Endogenous norepinephrine

OC-Adrenoceptor Blockers. Nonselective a-adrenoceptor blockers (Table 6), such as phentolamine, which block both a - and a2 adrenoceptors, produce vasodilation by antagonizing the effects of endogenous norepinephrine. They also produce severe tachycardia and have been replaced by selective a -adrenoceptor blockers, such as prazosin, terazosin, and doxazosin, which do not usually cause severe tachycardia. 

Arnold EB, Molinoff PB, Rutledge CO The release of endogenous norepinephrine and dopamine from cerebral cortex by amphetamine. J Pharmacol Exp Ther... 

Hashimoto Y, Miyazaki H. 1979. Simultaneous determination of endogenous norepinephrine and dopamine-beta-hyrox-ylase activity in biological materials by chemical ionization mass fragmentography. J Chromatogr 168 59. 

Tyramine, the only indirect-acting compound, exhibits sympathomimetic effects by causing the release of endogenic norepinephrine, and it has only found practical use in experiments. It inactivates monoaminooxidase very quickly. It has no practical clinical use. 

Dopamine is found in every sympathetic neuron and ganglion in the CNS. As a drug, and in addition to stimulation of dopaminergic receptors, dopamine indirectly stimulates both a- and )3-adrenoreceptors. Dopamine also causes a release of endogenous norepinephrine. The mechanism of action is based on the excitatory effect on )3-adrenoreceptors (in low and moderate doses), as well as on a-adrenoreceptors (in large doses). It has a positive inotropic effect on the heart, increases blood supply, selectively widens renal and mesenteric blood vessels, does not elevate blood pressure, and slightly increases the frequency of heartbeats. 

Gresch PJ, Sved AF, Zigmond MJ, Finlay JM (1995) Local influence of endogenous norepinephrine on extracellular dopamine in rat medial prefrontal cortex. J. Neurochem. 65 111-116. 

Spengler RN, Chensue SW, Giacherio DA, Blenk N, Kunkel SL (1994) Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. J. Immunol. 152 3024-3031. 

MAO inhibitors were the first widely used antidepressants, but because of various undesirable side effects they are employed today in only a more limited number of cases. People who are treated with MAO inhibitors, for example, must be careful of their diet. They should not eat food rich in tyramine or other biologically active amines. These foods include cheese, beer, and red wine. Individuals on MAO inhibitors are unable to inactivate tyramine present in the food. Because tyramine causes the release of endogenous norepinephrine, patients are susceptible to increased blood pressure (e.g., potential lethal cerebral hemorrhages) and cardiac arrhythmias. 

Endogenous norepinephrine stimulates cardiac beta receptors. Receptor-linked cAMP-dependent protein kinases phosphorylate calcium channels to increase intracellular calcium. Elevated intracellular calcium increases conduction velocity (phase 0) and decreases the threshold potential in normal SA and AV node cells (see Figure 12.13). Beta blockers slow spontaneous conduction velocity in the SA node by approximately 10-20 percent. In addition, beta blockers can slow conduction velocity while increasing the refractory period of the AV node. These effects control the ventricular rate in atrial fibrillation or flutter and terminate paroxysmal supraventricular tachycardias. They are also safer, although somewhat less effective, than other drugs for suppression of premature ventricular complexes (PVCs). Drugs in this class approved by the FDA for treatment of various arrhythmias include propranolol, acebutolol, and esmolol. Problems with the beta blockers include drowsiness, fatigue, impotence, and depressed ventricular performance. 

Janumpalli S, Butler LS, MacMillan LB, Limbird LE, McNamara JO. A point mutation (D79N) of the a2A adrenergic receptor abolishes the antiepilep-togenic action of endogenous norepinephrine. J Neurosci 1998 18 2004-2008. 

Dopamine often is recommended as the initial catecholamine in sepsis because it increases blood pressure by increasing myocardial contractility and vasoconstriction. Dopamine has been described to have dose-related receptor activity at DAj-, DA2-, fi -, and i-receptors. Unfortunately, this dose-response relationship has not been confirmed in critically ill patients. In patients with septic shock, there is a great overlap of hemodynamic effects even at doses as low as 3 mcg/kg per minute. Tachydysrhythmias are common owing to the release of endogenous norepinephrine by dopamine entering the sympathetic nerve terminal. Dopamine may increase the PAOP through pulmonary vasoconstriction. This drug also may depress ventilation and worsen hypoxemia in patients dependent on the hypoxic ventilatory drive. 

FIG U R E 2 Comparison of E , Fura 2 fluorescence, and isometric force in de-endothelialized rat tail artery segments stimulated with phenylephrine or high (in the presence of 3 pM phentolamine to block the effects of endogenous norepinephrine release). Tissues were stimulated for 5 min with the following stimuli 0.1 pM phenylephrine at 5 min, 0.3 pM phenylephrine at 15 min, 20 pM [K+] at 25 min, 30 mM [K+] at 35 min, and40mM [K+] at45min. The top panel shows mean 1 SEM (symbols without error bars imply that the SEM is smaller than the symbol size). The middle panel shows the normalized mean Fura 340/380 ratio (solid line) 1 SEM (dotted lines). The bottom panel is normalized force in grams from the Fura 2 experiments (solid and dotted lines). Force from the experiments was similar to the force measured in the Fura 2 experiments. The Fura 340/380 ratio was normalized to the measured response 5 min after stimulation with 90 mM [K+] . Data are replotted from Chen and Rembold (1995). 

Z1 Zabrodin, O. N. Pharmacological analysis of the participation of endogenous norepinephrine in the retrograde development of neurogenic gastric dystrophy. Farmakol. Tok-sikol. 35, 606-610 (1972) (Russ.)... 

The hydroxylation of the amino acid tyrosine to dopa (3,4-dihydroxyphenyl-alanine) is the rate-limiting step in catecholamine biosynthesis [231,257] (Table 1, p. 103). It is catalysed by the enzyme tyrosine hydroxylase. Norepinephrine synthesis is regulated at the tyrosine hydroxylase step by feed-back inhibition, i.e. tyrosine hydroxylase activity decreases as the concentration of endogenous norepinephrine increases [230]. 

On the erroneous assumption that the hypotensive effect of methyldopa is due to inhibition of the enzyme dopa decarboxylase, numerous substances were tested as possible dopa decarboxylase inhibitors [102, 171, 178, 179, 194, 229]. The hypotensive effect of these substances, in so far as it existed at all, is most probably due to a mechanism similar to that suggested in the case of methyldopa-i.e. the substance, or one of its metabolites, is taken up in place of endogenous norepinephrine. 

---