Inhibition of activity

Automaticity of cardiac fibers is controlled in part by activity of the sympathetic and parasympathetic nervous systems. Enhanced activity of the sympathetic nervous system may result in increased automaticity of the SA node or other automatic cardiac fibers. Enhanced activity of the parasympathetic nervous system tends to suppress automaticity conversely, inhibition of activity of the parasympathetic nervous system increases automaticity. Other factors may lead to abnormal increases in automaticity of extra-SA nodal tissues, including hypoxia, atrial or ventricular stretch [as might occur following long-standing hypertension or after the development of heart failure (HF)], and electrolyte abnormalities such as hypokalemia or hypomagnesemia. 

Carbon could also go subsurface and play a role in electronic inhibition of activity by affecting the adsorption and dissociation of CO.41... 

During chase incubation at 4°C, no significant change of the cell-associated fluorescence intensity should be detected over time. Because of the reduced incubation temperature, the metabolism of the cells is minimized, resulting in an inhibition of active uptake processes. Upon subsequent addition of monensin, the fluorescence emission signals should not be altered as well. In doing so, any direct influence of monensin on the quantum yield of the fluorescein label can be excluded [25],... 

Tyndale RE, Sunahara R, Inaba T, Kalow W, Gonzalez FJ, et al. 1991. Neuronal cytochrome P450IID1 (debrisoquine/spar-teine-type) potent inhibition of activity by (-)-cocaine and... 

It is not a requirement that binding of an allosteric modulator to an enzyme must result in inhibition of activity indeed, in some mixed inhibition systems described earlier, both a and P have values between 0 and 1. If an increase in substrate affinity outweighs a decrease in at lower substrate concentrations, an increase in enzyme activity may occur, relative to control values, and the use of the term inhibitor to classify such a compound is open to debate. 

Table 1. The modulatory elFect of general anesthetic drugs on ligand-gated ion channels. The effect of chnicaUy relevant concentrations of general anesthetic drugs. -I- indicates potentiation, 0 indicates no signihcant effect in the majority of studies and -indicates inhibition of activation. indicates insufficient data is available.

Yarbrough, J. M., Rake, J. B., and Eagon, R. G. (1980). Bacterial inhibitory effects of nitrite Inhibition of active transport, but not of group translocation, and of intracellular enzymes. Appl. Environ. Microbiol. 39, 831-834. 

Inhibiting of specific [3H]TPA binding (ED5o pmol/L) Inhibition of activation of protein kinase C (ED ) pmol/L) Inhibition of ODC induction (%)... 

Enhancement of the inhibitory activity was found in 3-oxo derivatives of 142 and 210, while either loss of oxygen functionality at C-3 of 210 or oxidation at C-3 of 147 led to the reduction of the activity [22]. Two 3-O-acetyl oleananes, 3-O-acetylerythrodiol (117 68% inhibition at lxlO3 mol ratio compound/TPA 80% cell viability) and acetyloleanolic acid (119 64% inhibition 80% viability), showed remarkable inhibitory effects with preserved higher viabilities of Raji cells than their free alcohols, erythrodiol (130 81% inhibition 50% viability) and 142 (70% inhibition 60% viability) [72]. Under the same assay conditions, betulinic acid (257) exhibited complete inhibition of activation with 80% cell viability [72]. Arjunolic acid triacetate (154 66% inhibition at lxl02 mol ratio compound/TPA) and arjunolic acid triacetate methylester (155 73%)... 

As with DNA and RNA (3), substrate affinity depends upon the Ca-+ concentration. The lowest /vmapp for nitroplienyl-pdTp-nitrophenyl occurs at mM Ca2+, but for nitrophenyl-pdTp it is 2.5 inM Ca-+. Apart from its effect on K, , Ca2+ increases the Kcnl directly (Fig. 4) maximal effects are observed with about 0.1 M Ca2+. Again in analogy with studies using DNA and RNA (S), all the synthetic substrates show an apparent inhibition of activity when the concentration of Ca2+ is raised above 0.05 M. This effect is solely the result of an increase in Km (Fig. 5). 

Animal tests can be extremely elaborate. Ezetimibe (Zetia, 2.25), a cholesterollowering drug, was developed in the mid-1990s through testing in rats (Figure 2.9). The mode of action was known to be inhibition of active transport of cholesterol in the small intestine, but the exact mechanism of transport was unknown. Without an established mode of action, a... 

Epidemiological studies indicate that elevated plasma tHcy increases the risk of venous thromboembolism (43,44), In homocystinuria, the presence of the factor V Leiden mutation further increases the risk of thromboembolism (45). It has been proposed that hyperhomocysteinemia might interfere with the inhibition of activated factor V by activated protein C, possibly via similar effects as those caused by the factor V Leiden mutation (46,47), However, one in vitro study (48) and one large clinical study failed to demonstrate an association between hyperhomocysteinemia and activated protein C resistance (49). 

Hui A, Min WX, Tang J, Cruz TE Inhibition of activator protein I activity by paclitaxel suppresses interleukin-1 -induced colla-genase and stromelysin expression by bovine chondrocytes. Arthritis Rheum 1998 4l(5) 869-876. 

Direct evidence that irreversible inhibition is the principle mechanism underlying in vivo drug-drug interactions (DDIs) is often lacking because of the requirement for either direct tissue sampling to reveal inactivated enzyme or in vivo inhibition of activity after drug is essentially eliminated from the body. Nevertheless the steady-state plasma concentrations of several clinically important CYP inhibitors are well below the in vitro estimated competitive inhibition constant, Kv This suggests that competitive inhibition is unlikely to occur in vivo, yet these compounds inhibit CYP activity in a time and concentration-dependant manner when cDNA-expressed CYPs or HLMs are used as an enzyme... 

The targets identified belong to families of oxidoreductases and transferases, many of which contain active-site Cys nucleophiles and react with nucleosides. Further confirmation of these enzymes reactivity towards showdomycin was achieved in the case of MurAl by an inhibition assay. This showed that showdomycin inhibited MurAl with an IC50 (concentration resulting in 50% inhibition of activity) of 10 pM. In the case of AhpC, analysis of the site of modification revealed showdomycin to be attached only to Cys residues 39 and 168. 

Anti-IL-26 Inhibition of activation of STAT 1 and 3 in tumor cells Hor et al. [98]... 

Active transport is required for the absorption and movement of biologically important molecules across a membrane against a concentration gradient. This process, which requires ATP, can be inhibited if DNOC is present. An in vitro study in the pig demonstrated DNOC inhibition of active transport by observing the uptake of gamma-globulin by neonatal intestinal epithelium (Lecce 1966). 

TABLE 9.1 K-Opioid Inhibition of Active Individuals from Screening of the Solution-Phase Discrete Focused Piperidine Library L16... 

Among several iron chelators used, only o-phenanthroline inhibited the soluble dehydrogenase (42). It was shown by Hateff et al. (42) that incubation of the enzyme with o-phenanthroline results in the loss of labile sulfide, while pretreatment with bathophenanthroline sulfonate, Tiron (1,2-dihydroxybenzene 3,5-disulfonate) or ethylenediamine tetraacetate protects the enzyme against the loss of labile sulfide and inhibition of activity upon subsequent incubation with o-phenanthroline. The unique destructive ability of o-phenanthroline has been demonstrated by these investigators for several iron-sulfur proteins (S5,96). 

N. Segil, M. Guermah, A. Hoffinaim, RG. Roeder, and N. Heintz. Mitotic regulation of TFUD inhibition of activator-dependent transcription and of changes in cellular localization. Genes Dev, 10, 2389 2400, 1996. 

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