graded potential changes in smooth muscle. It is well within the reach of available technology to accurately determine what fraction of total vascular calcium is external to the plasma membrane and how much is available at internal sites for excitation-contraction coupling. It will be equally suitable to determine whether the relative ion permeability changes produced by peptide and amine agonists are only quantitatively different or whether these different drugs have selective effects on different ion channels. The classification of vasodilators according to their effects on resting and on stimulated transmembrane calcium-fluxes will be essential to the understanding of their mechanism of action as well as a necessary first step in rigorously testing the possibility of the existence of auxiliary mechanisms that can regulate smooth muscle actomyosin ATPase without inhibiting Ca++-influx. The atherogenic role of vascular smooth muscle (Part I, section III B) and the possibility of hypertension as a vascular myopathy (section XXI) will probably undergo close scrutiny as interest in these diseases persists. Perhaps biochemical studies can reveal whether the increased AMPase activity of hypertensive vascular smooth muscle (Part I, section III D) is wholly nonspecific, or whether abnormal (low) cyclic AMP and other nucleotide levels are involved in the pathogenesis of hypertension. The above list is admittedly speculative and perhaps presumes too much in anticipating scientific trends. We have intentionally emphasized those areas of research that are largely peculiar to smooth muscle and to vascular smooth muscle in particular, rather than the exploration of the similarities to phasic striated muscles, without denying the usefulness and further need for the latter. Our choice of emphasis was strongly influenced by the role of vascular smooth muscle in the development of cardiovascular diseases and also by the belief that a specific field of research serves the general cause of Science better by asking it an occasional original question. 1970 by The Williams & Wilkins Co. ER -