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Decrease in internal H+ and positive inotropic effect of heptaminol hydrochloride: a 31P n.m.r. spectroscopy study in
F Berthiau1, D Garnier, J A Argibay
1Laboratoire de Biophysique Cellulaire, Faculté de Médecine, Tours, France.
Insights
Heptaminol hydrochloride enhances heart function during moderate ischemia by restoring intracellular pH, likely through Na-H exchange stimulation. This cardiotonic effect is lost in severe ischemia.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- The cardiotonic effects of heptaminol hydrochloride require further investigation.
- Intracellular pH regulation is crucial for cardiac function, especially during ischemic conditions.
Purpose of the Study:
- To investigate the cardiotonic effect of heptaminol hydrochloride.
- To determine if intracellular realkalinization mediates heptaminol's effect.
- To explore the role of Na-H exchange in heptaminol's action during ischemia.
Main Methods:
- Isolated rat hearts were perfused using the Langendorff method.
- Left ventricular pressure (LVP) and mechanical activity were measured.
- 31P-nuclear magnetic resonance (n.m.r.) spectroscopy was used to monitor intracellular pH (pHi), adenosine triphosphate (ATP), phosphocreatine (PCr), and inorganic phosphate (Pi).
- Experiments were conducted under normoxic, moderately ischemic, and severely ischemic conditions, with and without Na-H exchange inhibitors (amiloride, guanidinium chloride).
Main Results:
- In normoxia, heptaminol increased LVP and Pi but did not significantly alter pHi.
- During moderate ischemia, heptaminol restored both pHi and LVP, which were reduced by ischemia.
- In severe ischemia, heptaminol lost its ability to restore pHi and LVP.
- Na-H exchange inhibitors worsened pHi and LVP during moderate ischemia, and heptaminol could not reverse these effects when co-administered.
Conclusions:
- Heptaminol hydrochloride exhibits a positive inotropic effect during moderate ischemia.
- This effect appears to be mediated by the restoration of intracellular pH.
- The findings suggest that heptaminol's action during moderate ischemia involves stimulation of the Na-H exchange mechanism.
Abstract:
1. The cardiotonic effect of heptaminol hydrochloride (Hept-a-myl, Delalande) was studied using 31P-nuclear magnetic resonance (n.m.r.) spectroscopy and left ventricular pressure (LVP) measurements in rat isolated hearts. The possibility of this effect being mediated by an intracellular realkalinisation was tested. 2. Isolated hearts were perfused at 10 ml min-1 by the Langendorff method with Krebs-Henseleit solution at 37 degrees C and stimulated at 5 Hz. Mechanical activity was measured as variations of left ventricular pressure (LVP). 31P-n.m.r. spectra were recorded every 2 min. Changes in cardiac adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate (Pi) were followed and intracellular pH (pHi) was estimated from the chemical shift of Pi. 3. The effects of heptaminol were tested in different conditions: normoxia, moderate ischaemia, severe ischaemia, and moderate ischaemia in the presence of amiloride or guanidinium chloride as inhibitors of the Na-H exchange. 4. In normoxia, heptaminol induced a cyclic increase of systolic LVP, associated with an increase in Pi. No significant effect on pHi was observed. In changing from normoxia to moderate ischaemia, PCr and systolic LVP decreased; a mild intracellular acidification (pHi 6.96) was obtained. Heptaminol induced a restoration of pHi and increased LVP. In severe ischaemia, the realkalinization effect and the restoration of LVP induced by heptaminol were no longer observed. During moderate ischaemia, Na-H exchange inhibitors decreased pHi and LVP. Heptaminol applied in the presence of these inhibitors was unable to restore pHi and LVP. In severe ischaemia, the realkalinization effect and the restoration of LVP induced by heptaminol were no longer observed. During moderate ischaemia, Na-H exchange inhibitors decreased pHi and LVP. Heptaminol applied in the presence of these inhibitors was unable to restore pHi and LVP. 5. These results suggest that the positive inotropic effect of heptaminol during moderate ischaemia could be related to a restoration of internal pH, possibly mediated by a stimulation of the Na-H exchange.