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Modulation of endothelin-1 effects on rat hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP
Y Ebihara1, J V Haist, M Karmazyn
1Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Insights
Nitric oxide (NO) protects the heart from cardiotoxic effects of Endothelin-1 (ET-1). NO reduces ET-1-induced increases in left ventricular end-diastolic pressure and prevents ventricular fibrillation, possibly through cyclic GMP.
Area of Science:
- Cardiovascular Physiology
- Endothelial Biology
- Molecular Cardiology
Background:
- Endothelin-1 (ET-1) is implicated in cardiac disease.
- ET-1's direct cardiac effects are well-studied.
- Interactions between ET-1 and other endothelium-derived factors, like nitric oxide (NO), are less understood.
Purpose of the Study:
- To investigate whether nitric oxide (NO) modulates the cardiac effects of Endothelin-1 (ET-1).
- To determine the role of NO in ET-1-induced changes in cardiac function and electrophysiology.
Main Methods:
- Isolated rat hearts and ventricular myocytes were used.
- Experiments involved administration of ET-1 alone or in combination with NO synthase inhibitor (L-NAME) or NO donor (S-nitrosoacetylpenicillamine, SNAP).
- Measurements included left ventricular end-diastolic pressure (LVEDP), systolic/diastolic function, incidence of ventricular fibrillation, and intracellular Ca2+ levels.
Main Results:
- NO synthase inhibition (L-NAME) potentiated ET-1-induced increases in LVEDP.
- The NO donor SNAP blocked ET-1-induced LVEDP elevation and prevented ET-1-induced ventricular fibrillation.
- SNAP attenuated ET-1-induced increases in intracellular Ca2+ in cardiac myocytes.
Conclusions:
- Nitric oxide (NO) exerts a protective effect against the cardiotoxic actions of Endothelin-1 (ET-1).
- This protection may involve the inhibition of intracellular calcium (Ca2+) elevation.
- The findings suggest a role for the cyclic GMP pathway in mediating NO's protective effects against ET-1 cardiotoxicity.
Abstract:
Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 nM, ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10 microM of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 nM) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10 microM) although responses to 5 nM ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 nM ET-1 whereas the pro-fibrillatory actions of 5 nM ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2+ produced by ET-1 (5 nM). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2+) was mimicked by 8-bromo-cyclic GMP (50 microM). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2+ elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.