Isoproterenol actions

See also Glucagon, Kinase Cascade, Catecholamines, Isoproterenol, Action of Epinephrine, Norepinephrine... 

Daniell, H.B., Bagwell, E.E. and Walton, R.P. (1967). Limitation of myocardial function by reduced coronary blood flow during isoproterenol action. Circ. Res. 21 85-98. 

Because of the widespread nature of adrenoceptors, nonselective P-agonists can produce many undesirable side effects. Therefore, before adrenergic agonists could become widely used in the treatment of asthma, some selectivity in action was needed. Whereas epinephrine and ephedrine have significant agonist activity at both a and P adrenoceptors, isoproterenol is a selective agonist at the P receptor (39). However, isoproterenol does not distinguish between the P and receptors and it is not active orally. 

The answer is d. (Hardman, pp 212—213.) Only isoproterenol will lower mean blood pressure, decrease peripheral vascular resistance, and increase heart rate. Methacholine decreases heart rate as does propranolol. Atropine has no action on peripheral resistance. Norepinephrine causes intense vasoconstriction and raises the mean blood pressure. 

This complex, cardiostimulatory and vasodilating action is expressed by a significant increase of cardiac ontput and stroke volnme. In response to activation of j32-adrenorecep-tors, bronchodilation also increases. Isoproterenol is used in bronchospasms, asthma, cardiac block, and shock. Synonyms of isoproterenol are protemol, isoprenaline, isadrine, norisodrine, novodrin, and others. 

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... 

Slow intravenous infusion of therapeutic doses of isoproterenol in humans produces a marked decrease in total peripheral resistance, owing to the predominance of vasodilation in skeletal muscle vascular beds. As a consequence, diastolic and mean blood pressures fall (Fig. 10.4). The depressor action of isoproterenol is more pronounced than that of epinephrine because isoproterenol causes no vasoconstriction, whereas epinephrine does in some vascular beds. Systolic blood pressure may remain unchanged or may increase. When an increase in systolic blood pressure is seen, it is due to the marked increase in cardiac output produced by isoproterenol. 

Isoproterenol usually increases the heart rate and stroke volume more than does epinephrine. This is partly due to its ability to decrease mean blood pressure, which then reflexively diminishes vagal activity, and partly to its action on the heart. 

Bronchial smooth muscle is relaxed by epinephrine and isoproterenol through their interaction with P2-adrenoceptors. Epinephrine and isoproterenol are potent bronchodilators, while norepinephrine has a relatively weak action in this regard (see Chapter 39). 

The detrusor muscle (which contains (32-adrenoceptors) in the body of the urinary bladder is relaxed by epinephrine and isoproterenol. On the other hand, the trigone and sphincter (which contain aj-receptors) are contracted by norepinephrine and epinephrine this action inhibits the voiding of urine. 

Epinephrine, in therapeutic doses, mildly stimulates the CNS. The most noticeable features of this stimulation are apprehension, restlessness, and increased respiration. In therapeutic doses both isoproterenol and norepinephrine also have minor CNS stimulant properties. Since these compounds do not easily cross the blood-brain barrier, the mechanism of their stimulatory effects is not clear. It is likely that the stimulating effects are primarily, if not entirely, due to actions in the periphery that alter the neural input to the CNS. 

Terbutaline and albuterol are relatively selective Pj-adrenoceptor agonists. Both have a longer duration of action than isoproterenol because they are not metabolized by COMT. Like isoproterenol, they are not metabolized by MAO and are not transported into adrenergic neurons. Terbutaline and albuterol are effectively administered either orally or subcutaneously. Because of their selectivity for Pj-adrenoceptors, they produce less cardiac stimulation than does isoproterenol but are not completely without effects on the heart. 

IgE-medlated release of mast cell contents. Inset, Intact mast cell with histamine stored In granules. An IgE antibody molecule Is depicted adjacent to the mast cell. Two IgE molecules combine with a mast cell (sensitization). The attachment of an antigen (allergen) to the sensitized mast cell Initiates release of histamine (and other substances) from the mast cell. This degranulation can be prevented by such agents as isoproterenol, theophylline, epinephrine, and cromolyn sodium. H antihistamines do not interfere with degranulation but instead prevent actions of histamine at various pharmacological receptors. 

Isoproterenol is administered almost exclusively by inhalation from metered-dose inhalers or from nebulizers. The response to inhaled isoproterenol and other inhaled adrenomimetics is instantaneous. The action of isoproterenol is short-lived, although an objective measurement of pulmonary function has shown an effective duration of up to 3 hours. When it is administered by inhalation, the cardiac effects of isoproterenol are relatively mild, although in some cases a substantial increase in heart rate occurs. 

Matsui M et al Increased relaxant action of forskolin and isoproterenol against muscarinic agonist-induced contractions in smooth muscle from M2 receptor knockout mice. J Pharmacol Exp Ther 2003 305 106. [PMID 12649358]... 

Isoproterenol (isoprenaline) is a very potent 3-receptor agonist and has little effect on receptors. The drug has positive chronotropic and inotropic actions because isoproterenol activates 3 receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9-4 Figure 9-6). 

Isoproterenol is a potent bronchodilator when inhaled as a microaerosol from a pressurized canister, 80-120 meg isoproterenol causes maximal bronchodilation within 5 minutes. Isoproterenol has a 60- to 90-minute duration of action. An increase in the asthma mortality rate that occurred in the United Kingdom in the mid-1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol. It is now rarely used for asthma. 

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