Evidence that both ETA and ETB receptor subtypes are involved in the in vivo aldosterone secretagogue effect of endothelin-1 in rats

Endothelins (ET) are a family of vasoconstrictor peptides, secreted by vascular endothelium, which act through two main subtypes of receptors: ET_A and ET_B. ET-1 is known to stimulate aldosterone (ALDO) secretion by adrenal zona glomerulosa (ZG), and in vitro its effect was recently found to be exclusively mediated by ET_B receptors. In this study the involvement of ET_A and ET_B in the mediation of the in vivo acute ALDO secretagogue action of ET-1 was investigated by the use of their selective antagonists BQ-123 and BQ-788, respectively. The bolus intraperitoneal administration of ET-1 dose-dependently raised both basal and angiotensin II (ANG II)-enhanced plasma ALDO concentration (PAC) in rats. Both antagonists counteracted the stimulatory effect of ET-1 on basal PAC, and when administered together completely annulled it. Conversely, only BQ-788 reversed the effect of ET-1 on ANG II-enhanced PAC. ET-1 increased systolic blood pressure (BP) in normal rats, but not in animals simultaneously administered ANG II. The hypertensive effect of ET-1 was completely abolished by BQ-123, and not affected by BQ-788. In light of these findings the following conclusions can be drawn: (i) the in vivo ALDO secretagogue action of ET-1 is mediated by both ET_A and ET_B, this latter subtype of ET receptors playing a major role; and (ii) the mechanism whereby ET_A participates in this in vivo effect of ET-1 is indirect, and probably connected with the ET-1-induced rise in BP and adrenal blood flow.     

Typical endothelin ETA receptors mediate atypical endothelin-1-induced contractions in sheep isolated tracheal smooth muscle.

Contraction of vascular and nonvascular smooth muscle induced by the endothelin/sarafotoxin family of peptides frequently does not readily fit into the current classification criteria for ETA and ETB receptors, raising the possibility of additional atypical receptors. In the current study, isometric tension recording and radioligand binding techniques were used to characterize the ETA receptor population in sheep isolated tracheal smooth muscle. Endothelin-1 and sarafotoxin S6b induced similar concentration-dependent contractions, although endothelin-1 was 2.6-fold more potent (P <.05, n = 15-18). The ETA receptor-selective antagonists BQ-123 and FR139317 caused concentration-dependent inhibition of the contractions induced by endothelin-1 and sarafotoxin S6b, but both antagonists were significantly less potent in inhibiting contractions induced by endothelin-1 than sarafotoxin S6b. For example, 0.03 microM FR139317 shifted the endothelin-1 and sarafotoxin S6b concentration-effect curves to the right by 1.8- and 8.3-fold, respectively (P <.01, n = 6-8). Although the observed agonist dependence of antagonist potency may indicate the presence of atypical ETA receptors, competition binding studies using 125I-endothelin-1 and 125-I-sarafotoxin S6b identified only a single population of BQ-123- and sarafotoxin S6b-sensitive ETA receptors. Additional association-, dissociation-, and saturation-binding studies revealed that 125I-endothelin-1 binding to these ETA receptors was pseudoirreversible, whereas 125I-sarafotoxin S6b binding was readily reversible. Thus, marked differences in the kinetic profiles of ETA receptor binding to endothelin-1, sarafotoxin S6b, and BQ-123, rather than the existence of another ETA receptor subtype, may explain the stark agonist dependence of antagonist potency observed in contractile studies.     

Expression and cellular localisation of renal endothelin-1 and endothelin receptor subtypes in autosomal-dominant polycystic kidney disease

The major factors influencing the rate of progression of chronic renal disease in autosomal-dominant polycystic kidney disease (ADPKD) are unknown and there are currently no effective treatments for slowing the progression of chronic renal failure in ADPKD patients. As a first step in investigating the potential role of endothelin-1 (ET1) and its receptors (ETA and ETB) in the pathophysiology of progression in ADPKD, we have studied their expression and cellular localisation in ADPKD kidney. Immunoreactive ET1 was detected in cyst epithelia, mesangial cells and vascular smooth muscle cells suggesting continuing ET1 synthesis in the cystic kidney. Compared to healthy controls, ETA mRNA was 5-10-fold higher in ADPKD cystic kidney. In cystic kidney, neo-expression of ETA receptors was found overlying glomeruli and cysts and markedly increased in medium-sized renal arteries by microautoradiography. This is the first study to demonstrate a specific upregulation of ETA receptors in human renal disease. Future studies should address whether ETA selective antagonists may be effective in slowing renal disease progression in ADPKD.     

Hemodynamic and pharmacological evaluation of the vasodilator and vasoconstrictor effects of endothelin-1 in rats

In awake normotensive and spontaneously hypertensive rats as well as pentobarbital-anesthetized normotensive rats, endothelin-1 (ET-1, 0.063-0.5 nmol/kg i.v.) produced rapidly appearing, transient, dose-related falls in mean carotid artery blood pressure followed by slowly developing small pressor responses. In the latter preparation, the hypotension was due to a decrease in systemic vascular resistance inasmuch as cardiac output increased slightly. Bilateral vagotomy, BW 755c, glibenclamide, idazoxan, propranolol, methylatropine, methysergide or promethazine pretreatment failed to modify the hypotension induced by ET-1 (0.25 nmol/kg i.v.), but this effect was blocked entirely when ET-1 was injected 8 min after starting an i.v. infusion of ET-1 (0.1 nmol/kg/min for 10 min). In pithed rats, ET-1 (0.125-1.0 nmol/kg i.v.) produced sustained pressor responses which were accompanied by reductions in cardiac output. This peptide (0.25 nmol/kg i.v.) did not affect renal vascular resistance significantly but increased (200%) mesenteric resistance substantially more (3-fold) than systemic or hindquarter resistance. The pressor effects of ET-1 were reduced by diltiazem, nitrendipine, verapamil or cromakalim and unchanged after BW 755c, desipramine, enalapril, indomethacin, methysergide, phentolamine or SK&F 100273. The sustained pressor response evoked by an i.v. infusion of ET-1 (0.25 nmol/kg/min/60 min) was also antagonized markedly by nitrendipine and cromakalim. In pithed rats with vasopressin-supported blood pressure, ET-1 produced a short-lasting hypotension which faded entirely after three successive injections of the peptide. Finally, ET-1 (0.4-0.8 nM) evoked greater contractile responses in rat aortic rings deprived of a functional endothelium than in intact preparations. However, in the latter preparation precontracted with norepinephrine, ET-1, in contrast to acetylcholine, failed to evoke vasorelaxation. In aortic rings, the sustained contractile effects of ET-1 (3.2 nM) were reduced moderately by nitrendipine (50 nM) and markedly by cromakalim (0.8 microM). In contrast, the latter compounds antagonized strongly the contractile response to KCl (25 mM). In conclusion, ET-1 appears to produce active vasorelaxation and vasoconstriction via stimulation of specific receptors on blood vessels. The tolerance to the hypotensive effect of ET-1 may indicate that either the receptor site for ET-1 becomes refractory or, alternatively, it is coupled to easily depletable endogenous hypotensive mediators. Finally, inasmuch as the vasoconstrictor effects of ET-1 can be easily counteracted by calcium antagonists under in vivo but not in vitro conditions, the membrane coupling mechanism for ET-1 may not be exactly the same in conductance or resistance vessels.     

Contribution of peripheral endothelin ETA and ETB receptors in neuropathic pain induced by spinal nerve ligation in rats

Endothelins (ETs) contribute to the sensory changes seen in animals models of inflammatory, cancer and diabetic neuropathic pain, but little is known about their nociceptive role following peripheral nerve injury. The current study evaluated mechanisms by which ETs can drive changes in nociceptive responses to thermal stimulation of the hind paw of rats induced by unilateral lumbar L5/L6 spinal nerve ligation (SNL) injury. SNL sensitizes rats to acetone-evoked cooling of and radiant heat application (Hargreaves test) to the ipsilateral hind paw (throughout 3–40 and 9–40 days after surgery, respectively). At 12 days after SNL, intraplantar (i.pl.) injection of endothelin-1 (ET-1, 10 pmol) induces greater overt nociception that was reduced only by treatment with the selective ET_A peptidic antagonist (BQ-123, 10 nmol, i.pl), but unchanged by the selective ET_B peptidic antagonist (BQ-788). Cold allodynia evoked by cooling the ipsilateral hind paw with acetone was reduced by i.pl. injection of both antagonists BQ-123 or BQ-788 (3 or 10 nmol). In contrast, heat hyperalgesia evaluated by Hargreaves method was reduced only by BQ-123. SNL enhanced the [Ca⁺²]_i increases induced by ET-1 (100 nM) in neurons from L5/L6 (injured) and L4 (intact) cultured dorsal root ganglion, but did not change the responses of non-neuronal cells. Furthermore, Western blot analysis revealed that SNL increased ET_A and ET_B receptor protein expression in spinal nerves. Thus, SNL induces marked hind paw hypersensitivity to thermal stimulation in part via up-regulation of peripheral sensory nerve pronociceptive ET_A and ET_B receptor-operated mechanisms.     

The science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studies

Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ET_A or nonselective ET_A/ET_B blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease.     

运动训练对大鼠心肌内皮素含量及受体分型的影响

目的探讨运动训练对大鼠心肌组织内皮素-1（ET—1）含量、ET受体分型及受体特征的影响。方法选用健康雄性SD大鼠进行跑台运动训练，采用放射免疫法测定大鼠心肌ET-1含量，采用放射性配基结合受体分析法测定心肌组织ETAR及ETBR的变化情况。结果大鼠经运动训练后，其心肌细胞膜的ET—1含量下降（P〈0．01），心肌细胞膜ETAR最大结合量降低（P〈0．05），解离常数Kd值无显著改变；ETBR的最大结合容量升高（P〈0．01），解离常数Kd值显著降低（P〈0．01）。结论运动训练主要通过调节ET不同亚型受体的比例、亲和力及结合容量，从而对ET—1的生成、清除及与受体的结合能力产生影响，使ET的作用效力发生改变，从而增强心脏的调节功能。     

Acute haemodynamic effects of losartan in anaesthetized cirrhotic rats

BACKGROUND: Portal hypertension in cirrhosis is the result of increased intrahepatic vascular resistance to portal outflow as well as increased portal tributary blood flow. The angiotensin II type 1 receptor antagonist losartan has been suggested as a portal pressure-lowering drug in patients with cirrhosis. AIM: To investigate the systemic and splanchnic haemodynamic effects of different doses of losartan. METHODS: In 35 anaesthetized rats with secondary biliary cirrhosis, 3, 10 or 30 mg of losartan kg(-1) or solvent were administered intravenously. Ten sham-operated rats served as controls. Mean arterial pressure and portal pressure were measured by catheters in the femoral artery or portal vein. Systemic and splanchnic haemodynamics and mesenterico-systemic shunt rate were determined by the coloured microsphere method. RESULTS: Losartan reduced portal pressure (sham: 9.1 +/- 0.4. cirrhosis: 19.3 +/- 1.1, after 3 mg kg(-1) of losartan 16.4 +/- 0.4, after 10 mg kg(-1) of losartan 15.6 +/- 0.6, after 30 mg kg(-1) of losartan 14.9 +/- 0.6 mmHg) without reducing portal sinusoidal resistance. However, in cirrhotic rats it reduced portal tributary blood flow (sham: 4.3 +/- 0.6. cirrhosis: 8.6 +/- 1.4, after 3 mg kg(-1) of losartan 3.8 +/- 0.7, after 10 mg kg(-1) of losartan 4.7 +/- 0.5, after 30 mg kg(-1) of losartan 5.9 +/- 0.9 mmHg). This was owing either to an increase in splanchnic vascular resistance at the 3 mg kg(-1) dose or to a reduction in the splanchnic perfusion-pressure gradient secondary to a reduction in mean arterial pressure at the 10 and 30 mg kg(-1) doses (mean arterial pressure: sham: 109.7 +/- 4.8. cirrhosis: 109.4 +/- 2.8, after 3 mg kg(-1) of losartan 99.7 +/- 2.9, after 10 mg kg(-1) of losartan 89.9 +/- 3.4, after 30 mg kg(-1) of losartan 81.0 +/- 2.9 mmHg). CONCLUSIONS: Low doses of losartan reduce portal hypertension by an increase in splanchnic vascular resistance without hypotensive side-effects on arterial pressure.     

Influence of indomethacin on the haemodynamic effects of lipopolysaccharide in rats

Summary— This study was undertaken to evaluate the influence of the cyclooxygenase inhibitor indomethacin on the time course of the haemodynamic effects of lipopolysaccharide (LPS) intravenous infusion (10 mg·kg⁻¹·h⁻¹) in anaesthetized rats. LPS infusion produced a rapid (within 10 min) and prolonged (over the 90 min observation period) fall in mean arterial blood pressure (MABP) and a decrease in the pressor responses to noradrenaline (NA, 0.1, 0.3 and 1 μg·kg⁻¹, intravenously [iv]) elicited 60 and 90 min after the onset of LPS infusion. Indomethacin (7 mg·kg⁻¹ iv 30 min prior to the onset of saline or LPS infusion), which by itself did not affect basal MABP nor reactivity to NA in control rats, significantly attenuated the fall in MABP observed within 20 min after the onset of LPS infusion (but did not significantly modify the hypotension observed between 30 and 90 min). Indomethacin also completely prevented the hyporeactivity to NA observed 60 min after the onset of LPS infusion, but it did so only partially at 90 min. Aortic rings removed from LPS or LPS + indomethacin-treated rats showed an identical profile of contractile reactivity (hyporesponsiveness to NA, relaxation to L-arginine, and restoration of the contractile response by methylene blue). These results suggest that in this model, cyclooxygenase products are involved in the early haemodynamic effects of LPS. However, they do not seem to play an obligatory role in the onset of longer term haemodynamic changes.     

Action of the endothelin receptor (ETA) antagonist BQ-123 on forearm blood flow in young normotensive subjects

Endothelin-1 (ET-1) has been proposed to contribute to the regulation of vascular tone in humans. BQ-123, an ET(A) receptor antagonist, has also been reported to increase forearm blood flow (FBF) in vivo; however, the efficacy of BQ-123 as an antagonist of ET-1 has not been evaluated in the forearm. The present study investigated the effects of BQ-123 on changes in FBF in response to ET-1 and noradrenaline (NA; norepinephrine), taking into account the possible influence of vasodilator effects of BQ-123 on responses to vasoconstrictors. Six subjects (age 25-34 years) participated in a double-blind randomized study. FBF was measured by forearm occlusion plethysmography. Drugs were infused intra-arterially into the non-dominant arm (study arm) on four separate occasions; the non-infused arm was used as a control. The effects of BQ-123 (50 nmol/min for 60 min, or 300 nmol/min for 5 min followed by saline for 55 min) were compared with the effects of infusion of sodium nitroprusside (SNP; 12 nmol/min for 60 min) or saline on vasoconstriction induced by ET-1 (10 pmol/min for 7 min) and NA (120 pmol/min for 7 min). Infusion of BQ-123 at either dose did not significantly increase FBF, whereas SNP increased FBF by 134% (P=0.03). ET-1 significantly reduced FBF, and this effect was almost completely inhibited by both doses of BQ-123, but was unaffected by SNP. NA also reduced FBF, and this action was unaffected by BQ-123 or SNP. The data show that BQ-123 is a selective ET-1 antagonist, but do not confirm a major role for ET-1 in influencing resting forearm vascular tone in young normotensive subjects.     

Pharmacological profile of ZD1611, a novel, orally active endothelin ETA receptor antagonist.

The endothelins (ETs), potent vasoconstrictor peptides, have been implicated in the pathogenesis of various cardiovascular disorders. In the present study, we describe the novel, potent, orally active, selective ET(A) receptor antagonist ZD1611 [3-(4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl ]phenyl)- 2,2-dimethylpropanoic acid]. ZD1611 competitively inhibited (125)I-labeled ET-1 binding at human cloned ET(A) and ET(B) receptors with pIC(50) values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively, showing 1000-fold selectivity for the ET(A) receptor. ZD1611 caused a parallel rightward shift of the concentration response curve to ET-1 in the rat isolated aorta yielding a concentration of antagonist that caused a 2-fold rightward shift in the ET-1-response curve (pA(2)) of 7.5 +/- 0.3. When administered i. v. to anesthetized rats and dogs, ZD1611 caused dose-related rightward shifts of partial dose-response curves to the precursor of ET-1, big ET-1. Threshold doses for significant antagonist activity were determined as 0.1 mg/kg and 0.3 mg/kg in the rat and dog, respectively. Importantly, ZD1611 was able to reverse an established big ET-1-induced pressor response in pithed rats in the presence of continuous big ET-1 infusion. Failure of ZD1611 to inhibit the BQ3020 (ET(B)-selective)-induced depressor response in pithed rats indicated a lack of activity at the endothelial ET(B) receptor. ZD1611 was orally active in the rat at 0.3 mg/kg and had a duration of action of more than 7 h, and, in the dog, a dose of 0.6 mg/kg p.o. was active for at least 6 h. In conclusion, these data demonstrate that ZD1611 is a potent and orally active, selective ET(A) receptor antagonist with a long duration of action which may be of therapeutic use.     

Vasodilator activity of endothelin-1 and endothelin-3: rapid development of cross-tachyphylaxis and dependence on the rate of endothelin administration

In pentobarbital anesthetized cats, i.v. bolus injections of endothelin-1 (ET-1, 1 microgram) and ET-3 (3 micrograms) produced a rapidly appearing but short-lasting fall in aortic blood pressure followed in the case of ET-1 only by a small pressor response. When these peptides were administered repeatedly after 10- to 12-min intervals, there was a gradual attenuation of the hypotension that by the fourth injection was replaced by a monophasic pressor response. The i.v. infusion of ET-1 (0.3 microgram/min) or ET-3 (0.9 microgram/min) for 20 min produced sole systemic vasoconstriction. The decrease in blood pressure produced by an i.v. bolus injection of ET-1 and ET-3 was no longer observed 5 min after the end of the ET-1 or ET-3 infusion. In contrast, the hypotensive activity of bradykinin was not modified after the depressor responses to ET-1 and ET-3 had disappeared. Thus, the failure of i.v. bolus injections of ET-1 and ET-3 to lower blood pressure under these experimental conditions cannot be attributed to the development of tachyphylaxis to endogenous endothelium-derived relaxant factor, which is known to mediate the effects of bradykinin. These results suggest that ET-1 and ET-3 share a single vascular receptor for vasodilation, which becomes refractory upon repeated or maintained exposure to these peptides. Alternatively, this refractoriness may be due to depletion of an intracellular mediator(s) that is jointly used by the membrane binding sites of ET-1 and ET-3. Moreover, the present data suggest that the vasodilator activity of ETs depends on the rate of the peptide administration.     

A comparison of the hemodynamic effects of endothelin-1 and sarafotoxin S6b in conscious rats

The hemodynamic effects of sarafotoxin S6b (SRT) and endothelin-1 (ET-1) were studied in conscious, freely moving rats. Intravenous bolus administration of ET-1 produced an initial transient depressor response and skeletal muscle (hindquarters) vasodilation. This depressor activity was not observed after i.v. SRT except at a high dose. The initial fall in blood pressure was followed by a sustained pressor response and an increase in total peripheral resistance which were mediated, at least partially, by visceral (mesenteric) and skeletal muscle (hindquarters) vasoconstriction. The durations of the pressor responses and times required to achieve the peak pressor effects (peak time) were greater for ET-1 as compared to SRT. The results of qualitatively similar sustained hemodynamic effects and the strong correlation between the amplitude of the responses to ET-1 and SRT in individual rats suggest that the sustained pressor responses to these peptides are mediated by the same receptors, although the potency was significantly greater for ET-1 than for SRT. Furthermore, the initial depressor and sustained pressor responses appear to be mediated by distinct receptor subtypes inasmuch as the same dose of ET-1 was required for both vasodilator and vasoconstrictor activity but a higher dose of SRT was required to elicit its vasodilator as compared to constrictor effects. Thus, SRT may have relatively lower affinity for receptors mediating its initial hemodynamic responses whereas ET-1 binds with equal affinity to both receptors. These potent and vascular specific hemodynamic actions suggest a role of endothelin in regulating cardiovascular function.     

ETA receptors mediate vasoconstriction,whereas ETB receptors clear endothelin-1 in the splanchnic and renal circulation of healthy men

The contribution of the endothelin (ET) receptors ET(A) and ET(B) to basal vascular tone and ET-1-induced vasoconstriction in the renal and splanchnic vasculature was investigated in six healthy humans. ET-1 was infused alone and in combination with the selective ET(A) receptor antagonist BQ123 or the selective ET(B) receptor antagonist BQ788 on three different occasions. BQ123 did not affect basal arterial blood pressure, splanchnic vascular resistance (SplVR) or renal vascular resistance (RVR), but inhibited the increase in vascular resistance induced by ET-1 [64+/-18 versus -1+/-7% in SplVR ( P <0.05); 36+/-6 versus 12+/-3% in RVR ( P <0.0001)]. BQ788 increased basal SplVR and RVR [38+/-16% ( P =0.01) and 21+/-5% ( P <0.0001) respectively], and potentiated the ET-1-induced vasoconstriction. Plasma ET-1 increased more after ET(B) blockade than under control conditions or after ET(A) blockade. These findings suggest that the ET(A) receptor mediates the splanchnic and renal vasoconstriction induced by ET-1 in healthy humans. The ET(B) receptor seems to function as a clearance receptor and may modulate vascular tone by altering the plasma concentration of ET-1.     

The C-terminal fragment of big endothelin-1 does not potentiate the vasoactive effects of endothelin-1

The aim was to study the cardiovascular effects of the C-terminal (22–38) fragment of big endothelin-1, which is produced by the cleavage of big endothelin-1 (big ET-1) to endothelin-1 (ET-1). An intravenous infusion of the (22–38) fragment (4, 8 and 12 pmol kg^?1 min^?1, each dose for 10 min) was given to 10 healthy subjects. Four control subjects received 0·9% saline. Two additional subjects received ET-1 (0·2 and 4 pmol kg^?1 min^?1, each dose for 20 min) alone or combined with an equimolar infusion of the (22–38) fragment on two separate occasions. The fragment infusion did not alter heart rate, mean arterial blood pressure, cardiac output, systemic or pulmonary vascular resistance, splanchnic, cerebral or forearm blood flow. Renal blood flow showed a slight fall (11%, P<0·001) in the fragment group of the same magnitude as in a previous control study. After the fragment infusion, a decrease in mean pulmonary arterial pressure (MPAP) by 12% (P<0·01) and in pulmonary capillary wedge pressure (PCWP) by 31% (P<0·001) was noted, which did not differ from the pulmonary pressures in the saline-infused control group. The (22–38) fragment, when combined with ET-1, was not able to modify the effects of ET-1 on heart rate, mean arterial blood pressure, splanchnic and renal blood flow. Consequently, the exogenous (22–38) fragment does not seem to cause any significant cardiovascular effects in healthy humans.     

间歇低氧对大鼠内皮素及其受体基因表达的影响

目的观察慢性间歇低氧诱发大鼠高血压发病过程中内皮素(ET)及其受体的动态变化,探讨慢性间歇低氧诱发高血压的发病机制。方法将Wistar大鼠(n=72)随机均分为间歇低氧组(IH组)、实验对照组(SC组)和空白对照组(UC组)。IH组大鼠循环给予氮气和压缩空气(每一循环60s,使舱内最低氧浓度达4%~6%,然后恢复至21%,8h/d),SC组大鼠循环给予压缩空气,UC组大鼠不给予任何处理。观察第7、21、42天时各组大鼠的血压、血浆ET-1水平及不同组织ET-1和内皮素A型受体(ETAR)mRNA的表达。结果第42天时IH组大鼠平均动脉压(MAP)较实验前升高约8mmHg(P<0·01),而两对照组大鼠MAP无显著变化。IH组大鼠血浆ET-1水平随间歇低氧时间的延长逐渐升高,从第7天[(157±35)ng/L]开始显著高于SC组[(123±29)ng/L]和UC组[(119±28)ng/L]水平(P<0·05),并且与MAP呈正相关(r=0·605,P=0·002);其心脏和肾皮质ET-1mRNA的表达随间歇低氧时间的延长也逐渐增加,从第21天开始显著高于两对照组水平(P<0·05);其主动脉、心脏和肾皮质ETARmRNA的表达与两对照组比较,差异无显著性(P>0·05)。SC组与UC组比较,各项观察指标差异均无显著性(P>0·05)。结论慢性间歇低氧可导致ET-1表达增加,使血循环ET-1水平升高,而对ETAR的表达没有影响,提示ET-1的过度表达可能是慢性间歇低氧诱发高血压的重要原因之一。     

Role of endothelin and endothelin receptor antagonists in renal disease

Endothelin (ET)-1 is a potent vasoconstrictor peptide with pro-inflammatory, mitogenic, and pro-fibrotic properties that is closely involved in both normal renal physiology and pathology. ET-1 exerts a wide variety of biological effects, including constriction of cortical and medullary vessels, mesangial cell contraction, stimulation of extracellular matrix production, and inhibition of sodium and water reabsorption along the collecting duct, effects that are primarily mediated in an autocrine/paracrine manner. Increasing evidence indicates that the ET system is involved in an array of renal disorders. These comprise chronic proteinuric states associated with progressive glomerular and tubulointerstitial fibrosis, including diabetic and hypertensive nephropathy, glomerulonephritis and others. In addition, ET-1 is causally linked to renal disorders characterized by increased renal vascular resistance, including acute ischaemic renal failure, calcineurin inhibitor toxicity, endotoxaemia, hepatorenal syndrome and others. Furthermore, derangement of the ET system may be involved in conditions associated with inappropriate sodium and water retention; for example, in congestive heart failure and hepatic cirrhosis. Both selective and non-selective ET receptor antagonist have been developed and tested in animal models with promising results. As key events in progressive renal injury like inflammation and fibrosis are mediated via both ET(A) and ET(B) receptors, while constrictor effects are primarily transduced by ET(A) receptors, dual ET receptor blockade may be superior over selective ET(A) antagonism. Several compounds have been developed with remarkable effects in several models of acute and progressive renal injury. Thus, clinical studies are required to assess whether these results can be confirmed in humans, hopefully leading to novel and effective therapeutic options with few side effects.