Author: Zhang, Fan ; Quan, Shuo ; Balazy, Michael ; Gong, Weiying ; Nasjletti, Alberto ; Yang, LiMing ; Kaide, Jun Ichi ; Kemp, Rowena ; Abraham, Nader G. ; Jiang, Houli

Pulmonary intralobar arteries express heme oxygenase (HO)-1 and -2 and release carbon monoxide (CO) during incubation in Krebs buffer. Acute hypoxia elicits isometric tension development (0.77 ± 0.06 mN/mm) in pulmonary vascular rings treated with 15 μmol/l chromium mesoporphyrin (CrMP), an inhibitor of HO-dependent CO synthesis, but has no effect in untreated vessels. Acute hypoxia also induces contraction of pulmonary vessels taken from rats injected with HO-2 antisense oligodeoxynucleotides (ODN), which decrease pulmonary HO-2 vascular expression and CO release. Hypoxia-induced contraction of vessels treated with CrMP is attenuated ( P < 0.05) by endothelium removal, by CO (1–100 μmol/l) in the bathing buffer, and by endothelin-1 (ET-1) receptor blockade with L-754142 (10 μmol/l). CrMP increases ET-1 levels in pulmonary intralobar arteries, particularly during incubation in hypooxygenated media. CrMP also causes a leftward shift in the concentration-response curve to ET-1, which is offset by exogenous CO. In anesthetized rats, pretreatment with CrMP (40 μmol/kg iv) intensifies the elevation of pulmonary artery pressure elicited by breathing a hypoxic gas mixture. However, acute hypoxia does not elicit augmentation of pulmonary arterial pressure in rats pretreated concurrently with CrMP and the ET-1 receptor antagonist L-745142 (15 mg/kg iv). These data suggest that a product of HO activity, most likely CO, inhibits hypoxia-induced pulmonary vasoconstriction by reducing ET-1 vascular levels and sensitivity.

01 Sep 2003·Brain ResearchQ4 · MEDICINE

Role of prostaglandin, endothelin and sympathetic nervous system on the l-NAME-induced pressor responses in spontaneously hypertensive rats

Q4 · MEDICINE

Article

Author: Summy-Long, Joan Y. ; Kadekaro, Massako ; Salas, Nilson ; Terrell, Mary Lee A.

We tested the hypothesis that in spontaneously hypertensive rat (SHR) NO produced centrally influences the resting arterial blood pressure by attenuating mechanisms involving prostaglandins, angiotensin II, endothelin and sympathetic nervous system. L-NAME (200 micro g/5 micro l), an inhibitor of NO synthase, administered intracerebroventricularly (i.c.v.) to awake and freely moving rats increased mean arterial blood pressure (MABP) in a biphasic pattern: an early transient increase within 1 min and a late prolonged response starting at 45 min and persisting for the duration of experiment (180 min). The two pressor responses involve different neurochemical mechanisms and, based on their latencies, they appear to reflect different anatomical sites of action of L-NAME. The late, but not the early pressor response, was prevented by pretreatment with chlorisondamine (2.5 mg/kg, i.v.), a ganglionic blocker, indicating its dependence on the sympathetic nervous system. Both pressor responses were abolished by i.c.v. pretreatment with indomethacin (200 micro g/5 micro l, i.c.v.), an inhibitor of cyclo-oxygenase, showing that they are mediated by prostaglandin(s). In contrast, losartan (25 micro g/5 micro l), an angiotensin II AT(1) receptor antagonist, had no effect. The initial pressor response was also attenuated by pretreatment with the endothelin ET(A)/ET(B) receptor antagonist, PD 145065 (48 micro g/2 micro l, i.c.v.). Intravenous pretreatment with another ET(A)/ET(B) receptor antagonist, L-754,142 (15 mg/kg as a bolus+15 mg/kg/h for 180 min), however, attenuated both responses to L-NAME. It is possible that L-754,142 crossed the blood-brain barrier and blocked, in addition, central ET(A)/ET(B) receptors. These studies show that NO synthesized in the brain attenuates pressor mechanisms involving prostaglandin, endothelin and sympathetic nervous system, but not angiotensin II, to modulate resting arterial blood pressure.

01 Jun 2002·Pharmacological ReviewsQ1 · MEDICINE

International Union of Pharmacology. XXIX. Update on Endothelin Receptor Nomenclature

Q1 · MEDICINE

Review

Author: Davenport, Anthony P

In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3. ET-1 is the principal isoform in the human cardiovascular system and remains the most potent and long-lasting constrictor of human vessels discovered. In humans, endothelins mediate their actions via only two receptor types that have been cloned and classified as the ET(A) and ET(B) receptors in the first NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) report on nomenclature in 1994. This report was compiled before the discovery of the majority of endothelin receptor antagonists (particularly nonpeptides) currently used in the characterization of receptors and now updated in the present review. Endothelin receptors continue to be classified according to their rank order of potency for the three endogenous isoforms of endothelin. A selective ET(A) receptor agonist has not been discovered, but highly selective antagonists include peptides (BQ123, cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp-]; FR139317, N- [(hexahydro-1-azepinyl)carbonyl]L-Leu(1-Me)D-Trp-3 (2-pyridyl)-D-Ala) and the generally more potent nonpeptides, such as PD156707, SB234551, L754142, A127722, and TBC11251. Sarafotoxin S6c, BQ3020 ([Ala(11,15)]Ac-ET-1((6-21))), and IRL1620 [Suc-(Glu(9), Ala(11,15))-ET-1((8-21))] are widely used synthetic ET(B) receptor agonists. A limited number of peptide (BQ788) and nonpeptide (A192621) ET(B) antagonists have also been developed. They are generally less potent than ET(A) antagonists and display lower selectivity (usually only 1 to 2 orders of magnitude) for the ET(B) receptor. Radioligands highly selective for either ET(A) ((125)I-PD151242, (125)I-PD164333, and (3)H-BQ123) or ET(B) receptors ((125)I-BQ3020 and (125)I-IRL1620) have further consolidated classification into only these two types, with no strong molecular or pharmacological evidence to support the existence of further receptors in mammals.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Preclinical	US	Merck & Co., Inc.	-

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