Endogenous muscle physiology

Asghar, A. and Bhatti, A.R., Endogenous proteolytic enzymes in skeletal muscle their significance in muscle physiology and during postmortem aging events in carcasses, Adv. Food Res., 31, 343, 1987. 

Many people consider this to be the most important of all the criteria. Obviously a substance must have an effect of some kind if it is to be a NT but not all substances that have an effect on neurons need to be NTs. It may seem unnecessary to say this but the literature contains many accounts of the study of various substances on neuronal activity from which a NT role is predicted without any attempt to compare its effect with that of physiologically evoked (endogenous NT) effects. The importance of this safeguard is highlighted by the ease with which both smooth muscle and neurons will respond to a range of substances that are not released onto them as NTs. Thus the value of this criterion depends very much on the rigour with which it is applied and on its own is no more or less important than any other approach. 

An instructive example is the physiological variable serum creatinine. Creatinine is an endogenous metabolite formed from, and thus reflecting, muscle mass. Total body muscle mass is sufficiently constant to render measurement of serum creatinine useful for assessing actual renal function. The serum value of creatinine (R) is namely dependent on the continuous (zero-order) input of creatinine into the blood (A in) and its renal elimination rate, which is a first-order rate process (A out x ) In case of an extensive muscle breakdown, kin will temporarily increase. It may also be permanently low, for example in old age when muscle mass is reduced. Likewise, creatinine clearance may decrease for various reasons, described by a decrease in A out- An increase in creatinine clearance may occur as well, for example following recovery from renal disease. According to pharmacodynamic indirect response models. 

Mitochondria are not involved in storing activator Ca in smooth muscle (Twort and van Breemen, 1989). Despite the importance of Ca transport systems within the mitochondria for controlling cellular metabolism, the endogenous Ca " content of mitochondria is low (Bond etal., 1984), and mitochondria in smooth muscle only accumulate Ca " at pathological (10 fiM) rather than physiological (100 nM) cytosolic Ca concentrations (Yamamoto and van Breemen, 1986). 

Endothelin-1 is a potent vasoconstrictor peptide derived from endothelial cells.100 Its physiological function is mediated by two receptors the ET-A and ET-B. Table 1. Figure 11. ET-A and ET-B receptors are located in vascular smooth muscle and their activation causes vasoconstriction, whereas ET-B receptor is also located in the endothelium and its activation results in vasodilation by increasing nitric oxide or prostacyclin. Endothelin is released following myocardial ischemia and reperfusion. Endothelin reduces infarct size in a perfused rat heart model of ischemia and reperfusion through activation of protein kinase C and KATp channel.101 Furthermore, in neonatal rat ventricular myocytes, endothelin is shown to activate the calcineurin-NFAT (nuclear factor of activated cells) pathways and enhance the expression of Bcl-2.102 However, endogenous blockade of endothelin at the level of the ET-A receptor reduced infarct size in a pig model of coronary occlusion and reperfusion.103... 

My guess is that serotonin will be found to be part of the equilibrated system of chemical controls of smooth muscle and that the gross effects most of us study with present crude methods bear little relationship to the physiological mechanisms of the circulation. The story may well have a parallel with norepinephrine. Until von Euler got the idea that norepinephrine was a transmitter, and then distinguished between exogenous and endogenous stores, the understanding of this catecholamine was pretty muddy as well. 

---