Isoproterenol 3-agonist

Cerrina, J., Ladurie, M., Le, R., Labat, C., Raffestin, B., Bayol, A. and Brink, C. (1986). Comparison of human bronchial muscle responses to histamine in vivo with histamine and isoproterenol agonists in vitro. Am. Rev. Respir. Dis. 137, 57-61. 

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. 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Isoproterenol. Isoproterenol hydrochloride is an nonselective P-adrenoceptor agonist that is chemically related to NE. It mimics the effects of stimulation of the sympathetic innervation to the heart which are mediated by NE. It increases heart rate by increasing automaticity of the SA and AV nodes by increasing the rate of phase 4 diastoHc depolarization. It is used in the treatment of acute heart block and supraventricular bradyarrhythmias, although use of atropine is safer for bradyarrhythmias foUowing MI (86). 

FIGURE 2.18 Inotropic and lusitropic responses of guinea pig left atria to (3-adrenoceptor stimulation. Panels A to C isometric tension waveforms of cardiac contraction (ordinates are mg tension abscissae are msec), (a) Effect of 0.3 nM isoproterenol on the waveform. The wave is shortened due to an increase in the rate of diastolic relaxation, whereas no inotropic response (change in peak tension) is observed at this concentration, (b) A further shortening of waveform duration (lusitropic response) is observed with 3 nM isoproterenol. This is concomitant with positive inotropic response (increase maximal tension), (c) This trend continues with 100 nM isoproterenol, (d) Dose-response curves for ino tropy (filled circles) and lusitropy (open circles) in guinea pig atria for isoproterenol, (e) Dose-response curves for inotropy (filled circles) and lusitropy (open circles) in guinea pig atria for the P-adrenoceptor partial agonist prenalterol. Data redrawn from [6]. 

FIGURE 2.21 Effects of desensitization on inotropic responses of guinea pig atria to isoproterenol (panel a) and prenalterol (panel b). Ordinates response as a percent of the maximal reaponse to isoproterenol. Abscissae logarithms of molar concentrations of agonist (log scale). Responses shown after peak response attained (within 5 minutes, filled circles) and after 90 minutes of incubation with the agonist (open triangles). Data redrawn from [6]. 

FIGURE 9.21 Changes in heart rate (ordinates) for agonist-induced changes in cardiac inotropy (changes in rate of ventricular pressure) in anesthetized cats. Responses shown to isoproterenol (filled circles) and dobutamine (open circles), (a) Response in normal cats shows inotropic selectivity (less tachycardia for given changes in inotropy) for dobutamine over isoproterenol, (b) The inotropic selectivity of dobutamine is reduced by previous a-adrenoceptor blockade by phentolamine. From [61],... 

Isoproterenol (104) is an important agent for classification because of its selective p-receptor agonist activity. It is of special interest that its chronotropic (increase in heart rate) and inotropic (increase in force of contraction) effects exceed that of epinephrine it is also used in the management of mild to moderate asthma due to its bronchodilating effect, resulting in increased vital capacity of the lungs. 

The (R)-amino ketone is hydrogenated enantioselectively by a neutral complex [ (S)-(i )-BPPFOH RhCl]2 to give the (R,R)-isoproterenol analogue, a compound which has been shown to possess very potent /9-adrenoreceptor agonistic activity... 

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