Adrenergic transmissions

Guanethidine (77) was the first of a series of antihypertensive agents which act by interfering with adrenergic transmission. It was subsequently found that simple substitution of the guanidine function onto a nucleus with appropriate lipophilicity almost invariably affords such sympathetic inhibitors. 

The mechanism of action of doxepin is presumable linked to the effect on the adrenergic transmission in the CNS, in particular to the blockage of neuronal norepinephrine uptake. Doxepin is used in anxious-depressive and anxious conditions, neuroses, alcoholism, organic illnesses of the CNS, and psychoses. The most frequently used synonyms are adapin and sinequan. 

The drugs listed in Table 9.2 affect specific steps in cholinergic or adrenergic transmission. These and many other drugs that alter transmission are discussed in subsequent chapters. 

TankJ, Diedrich A, Szczech E, et al. Alpha-2 adrenergic transmission and human baroreflex regulation. Hypertension. 2004 43 1035-1041. 

It is well know that /3-adrenoceptors couple to adenylate cyclases to activate a protein kinase A (PKA), but no direct evidence exists for the involvement of the /3-adrenoceptor-PKA signaling pathway in the affective component of pain. Thus, we examined the effect of intra-vBNST administration of a selective PKA inhibitor on isoproterenol- and pain-induced aversion. CPA induced by the intra-vBNST injection of isoproterenol was reversed by the coinjection of Rp-cyclic adenosine monophosphorothioate (Rp-cAMPS), a selective PKA inhibitor. Furthermore, intra-vBNST injection of Rp-cAMPS dose-dependently attenuated the F-CPA. These data suggest that PKA activation within the vBNST via the enhancement of /3-adrenergic transmission is important for the negative affective component of pain (Fig. 3). 

Adrenergic transmission is well known to be involved in the regulation of homeostatic control through its functions in the autonomic nervous system. Additionally, adrenergic projections in the brain have been identified with important roles in neurocognition. Adrenoreceptors are seven transmembrane G-protein-coupled receptors that mediate the physiological responses of epinephrine and norepinephrine. The first classification of these receptors resolved a (alpha)-adrenoreceptors (aARs) from P (beta)-adrenoreceptors (PARs) (Ahlquist, 1948). Since then, additional subtypes and variants have been described. 

Adenosine (694, X = CH2OH) and derivatives of 694 inhibit adrenergic transmission presynaptically. Therefore these substances are useful as cardiovascular stimulating... 

Rang H.P. Dale M.M., In Pharmacology. Adrenergic Transmission. Churchill Livingstone, Edinburgh, 1991, p 200. 

Ueyama, T., Hano, T., Hamada, M., Nishio, 1. and Masuyama, Y. (1991) New role of nerve growth factor - an inhibitory neuromodulator of adrenergic transmission. Brain Res. 559 293-296. 

As a further disproof of prejunctional NO effects, evidence has been provided for a postjunctional site of action in many vascular beds, whereby NO would attenuate adrenergic transmission. Thus, NO synthase inhibitors diminish the vasoconstriction elicited by sympathetic nerve stimulation and exogenous NE in the tail (Vo et al., 1991) and iliac (Gonzalez etal., 1992) arteries of the rat, in the pulmonary artery of the guinea pig (Liu et al., 1991 Cederqvist and Gustafsson, 1994) and the rabbit (Shinozuka et al.,... 

Adrenergic transmission Norepinephrine (NE) is the primary transmitter at the sympathetic postganglionic neuron-effector cell synapses in most tissues. Important exceptions include sympathetic fibers to thermoregulatory (eccrine) sweat glands and probably vasodilator sympathetic fibers in skeletal muscle, which release ACh. Dopamine is an important vasodilator transmitter in renal blood vessels. 

Peripheral presynaptic anti-adrenergics inhibit norepinephrine release from the presynaptic terminal. Guanadrel and reserpine deplete norepinephrine from presynaptic vesicles. As a result, guanadrel initially releases norepinephrine from the terminal causing a transient increase in adrenergic transmission. 

Powerful inhibitors of the next enzyme in the pathway, aromatic L-amino acid decarboxylase (e.g., carbidopa), have proven clinically useful, but not as modulators of peripheral adrenergic transmission. Rather, these agents are used to inhibit the metabolism of exogenous L-dopa administered in the treatment of Parkinson s disease (see Chapter 25). 

Hypothetically, inhibitors of any of the three enzymes involved in the conversion of L-tyrosine to norepinephrine (see Fig. 13.1) could be used as drugs to moderate adrenergic transmission. Inhibitors of the rate-limiting enzyme tyrosine hydroxylase would be the most logical choice. One inhibitor of tyrosine hydroxylase, metyrosine or a-methyl-L-tyrosine, a competitive inhibitor of tyrosine hydroxylase, is in limited clinical use to help control hypertensive episodes caused by excess catecholamine biosynthesis. The drug also can control other symptoms of catecholamine overproduction in patients with the rare adrenal tumor pheochromocytoma. Although metyrosine is useful in treating hypertension... 

Restore Deficient Central Adrenergic Transmission - Mainly Dopamine)... 

Hughes, J., Kosterlitz, H. W., and Leslie, F. M., 1975a, Effect of morphine on adrenergic transmission in the mouse vas deferens. Assessment of agonist and antagonist potencies of narcotic analgesics, Br.J. Pharmacol. 53 371-381. 

Yohimbine is derived from the bark of Aspidosperma quebracho (Apocynaceae) and Pausinystalia yohimba (Rubiaceae). These plants are reputedly aphrodisiacs. Yohimbine blocks a-adrenergic transmissions but stimulates p-adrenergic sites (Robinson 1981). Yohimbine and strychnine are sometimes combined in pharmaceutical preparations for use as aphrodisiacs and nerve tonics. 

Cooper, G. P. and Steinberg, D. (1977). Effects of cadmium and lead on adrenergic transmission in the rabbit. Am. J. Physiol, 232, C128-C131 Cory-Slechta, D. A., Bissen, S. T., Young, A. M. and Thompson, T. (1981). Chronic postweaning lead exposure and response duration performance. Toxicol. Appl. Pharmacol, 60, 78... 

---