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(Hypertension. 2004;44:210.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Vascular CO Counterbalances the Sensitizing Influence of 20-HETE on Agonist-Induced Vasoconstriction

Jun-Ichi Kaide; Fan Zhang; Yuan Wei; WenHui Wang; Venkat Raj Gopal; John R. Falck; Michal Laniado-Schwartzman; Alberto Nasjletti

From the Department of Pharmacology (J.-I.K., F.Z., Y.W., W.W, M.L.-S., A.N.), New York Medical College, Valhalla, and Department of Biochemistry and Pharmacology (V.R.G., J.R.F.), University of Texas Southwestern Medical School, Dallas.

Correspondence to Alberto Nasjletti, MD, Department of Pharmacology, New York Medical College, Valhalla, New York 10595. E-mail alberto_nasjletti{at}nymc.edu

We examined the influence of interactions between CO and 20-hydroxyeicosatetraenoic acid (20-HETE) on vascular reactivity to phenylephrine and vasopressin. Renal interlobar arteries incubated in Krebs buffer released CO at a rate that is decreased (from 125.0±15.2 to 46.3±8.8 pmol/mg protein per hour, P<0.05) by the heme oxygenase inhibitor chromium mesoporphyrin (CrMP; 30 µmol/L). The level of 20-HETE in vessels was not affected by CrMP (74.3±6.1 versus 72.5±16.2 pmol/mg protein), but was decreased (P<0.05) by CO (1 µmol/L; 33.2±7.9 pmol/mg protein) or the cytochrome P450–4A inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 µmol/L; 11.4±3.3 pmol/mg protein). Phenylephrine elicited development of isometric tension in vascular rings mounted on a wire-myograph (EC₅₀, 0.29±0.02 µmol/L; R_max, 3.78±0.19 mN/mm). The sensitivity to phenylephrine was decreased (P<0.05) by CO (1 µmol/L; EC₅₀, 0.60±0.04 µmol/L) or DDMS (EC₅₀, 0.71±0.12 µmol/L) and increased (P<0.05) by 20-HETE (10 µmol/L; EC₅₀, 0.08±0.02 µmol/L) or CrMP (EC₅₀, 0.11±0.02 µmol/L). Notably, neither CO nor CrMP changed the sensitivity to phenylephrine in vessels treated with DDMS. Refractoriness to CO and CrMP in such a setting was eliminated by inclusion of 20-HETE (1 µmol/L) in the bathing buffer. The aforementioned interventions affected the vascular reactivity to vasopressin in a similar manner. These data indicate that the reactivity of renal arteries to phenylephrine and vasopressin is reciprocally influenced by CO and 20-HETE of vascular origin and that CO desensitizes the vascular smooth muscle to constrictor agonists by interfering with the sensitizing influence of 20-HETE.

Key Words: adrenergic receptor agonists • vasopressins • potassium channels • renal circulation

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