Effects of catecholamines

Effects of noradrenaline and adrenaline are often called adrenergic and those of dopamine dopaminergic. Comparison of the activity of various adrenergic agonists and adrenergic antagonists led to distinguish several types of receptors responsible for specific effects. We use either the terms effects or receptors: for example alpha or beta adrenergic effects or receptors. The coupling of adrenergic receptors is carried out via G proteins which modulate the activity of phospholipase C and calcium and of adenylcyclase which can be inhibited or be activated.

Alpha and beta adrenergic effects

Peripheral effects
The principal peripheral adrenergic effects of alpha (alpha1, alpha-2) and beta (beta-1, beta-2 and beta-3) stimulation are summarized in the table which follows.

Stimulation of postsynaptic alpha-1 receptors results primarily in vasoconstriction, uterine contractions, platelet aggregation, mydriasis and contraction of the urethral sphincter. Alpha-2 receptors are mainly presynaptic and their stimulation results in a decrease of noradrenaline release. There are however postsynaptic alpha-2 receptors whose stimulation induces platelet aggregation.

Beta-1 receptors are postsynaptic and localized primarily in the heart. Their stimulation results in a positive inotropic effect (increase of the strength of contractions), positive chronotropic effect (rate acceleration), positive dromotropic effect (conduction acceleration) and positive bathmotropic effect (increase of excitability). Beta-2 receptors are primarily postsynaptic. Their stimulation induces vasodilation, bronchodilatation, uterus relaxation and cardiac stimulation which is less important than that induced by beta-1stimulation. It is estimated that the distribution of beta receptors in heart is approximately 80% of beta-1 receptors and 20% of beta-2 receptors. The stimulation of beta-2 receptors increases potassium uptake by muscles, which can lead to a decrease of its plasma concentration. Postsynaptic beta-3 receptors present in adipocytes, by activation adenylcyclase, induce cAMP formation, lipolysis and stimulation of mitochondrial respiration with dissipation of heat. Certain obese patients could have a deficiency of beta- 3 lipolytic activity and the use of bta-3 agonists in the treatment of obesity is considered. Presynaptic beta- 3 receptors modulate the release of catecholamines.

Effects of the stimulation of adrenergic receptors Recept alpha-1 alpha-2 beta-1 beta-2 ors Phospholipa Adenylcycla Adenylcycl Adenylcycla se C se inhibition ase se activation activation activation Heart Positive Positive inotropic chronotropi

and chronotrop ic effects Vessels Vasoconstri Vasoconstri ction ction Bronchi Digesti Decrease Decrease ve tract Motility and tone Uterus Contractions Platelet Aggregation Aggregation s Eyes Mydriasis Urethra Increase l tone

c effect

Vasodilatio n Bronchodila tion Decrease Decrease

Relaxation

Main alpha and beta peripheral effects of catecholamines; in red effects with therapeutic consequences by agonist or antagonist use.

Central adrenergic effects

The effects of catecholamines on the central nervous system are complex and difficult to systematize.

Norepinephrine is involved in the regulation of mood and the drugs which increase its concentration in synapsis by inhibiting its reuptake have an

antidepressant effect and can increase attention and vigilance. Stimulation of presynaptic alpha-2 receptors inhibit noradrenaline release, what reduces sympathetic tonus (decrease of action potential frequency in sympathetic presynaptic fiber) and noradrenaline release by the peripheral adrenergic terminations. Their stimulation by alpha--methylnoradrenaline, metabolite of alpha-methyldopa, causes hypotensive and sedative effects. The drugs acting as alphamethyldopa are usually called sympatholytic or centrally acting hypotensive drugs. There are receptors called imidazolines which could have an endogenous agonist, endazoline, and whose stimulation effects are similar to those of stimulation of alpha-2 adrenergic receptors. Their activation by drugs such as clonidine induces an inhibition of the sympathetic system and decrease of arterial pressure.

Dopaminergic effects
Dopamine has peripheral and central effects

Peripheral effects
In low doses dopamine has specific peripheral effects:

renal, mesenteric, coronary and cerebral vasodilation (by effect on D1 receptors) with lowering of arterial pressure decrease of tubular reabsorption of Na+ (D2) decrease of aldosterone and renin release

inhibition of gastroduodenal motility, probably via an inhibition of the secretion of motilin, polypeptide of 22 amino acid residues. nausea and vomiting by stimulation of the chemoreceptor trigger zone which, although central, can be reached by circulating drugs which do not cross the blood-brain barrier.

The nonspecific effects, which appear during intravenous administration of high dose of dopamine, result from the release of endogenous noradrenaline and stimulation of the adrenergic alpha and beta receptors (see previously).

Central effects
Effects of transmitters, among which dopamine, on the central nervous system are complex and it is not possible to give a precise description of them. However a certain number of anatomical, biological and pathophysiological data are useful for the general comprehension of the mode of action of drugs interacting with the dopaminergic system. 1. From an anatomical point of view there are three principal dopaminergic structures: o mesocorticolimbic bundle, going from the ventral part of the tegmen to Nucleus accumbens and involved in emotion control and where D3 receptors prevail o nigrostriatal bundle , involved in movement control, where D1 and D2 receptors prevail and which is impaired in patients with Parkinson's disease

tubero-infundibular bundle located in hypothalamic-pituitary area, involved in prolactin secretion and where D2 receptors prevail 2. From a biological point of view, dopaminergic receptors are generally divided into five types D1, D2, D3, D4 and D5 and they can be localized at presynaptic and postsynaptic sites .D1 and D5 receptors, called D1-like receptors, have similarities and D2, D3 and D4 receptors, called D2-like receptors, with D2 receptors. The activation of the D1 receptors induces a stimulation of adenylcyclase and an increase of cyclic AMP. The activation of D2 receptors inhibits adenylcyclase. But it is difficult to attribute precise roles to each type of receptors. which could, moreover, like D4 receptors, present polymorphic differences according to individuals, i.e. to be divided in sub-groups. The existence of a particular sub-group could be linked to a particular susceptibility for certain diseases, such as psychoses, and to different effects of drugs in patients. 3. From a pathophysiological point of view the consequences of a dopamine deficiency or excess are, at least partially, known. Dopamine deficiency by alteration of dopaminergic neurons in substantia nigra is responsible for Parkinson's disease disorders, tremor, akinesia and rigidity. These symptoms result partially from a relative cholinergic hyperactivity, imbalance resulting from dopamine deficiency. Conversely, an hyperactivity of the limbic dopaminergic system seems responsible of at least a certain number of symptoms observed during
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psychoses and the administration of neuroleptic agents, i.e. dopaminergic antagonists of type D2 and D4, attenuates them. There would be in certain schizophrenics a D1 hypoactivity and a D2 hyperactivity. There are presynaptic dopaminergic receptors which, when stimulated by dopamine, inhibit its own release. Products or drugs which activate dopaminergic receptors, directly or indirectly by increase of dopamine concentration in synapses, by inhibiting its reuptake or by increasing its release, induce a certain number of characteristic symptoms: o increased vigilance with decreased sleep requirement, insomnia o locomotor stimulation, logorrhea o reduction of fatigue o anorexia o nausea and vomiting o tendency to psychic addiction: the increase of dopamine in the Nucleus accumbens is involved in reward and addiction mechanisms o appearance of delusion, hallucinations. 4. From an endocrine point of view , the major effect of dopamine, by D2 receptor stimulation, is inhibition of prolactin secretion. Dopamine increases growth hormone secretion, except in acromegalic patients.