Comparison of the positive inotropic effects of serotonin, histamine, angiotensin II, endothelin and isoprenaline in the isolated human right atrium

Abstract

The receptor systems through which serotonin (5-HT), histamine, angiotensin II and endothelin increase the force of contraction were studied in isolated right atria from patients without apparent heart failure. All agonists increased the atrial force of contraction in a concentration-dependent manner; maximal effects, however, were significantly less than those evoked by isoprenaline or Ca2+. 5-HT and histamine, but not angiotensin II and endothelin, activated adenylate cyclase, whereas endothelin and angiotensin II stimulated inositol phosphate generation. Experiments with subtype-selective antagonists revealed that histamine effects were mediated by H2-receptors (sensitive to ranitidine), 5-HT-effects by 5-HT4-receptors (sensitive to SDZ 205-557) and angiotensin II effects by AT1-receptors (sensitive to losartan). We conclude that in human right atria the force of contraction can be increased by cyclic AMP-dependent (histamine, 5-HT) and -independent (angiotensin II, endothelin) pathways. Compared to beta-adrenoceptors, however, all other receptor systems increase the force of contraction only submaximally indicating that the beta-adrenoceptor pathway is the most important physiological mechanism to regulate force of contraction and/or heart rate in the human heart.

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

“…The atrial myocardium expresses numerous receptors coupling to the PIP 2 -PLC-IP 3 cascade. Increased phosphoinositide breakdown and inositol phosphate generation in atrium is mediated by receptors for acetylcholine (muscarinic, M 1 and M 3 ), angiotensin II (AT 1 ), endothelin (ET A ), histamine (H 1 ), 5-hydroxytryptamine (5-HT 2 ), norepinephrine (α 1 ) and vasopressin in various species including cat, chick, guinea-pig, mouse, rat and human [10,[112][113][114][115][116][117][118][119][120][121][122][123][124][125]. Furthermore, expression of IP 3 Rs in atrial myocytes has been demonstrated at mRNA and protein levels in various organisms, including mouse, rabbit, rat and human [15,17,41,58].…”

“…Furthermore, cardiac tissue levels of endothelin and angiotensin II are elevated in cardiac diseases associated with AF. Both endothelin and angiotensin II increase IP 3 generation [122,123] and elicit arrhythmias in isolated human atrial myocardium [134,135]. Thus, endothelin-and angiotensin II-induced IP 3 signaling may be involved in the initiation and progression of AF.…”

Selectivity of [125I]‐PD 151242 for human, rat and porcine endothelin ETA receptors in the heart

“…Like angiotensin II, ET-1 is a potent positive inotropic agent with nanomolar affinity for cardiac muscle receptors (Davenport et al, 1989;Brodde et al, 1992;Zerkowski et al, 1992). The in vitro positive inotropic effect on human cardiac muscle strips was observed on both atrial and ventricular muscle (Schomisch Moravec et al, 1989).…”

Blockade of human atrial 5‐HT4 receptors by GR 113808

“…Subsequently a variety of drugs were found to antagonize competitively 5-HT-induced inotropic effects in human atrium. These compounds include the partial agonists renzapride and cisapride (Kaumann et al, 1991) and the antagonists DAU 6285 (Turconi et al, 1991) and SDZ 205-557 (Zerkowski et al, 1993). The affinity of these drugs for human atrial 5-HT4 receptors is, however, modest (pKB < 7.7) and all but SDZ 205-557 are potent antagonists of 5-HT3 receptors.…”