Inhibition of Endothelin-converting Enzyme Activity in the Rabbit Basilar Artery

Zimmermann, Michael; Jung, Carla S.; Raabe, Andreas; Spanehl, Oliver; Fach, Kilian; Seifert, Volker

doi:10.1227/00006123-200104000-00043

Cited by 5 publications

(5 citation statements)

References 58 publications

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“…Drugs used were quinapril (Parke‐Davis), to inhibit the angiotensin‐converting enzyme, and a peptide fragment of big endothelin‐1 (Sigma), which has been shown to inhibit the endothelin‐converting enzyme (Zimmermann et al . 2001) The water‐soluble form of 17β‐oestradiol (Sigma) was also used.…”

Section: Methodsmentioning

confidence: 99%

Sex differences in the modulation of K⁺ currents in diabetic rat cardiac myocytes

Shimoni

Liu

2003

The Journal of Physiology

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A transient (Ipeak) and a sustained (Isus) outward K+ current were measured, using whole‐cell voltage‐clamp methods, in isolated rat ventricular myocytes obtained by enzymatic dispersion. A comparison was made between male and female rats following induction of (insulin‐deficient) diabetes with streptozotocin (STZ). In control (non‐diabetic) rats, both currents were smaller in cells obtained from females, as compared to males (P < 0.005). However, whereas inducing diabetes in male rats significantly attenuated both Ipeak and Isus (P < 0.005), Ipeak was unchanged in female diabetic rats. Isus was significantly (P < 0.005) reduced, but the extent of reduction was smaller (P < 0.02) than in males. The formation of angiotensin II (ATII) or endothelin‐1 (ET‐1) was blocked using inhibitors of angiotensin‐converting enzyme (ACE) and endothelin‐converting enzyme (ECE), respectively. In cells from diabetic males both inhibitors significantly (P < 0.005) enhanced K+ currents. In contrast, no effect was observed in cells from female diabetic rats. However, in ovariectomized (Ovx) diabetic females the in vitro inhibition of ATII and ET‐1 formation augmented the two K+ currents, but not when oestradiol was administered in vivo prior to cell isolation. In cells from diabetic males, incubation with 100 nM 17β‐oestradiol significantly (P < 0.005) enhanced both Ipeak and Isus. This effect was blocked if ATII or ET‐1 was added to the medium. These results show that autocrine modulation of K+ currents by renin‐angiotensin and endothelin systems is attenuated or absent in female diabetic rats. Oestradiol plays a key role in reducing this modulation. These results may underlie some of the sex differences associated with development of cardiac arrhythmias.

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Section: Methodsmentioning

confidence: 99%

Sex differences in the modulation of K⁺ currents in diabetic rat cardiac myocytes

Shimoni

Liu

2003

The Journal of Physiology

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“…cerebral vasospasm; rabbit cerebral artery; signal transduction A POTENT VASOACTIVE PEPTIDE generated in vascular endothelial and smooth muscle cells, endothelin-1 (ET-1), has been implicated in the pathogenesis of a number of cerebrovascular disorders, including stroke, ischemia, and, in particular, cerebral vasospasm, which develops after aneurysmal subarachnoid hemorrhage (SAH) (1,2,29,46). The following findings favor of a role for ET-1 in the pathogenesis of cerebral vasospasm: 1) intracisternal injections of this peptide induce vasospasm in experimental animals (10), 2) the levels of ET-1 are elevated in the cerebrospinal fluid of patients after SAH (29,32,36,46), and 3) selective antagonists of ET type A (ET A ) receptors and inhibitors of ET-1 synthesis attenuate vasospasm in animal models (1,13,45,46). Furthermore, evidence has been provided that synthesis of ET-1 is stimulated by a number of vasoactive agents, including oxyhemoglobin (OxyHb) and thrombin, which are liberated during posthemorrhagic clot lysis (9,21).…”

mentioning

confidence: 99%

Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C

Lan

Das

Wloskowicz

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Endothelin-1 (ET-1) and oxyhemoglobin (OxyHb) have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage. However, the contribution of ET-1 to this condition has not been definitely established. In this study, we investigated whether threshold concentration of ET-1 enhances cerebrovascular smooth muscle (CVSM) contraction to OxyHb by activating the RhoA/Rho kinase and protein kinase C (PKC) pathways. CVSM contraction was measured in endothelium-denuded rabbit basilar arteries. Cytosolic and particulate fractions of CVSM cells were examined for RhoA and PKC reactivity with specific antibodies using immunoblotting procedures. ET-1 (0.1 nM) alone did not produce any significant contraction, but it markedly potentiated the magnitude (223% of control) and rate (149% of control) of contraction in response to OxyHb, which was attenuated by the inhibitors of Rho kinase Y-27632 and HA-1077. ET-1-mediated potentiation of the contraction was also inhibited by inhibitors of PKC, Ro-32-0432, and GF-109203X. BQ-123 prevented potentiation of vasoconstriction mediated by ET-1, indicating that the action of ET-1 was mediated by the endothelin type A receptor. Pretreatment with ET-1 significantly enhanced OxyHb-mediated RhoA translocation in CVSM cells and intact basilar arteries. ET-1 also caused potentiation of PKC-epsilon expression in membranes of CVSM cells exposed to OxyHb for 10 and 60 min but did not markedly change the distribution of PKC-alpha. Thus, in CVSM, threshold concentration of ET-1 potentiates contraction induced by OxyHb via RhoA/Rho kinase- and PKC-epsilon-dependent mechanisms. This process may contribute to the pathological contraction of cerebral arteries observed after subarachnoid hemorrhage.

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“…These are: a) reducing extracellular ET-1 levels by specific anti-ET-1 antibodies [13], b) blocking the biosynthesis of ET-1 [3,9,11,[48][49][50][51][52][53][54][55][56][57][58][59][60], and c) antagonizing ET receptors [2,3,11,. In a canine twohemorrhage model, vasospasm of basilar artery was moderately reversed by topical application of monoclonal anti-ET-1 antibodies on day 2 but not on day 7 [13].…”

Section: The Role Of Et-1 In Cerebral Vasospasm After Sahmentioning

confidence: 99%

“…Zimmermann et al showed that intracisternal pretreatment with [ D -Val 22 ]big ET-1(16-38), a highly selective peptidic ECE-1 inhibitor, decreased the big ET-1-induced contraction of the rabbit basilar artery [52]. To date, CGS 35066 is the only non-peptidic selective ECE-1 inhibitor reported for the treatment of SAH-induced cerebral vasospasm.…”

Section: Selective Ece-1 Inhibitorsmentioning

confidence: 99%

Endothelin and Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: Pathogenesis and Treatment

Lin

Jeng²,

Howng³

et al. 2004

Current Medicinal Chemistry

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Endothelin (ET)-mediated vasoconstriction has been implicated in the pathophysiology of various disorders, e.g. hypertension, chronic heart failure, acute renal failure, pulmonary hypertension, and subarachnoid hemorrhage (SAH)-induced cerebral vasospasm. The potential involvement of ETs in cerebral vasospasm following SAH has triggered considerable interest in designing therapeutic strategies to inhibit biological effects of ET. Major approaches include: (a) reducing the levels of circulating ET- 1 by the the specific anti- ET- 1 antibodies, (b) antagonizing the ET receptors, and (c) suppressing the biosynthesis of ET-1. To date, numerous antagonists of ET(A) and/or ET(B) receptors have been discovered, and some are under clinical evaluation. Inhibitors of endothelin-converting enzymes (ECEs), which catalyze the biosynthesis of ET-1, have also been synthesized. Two types of ECE-1 inhibitors have been evaluated in various animal disease models: dual ECE-1/neutral endopeptidase 24.11 (NEP) inhibitors and selective ECE-1 inhibitors. In this article, the effects of ET receptor antagonists and ECE-1 inhibitors on the prevention and reversal of SAH-induced cerebral vasospasm in preclinical animal models are reviewed.

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Inhibition of Endothelin-converting Enzyme Activity in the Rabbit Basilar Artery

Cited by 5 publications

References 58 publications

Sex differences in the modulation of K⁺ currents in diabetic rat cardiac myocytes

Sex differences in the modulation of K⁺ currents in diabetic rat cardiac myocytes

Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C

Endothelin and Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: Pathogenesis and Treatment

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Inhibition of Endothelin-converting Enzyme Activity in the Rabbit Basilar Artery

Cited by 5 publications

References 58 publications

Sex differences in the modulation of K+ currents in diabetic rat cardiac myocytes

Sex differences in the modulation of K+ currents in diabetic rat cardiac myocytes

Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C

Endothelin and Subarachnoid Hemorrhage-Induced Cerebral Vasospasm: Pathogenesis and Treatment

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Sex differences in the modulation of K⁺ currents in diabetic rat cardiac myocytes

Sex differences in the modulation of K⁺ currents in diabetic rat cardiac myocytes