Published Online
on June 28, 2004

A more recent version of this article appeared on August 1, 2004

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Submitted on March 11, 2004
Revised on June 2, 2004

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; and 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.

^* To whom correspondence should be addressed. E-mail: alberto_nasjletti{at}nymc.edu.

Abstract--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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