Endothelial expression and the release of endothelin‐1 (ET‐1) in levels sufficient to initiate vasoconstriction is considered to be a hallmark feature of pathological endothelial dysfunction.

During the immediate postnatal period, arterial endothelial cells undergo remarkable structural and functional changes as they transition to a mature protective cell layer, which includes a marked increase in NO dilator activity.

The present study demonstrates that endothelial cells lining newborn central arteries express high levels of ET‐1 peptides and, in response to endothelial stimulation, rapidly release ET‐1 and initiate powerful ET‐1‐mediated constriction. This activity is lost as the endothelium matures in the postnatal period.

Heightened activity of ET‐1 in the neonatal endothelium might contribute to inappropriate responses of immature arteries to stress or injury. Indeed, the immature endothelium resembles dysfunctional endothelial cells, and retention or re‐emergence of this phenotype may contribute to the development of vascular disease.

AbstractEndothelial cells lining fetal and newborn arteries have an unusual phenotype, including reduced NO activity, prominent actin stress fibres and poorly developed cellular junctions. Experiments were performed to determine whether the immature endothelium of newborn arteries also expresses and releases endothelin‐1 (ET‐1) and initiates endothelium‐dependent constriction. Carotid arteries were isolated from newborn (postnatal day 1; P1), postnatal day 7 (P7) and postnatal day 21 (P21) mice and assessed in a pressure myograph system. Endothelial stimulation with A23187 or thrombin caused constriction in P1 arteries, no significant change in diameter of P7 arteries, and dilatation in P21 arteries. In P1 arteries, constriction to thrombin or A23187 was inhibited by endothelial‐denudation, by ET‐1 receptor antagonists (BQ123 plus BQ788) or by inhibition of endothelin‐converting enzyme (phosphoramidon or SM19712). ET‐1 receptor antagonism did not affect responses to thrombin or A23187 in more mature arteries. Exogenous ET‐1 caused similar concentration‐dependent constrictions of P1, P7 and P21 arteries. Endothelial stimulation with thrombin rapidly increased the endothelial release of ET‐1 from P1 but not P21 aortas. Endothelial expression of ET‐1 peptides, as assessed by immunofluorescence analysis, was increased in P1 compared to P21 arteries. Therefore, newborn endothelial cells express high levels of ET‐1 peptides, rapidly release ET‐1 in response to endothelial stimulation, and initiate ET‐1‐mediated endothelium‐dependent constriction. This activity is diminished as the endothelium matures in the immediate postnatal period. Heightened activity of ET‐1 in neonatal endothelium probably reflects an early developmental role of the peptide, although this might contribute to inappropriate responses of immature arteries to stress or injury.

01 May 2011·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Contribution of Nitric Oxide in Big Endothelin-1–induced Cardioprotective Effects on Ischemia/Reperfusion Injury in Rat Hearts

Q4 · MEDICINE

Article

Author: Ayajiki, Kazuhide ; Matsumura, Yasuo ; Fukumoto, Taiki ; Okamura, Tomio ; Imamura, Takeshi ; Tawa, Masashi ; Yamashita, Naoto ; Geddawy, Ayman ; Ohkita, Mamoru

We have recently shown that an appropriate amount of exogenous big endothelin-1 (ET-1) has beneficial effects on ischemia-/reperfusion-induced norepinephrine overflow and cardiac dysfunction in rat hearts and that these effects occur through a conversion to ET-1 by endothelin-converting enzyme and following stimulation of ETB receptor. In this study, we examined the possible involvement of nitric oxide (NO) in the big ET-1-induced cardioprotective effects. According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Exogenous big ET-1 (0.3 nM) significantly increased NOx (NO2/NO3) level in the coronary effluent after onset of reperfusion. This effect was markedly attenuated by treatment with SM-19712 (selective endothelin-converting enzyme inhibitor), A-192621 (selective ETB receptor antagonist), or NG-nitro-l-arginine (nonselective NO synthase inhibitor), respectively. In addition, N-nitro-l-arginine blunted big ET-1-induced suppression of norepinephrine overflow and improvement of cardiac dysfunction after ischemia/reperfusion. These findings suggest that NO produced by ETB receptor activation plays an important role in exogenous big ET-1-induced actions.

01 Feb 2011·Hypertension ResearchQ3 · MEDICINE

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Q3 · MEDICINE

Article

Author: Masashi Tawa ; Kazuhide Ayajiki ; Yasuo Matsumura ; Tomio Okamura ; Takeshi Imamura ; Taiki Fukumoto ; Naoto Yamashita ; Ayman Geddawy ; Mamoru Ohkita

Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET(A) receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt(max)) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET(B) receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET(A) receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET(B) receptors to exert its related beneficial actions.

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Indication	Highest Phase	Country/Location	Organization	Date
Renal Insufficiency	Preclinical	JP	Sumitomo Pharmaceuticals Co., Ltd.	-
Reperfusion Injury	Preclinical	JP	Sumitomo Pharmaceuticals Co., Ltd.	-

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