Tissue binding of noradrenaline.

Abstract

The substance noradrenaline is found in two sites in the body. First in certain nerves, and secondly in association with adrenaline in the adrenal medulla. In nerves this noradrenaline is stored in granules concentrated in the terminal nerve fibre. Its prime function is to transmit the effects of nerve impulses across the gap between the nerve ending and the cell served. This point is illustrated in figure 1 ( a ). When the nerve impulses, travelling down the nerve fibre, invades the nerve terminal, this releases some of the noradrenaline which passes into the space between nerve and muscle. This noradrenaline then diffuses across the gap to the smooth muscle, where it combines with a specialized part of the membrane, a part originally referred to by Langley (1905) as the ‘receptive substance’, and today more briefly termed the receptors. A consequence of this combination is a change in activity of the cell, the response. From this brief account it is clear that the most obvious binding sites for noradrenaline are the receptors for this substance on effector cells. Studies on the relationship between drug concentrations and the tissue response and the effect on this relationship of such irreversible blocking agents as phenoxybenzamine have led pharmacologists to suggest that only a small fraction, perhaps as low as 4 to 5% of the total receptors on the effector cell are involved in producing even a maximum response (Stephenson 1956). There is therefore a large reserve of ‘spare receptors’ (figure 1 ( a )), all potentially binding sites but not all simultaneously occupied under physiological conditions. A second binding site is shown in figure 1 ( b ). There are other substances and tissues in the body potentially capable of binding noradrenaline, the ground substance of con­nective tissue would be one example. Such binding would produce no response from the tissues themselves, and for this reason these sites are sometimes referred to as ‘silent receptors’ (Goldstein 1949). Nevertheless, the effector cell response may be affected in various ways. The response may be diminished by the silent receptors acting as a ‘site of loss’, so that less noradrenaline is available to the true receptors. There may be a secondary release from the silent receptors, so pro­longing the response. At present the evidence for the existence of these silent receptors is indirect and the extent of their involvement in vivo is obscure.