Norepinephrine vascular effects

Cardiovascular effects of Infusion of norepinephrine, epinephrine, Isoproterenol, and dopamine in humans. Infusions were made intravenously during the time indicated by the broken lines. Heart rate is given in beats per minute, blood pressure in millimeters of mercury, and peripheral resistance in arterial blood pressure. (Reprinted with permission from Allwood MJ, Cobbald AF, and Ginsburg J. Peripheral vascular effects of noradrenaline, isopropyl-noradrenaline, and dopamine. Br Med Bull 19 132, 1963. Reproduced by permission of the Medical Department, The British Council. 

Adrenal medulla Epinephrine, Norepinephrine Vascular and metabolic effects that facilitate increased physical activity... 

Guanadrel (u-28288D, VII), equipotent to guanethldlne in the clinic, appears to offer more stable blood pressure control during the day with less frequent diarrhea Studies on guancydine (vill) continued to support the mechanism of a direct vascular effect with partial depletion of norepinephrine stores observed only after high chronic dosing under certain conditions ... 

The major circulating hormones that influence vascular smooth muscle tone are the catecholamines epinephrine and norepinephrine. These hormones are released from the adrenal medulla in response to sympathetic nervous stimulation. In humans, 80% of catecholamine secretion is epinephrine and 20% is norepinephrine. Stimulation of cy-adrenergic receptors causes vasoconstriction. The selective a,-adrenergic receptor antagonist, prazosin, is effective in management of hypertension because it causes arterial and venous smooth muscle to relax. 

Angiotensin II causes vasoconstriction by direct stimulation of ATj receptors on the vascular smooth muscle. It also enhances release of the neurotransmitter norepinephrine from the sympathetic nerve fibers present in the blood vessels. The vasopressor effects of Ag II may be inhibited pharmacologically in order to decrease TPR and treat hypertension. An important class of orally active drugs is the ACE inhibitors, including captopril and enalopril, which prevent formation of Ag II. More recently, angiotensin receptor antagonists have been developed that act at the vascular smooth muscle. These drugs, which include losartin and valsartan, are also orally active. 

The contractile effect of various doses of norepinephrine (Nil) (X) alone on vascular smooth muscle is represented in the figure below. 

TBTC1 produced a dose-dependent inhibition of ANP on vascular smooth muscle responses with an effect on norepinephrine, nitroprusside and atrial natriuretic peptide in isolated aortic rings of rats. The inhibition of vasorelaxation was accompanied by a parallel inhibition of ANP-induced cGMP generation29. 

Vasopressin causes vasoconstrictive effects that, unlike adrenergic receptor agonists, are preserved during hypoxia and severe acidosis. It also causes vasodilation in the pulmonary, coronary, and selected renal vascular beds that may reduce pulmonary artery pressure and preserve cardiac and renal function. However, based on available evidence, vasopressin is not recommended as a replacement for norepinephrine or dopamine in patients with septic shock but may be considered in patients who are refractory to catecholamine vasopressors despite adequate fluid resuscitation. If used, the dose should not exceed 0.01 to 0.04 units/min. 

Mechanisms of action. The tonus of vascular smooth muscle can be decreased by various means. ACE inhibitors, antagonists at ATI-receptors and antagonists at a-adrenoceptors protect against the effects of excitatory mediators such as angiotensin 11 and norepinephrine, respectively. Prostacyclin an-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

On the other hand, )3-adrenoblockers have a minor effect on vascular tonicity. In addition, 8-adrenoblockers prevent the vasodilatory effect of epinephrine. In organs such as the heart, which are regulated mainly by )3-adrenoreceptors, )3-adrenoblockers counteract the excitatory effect of norepinephrine. 

The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug, the response characteristics of the effector cells, and the predominant type of adrenoceptor found on the cells. For example, the smooth muscle cells of many blood vessels have only or predominantly a-adrenoceptors. The interaction of compounds with these adrenoceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for a-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains p2-adrenoceptors, the response in this tissue elicited by the action of p2-adrenoceptor agonists is relaxation of smooth muscle cells. Epinephrine and isoproterenol, which have high affinities for p2-adrenoceptors, cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for p2-adrenoceptors and has relatively weak bronchiolar relaxing properties. 

The cardiovascular effects of norepinephrine, epinephrine, and isoproterenol are shown in Table 10.1. Differences in the action of these three catecholamines on various vascular beds are due both to the different... 

Although several factors can influence the flow of blood through the coronary vessels, the most important of these is the local production of vasodilator metabolites that results from stimulation-induced increased work by the heart. a-Adrenoreceptors and -adrenoceptors in the coronary vascular beds do not play a major role in determining the vasodilator effects of the administration of epinephrine or norepinephrine. 

In any blood vessel, the final integrated response to either neuronally released norepinephrine or to circulating epinephrine probably depends on the relative participation of at least four populations of a-adreno-ceptors postjunctional i- and az-adrenoceptors mediate constriction of vascular smooth muscle, while prejunctional and endothelial az-adrenoceptors mediate vasodilation. An understanding of the vessel vascular response to adrenomimetic drugs also must include the effects of drugs on adventitial innervation, smooth muscle, and other vascular factors that may be present. 

Hemodynamic effects Decreased peripheral vascular resistance and blood pressure Venodilation is prominent Cardiac stimulation occurs because of cardiovascular reflexes and enhanced release of norepinephrine Similar to phenoxybenzamine Decreased peripheral vascular resistance and blood pressure Veins seem to be less susceptible to antagonism than arteries thus, postural hypotension is less of a problem Cardiac stimulation is less because release of norepinephrine is not enhanced... 

Activation of endothelial cell muscarinic receptors by acetylcholine (Ach) releases endothelium-derived relaxing factor (nitric oxide), which causes relaxation of vascular smooth muscle precontracted with norepinephrine, 10-8M. Removal of the endothelium by rubbing eliminates the relaxant effect and reveals contraction caused by direct action of Ach on vascular smooth muscle. (NA, noradrenaline [norepinephrine]. Numbers indicate the log concentration applied at the time indicated.)... 

Cholinesterase inhibitors have minimal effects by direct action on vascular smooth muscle because most vascular beds lack cholinergic innervation (coronary vasculature is an exception). At moderate doses, cholinesterase inhibitors cause an increase in systemic vascular resistance and blood pressure that is initiated at sympathetic ganglia in the case of quaternary nitrogen compounds and also at central sympathetic centers in the case of lipid-soluble agents. Atropine, acting in the central and peripheral nervous systems, can prevent the increase of blood pressure and the increased plasma norepinephrine. 

The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on heart rate, myocardial function, peripheral vascular resistance, and venous return (see Figure 6-7 and Table 9-4). The endogenous catecholamines, norepinephrine and epinephrine have complex cardiovascular effects because they activate both and 13 receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoreceptor. 

Intravenous administration of dopamine promotes vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels, via activation of Di receptors. Activation of the Di receptors in the renal vasculature may also induce natriuresis. The renal effects of dopamine have been used clinically to improve perfusion to the kidney in situations of oliguria (abnormally low urinary output). The activation of presynaptic D2 receptors suppresses norepinephrine release, but it is unclear if this contributes to cardiovascular effects of dopamine. In addition, dopamine activates Bj receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular a. receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. 

Phentolamine is a potent competitive antagonist at both K and k2 receptors (Table 10-1). Phentolamine reduces peripheral resistance through blockade of K receptors and possibly k2 receptors on vascular smooth muscle. Its cardiac stimulation is due to antagonism of presynaptic k2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms. Phentolamine also has minor inhibitory effects at serotonin receptors and agonist effects at muscarinic and Hi and H2 histamine receptors. Phentolamine s principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia. Phentolamine has been used in the treatment of pheochromocytoma. Unfortunately oral and intravenous formulations of phentolamine are no longer consistently available in the United States. 

Nefazodone [Serzone] Slight inhibition of serotonin and norepinephrine reuptake may also block CNS serotonin receptors Sedating useful in agitation May cause orthostatic hypotension because of antagonistic effect on vascular alpha-1 receptors... 

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