Adrenoceptor activation

Diltiazem inhibits calcium influx via voltage-operated channels and therefore decreases intracellular calcium ion. This decreases smooth muscle tone. Diltiazem dilates both large and small arteries and also inhibits a-adrenoceptor activated calcium influx. It differs from verapamil and nifedipine by its use dependence. In order for the blockade to occur, the channels must be in the activated state. Diltiazem has no significant affinity for calmodulin. The side effects are headache, edema, and dizziness. 

The effect of receptor stimulation is thus to catalyze a reaction cycle. This leads to considerable amplification of the initial signal. For example, in the process of visual excitation, the photoisomerization of one rhodopsin molecule leads to the activation of approximately 500 to 1000 transdudn (Gt) molecules, each of which in turn catalyzes the hydrolysis of many hundreds of cyclic guanosine monophosphate (cGMP) molecules by phosphodiesterase. Amplification in the adenylate cyclase cascade is less but still substantial each ligand-bound P-adrenoceptor activates approximately 10 to 20 Gs molecules, each of which in turn catalyzes the production of hundreds of cyclic adenosine monophosphate (cAMP) molecules by adenylate cyclase. 

Hoffman, B.B., Adrenoceptor-activating and other sympathomimetic drugs, in Basic and Clinical Pharmacology, 8th ed., Katzung, B.G., Ed., Lange Medical Books/McGraw-Hill, New York, 2001, chap. 9. 

TRP6-specific antisense oligonucleotides, and consequently, cationic current and Ba2+ influx evoked in response to oq -adrenoceptor activation were both greatly attenuated. Importantly, Ba2+ influx induced by thapsigargin, which is an indication of store operated divalent cation entry, was not significantly affected... 

Helliwell RM, Large WA 1997 Alphal-adrenoceptor activation of a non-selective cation current in rabbit portal vein by 1,2-diacyl-sn-glycerol. J Physiol 499 417-428 Hofmann F, Lacinova L, Klugbauer N 1999 Voltage-dependent calcium channels from structure to function. Rev Physiol Biochem Pharmacol 139 33—87 Hofmann T, Schaefer M, Schultz G, Gundermann T 2000 Transient receptor potential channels as molecular substrates of receptor-mediated cation entry. J Mol Med 78 14—25 Inoue R, Okada T, Onoue H et al 2001 The transient receptor potential protein homologue TRP6 is the essential component of vascular aj-adrenoceptor-activated Ca2+-permeable cation channel. Circ Res 88 325—332... 

Phospholamban is a protein that inhibits the SERCA pumps by decreasing their affinity for Ca2+. It can be phosphorylated by protein kinase A, for instance in response to /1-adrenoceptor activation, resulting in inhibition of its effects and enhanced SERCA activity. The effects of phospholamban on contraction depend on the relative importance of Ca2+ uptake or release in the smooth muscle in... 

Figure 15. Relationship between peripheral a-adrenoceptor activity, lipoid solubility, and centrally mediated cardiodepressor activity. Abscissa natural logarithms of the product of relative activity on peripheral a-adrenoceptors as derived from blood pressure decreases in spinal rats multiplied by percentage of distribution between octanol/buffer (Figure 4). Ordinate natural logarithms of the relative CNS activity as derived from bradycardia test in vagotomized...

Smooth muscle effects. The opposing effects on smooth muscle (A) of a-and p-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). ai-Receptor stimulation leads to intracellular release of Ca + via activation of the inositol tris-phosphate (IP3) pathway. In concert with the protein calmodulin, Ca + can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin. cAMP inhibits activation of myosin kinase. Via the former effector pathway, stimulation of a-receptors results in vasoconstriction via the latter, P2-receptors mediate vasodilation, particularly in skeletal muscle - an effect that has little therapeutic use. 

Adrenaline but not noradrenaline is useful in the therapy of bronchial asthma since the dilatory effects on the smooth muscle in this area are mediated via /82-adrenoceptors. Furthermore, a swelling of the mucosa, which might considerably contribute to the airway resistance, is reduced by /82-adrenoceptor activation. In this indication selective /82-mimetics are useful due to less circulatory side effects. 

The hydroxyl groups of the phenyl ring are a prerequisite for the activation of all adrenoceptors, if both are absent the molecule has only an indirect sympathomimetic effect (see Fig. 5). Indirect sympathomimetics only have a -, a2 and -adrenoceptor activity since they act via an increase of the noradrenaline concentration in the synaptic cleft. If the methyl-group at the N-position of adrenaline is substituted by a longer or more bulky moiety the molecule gains affinity for the and loses affinity for O -adrenoceptors. An isopropyl moiety is already the optimum for the affinity towards 0-adrenoceptors (isoprenaline), larger substituents enhance only the binding to the 2-subtype (for example fenoterol). 

A newer approach is offered by the discovery of central imidazoline (Ii)-receptors in the rostro-ventrolateral medullary region (RVLM). When stimulated with Ii-receptor agonists peripheral sym-pathoinhibition occurs, thus resembling the mechanistic sequelae of central o 2-adrenoceptor activation by the classic drugs. 

Marek, G.J. and Aghajanlan, G.K. (1999) 5-HT2A receptor or al-phal-adrenoceptor activation Induces EPSCs In layer V pyramidal cells of the medial prefrontal cortex. Eur ] Pharmacol 367 197-206. 

Since Ahlquist first proposed the existence of two adrenoceptor subtypes, o and 3, in 1948, the number of receptors has considerably expanded and at present nine distinct adrenoceptor subtypes have been identified. There are two subtypes of the o receptor (ol and o2, with subfamiiies of each of these) and three subtypes of the 3 receptor, 31, (32 and 33. The adrenoceptors are G protein-coupied receptors, but second messenger and G protein iinkage differ between the subtypes, ol-Adrenoceptor activation increases phosphoiipase C via a Gq protein, resuiting in an eievation in intraceiiuiar Ca2+-a2- Adrenoceptors are coupied to a Gi protein and... 

Dobutamine is a directly acting synthetic catecholamine with predominant effects at pi receptors. It has weak 32 and a effects. It is a racemic mixture and both stereoisomers are p-adrenoceptor agonists. The (+) isomer is approximately ten times more potent as a p-receptor agonist than the (-) isomer, which is mainly responsible for the o-adrenoceptor activity. Unlike dopamine, dobutamine does not act by releasing noradrenaline or via dopaminergic receptors. 

This suggests that the above mentioned mechanism is unlikely to have caused lactic acidosis in this patient. Rather, it may have resulted from beta2-adrenoceptor activation, with subsequent excess glycogenolysis and lipolysis, production of pyruvate, and final conversion to lactate. 

Antimuscarinic drugs should never be used for mydriasis unless cycloplegia or prolonged action is required. Alpha-adrenoceptor stimulant drugs, eg, phenylephrine, produce a short-lasting mydriasis that is usually sufficient for funduscopic examination (see Chapter 9 Adrenoceptor-Activating Other Sympathomimetic Drugs). 

Chapter 9. Adrenoceptor-Activating Other Sympathomimetic Drugs... 

Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 9. Adrenoceptor-Activating Other Sympathomimetic Drugs > ... 

The amount of trigger calcium that enters the cell depends on the availability of calcium channels (primarily the L type) and the duration of their opening. As described in Chapter 6 Introduction to Autonomic Pharmacology and Chapter 9 Adrenoceptor-Activating Other Sympathomimetic Drugs, sympathomimetics cause an increase in calcium influx through an action on these channels. Conversely, the calcium channel blockers (see Chapter 12 Vasodilators the Treatment of Angina Pectoris) reduce this influx and depress contractility. 

Monoamine oxidase inhibitors (eg, tranylcypromine, phenelzine) are a group of older antidepressants that are occasionally used for resistant depression. They can cause severe hypertensive reactions when interacting foods or drugs are taken (see Chapter 9 Adrenoceptor-Activating Other Sympathomimetic Drugs) and they can interact with the selective serotonin reuptake inhibitors (SSRIs). 

This chapter provides an evidence-based approach to the pharmacology and clinical efficacy of several of the commonly used and commercially available botanicals and dietary supplements. Ephedrine, the active principle in Ma-huang, is discussed in Chapter 9 Adrenoceptor-Activating Other Sympathomimetic Drugs. 

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