Serotonin acts solely via 5-HT₄-receptors to control human cardiac contractile function. The effects of serotonin via 5-HT₄-receptors lead to positive inotropic and chronotropic effects, as well as arrhythmias, in the human heart. In addition, 5-HT₄-receptors may play a role in sepsis, ischaemia, and reperfusion. These presumptive effects of 5-HT₄-receptors are the focus of the present review. We also discuss the formation and inactivation of serotonin in the body, namely, in the heart. We identify cardiovascular diseases where serotonin might play a causative or additional role. We address the mechanisms which 5-HT₄-receptors can use for cardiac signal transduction and their possible roles in cardiac diseases. We define areas where further research in this regard should be directed in the future, and identify animal models that might be generated to this end. Finally, we discuss in what regard 5-HT₄-receptor agonists or antagonists might be useful drugs that could enter clinical practice. Serotonin has been the target of many studies for decades; thus, we found it timely to summarise our current knowledge here.

Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, or absent, or even negative inotropic effects occurred. We can discern five dopamine receptors. In addition, the signal transduction by dopamine receptors and the regulation of the expression of cardiac dopamine receptors will be of interest to us, because this might be a tempting area of drug development. Dopamine acts in a species-dependent fashion on these cardiac dopamine receptors, but also on cardiac adrenergic receptors. We will discuss the utility of drugs that are currently available as tools to understand cardiac dopamine receptors. The molecule dopamine itself is present in the mammalian heart. Therefore, cardiac dopamine might act as an autocrine or paracrine compound in the mammalian heart. Dopamine itself might cause cardiac diseases. Moreover, the cardiac function of dopamine and the expression of dopamine receptors in the heart can be altered in diseases such as sepsis. Various drugs for cardiac and non-cardiac diseases are currently in the clinic that are, at least in part, agonists or antagonists at dopamine receptors. We define the research needs in order to understand dopamine receptors in the heart better. All in all, an update on the role of dopamine receptors in the human heart appears to be clinically relevant, and is thus presented here.

In an integrative approach, we studied the role of histamine H₂ receptors in the mouse heart. We noted that histamine, added cumulatively to the organ bath, failed to affect the force of contraction in left atrial preparations and did not change spontaneous heart rate in right atrial preparations from wild-type mice. By contrast, in the same preparations from mice that overexpressed the human H₂ receptor in a cardiac-specific way, histamine exerted concentration- and time-dependent positive inotropic and positive chronotropic effects. Messenger RNA of the human H₂ receptor was only detected in transgenic mice. Likewise, immunohistology and autoradiography only gave signals in transgenic but not in wild-type cardiac preparations. Similarly, a positive inotropic and positive chronotropic effect was observed with histamine in echocardiography of living transgenic mice and isolated perfused hearts (Langendorff preparation). Phosphorylation of phospholamban was increased in atrial and ventricular preparations from transgenic mice, but not in wild-type animals. The effects of histamine were mimicked by dimaprit and amthamine and antagonized by cimetidine. In summary, we generated a new model to study the physiologic and pathophysiologic cardiac role of the human H₂ receptor.

Background: Adenosine can be produced in the heart and acts on cardiac adenosine receptors. One of these receptors is the A_2A-adenosine receptor (A_2A-AR). Methods and Results: To better understand its role in cardiac function, we generated and characterized mice (A_2A-TG) which overexpress the human A_2A-AR in cardiomyocytes. In isolated atrial preparations from A_2A-TG but not from WT, CGS 21680, an A_2A-AR agonist, exerted positive inotropic and chronotropic effects. In ventricular preparations from A_2A-TG but not WT, CGS 21680 increased the cAMP content and the phosphorylation state of phospholamban and of the inhibitory subunit of troponin in A_2A-TG but not WT. Protein expression of phospholamban, SERCA, triadin, and junctin was unchanged in A_2A-TG compared to WT. Protein expression of the α-subunit of the stimulatory G-protein was lower in A_2A-TG than in WT but expression of the α-subunit of the inhibitory G-protein was higher in A_2A-TG than in WT. While basal hemodynamic parameters like left intraventricular pressure and echocardiographic parameters like the systolic diameter of the interventricular septum were higher in A_2A-TG than in WT, after β-adrenergic stimulation these differences disappeared. Interestingly, A_2A-TG hearts sustained global ischemia better than WT. Conclusion: We have successfully generated transgenic mice with cardiospecific overexpression of a functional A_2A-AR. This receptor is able to increase cardiac function per se and after receptor stimulation. It is speculated that this receptor may be useful to sustain contractility in failing human hearts and upon ischemia and reperfusion.

This review presents an overview of cardiac A_2A-adenosine receptors The localization of A_2A-AR in the various cell types that encompass the heart and the role they play in force regulation in various mammalian species are depicted. The putative signal transduction systems of A_2A-AR in cells in the living heart, as well as the known interactions of A_2A-AR with membrane-bound receptors, will be addressed. The possible role that the receptors play in some relevant cardiac pathologies, such as persistent or transient ischemia, hypoxia, sepsis, hypertension, cardiac hypertrophy, and arrhythmias, will be reviewed. Moreover, the cardiac utility of A_2A-AR as therapeutic targets for agonistic and antagonistic drugs will be discussed. Gaps in our knowledge about the cardiac function of A_2A-AR and future research needs will be identified and formulated.