Sympathetic tone

In randomized, controlled, clinical trials, calcium channel blockers were as effective as p-blockers at preventing ischemic symptoms. Calcium channel blockers are recommended as initial treatment in IHD when /3-blockers are contraindicated or not tolerated. In addition, CCBs may be used in combination with /3-blockers when initial treatment is unsuccessful. However, the combination of a (1-blocker with either verapamil or diltiazem should be used with extreme caution since all of these drugs decrease AV nodal conduction, increasing the risk for severe bradycardia or AV block when used together. If combination therapy is warranted, a long-acting dihydropyridine CCB is preferred. (3-Blockers will prevent reflex increases in sympathetic tone and heart rate with the use of calcium channel blockers with potent vasodilatory effects. 

Sympathetic and parasympathetic nerves innervate the penis. In the flaccid state, OC2-adrenergic receptors mediate tonic contraction of the arterial and corporal smooth muscles. This maintains high penile arterial resistance and a balance exists between blood flow into and out of the corpora. With sexual stimulation, nerve impulses from the brain travel down the spinal cord to the thoracolumbar ganglia.3 A decrease in sympathetic tone and an increase in parasympathetic activity then occurs, causing a net increase in blood flow into the erectile tissue. Erections may also occur as a result of a sacral nerve reflex arc while patients are sleeping (nocturnal erections). 

Sympathetic nerves. The afferent and efferent arterioles are densely innervated with sympathetic nerves. Norepinephrine released directly from the nerves or circulating epinephrine released from the adrenal medulla stimulates a, adrenergic receptors to cause vasoconstriction. The predominant site of regulation is the afferent arteriole. Under normal resting conditions, there is little sympathetic tone to these vessels so that RBF is comparatively high. As discussed previously, this facilitates glomerular filtration. 

Clonidine, guanabenz, guanfacine, and methyldopa lower BP primarily by stimulating a2-adrenergic receptors in the brain, which reduces sympathetic outflow from the vasomotor center and increases vagal tone. Stimulation of presynaptic oq-receptors peripherally may contribute to the reduction in sympathetic tone. Consequently, there may be decreases in heart rate, cardiac output, total peripheral resistance, plasma renin activity, and baroreceptor reflexes. 

Reserpine depletes norepinephrine from sympathetic nerve endings and blocks the transport of norepinephrine into its storage granules. When the nerve is stimulated, less than the usual amount of norepinephrine is released into the synapse. This reduces sympathetic tone, decreasing peripheral vascular resistance and BP. 

Since the discovery that norepinephrine release at the adrenergic nerve terminal is the mechanism whereby the human body maintains sympathetic tone, medicinal scientists have searched for agents which reduce sympathetic tone through interference with norepinephrine peripherally. Reduction of the effect of norepinephrine should lead to a lowering of blood pressure which might be achieved in the following ways ... 

The inhibition of sympathetic tone to the venous system (capacitance vessels) results in increased pooling of blood in the venous vascular bed with consequent decreased venous return to the heart and decreased cardiac output. This phenomenon is more pronounced in upright positions because of the effect of gravity. The hemodynamic effects of ganglionic blockers include decreases in cardiac output, renal blood flow, cerebral blood flow and orthostatic hypotension(20,21). 

In 1967, Henning and Van Zwieten provided conclusive evidence that the most important effect of methyldopa is on the vasomotor centers in the central nervous system(22). This central effect results in a decrease in sympathetic tone to the periphery. 

Antiadrenergics are drugs capable of lowering transmitter output from sympathetic neurons, i.e sympathetic tone . Their action is hypotensive (indication hypertension, p. 312) however, being poorly tolerated, they enjoy only limited therapeutic use. 

In the sympathetic nervous system there is the possibility to reduce the release of noradrenaline. The alkaloid reserpine is known to interfere with the ability of the postganglionic sympathetic nerves to store noradrenaline. This results in a reduction of the sympathetic tone which is a useful measure in the treatment of essential hypertension. These type of drugs are classified as antisympathotonics. 

In contrast to the highly specific structural requirement for ligands at the various adrenoceptor subtypes the re-uptake mechanism (into the axon and into the vesicle) are less discriminative. Compounds without hydroxyl moieties at the phenyl ring have no affinity towards the adrenoceptors but serve as a substrate for the re-uptake mechanisms, thereby competing with noradrenaline and as a consequence increasing its concentration in the synaptic cleft. Drugs enhancing the sympathetic tone by this mechanism are called indirect sympathomimetics, for example tyramine, ephedrine, amphetamine. 

Since the main clinical use for antisympathotonics is in the treatment of essential hypertension, such drugs will be discussed in Chapter 20 in more detail. The alkaloid reserpine from Rauwolfia serpentina was the first drug used clinically to reduce sympathetic tone. Reserpine reduce the ability of storage and release of various transmitters (adrenaline, noradrenaline, serotonine and dopamine) by an irreversible destruction of the axonal vesicle membranes. The duration of the reserpine effect is actually determined by the de novo synthesis of these structure. Beside various central side effects like sedation, depression, lassitude and nightmares the pattern of unwanted effects of reserpine is determined by the shift of the autonomic balance towards the parasympathetic branch myosis, congested nostrils, an altered saliva production, increased gastric acid production, bardycardia and diarrhea. As a consequence of the inhibition of central dopamine release, reserpine infrequently shows Parkinson-like disturbances of the extrapyramidal system. 

Another, new group of compounds act via the same central mode of action the imidazoline receptor agonists. The central regulation of sympathetic tone in the medulla oblongata is sensitive not only to 2-adrenoceptors but to so called imidazoline receptors as well. Two drugs with high affinity towards... 

Volatile anesthetics have a direct relaxating effect on cardiac and vascular muscle added to indirect effects through reductions in sympathetic tone. 

An increase in sympathetic neuronal activity causes an increase in heart rate (positive chronotropic effect, or tachycardia) and an increase in cardiac contractile force (positive inotropic effect) such that the stroke output is increased. Cardiac output, which is a function of rate and stroke output, is thus increased. A physiological increase in sympathetic tone is almost always accompanied by a diminution of parasympathetic vagal tone this allows full expression of the effects of increased sympathetic tone on the activity of the heart. 

An increase in sympathetic tone constricts blood vessels in most vascular beds and therefore causes a net increase in total peripheral resistance. Increased sympathetic tone increases neural release of norepinephrine and its interaction both with 3-adrenoceptors on cardiac cells and with a-adrenoceptors on vascular smooth muscle cells. As a consequence, the systolic and diastolic blood pressures are elevated. It follows that the mean arterial blood pressure must also be increased. 

Most clinically used concentrations of phenytoin do not significantly alter sinus rate in humans. However, the hypotension that may follow IV administration of phenytoin can result in an increase in sympathetic tone and therefore an increased sinus heart rate. 

Verapamil must be used with extreme caution or not at all in patients who are receiving p-adrenoceptor blocking agents. Normally, the negative chronotropic effect of verapamil will in part be overcome by an increase in reflex sympathetic tone. The latter is be prevented by simultaneous administration of a p-adrenoceptor blocking agent, which exaggerates the depressant effects of... 

C. Nitroglycerin can increase heart rate via an increase in sympathetic tone to the heart due to an excessive decrease in blood pressure propranolol would block the p-receptors responsible for the tachycardia. Propranolol does not decrease preload, and its effect to decrease afterload would exacerbate the decrease in afterload produced by nitroglycerin. Propranolol does not increase myocardial contractile force and could actually increase the incidence of vasospasm by unmasking a-adrenocep-tors in the coronary blood vessels. 

Answer Nifedipine, unless formulated for slow, sustained release, is characterized by relatively rapid onset of vasodUatory effects. This man s side effects reflect the rapid and intense fall in blood pressure and consequent reflex increases in sympathetic tone. The increase in anginal episodes also is a result of drug-induced periodic increases in heart rate. 

It is also clear that anxiety symptoms are common among primary alcoholic patients [although abstinence leads to a reduction in symptoms even without any specific pharmacological or psychosocial treatments [S. A. Brown et al. 1991]]. Repeated alcohol withdrawals may result in kindling of the limbic system, producing chronic elevation in sympathetic tone [D. T. George et al. 1988]. This in turn can result in further anxiety symptoms and hence maintenance of drinking behavior. 

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