P adrenoceptor stimulants

FIGURE 9.13 Cardiovascular responses to the PDE inhibitor fenoximone in different contexts, (a) In vivo effects of fenoximone in anesthetized dogs. Ordinates reflect positive inotropy. Redrawn from [47]. (b) In vitro effects of fenoximone in guinea pig untreated isolated left atria (filled circles) and atria in the presence of sub threshold P-adrenoceptor stimulation with prenalterol (open circles). Redrawn from [48]. 

Similar to a P-adrenoceptor stimulation intracellular cAMP can be increased by inhibition of phosphodiesterase. Thus, in turtle retina cells, cAMP leads to uncoupling and this can be mimicked by stimulation of adenylate cyclase with forskolin and concomitant inhibition of phosphodiesterase by IBMX [Piccolino et al., 1984]. In cardiac cells inhibition of phosphodiesterase has been investigated using methylxanthine derivates [De Mello, 1989], resulting in an enhancement of intercellular coupling. 

Schafer M, PonickeK, Heinroth-HoffmannI, Brodde OE, PiperHM, Schluter KD. p-Adrenoceptor stimulation attenuates the hypertrophic effect of a-adrenoceptor stimulation in adult rat ventricular cardiomyocytes. J Am Coll Cardiol 2001 37 300-307. 

O Callaghan CJ, Williams B. The regulation of human vascular smooth muscle extracellular matrix protein production by a- and P-adrenoceptor stimulation. J Hypertens 2002 20 287-294. 

Tamada A., Hattori Y., Houzen H., Yamada Y., Sakuma L, Kitabatake A., Kanno M. Effects of P-adrenoceptor stimulation on contractility, [Ca ji, and Ca current in diabetic rat cardiomyocytes. Am. J. Physiol. 274 (1998) H1849-H1857. 

There is evidence that NO is involved in the chronotropic, the inotropic, and the vasodilator response to P-adrenoceptor agonists (Schmetterer et al. 1999). N -Monomethyl-L-arginine significantly blunted the human heart rate response to p-adrenoceptor stimulation by isoprenahne (0.1-0.8 pg/min) in a dose-dependent manner. 

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 2.4 Noradrenergic inhibition of Ca " currents and transmitter release in sympathetic neurons and their processes, (a) Inhibition of currents through N-type Ca " channels by external application of noradrenaline (NA) or by over-expression of G-protein P y2 subunits, recorded from the soma and dendrite of a dissociated rat superior cervical sympathetic neuron. Currents were evoked by two successive 10 ms steps from —70 mV to OmV, separated by a prepulse to -1-90 mV. Note that the transient inhibition produced by NA (mediated by the G-protein Go) and the tonic inhibition produced by the G-protein Piy2 subunits were temporarily reversed by the -1-90 mV depolarisation. (Adapted from Fig. 4 in Delmas, P et al. (2000) Nat. Neurosci. 3 670-678. Reproduced with permission), (b) Inhibition of noradrenaline release from neurites of rat superior cervical sympathetic neurons by the 2-adrenoceptor stimulant UK-14,304, recorded amperometrically. Note that pretreatment with Pertussis toxin (PTX), which prevents coupling of the adrenoceptor to Gq, abolished inhibition. (Adapted from Fig. 3 in Koh, D-S and Hille, B (1997) Proc. Natl. Acad. Sci. USA 1506-1511. Reproduced with permission)...

The effect of receptor stimulation is thus to catalyze a reaction cycle. This leads to considerable amplification of the initial signal. For example, in the process of visual excitation, the photoisomerization of one rhodopsin molecule leads to the activation of approximately 500 to 1000 transdudn (Gt) molecules, each of which in turn catalyzes the hydrolysis of many hundreds of cyclic guanosine monophosphate (cGMP) molecules by phosphodiesterase. Amplification in the adenylate cyclase cascade is less but still substantial each ligand-bound P-adrenoceptor activates approximately 10 to 20 Gs molecules, each of which in turn catalyzes the production of hundreds of cyclic adenosine monophosphate (cAMP) molecules by adenylate cyclase. 

The effect of stimulation of cardiac adrenoceptors is even more leisurely because several more steps follow activation of the Gs protein by the p-adrenoceptor. For example, to increase the force of cardiac contraction, we have (1) activation of adenylate cyclase by Gas-GTP, (2) formation of cAMP, (3) activation of protein kinase A by the cAMP, then (4) phosphorylation of the calcium channel protein by the kinase. As a result, it takes about 5 to 6 sec from the time the receptors are... 

Inverse enantioselectivity at another receptor. An enantiomer may possess an unfavorable configuration at one receptor that may, however, be optimal for interaction with another receptor. In the case of dobutamine, the (+)-enantiomer has affinity at p-adreno-ceptors 10 times higher than that of the (-)-enantiomer, both having agonist activity. However, the a-adrenoceptor stimulant action is due to the (-)-form (see above). 

Smooth muscle effects. The opposing effects on smooth muscle (A) of a-and p-adrenoceptor activation are due to differences in signal transduction (p. 66). This is exemplified by vascular smooth muscle (A). ai-Receptor stimulation leads to intracellular release of Ca + via activation of the inositol tris-phosphate (IP3) pathway. In concert with the protein calmodulin, Ca + can activate myosin kinase, leading to a rise in tonus via phosphorylation of the contractile protein myosin. cAMP inhibits activation of myosin kinase. Via the former effector pathway, stimulation of a-receptors results in vasoconstriction via the latter, P2-receptors mediate vasodilation, particularly in skeletal muscle - an effect that has little therapeutic use. 

The decreased work capacity of the in-farcted myocardium leads to a reduction in stroke volume (SV) and hence cardiac output (CO). The fall in blood pressure (RR) triggers reflex activation of the sympathetic system. The resultant stimulation of cardiac 3-adreno-ceptors elicits an increase in both heart rate and force of systolic contraction, which, in conjunction with an a-adren-oceptor-mediated increase in peripheral resistance, leads to a compensatory rise in blood pressure. In ATP-depleted cells in the infarct border zone, resting membrane potential declines with a concomitant increase in excitability that may be further exacerbated by activation of p-adrenoceptors. Together, both processes promote the risk of fatal ventricular arrhythmias. As a consequence of local ischemia, extracellular concentrations of H+ and K+ rise in the affected region, leading to excitation of nociceptive nerve fibers. The resultant sensation of pain, typically experienced by the patient as annihilating, reinforces sympathetic activation. 

While the inhibition of noradrenaline re-uptake exerts predominantly an a-adrenergic effect, a selective jS-adrenergic effect can not be obtained by such an indirect mechanism. All selective /3-sympathomi-metics activate the receptors, P -, P2- or both sub-types, directly. The first pure jS-sympathomimetic in clinical use was isoproterenol which is structurally identical to adrenaline except the methyl-moiety at the N-position in the side-chain is replaced by an isopropyl-group. All effects produced by isoproterenol are due to either P -or 62-adrenoceptor stimulation tachycardia, increased stroke volume, decreased vascular resistance, broncho dilatation and, in pregnancy, uterus relaxation. The metabolic effects of isoproterenol are less pronounced than those of adrenaline. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

A. Control recording showing the spontaneous diastolic depolarization. B. The effect of norepinephrine is to increase the slope of diastolic depolarization. The frequency of spontaneous discharge is increased. This effect is mediated through the activation of p-adrenoceptors in sinoatrial nodal cells. C. Acetylcholine stimulates muscarinic receptors in sinoatrial nodal cells. 

Another group of transmitters involved in the control of the cardiovascular system by the autonomous nervous system includes the catecholamines, adrenaline and noradrenaline. In acinar submandibular gland cells of the rat the administration of 10 4 mol/1 adrenaline elicits a reduction in dye coupling from 97 to 75.3% dye-coupled cells [Kanno et al., 1993]. This could not be mimicked with isoprenaline, but was inhibited with phenoxybenzamine. Thus, the uncoupling effect of adrenaline in this preparation is mediated by stimulation of the a-adre-noceptor, whereas a stimulation of the P-adrenoceptor has no effect. 

Similarly, De Mello [1989] reported on an improvement in intercellular coupling by the P-adrenoceptor agonist isoproterenol in cardiac cell pairs. Thus, stimulation of P-adrenoceptors can be assumed to result in enhancement of intercellular coupling, at least in some preparations. However, on the basis of the hndings of Kwak and Jongsma [1996] on a lack of the effect of PKA to alter gap junction conductance in rat cardiomyocytes, caution seems necessary and species variability or tissue variability seems to play an important role. 

In 12 patients clonidine 50-100 micrograms/day relieved clozapine-induced sialorrhea, with good results in three and partial results in eight (178). Theoretically, the reduction in sialorrhea with clonidine could have been due to reduced plasma noradrenaline concentrations, resulting in less stimulation of unopposed p-adrenoceptors in the salivary glands. 

More broadly, timolol therapy should be considered with caution in patients with any significant sign, symptom, or history for which systemic beta-blockade would be medically imwise.This includes disorders of cardiovascular or respiratory origin (e g., asthma, chronic bronchitis, and emphysema) as well as many other conditions. Spirometric evaluation after institution of timolol therapy may help to identify patients in whom bronchospasm develops after commencement of therapy. In general, however, patients with asthma and other obstructive pulmonary diseases should avoid this drug. Sympathetic stimulation may be essential to support the circulation in individuals with diminished myocardial contractility, and its inhibition by P-adrenoceptor antagonists may precipitate more severe cardiac feilure. 

Cyclic AMP accumulation by catecholamines is generally associated with /3-adrenoceptor stimulation, but there is recent evidence that a adrenoceptor stimulation also can lead to cyclic AMP accumulation. For example, in slices of rat cerebral cortex, the effect of isoprenaline on the cyclic AMP level was inhibited by a /3-adrenoceptor blocking drug and yet inhibition of the effect of noradrenaline required the combination of a P and an a-adrenoceptor blocking drug [65,66]. 

Tenamfetamine ( ecstasy, MDMA methylenedioxymethamphetamine) is structurally related to mescaline as well as to amphetamine. It was originally patented in 1914 as an appetite suppressant and has recently achieved widespread popularity as a dance drug at rave parties (where it is deemed necessary to keep pace with the beat and duration of the music popular names reflect the appearance of the tablets and capsules and include White Dove, White Burger, Red and Black, Denis the Menace). Tenamfetamine stimulates central and peripheral a-and p-adrenoceptors thus the pharmacological effects are compounded by those of physical exertion, dehydration and heat. In susceptible individuals (poor metabolisers who exhibit the CYP450 2D6 polymorphism) a severe and fatal idiosyncratic reaction may occur with fulminant hyperthermia, convulsioirs, disseminated intravascular coagulation, rhabdomyolysis, and acute renal and hepatic failure. Treatment includes activated charcoal, diazepam for convulsions, P-blockade (atenolol) for tachycardia, a-blockade (phentolamine) for hypertension, and dantrolene if the rectal temperature exceeds 39°C. 

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