Cellular Actions

Historically, the NO donors have been used primarily for their vasodilating actions, but recent studies have shown that endogenous NO plays an important role in regulating several cellular interactions, including platelet aggregation, neutrophil adhesiveness, and vascular cell growth. Several in vitro and in vivo studies have shown that NO donors have similar actions, and these cellular effects may be important aspects of NO donor therapy that have previously been unrecognized. 

1988 Loscalzo, 1992). The mechanism of nitrate action on platelets is apparently related to the metabolic production of NO, but some synergistic effect of nitroglycerin with prostacyclin may also exist (Stamler etai, 1989). 

Using an animal model of ischemia and reperfusion injury, A. M. Lefer etal. (1993) recently showed that sydnonimine C87-3754 infusion, initiated 10 min prior to reperfusion, attenuated myocardial necrosis, prevented neutrophil adherence to the endothelium, and reduced the neutrophil release of damaging superoxide radicals. These effects appear to be related to pharmacological NO donation, since a non-NO compound with a similar chemical structure had no effect in this animal model. Antineutrophil and myocardial protective actions of an experimental NO donor (SPM-5185, a cysteine-containing mononitrate that releases NO) have also been shown in a dog model of myocardial infarction (D. J. Lefer et al., 1993), and in vitro studies have shown that NO donors inhibit activation of human polymorphonuclear leukocytes (Moilanen et al., 1993). 

Study of the cellular modulating effects of NO donors is new and exciting, and many questions remain to be answered. For example, do all NO donors share these actions equally, or do potency differences exist among the various chemical classes Time- and dose-dependent aspects (e.g., the potential for tolerance development) also remain to be defined, but these studies strongly suggest that the therapeutic utility of NO donors may expand beyond their traditional hemodynamic uses to include cytoprotec-tive, antiproliferative, and other actions as well. 

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Adrenaline (epinephrine) is a catecholamine, which is released as a neurotransmitter from neurons in the central nervous system and as a hormone from chromaffin cells of the adrenal gland. Adrenaline is required for increased metabolic and cardiovascular demand during stress. Its cellular actions are mediated via plasma membrane bound G-protein-coupled receptors. 

Those receptors are linked to different cellular actions and/or are located in different brain regions or parts of the neuron so as to produce different functional effects. 

In view of the known cellular actions of DA, such as increased K+ efflux and reduced Ca + currents associated with Dj receptor activation in cell lines, inhibition would be the expected response to DA, especially as cyclic AMP, which is increased by Dj receptor activation also inhibits striatal neurons. In fact although many DA synaptic effects are blocked by Dj antagonists like haloperidol, the role of Di receptors should not be overlooked. 

More than one type of G-protein, each with characteristic cellular actions, may be present in many cells. 

The cellular actions of cannabinoids clearly support the proposal that the cannabinoid receptor is inhibitory and, consequently, reduces the firing rate of target neurons. However, this is not wholly confirmed by electrophysiological measurements, which suggest that cannabinoid compounds can stimulate neurons in the hippocampus. This apparent discrepancy may be due to the ability of cannabinoids to inhibit the release of an inhibitory substance in the hippocampus and, thus, produce a net excitation. 

A 75-year-old female in congestive heart failure (CHF) is unable to climb a flight of stairs without experiencing shortness of breath. Digoxin is administered to improve cardiac muscle contractility. Within two weeks, she has a marked improvement in her symptoms. What cellular action of digoxin accounts for this ... 

None of these findings undermines the importance of the intracellular genomic actions of steroids. Rather, they increase the richness of the cellular actions of steroid hormones and raise the possibility that there may be connections between genomic and nongenomic actions of steroids. For example, genomic action may induce receptors that mediate nongenomic effects. Moreover, the activation of oxytocin receptors by progesterone is dependent... 

Anti-diuretic hormone is a small peptide shown as Figure 8.9, which is secreted by the pituitary gland located at the base of the brain. The cellular actions of ADH are mediated by activation of a G-protein linked receptor generating cAMP as second messenger. Absence of ADH or a functional defect in the action of ADH-stimulated water reabsorption in the collecting duct results in the condition diabetes insipidus, characterized by the passing of large volumes (= diabetes) of dilute (= insipidus) urine. 

Which of the following statements most accurately characterize the cellular action of the calcium channel blockers ... 

A) Uncoupling excitation-contraction in myome-trial cells through inhibition of cellular action potentials... 

Gibbs, J.W., Sombati, S., DeLorenzo, R.J., and Coulter, D.A. (2000) Cellular actions of topiramate blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 41 S10-S16. 

In recent years, tremendous progress has been achieved in the elucidation of the cellular and molecular mechanisms of insulin action. Tire acute cellular action of insulin is initiated by rapid clustering of occupied receptors on the cell surface. Within three minutes, a redistribution of glucose transporters from the cytoplasm to the plasma membrane can be measured lipolysis is also increased. 

Figure 7.2 G protein-mediated mechanisms of opioid cellular actions. Activation of the p receptor results in inhibition ofadenylyl cyclase (AC), the enzyme responsible for the formation ofcAMP, via the Gi protein, and increased potassium conductance and decreased calcium conductance, mediated via Go proteins.

General outlines of the cellular actions of sympathomimetics are presented in Tables 6-3 and 9-3. Sympathomimetics have prominent cardiovascular effects because of widespread distribution of a and 3 adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation. The net effect of a given sympathomimetic in the intact organism depends not only on its relative selectivity for cx or 3 adrenoceptors and its pharmacologic action at those receptors any effect these agents have on blood pressure is counteracted by compensatory baroreflex mechanisms aimed at restoring homeostasis. 

Chiou, L.-C. and How, C.-H. ATP-sensitive kC channels and cellular actions of morphine in periaqueductal gray slices of neonatal and adult rats, The Journal of Pharmacology and Experimental Therapeutics 2001, 298, 493-500. 

Mechanism of action. The cellular actions of bot-ulinum toxin at the neuromuscular junction have recently been clarified.84 This toxin is attracted to glycoproteins located on the surface of the presynaptic terminal at the skeletal neuromuscular junction.33 Once attached to the membrane, the toxin enters the presynaptic terminal and inhibits proteins that are needed for acetylcholine release (Figure 13-4).84 Normally, certain proteins help fuse presynaptic vesicles with the inner surface of the presynaptic terminal, thereby allowing the vesicles to release acetylcholine via exocytosis. Botulinum toxin cleaves and destroys these fusion proteins, thus making it impossible for the neuron to release acetylcholine into the synaptic cleft.32,84 Local injection of botulinum toxin into specific muscles will therefore decrease muscle excitation by disrupting synaptic transmission at the neuromuscular junction. The affected muscle will invariably undergo some degree of paresis and subsequent... 

Vaughan CW, Bagley EE, Drew GM, et al. Cellular actions of opioids on periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1. Br J Pharmacol. 2003 139 362-367. 

While the toxicity of any mycotoxin will be dependent on the dose, it is not the actual administered dose of toxin but the actual concentration of the mycotoxin at the site(s) of cellular action that will determine cytotoxicity. The... 

Before opposing two interpretations of a phenomenon that is not yet completely demonstrated (cardiovascular and renal benefits independent of a fall in blood pressure), it is worthwhile to reemphasize that the clinical measurement of blood pressure by physicians or nurses is an insensitive and imprecise method for investigating the human organism s hemodynamics. Failure to detect a fall in blood pressure by this method does not eliminate a hemodynamic effect. The cellular actions of angiotensin II (290) and its hemodynamic effects are so closely linked that attributing cardiovascular changes to one at the expense of the other is probably an intellectual exercise more than a realistic approach. 

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