Smooth muscle, active stresses

Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor- in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD. 

MR are present in, e.g. the central nervous system (CNS, for respiratory and cardiovascular activity, cognition and stress processing), peripheral nervous system (PNS, for smooth muscle contraction, control of heart rate, vasodilatation), as well as the sympathetic and parasympathetic ganglion cells [1], Five metabotropic cholinergic MR subtypes (M1-M5) were identified [1], but selectivity of TA is merely apparent [9] except for tiotropium and ipratropium [31]. 

Hoare, G.S., Marczin, N., Chester, A.H., and Yacoub, M.H. 1999. Role of oxidant stress in cytokine-induced activation of NF-kappaB in human aortic smooth muscle cells. Am J Physiol 277 H1975-H1984. 

Active stresses exerted by smooth muscle cells appear to increase the internal stresses that exist in vessel wall. The effects of passive and active muscular contraction on the residual stress in the wall have been considered. Their results suggest that basal muscle tone, which exists under physiological conditions, reduces the strain gradient in the arterial wall and yields a near uniform stress distribution. Increased muscular tone that accompanies elevated blood pressure tends to restore the distribution of circumferential strain in the arterial wall, and to maintain the flow-induced wall shear stress at normal levels. It appears that the active stresses exerted by smooth muscle cells may balance the tension within the vessel wall in a similar manner to the way that active fibroblast tension balances the stress in the dermis. 

Oxidative stress is now widely believed to be the major mechanism of athero-genesis. Interestingly, it was demonstrated 47 years ago that atheromatous plaques contain abundant lipoperoxides and other lipid peroxidation products (G9). More recently, our understanding of this process was advanced when evidence was provided for significant free radical activity and the lipid oxidative modification hypothesis was presented (P10). A subsequent study provided further evidence that oxidatively modified low-density lipoproteins (LDL) play a major role in the formation of the fatty streak, the earliest visible atherosclerotic lesion, and the subsequent production of the atheroscelrotic plaque (S27). The proposed sequence, which involves arterial endothelial and smooth muscle cells, as well as mono-cytes/macrophages, is as follows (Ql, S25). 

Nitric oxide and NOS can be constitutive or inducible. Constitutive nNOS and eNOS occur in neuronal and endothelial cells, respectively, and are activated by CaM. In endothelial cells acetylcholine, bradykinin or blood flow derived shear stress elevate cytosolic Ca2+ with the successive consequences of eNOS activation by CaM, NO production, GC activation by NO, elevation of cGMP, PKG activation, specific protein phosphorylation, vascular smooth muscle relaxation and vascular dilation. 

---