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Positive inotropic effect in the heart produced by acetylcholine
1Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
Insights
Acetylcholine (ACh) can surprisingly increase cardiac muscle contractility in human atrial strips and rat hearts, challenging the typical negative effects. This positive inotropic effect, mediated by muscarinic receptors, suggests inositol trisphosphate (IP3) as a key signaling molecule.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Molecular Cardiology
Background:
- Muscarinic receptor activation in cardiac tissue typically elicits negative chronotropic and inotropic responses.
- The precise effects of acetylcholine (ACh) on cardiac contractility and hemodynamics require further elucidation, especially in human tissues.
Purpose of the Study:
- To investigate the inotropic and hemodynamic effects of acetylcholine (ACh) on human atrial muscle and isolated working rat hearts.
- To explore the potential signaling pathways, such as inositol phosphates, involved in ACh-mediated cardiac responses.
Main Methods:
- Experiments were conducted using human right atrial strips and isolated working rat hearts.
- Acetylcholine (ACh) was applied in varying concentrations (10(-7) - 10(-4) M) to assess dose-dependent effects.
- Measurements included contractility (inotropic state), coronary flow, and cardiodynamic indices; atropine was used as an antagonist, and [3H]phosphoinositide breakdown was measured in rat ventricular strips.
Main Results:
- Acetylcholine (ACh) induced a tri-phasic (positive-negative-positive) inotropic effect in approximately 40% of human atrial strips, with positive effects also observed upon washout.
- In rat hearts, ACh initially decreased coronary flow and cardiac function, but potentiated cardiodynamic indices when adenosine was co-administered.
- Cholinergic stimulation increased inositol phosphate formation in rat ventricular strips, suggesting a role for IP3.
Conclusions:
- Cholinergic muscarinic stimulation can paradoxically produce positive inotropic effects in both human and rat cardiac muscle.
- The vasodilator adenosine may unmask or enhance ACh-induced positive inotropic effects in the working rat heart.
- Inositol trisphosphate (IP3) is suggested as a potential mediator of these positive inotropic responses to acetylcholine.
Abstract:
The effect of acetylcholine on cardiac muscle contractility and hemodynamics was investigated in human atrial strips and in isolated working rat heart. Activation of the muscarinic receptor in the heart muscle is generally known to result in negative chronotropic and inotropic effects. In our study, positive inotropic effects of acetylcholine (ACh) were observed in both human right atrial strips and in the working rat heart. Exposure of the human right atrial strips to ACh (10(-7)-10(-4) M) produced a dose dependent tri-phasic (positive-negative-positive) inotropic effect in approximately 40% of the strips. In muscle strips that exhibited only a negative inotropic effect, a positive response was observed following washout of ACh. Both positive and negative effects were antagonized by atropine. Exposure of the paced working rat heart to ACh (10(-7) - 10(-5) M) resulted in a dose dependent decrease in mean coronary flow followed by depression in cardiac function. When the heart was initially treated with the vasodilator adenosine (2 x 10(-6) M), exposure to ACh (10(-7) - 10(-5) M) had no effect on coronary flow and produced a dose dependent augmentation of all cardiodynamic indices: left ventricular pressure, isovolumic pressure, cardiac output, maximal aortic flow and stroke work. This positive response was antagonized by atropine. Exposure of the rat ventricular strips increased the formation of [3H]phosphoinositide breakdown products (e.g. inositol phosphates IP, IP2, IP3). These observations demonstrate that cholinergic muscarinic stimulation may produce positive inotropic effects in both human and rat cardiac muscle. Furthermore, our results suggest that IP3 may be a mediator in this process.