Adrenoceptor agonists inotropes

Glucagon has a potent inotropic and chronotropic effect on the heart, mediated by the cAMP mechanism described above. Thus, it produces an effect very similar to that of B-adrenoceptor agonists without requiring functioning receptors. 

Dobutamine is a racemic mixture of d- and 1-dobutamine. The racemate behaves primarily a pj-adrenoceptor agonist with greater inotropic than chronotropic effects on the heart it has some a-agonist effect, but less than dopamine. It is useful in shock (with dopamine) and in low output heart failure (in the absence of severe h5 ertension). 

Dopexamine is a synthetic catecholamine whose principal action is as an agonist for the cardiac P -adrenoceptors (positive inotropic effect). It is also a weak dopamine agonist (thus causing renal vasodilatation) and inhibitor of noradrenaline uptake thereby enhancing stimulation of cardiac Pj-receptors by noradrenaline. It is used occasionally to optimise the cardiac output, particularly perioperatively. 

Dobutamine is a relatively selective betai-adrenoceptor agonist with only slight beta2- and alpha-adrenoceptor activity. It has been developed as a positive inotropic agent that is less vasoconstrictive than high doses of dopamine. 

Gauthier C, Tavernier G, Trochu JN, et al. Interspecies differences in the cardiac negative inotropic effects of p3-adrenoceptor agonists. J Pharmacol Exp Ther 1999 290 687-693. 

In the treatment of acute myocardial failure with associated pulmonary oedema, the objectives are to improve gas exchange, increase myocardial contractility and reduce the workload of the left ventricle. Dobutamine, a somewhat selective pi -adrenoceptor agonist, produces a pronounced inotropic effect that results in an increased cardiac output (where contractility is the limiting factor) and an elevation of arterial blood pressure. The drug preparation, following appropriate dilution, is administered by continuous intravenous infusion at a rate of 1-5 (ig/kg min. An intravenous dose (0.5 mg/kg) of furosemide (loop diuretic) increases venous capacitance by redistributing venous blood from the lungs to the peripheral circulation, which... 

Answer In the case of enzyme antagonists, a basal stimulation of the system may be required to observe any effect of enzyme inhibition. In this case, the enzyme is phosphodiesterase (PDE), which hydrolyzes elevated levels of cytosolic cyclic AMP. In vivo, the heart is under a tonic sympathetic (3-adrenoceptor stimulation, but the cardiotonic effect of this stimulation is kept to a subthreshold level by the hydrolysis of the resulting cyclic AMP by PDE. Inhibition of this braking effect through inhibition of PDE allows the cyclic AMP levels in the cell to be elevated with a resulting positive inotropic effect. Without this stimulation of the system, no effect of PDE blockade will be observed. In terms of system stimulation, a PDE inhibitor will potentiate the effects of a (3-adrenoceptor agonist. If the in vitro assay is placed under a subthreshold level of (3-adrenoceptor stimulation, then blockade of PDE will potentiate the subthreshold effect to a visible effect, that is, a curve will appear with PDE blockade (see Figure 14.25). Therefore, the in vitro cardiac preparation should be carried out with a subthreshold level of (3-adrenoceptor stimulation to better simulate in vivo conditions. 

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. 

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 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],... 

Dopexamine, an agonist of cardiac /32-adrenoceptors and renal DAi-receptors, may be considered an inotropic drug with additional renal and peripheral vasodilator activities. Its duration of action is rather short and the drug is rarely used at present. 

Early evidence that prejunctional histamine H3-receptors may modulate the sympathetic nerve activity on the heart was provided by Luo et al., (1991). These authors clearly stated that the selective H3-agonist (R)a-methylhistamine attenuates the inotropic response induced by transmural stimulation of the adrenergic nerve terminals in the isolated right atrium, without affecting basal contractile force of the preparation or the positive inotropic effect elicited by exogenous noradrenaline. The effect of (R)a-methylhistamine, which is not modified by Hi and H2-receptor blockade, was reversed by the specific H3-receptor antagonist thioperamide, at concentrations which do not influence the inhibitory activity mediated by other presynaptic receptors, like a2-adrenoceptors. 

The under-reporting of the results of clinical trials in patients with heart failure has been reviewed (7). Some trials that have been unpublished or published only in abstract or preliminary form have involved drugs with positive inotropic effects, such as the phosphodiesterase inhibitor vesnarinone (SEDA-23, 195), the beta-adrenoceptor partial agonist xamoterol, and the dopamine receptor agonist ibopamine. 

Phenylephrine is a selective ai adrenergic agonist, with a pharmacological structure similar to norepinephrine (noradrenaline), which causes peripheral vasoconstriction. Stimulation of adrenoceptors in the myocardium has an inotropic effect. However, phenylephrine produced no increase in cardiac output, increased systemic vascular resistance and mean arterial pressure and reduced muscle blood flow in anaesthetized horses (Lee et al 1998). Phenylephrine should be reserved for critical conditions where the perfusion of essential organs is compromised and inotropes are not effectively maintaining organ function. The recommended infusion rates are shown in Table 12.3. 

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