Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries

Petersson, Jesper; Hanson, G. C.; Lindberg, Bengt; Högestätt, Edward D.

doi:10.1007/bf00170842

Cited by 18 publications

(6 citation statements)

References 48 publications

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“…Functional evidence in our study showing the almost equal to 50% reduction in constriction of denuded retinal arterioles to big ET-1 supports the equal importance of endothelial and smooth muscle layers contributing to the overall production of ET-1. In contrast with our findings, vasoconstriction to big ET-1 was shown to be endothelium-independent in porcine coronary arteries, 29 and in rabbit basilar 30 and saphenous 31 arteries. Hence, an essentially equal functional role for endothelium and smooth muscle in processing exogenous big ET-1 to vasoactive ET-1 appears to be a unique feature of the retinal arterioles.…”

Section: Discussioncontrasting

confidence: 99%

Role of Endothelium in Vasomotor Responses to Endothelin System and Protein Kinase C Activation in Porcine Retinal Arterioles

Potts

Bradley

et al. 2013

Investigative Ophthalmology & Visual Science

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PURPOSE. Endothelial cells synthesize vasodilator nitric oxide (NO) and vasoconstrictor endothelin-1 (ET-1) from NO synthase (eNOS) and endothelin-converting enzyme-1 (ECE-1), respectively. Protein kinase C (PKC) and Rho kinase (ROCK) are major signaling molecules mediating vasoconstriction. Although endothelial cells express eNOS, ECE-1, endothelin B (ET B ) receptors, PKC, and ROCK, their influences on ET-1-induced vasoconstriction remain elusive. We studied whether these endothelial signaling molecules modulate retinal arteriolar constriction to ET-1. METHODS.Porcine retinal arterioles were isolated and pressurized for vasomotor study, under conditions with intact or denuded endothelium, using videomicroscopic techniques. RESULTS.Retinal arterioles developed similar resting tone (»45% of maximum diameter) with or without endothelium. Endothelial denudation attenuated vasoconstriction to ET-1 precursor, big ET-1, by almost equal to 50%, but did not affect vasoconstrictions to ET-1, ET B agonist sarafotoxin S6c, or PKC activator phorbol-12, 13-dibutyrate (PDBu). The ROCK inhibitor H-1152 caused vasodilation, and abolished vasoconstrictions to ET-1 and PDBu independent of endothelium. With L-type voltage-operated calcium channel (L-VOCC) blocker nifedipine, PDBu-induced vasoconstriction was abolished and converted to NO-mediated vasodilation in the presence of endothelium. The ET-1-induced vasoconstriction was unaffected by NO released from endothelium during flow elevation.CONCLUSIONS. Endothelial and smooth muscle ECE-1 contribute equally to synthesis of vasoactive ET-1 in retinal arterioles, with nominal role of endothelial ET B receptors in vasoconstriction to ET-1. The PKC activation leads to endothelium-dependent NO-mediated vasodilation when smooth muscle contraction is ablated by L-VOCC blockade. Endothelial cells and NO appear to have modest roles in modulating ROCK-dependent vasoconstriction, and are insufficient to counteract smooth muscle contractions to ET-1 and PKC activation.

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Section: Discussioncontrasting

confidence: 99%

Role of Endothelium in Vasomotor Responses to Endothelin System and Protein Kinase C Activation in Porcine Retinal Arterioles

Potts

Bradley

et al. 2013

Investigative Ophthalmology & Visual Science

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“…The receptor pharmacology of the ET1 effects suggests involvement only of the ET A subtype of ET receptor in pial arterioles. There is a similar dominant role of ET A receptors in mediating vasoconstriction, and expression of ET A receptors in vascular smooth muscle cells, in human and rabbit cerebral arteries (Yu et al 1995; Petersson et al 1996; reviewed by Rubanyi & Polokoff, 1994). There are reports of a dilatory function of ET B receptor activation (Patel et al 1996 b ), but an ET B receptor effect was not evident in our recordings from cerebral arterioles, perhaps because ET B agonists were applied only under basal conditions or while ET A receptors were also activated by ET1.…”

Section: Discussionmentioning

confidence: 99%

Positive and negative coupling of the endothelin ET_A receptor to Ca²⁺‐permeable channels in rabbit cerebral cortex arterioles

Guibert

Beech

1999

The Journal of Physiology

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Arteriolar segments were isolated from pial membrane and studied within 10 h. Current‐clamp and voltage‐clamp measurements were made by patch‐clamp recording from smooth muscle cells within arterioles. [Ca2+]i was measured from the smooth muscle cell layer by digital imaging of emission from fura‐PE3 which was loaded into arterioles by pre‐incubation with the acetoxymethyl ester derivative. The external diameter of arterioles was measured using a video‐dimension analyser. Endothelin‐1 (ET1) was a potent constrictor of isolated arterioles and induced a sustained depolarization up to ‐27 mV and reduced membrane resistance (EC50 140‐170 pm). At a constant holding potential of ‐60 mV ET‐1 induced a transient followed by a sustained inward current. ET1 inhibited L‐type voltage‐dependent Ca2+ current. ET1 induced a transient followed by sustained elevation of [Ca2+]i. The sustained effect was dependent on extracellular Ca2+. It occurred at a constant holding potential of ‐60 mV and was not inhibited by the Ca2+ antagonists nicardipine (1 μM) or D600 (10 μM). Thapsigargin (1 μM) completely depleted Ca2+ from caffeine‐ and ET1‐sensitive sarcoplasmic reticulum but did not inhibit the ET1‐induced sustained elevation of [Ca2+]i. ET1 effects on [Ca2+]i were prevented by the ETA receptor antagonist BQ123 (cyclo‐D‐Asp‐Pro‐D‐Val‐Leu‐D‐Trp). The data suggest that ETA receptors are negatively coupled to L‐type Ca2+ channels and positively coupled to receptor‐operated Ca2+‐permeable channels. Inhibition of L‐type Ca2+ channel activity may suppress autoregulation, and Ca2+ influx through receptor‐operated channels may have a major functional role in the potent long‐lasting constrictor effect of endothelin‐1 in the cerebral microcirculation.

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“…Incubation was terminated by boiling for 4 min, 25 Ìl of acetonitrile/acetate/water 10:80:10 (v/v/v) was added, the samples were centrifuged at 3,000 g, +4°C for 10 min, and the supernatant was loaded on a Deltapak C 18 reverse-phase column (Waters, Millipore, USA). High-pressure liquid chromatography (HPLC) was performed as previously described [12]. The separation products were identified by establishing their retention times and comparing them to those of standard amounts of synthetic endothelin-1 (ET-1) and bigET-1.…”

Section: Incubation Experimentsmentioning

confidence: 99%

Conversion of Big Endothelin-1 and Characterization of Its Contractile Effects on Isolated Human Placental Arteries

Hanson¹,

Wide-Swenson

Andersson³

et al. 1998

Gynecol Obstet Invest

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Objectives: To study the conversion of human big endothelin-1 (bigET-1) to endothelin-1 (ET-1) and to characterize contractile ET-1 receptors in human placental arteries. Methods: BigET-1 was incubated with artery membranes and the formation of ET-1 was investigated. ET-1 and bigET-1-induced contractile responses were studied in the absence or presence of the metalloprotease inhibitor phosphoramidon, the ET_A-receptor antagonist BQ 123, or the ET_B-receptor antagonists IRL 1038 and RES 701-1. Results: The artery membranes hydrolysed bigET-1 to ET-1 through a partly phosphoramidon-sensitive pathway. The contractile responses to ET-1 and bigET-1 were similar, with pEC_50% values of 8.1 ± 0.2 and 7.8 ± 0.1, respectively (NS; n = 17). Phosphoramidon decreased pEC_50% for bigET-1-evoked contractions (p < 0.05; n = 8), without affecting the response to ET-1. A Schild plot of BQ 123 effects on ET-1 and bigET-1-induced contractions resulted in identical pA₂ values and a slope of 0.56 ± 0.2 and 0.47 ± 0.01, respectively. IRL 1038 and RES 701-1 did not affect the contractile responses. Conclusion: BigET-1-evoked contractions in isolated human placental arteries depend on a rapid and metalloprotease-dependent hydrolytic conversion to ET-1, which in turn causes a, mainly ET_A-receptor-mediated, contraction.

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Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries

Cited by 18 publications

References 48 publications

Role of Endothelium in Vasomotor Responses to Endothelin System and Protein Kinase C Activation in Porcine Retinal Arterioles

Role of Endothelium in Vasomotor Responses to Endothelin System and Protein Kinase C Activation in Porcine Retinal Arterioles

Positive and negative coupling of the endothelin ET_A receptor to Ca²⁺‐permeable channels in rabbit cerebral cortex arterioles

Conversion of Big Endothelin-1 and Characterization of Its Contractile Effects on Isolated Human Placental Arteries

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Contractile effect of big endothelin-1 and its conversion to endothelin-1 in rabbit cerebral arteries

Cited by 18 publications

References 48 publications

Role of Endothelium in Vasomotor Responses to Endothelin System and Protein Kinase C Activation in Porcine Retinal Arterioles

Role of Endothelium in Vasomotor Responses to Endothelin System and Protein Kinase C Activation in Porcine Retinal Arterioles

Positive and negative coupling of the endothelin ETA receptor to Ca2+‐permeable channels in rabbit cerebral cortex arterioles

Conversion of Big Endothelin-1 and Characterization of Its Contractile Effects on Isolated Human Placental Arteries

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Positive and negative coupling of the endothelin ET_A receptor to Ca²⁺‐permeable channels in rabbit cerebral cortex arterioles