Tumor necrosis factor-alpha impairs endothelium-dependent relaxation of rat renal arteries, independent of tyrosine kinase.
We hypothesized that tumor necrosis factor-alpha (TNF-alpha) mimics endotoxin in attenuating endothelium-dependent vasodilation and smooth muscle constriction of rat renal arteries, and that tyrosine kinase is involved. Isolated rat renal arteries (n =6 per group), pretreated for 2 h by genistein (4',5,7-trihydroxyisoflavone, 10 microg/mL, a tyrosine kinase inhibitor) or vehicle, were exposed for 2 h to recombinant human (rh) TNF-alpha (100 ng/mL) or vehicle. rhTNF-alpha attenuated (P < 0.05) the constriction response to depolarizing 125 mM KCl (952.6+/-125.3 mg/mm vs. 1191.4+/-136.8 mg/mm in rhTNF-alpha-exposed and control segments, respectively), but did not affect the constriction response to norepinephrine (NE, 0.01-10 microM). Genistein did not affect the constriction response to KCl. The concentration-response relation to NE in genistein-pretreated control segments showed (P < 0.05) a rightward shift, while the maximum constriction was not affected. Genistein did not prevent a reduction (P < 0.05) by rhTNF-alpha in the maximum response to NE (721.7+/-42.4 mg/mm vs. 999.8+/-84.4 mg/mm in controls). The endothelium-dependent relaxation induced by (acetyl choline) ACh (0.001-1.0 microM) was attenuated (P < 0.05) by rhTNF-alpha (39.4%+/-6.7% and 77.4%+/-10.0% in rhTNF-alpha-exposed and control segments, respectively). The reduction (P < 0.05) in maximum ACh-induced relaxation after exposure to rhTNF-alpha was not affected by genistein (44.6%+/-3.4% and 70.8% x 2.2% in genistein-pretreated rhTNF-alpha-exposed and control segments, respectively). Hence, the attenuated endothelium-dependent relaxation and smooth muscle constriction of rat renal arteries following short-term rhTNF-alpha exposure, mimicking the effect of endotoxin, does not involve the activity of tyrosine kinase. The latter may be involved in pharmacomechanical coupling, by increasing Ca2+ sensitivity, but less in the electromechanical coupling of smooth muscle constriction.
Piepot
Harro A
HA
Laboratory for Physiology, Institute for Cardiovascular Research Vrije Universiteit, Amsterdam, The Netherlands.
Groeneveld
A B Johan
AB
van Lambalgen
Antonie A
AA
Sipkema
Pieter
P
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D011189:Potassium Chloride; D019833:Genistein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011505:Protein-Tyrosine Kinases; D000109:Acetylcholine; D009638:Norepinephrine