Inotropes receptor selectivity

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. 

Receptor Pharmacology of Selected Inotropic and Vasopressor Agents Used in Septic Shock1... 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

Dopamine is found in every sympathetic neuron and ganglion in the CNS. As a drug, and in addition to stimulation of dopaminergic receptors, dopamine indirectly stimulates both a- and )3-adrenoreceptors. Dopamine also causes a release of endogenous norepinephrine. The mechanism of action is based on the excitatory effect on )3-adrenoreceptors (in low and moderate doses), as well as on a-adrenoreceptors (in large doses). It has a positive inotropic effect on the heart, increases blood supply, selectively widens renal and mesenteric blood vessels, does not elevate blood pressure, and slightly increases the frequency of heartbeats. 

It is a derivative of dopamine and has relatively P -selective action and it also activates receptors and do not have or receptor agonistic property. It increases the force of myocardial contraction and cardiac output without significant change in heart rate, blood pressure and peripheral resistance. It is used as inotropic agent and for short term management of CHF and also in patients who are unresponsive to digitalis. 

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. 

Beta-blockers are one of the antihypertensive agents useful in patients with CAD because they have been shown to reduce morbidity and mortality. Beta-blockers competitively block both p, and P2 but with different selectivity. Blocking P, receptors, which are found primarily on cardiac muscle, will lead to negative chronotropic and inotropic effects. In hypertensive patients, this will lower their blood pressure. P2 receptors are found predominantly on the outer membrane of the smooth muscle cells of the vasculature, bronchioles, and myometrium and regulate the relaxation of these cells. Blockage of this receptor can lead to vasoconstriction and bronchoconstriction. 

In vivo, racemic dobutamine increases the inotropic activity of the heart to a much greater extent than it increa.ses chronotropic activity. This pharmacological profile has led to its use in treating congestive heart failure. Since /3 receptors are involved positively in both inotropic and chronotropic effects of the heart, the selective inotropic effect. seen with dobutamine cannot simply be due to its activity at P% receptors. Rather, this effect is the result of a combination of the inotropic effect of (-t- )-dohutamine on Px receptors and that of (-)-dobutamine mediated through 0 receptors. Thus, this is a case where a racemic mixture provides a more desirable pharmacological and therapeutic cITect than would cither enantiomer alone. 

The cardiovascular effects of racemic dobutamine are a composite of the pharmacological properties of the (—) and (-V) stereoisomers. Dobutamine has relatively more prominent inotropic than chronotropic effects, compared to isoproterenol. This useful selectivity may arise because peripheral resistance is relatively unchanged due to a counterbalancing ofa receptor-mediated vasoconstriction and receptor-mediated vasodilation. Alternatively, cardiac receptors may contribute to the inotropic effect. At equivalent inotropic doses, dobutamine enfumces automatic-ity of the sinus node to a lesser extent than does isoproterenol however, enhancement of AV and intraventricular conduction is similar for both drugs. 

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