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Effects of cardiotrophin-1 on haemodynamics and cardiac function in conscious rats
1Department of Cardiovascular Research, Genentech Inc., South San Francisco, CA 94080, USA. hkj@gene.com
Insights
Cardiotrophin-1 (CT-1) administration in rats decreased blood pressure and increased heart rate, mediated by nitric oxide. CT-1 did not significantly alter cardiac contractility.
Area of Science:
- Cardiovascular Physiology
- Cytokine Signaling
- Pharmacology
Background:
- Cardiotrophin-1 (CT-1) is a cytokine known to induce cardiac hypertrophy.
- The precise haemodynamic effects and underlying mechanisms of CT-1 require further investigation.
Purpose of the Study:
- To investigate the effects of Cardiotrophin-1 (CT-1) on haemodynamics and cardiac function in vivo.
- To elucidate the role of nitric oxide in mediating CT-1's cardiovascular effects.
Main Methods:
- Haemodynamic parameters were measured in conscious rats using in-dwelling catheters and flow probes.
- Cardiotrophin-1 was administered intravenously in a dose-dependent manner.
- The effect of nitric oxide synthase inhibition on CT-1 responses was assessed.
Main Results:
- CT-1 administration caused a dose-dependent decrease in mean arterial pressure (MAP) and an increase in heart rate (HR).
- CT-1 significantly increased cardiac output and decreased systemic vascular resistance, while stroke volume remained unchanged.
- Inhibition of nitric oxide synthase attenuated the depressor and tachycardic effects of CT-1.
- Left ventricular maximal dP/dt was not significantly altered, suggesting no major change in contractility.
Conclusions:
- Nitric oxide plays a crucial role in mediating the haemodynamic effects of Cardiotrophin-1.
- CT-1's cardiovascular effects, primarily increased heart rate and decreased blood pressure, are largely mediated through the nitric oxide pathway.
Abstract:
Cardiotrophin-1 (CT-1), a newly discovered cytokine, has been shown to induce cardiac hypertrophy in vitro and in vivo. The present study examined the effects of CT-1 on haemodynamics and cardiac function. The measurements of haemodynamic parameters were made using in-dwelling catheters and flow probes in conscious, unrestrained rats. Intravenous administration of CT-1 caused a dose-dependent decrease in mean arterial pressure (MAP), and an increase in heart rate (HR). CT-1 (100 micrograms/kg) significantly elevated cardiac output and HR, and decreased MAP and systemic vascular resistance. Stroke volume was unaltered, suggesting that the CT-1 induced increase in cardiac output was secondary to increased HR. There was no significant difference in left ventricular maximal dP/dt between the CT-1-treated and vehicle-treated groups, suggesting that CT-1 might not induce a meaningful change in ventricular contractility. Pretreatment with intravenous N omega-nitro-L-arginine methyl ester, a specific inhibitor of nitric oxide synthase, significantly attenuated the depressor and tachycardic responses to CT-1. These results indicate that nitric oxide plays an important role in mediating the haemodynamic effects of CT-1.