Haemodynamic effects of endothelin receptor antagonist, tezosentan, in tumour necrosis factor-alpha treated anaesthetized rats.
Administration of tumour necrosis factor-alpha (TNF-alpha) produces progressive reduction in cardiac output (CO) by affecting preload, afterload and cardiac contractility. We have examined the effect of an endothelin receptor antagonist, tezosentan (1, 3 or 10 mg/kg), on CO, heart rate (HR), blood pressure (BP), mean circulatory filling pressure (P(mcf)), resistance to venous return (RVR), arterial resistance (AR), dP/dt, stroke volume (SV), plasma levels of NO(2)(-)/NO(3)(-), and inducible nitric oxide synthase (iNOS) activity in lungs, ex vivo, following treatment with TNF-alpha (30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha alone resulted in significant reduction in CO (40+/-4%), dP/dt (24+/-2%), P(mcf) (24+/-2%), BP (21+/-3%) and SV (38+/-5%) ( n=6; mean +/- SEM), and significant increases in RVR (38+/-9%) and AR (45+/-6%). There were no significant changes in HR or in plasma levels of NO(2)(-)/NO(3)(-) in animals treated with TNF-alpha but there was a modest but significant increase in iNOS activity. Tezosentan alone did not have any effect on haemodynamics, plasma levels of NO(2)(-)/NO(3)(-) or iNOS activity. Tezosentan at the highest dose abolished the effects of TNF-alpha on dP/dt, AR, and RVR. In animals treated with a combination of TNF-alpha and highest dose of tezosentan CO, P(mcf), BP, and SV were reduced by 28+/-5%, 16+/-3%, 21+/-4%, and 27+/-5%, respectively. Tezosentan was able to inhibit the negative impact of TNF-alpha on AR and dP/dt but not on P(mcf). It is likely that the negative impact of TNF-alpha on CO in tezosentan-treated animals could be entirely attributed to reduction in preload.
Tabrizchi
Reza
R
Division of Basic Medical Sciences, Faculty of Medicine, Memorial University of Newfoundland, A1B 3V6, St John's, NL, Canada. rtabrizc@mun.ca
Ford
Carol Ann
CA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D009566:Nitrates; D009573:Nitrites; D011725:Pyridines; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C120582:tezosentan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat