Recent Advances in Endothelin Research on Cardiovascular and Endocrine Systems

Home , Endothelin, Endothelin 3, Somatomedin

Endocrine Journal 1994, 41(5), 491-507

Review

MITSUHIDE NARUSE, KIYoxo NARUSE, AND HIR0SH1 DEMURA Department of Medicine, Institute of Clinical Endocrinology, TokyoWomen's Medical College, Tokyo162, Japan

Introduction Structure of ET and ET Receptor

Since the quite exciting discovery in 1988 of The molecular and biochemical aspects of ET endothelin (ET) in the culture medium of aortic en- family peptides and ET receptors have been re- dothelial cells by Yanagisawa and coworkers [1], viewed by Masaki and Yanagisawa [13] and others evidence has accumulated to support its important [14-16]. We here describe the fundamentals. roles in the regulation of blood pressure and body fluid homeostasis and its pathophysiological sig- 1. ET Peptides nificance in various cardiovascular diseases. The discovery of ET and the opponent substances in- The ET molecule consists of 21 amino acid resi- cluding nitric oxide [2] and natriuretic peptides [3] dues with two intramolecular disulfide bonds be- during the last decade was epoch-making in the tween cystein residues at 1 and 15 and 3 and 11, field of "Cardiovascular Endocrinology". respectively. The ring structure and the hydropho- Because of its impressive potency and the long bic amino acid residues at the C-terminus are in- duration of its pressor action [1], the roles of ET in dispensable to its full biological activities. There the regulation of cardiovascular homeostasis have are three distinct isof orms of ET: ET-1, ET-2, and been extensively studied. However, the co-expres- ET-3 [13]. The difference in the amino acid se- sion or close localization of ET and its receptors in quence is seen in the ring structure, while they various tissues other than the vascular vessels sug- share the same sequence in the linear C-terminal gest non-vascular roles of ET [4-6]. In the present portion. Interspecies differences are minimal [13- review, we firstly integrate the information rel- 16]. Interestingly, the amino acid sequence of a evant to its physiological role in blood pressure family of rare snake venoms, the sarafotoxins, is regulation and possible pathogenic role in hyper- very similar to the sequence of ET [16], composing tension. We secondarily focus on the possible the ET-sarafotoxin family and suggesting the im- roles of ET in the endocrine system, especially in portance of the peptide in evolution. the pituitary and adrenal. Substantial review ar- PreproET-1, the precursor of the peptide, is syn- ticles on ET in the kidney [7, 8], ET and the heart thesized through the gene transcription and trans- [9], the growth regulating properties of ET [10], lation. Expression of the preproET-1 mRNA in the and ET in bronchial diseases [11, 12] have been endothelial cells is stimulated by various humoral published. and physical factors: thrombin, TGF-f3, interleukin- 1, TNF-a, angiotensin II (Ang II), vasopressin, and shear stress (for review see [13-15]). Production of This review was written as a memorial article for the Re- ET-1 in the endothelial cells is mediated by an in- search Encouragement Prize of the Japan Endocrine Soci- ety awarded to the author on June 3, 1993. crease in [Ca2+]i and activation of protein kinase Correspondence to: Dr. Mitsuhide NARUSE, Department C. On the other hand, increased cGMP caused by of Medicine, Institute of Clinical Endocrinology, Tokyo natriuretic peptides and nitric oxide inhibits the Women's Medical College, 8-1 Kawada-cho, Shinjuku-ku, production of ET-1 [17-19], suggesting a close in- Tokyo 162, Japan terrelationship between the vasoconstrictive and 492 NARU5E et a1.

vasodilatory systems. vascular smooth muscle cells predominantly ex- After deletion of the signal peptide, the pro-seg- press the ETA receptor, while there is also an ETB ment of the proET-1 is initially cleaved by an en- receptor [25, 26]. The vascular endothelial cells dopeptidase specific for a pair of dibasic amino ac- predominantly express ETB receptor. In addition, ids to produce an inactive 38-amino acid peptide, both receptors are expressed in various tissues in- big-ET-1, which is finally cleaved into the mature cluding lung, heart, brain, kidney and adrenal form, ET-1, by a specific ET-converting enzyme. gland. The enzyme is a phosphoramidon-sensitive mem- The primary structures of the receptors deter- brane-bound metalloprotease [20]. Both big ET-1 mined from the sequences of the cDNA clones in- and ET-1 are secreted into the culture medium. dicate that both receptors are single chain peptides The immunocytochemical demonstration of ET-1 containing seven stretches of hydrophobic amino in cytoplasmic vesicles suggests a constitutive acid residues. The homology of the amino acid pathway for the secretion of ET-1 [21]. sequence of ETA and ETB is about 60%. The se- Northern blot analysis demonstrated that quence of the transmembrane region is very simi- mRNAs corresponding to the three distinct ETs are lar for each receptor, while that of the N-terminal expressed in different proportions in non-vascular extracellular domain shows practically no homol- tissues as well as vascular tissues where ET-1 is ogy. Both receptors have two N-linked predominantly produced. In addition, the exist- glycosilation sites in the N-terminal domain, and ence of ET was also shown by immunoassay in a serine/threonine residues in the intracellular third variety of tissues other than the vascular endothe- loop and C-terminus. The third type of receptor lium [22]. The ET-1 content is the highest in the more specific to ET-3 has been predicted but is still posterior pituitary and the lung followed by the unidentified. anterior pituitary, brain, and adrenal gland. The The distribution of the ET determined from pep- ET-3 content is highest in the posterior and ante- tide content and mRNA expression is very similar rior pituitaries. The ET-1 content is significantly to that of the ET receptor determined by the bind- higher than that of ET-3 in all the tissues except for ing study and the expression of mRNA [4-6]. the anterior pituitary (Fig. 1). These findings suggest that ET acts mainly in a paracrine/autocrine fashion rather than in a classi- 2. ET Receptors cal endocrine fashion.

There are at least two subtypes of ET receptors: ETA receptor with a higher affinity for ET-1 and Biological Actions ET-2 than for ET-3 and ETs receptor with an equivalent affinity for all three ETs [23, 24]. The The three ETs show somewhat different biological activities in relation to the affinity to and the distribution of each receptor subtype; ET-1 and ET- 2 are more potent than ET-3 in pressor response, while ET-3 is relatively more potent in vasodilation. In addition to the vasoconstrictive actions, ETs have diverse biological actions on the cardiovascular, neural, renal, endocrine, metabolic, gas- trointestinal, and genitourinary systems (Table 1), but the physiological significance of these effects remains to be elucidated. ET elicits the biological actions by activating phospholipase C to produce inositol triphosphate and diacylglycerol which in turn activates protein kinase C, and by increasing the influx of calcium Fig. 1. Tissue content of immunoreactive ET-1 and ET-3 in ion via activation of the calcium channel. These rats. Note ubiquitous but tissue-specific distribution two major mechanisms are closely interrelated to of ETs. each other. The ET-stimulated intracellular signal REVIEW: RECENT PROGRESS IN ENDOTHELIN RESEARCH 493

Table 1. Diverse b iological actions of ET

transduction mechanism is detailed in other re- The acute administration of ET-1 to rats view articles [13-15]. produces a transient decrease in blood pressure followed by a strong and long-lasting increase in blood pressure [1]. The first depressor effect is ET in the Cardiovascular System attributed to the release of vasodilator substances including prostacyclin and endothelium-derived The anatomically close site of production to the nitric oxide through the ETB receptor on the vascular smooth muscle cells and the potent vaso- endothelial cells, while the latter pressor effect is constrictive property indicate the potential impor- through the ETA receptor on the vascular smooth tance of ETs in the regulation of cardiovascular ho- muscle cells. The ETB receptor on the vascular meostasis and their pathophysiological signifi- smooth muscle cells was recently shown to cance in various cardiovascular diseases, especially contribute also to vasoconstriction [25, 26]. in hypertension. In addition to the direct action on the vascular smooth muscle cells, ET-1 has non-vascular actions 1. Significanceof ETs in SystemicHypertension which might affect blood pressure: central activation of the sympathetic nervous system [27], 1) Essential Hypertension secretion of vasopressin [28], aldosterone [29] and 494 NARUSE et al.

catecholamine [30], positive isotropic and normotensive rats with antiserum to ET-1 does not chronotropic actions [31], and a decrease in the affect the blood pressure, providing evidence glomerular filtration rate and renal blood flow (for against the physiological role of ET-1 in regulating review see [6]). ET-1 potentiates the actions of vascular tone in a steady state condition [36]. Even other vasoconstrictive substances such as an increase in blood pressure in rats with the ET-1 norepinephrine and serotonin [32]. In addition, gene knocked out by gene targeting techniques is ET-1 promotes a proliferation of vascular smooth in agreement with this concept [37]. This is quite muscle cells and fibroblasts (for review see [9]), in contrast to the case of nitric oxide which plays which may result in the morphological changes in an important role in the maintenance of basal vas- the vascular wall. All these direct and indirect cular tone [38, 39]. actions contribute to the acute and chronic increase The chronic infusion of ET-1 for one week re- in blood pressure. sulted in a sustained increase in blood pressure On the other hand, ET-1 stimulates ANP secre- [40, 41]. Interestingly, however, the administration tion, while it suppresses renin secretion [33], NaV of ET-1 over a period of 4 weeks in normal rats K+ ATPase activity [34], and vasopressin action in was associated with normalization of the once el- the kidney [35]. These actions in addition to the evated blood pressure despite the sustained in- vasodilatory action through the ETs receptor on crease in plasma ET-1 [42]. This suggests that only the endothelial cells may contribute to the decrease the increase in plasma ET is not a factor eliciting in the blood pressure. Pressor effects of ET-1 could chronic hypertension. This is supported by the be partly counterbalanced by these depressor ef- fact that transgenic rats harboring the human ET-2 fects. Fig. 2 shows the biological actions of ET pos- gene do not show any hypertension despite an in- sibly involved in the blood pressure control. crease in plasma ET-2 [43]. Counter-regulatory Considering the long duration of its effects and mechanism(s) including endothelium-dependent the strong binding to the receptors, ET is expected vasorelaxation may suppress the increase in blood to be involved in the long-term regulation of the pressure in intact rats. vascular tone. However, passive immunization of The pathophysiological role of ET in systemic hypertension is still controversial [44, 45]. Reports on plasma levels of ET-1 are not unanimous: a moderate but a significant increase in some reports [46-,48] and no change in others [49, 50]. We demonstrated that plasma ET-1 is increased in patients with essential hypertension of the stage III of the WHO classification. There was a close correlation between impaired renal function and the plasma levels [51]. Although Saito et al. [46] have shown that plasma levels are increased even in the stage III patients with normal renal function, increased plasma levels of ET-1 are generally associated with renal failure [47, 51, 52] and/or atherosclerosis [52, 53]. In addition, plasma levels of ET-1 are not high or even decreased in rat models of hypertension [54]. Most of the ET produced by the endothelial cells is secreted on the abluminal side rather than on the luminal side [55]. It is therefore not surprising that plasma ET levels do not accurately reflect the local production of ET. It is more precise to say that plasma ET levels partly reflect the local events. Therefore, caution must be taken especially when Fig. 2. Diverse biological actions of ET possibly involved interpretating marginally changed plasma levels. in the regulation of blood pressure. The next issue to be taken into account is the REVIEW: RECENT PROGRESS IN ENDOTHELIN RESEARCH 495

responsiveness to ET, since the biological action of It is tentatively concluded that ET-1 is partially ET could also be determined by sensitivity on the involved in the development and maintenance of receptor side. However, changes in the pressor re- hypertension in some experimental models and sponse in vivo [56, 57] and in the vasoconstrictive human essential hypertension. The long term ef- response of isolated arteries in vitro [58-61] of SHR fects on the vascular structure are of potential im- are inconclusive. Increased sensitivity to ET-1 de- portance in the development of hypertension. spite the normal plasma levels reported in some Studies with ET receptor antagonists for a longer studies in SHR [56, 59] could be partly involved in period are obviously critical for the issue. the maintenance of hypertension. How can the role of endogenous ET be assessed 2) Secondary Hypertension in vivo? To better address the issue, we have uti- There are several clinical conditions in which ET lized anti-ET antiserum to block the action of ET is believed to play a crucial role in hypertension. [36]. The infusion of ET-specific antibodies into One of the most interesting conditions is the ET- SHR decreased the mean arterial pressure by ap- secreting malignant hemangioendothelioma [67]. proximately 10% and renal vascular resistance by Increased plasma ET, positive immunohistochemi- approximately 35%. Both the glomerular filtration cal staining for ET, the presence of immunoreac- rate and renal plasma flow increased by approxi- tive ET, expression of ET mRNA, and normaliza- mately 50% over the control. By contrast to this, tion of blood pressure and plasma ET levels after the infusion of normal rabbit serum in SHR or of removal of the tumor, all indicate an excess pro- ET-specific antibodies in WKY rats did not result duction of ET from the tumor as a cause of hyper- in any significant changes in these hemodynamic tension. Although this is definitely the discovery parameters. These findings suggest that endo- of a new type of secondary hypertension, the sig- genous ET plays an important role in the modula- nificance of the disease waits additional case re- tion of systemic blood pressure and renal function ports. in SHR. The fact that the plasma ET-1 level in SHR Hypertension following erythropoietin therapy was even lower than that in WKY indicates diffi- in patients under chronic hemodialysis may be an- culty in ascertaining the role of ET from the plasma other model of "ET-dependent hypertension" [68]. levels. The profound effect of ET-1 on renal func- The plasma ET-1 levels were significantly higher in tion may play a key role in the development of patients with hypertension than in those without hypertension, since the kidneys play a central role hypertension. Changes in plasma ET-1 occurred in in pressure-volume homeostasis [62]. parallel to that of mean blood pressure. Discon- This finding is in agreement with the findings tinuance of the erythropoietin therapy resulted in a obtained with phosphoramidon, a non-selective in- parallel decrease in plasma ET-1 and blood pres- hibitor of ET-converting enzyme (our unpublished sure. Since the endothelial cells possess a receptor data). The development of specific antagonists for for erythropoietin, erythropoietin may directly act ETA receptor [63, 64] enabled us to evaluate more to stimulate ET-1 production by the endothelial specifically the role of ET-1 in hypertension. De- cells. This is supported by the fact that erythropoi- spite the specificity of the blockade, the results do etin increases the secretion of ET from the cultured not completely coincide with each other. Bazil et endothelial cells in vitro (our unpublished observa- al. [65] demonstrated that BQ-123 has a mild tion). antihypertensive effect in SHR and DOCA/salt Cyclosporine therapy is often associated with hypertensive rats but not in renin-dependent hypertension [69]. Cyclosporine increases ET-1 re- hypertensive rats. However, Nishikibe et al. [66] lease from cultured endothelial cells [70]. In addi- reported a significant reduction in blood pressure tion, cyclosporine-induced renal vasoconstriction in SHR-SP, a model of malignant hypertension, es- is mediated by ET-1 and is protected by prior ad- pecially after salt loading for 6 weeks, but not in ministration of an ETA receptor antagonist [71]. SHR. Differences in the results may be partly at- Therefore, ET-1 may play an important part in tributed to the different pathogenesis in each hy- cyclosporine-induced hypertension. Furthermore, pertension model and dosage of the antagonists. hypertension associated with disseminated intra- ETB receptor-mediated action [25, 26] may also vascular coagulation [72] and eclampsia [73] may modify the effects of the ETA receptor antagonist. be attributed, at least in part, to the increased 496 NARUSE et al.

plasma ET-1. contents in the lungs differ from our preliminary However, whether an increase in plasma ET-1 is results which showed a significant increase of lung central to the pathogenesis of these secondary hy- ET-1 [80], endogenous ET-1 may contribute to the pertension or merely a phenomenon secondary to progression of hemodynamic changes in vascular injury and/or atherosclerosis remains un- monocrotaline-induced pulmonary hypertension. clear. Recently, an orally active ET receptor an- A similar close relationship between the plasma tagonist has been developed [74]. This antagonist ET-1 levels and pulmonary vascular resistance was capable of blocking both ETA and ETB receptors found in patients with pulmonary hypertension decreases blood pressure in sodium-depleted mon- [81-85], suggesting a role of ET-1 in humans also. keys and prevents renal vasospasm after renal In addition, ET-1 is synthesized and released from ischemia and cerebral vasospasm after subarach- respiratory epithelial cells, suggesting a potential noid hemorrhage. Blockade of the ETB receptor as pathological role in bronchial asthma (for review well as the ETA receptor appears to be of clinical see [11, 12]). Blockade of the ETA receptor could significance. therefore be a useful therapeutic tool in the treatment of various pulmonary diseases. 2. Pulmonary Hypertension 3. Disease States Associated with Hypotension The lung contains a large amount of ET peptides, expresses abundant ET mRNA, and takes up Although hypertensinogenic aspects have been large quantities of the peptide during passage [75]. emphasized in discussing the significance of ET, it These findings indicate that the lung is one of the may not always be a pathological factor, but a pro- major sites of the production and action of ET. ET tective factor. The remarkable increase in plasma stimulates DNA synthesis and cell proliferation of ET demonstrated in endotoxin shock [86], cardio- pulmonary vascular smooth muscle cells [76]. In genic shock [87], and septic shock [88] may imply a this regard, pulmonary hypertension is another physiological, defensive role rather than a patho- pathological state in which the role of ET has been logical role of ET, although the possibility that the extensively studied. Hypoxic stress is associated increased ET may act as a deteriorating factor by with increases in the plasma ET-1 level, and in ET- reducing the renal blood flow and renal function 1 content and the expression of ET-1 mRNA of the cannot be completely excluded. lung, suggesting that the lungs are a source of We determined the plasma ET-1 levels during plasma ET-1 and may play a role in the develop- whole body hyperthermic therapy in patients with ment of hypoxia-induced pulmonary hypertension advanced lung cancer [89]. The hyperthermia in- [77]. In addition, the rat model of idiopathic pul- duced a significant hyperdynamic state; approxi- monary hypertension named fawn-hooded rats mately a 2-fold increase in the heart rate and car- shows increased ET-1 content and ET-1 mRNA ex- diac output. By contrast, the mean arterial pres- pression in the lung prior to the development of sure and peripheral vascular resistance decreased pulmonary hypertension. Changes in lung ET-1 significantly. These changes were reversed after are therefore not the consequence but probably a cooling off the body. Plasma ET-1 showed a 5-fold cause of pulmonary hypertension [78]. increase as a function of time. The significant in- In monocrotaline-induced pulmonary hyperten- crease in plasma ET-1 associated with hypotension sion in rats, Miyauchi et al. [79] showed an increase suggests a role of ET-1 in maintaining the periph- in plasma ET-1 associated with an increase in the eral circulation. Although not yet conclusive, the expression of ET-1 mRNA in the kidneys and role of ET in the hypotensive state is obviously dif- hearts. On the contrary, the expression of ET-1 ferent from that in the hypertensive state. mRNA and ET-1 content in the lungs decreased gradually as pulmonary hypertension developed, suggesting that the lungs are not the source of ET in the Endocrine System plasma ET-1. In addition, continuous infusion of BQ-123 significantly inhibited the progression of 1. Adrenal Gland both pulmonary hypertension and right ventricu- lar hypertrophy. Although the results on ET-1 Surgical and autoptic specimens of human adre- REVIEW: RECENT PROGRESS IN ENDOTHELIN RESEARCH 497

nal tissues contain a sizable amount of ET (Fig. 3). The highest content was seen in a patient who died of acute myocardial infarction, while the lowest value was seen in the adenoma tissue of a patient with Cushing's syndrome. The ET-1 content was significantly higher than the ET-3 content in all the tissues examined. The fact that the human adrenal contains ET and expresses ET mRNA [6] indicates local production of ET, but it is too early to con- clude that there is any correlation between ET content and the disease state. What is the function of ET in the adrenal gland? The immunohistochemical localization of ET-1 in the zona glomerulosa cells of the human adrenal cortex (Fig. 4) suggests a possible role of ET in the regulation of adrenocortical function, especially in the zona glomerulosa. This is supported by the fact that the addition of ET-1 stimulates aldosterone secretion in vitro from the adrenocortical tissue of various animal species [29, 90-94]. However, no data are available in man. Fig. 3. ET content in autoptic and surgical specimens of human adrenal tissues. Nos. 4, 7 and 9 are the We examined the effects of ET-1 on the steroid adenoma portion and Nos. 8 and 10 are the adjacent secretion from human adrenocortical tissue [95]. portion in primary aldosteronism. Nos. 4 and 8, ET-1 stimulated the secretion of aldosterone but and Nos. 9 and 10 are from the same patient, respectively. not cortisol from normal adrenal tissues and adjacent tissue in primary aldosteronism. The effects were dose-dependent and Cat+-dependent. There

Fig. 4. Immunohistochemical localization of ET-1 in human adrenal tissue. Note specific staining in the zona glomerulosa (ZG). ZF: Zona fasciculata. 498 NARUSE et al. was no such stimulatory effect in the adenoma tis- ETB receptor is the predominant form [99, 100]. sue of primary aldosteronism. These findings sug- Stimulation of aldosterone secretion is therefore gest that ET-1 is also a stimulatory factor selective assumed to occur through the ETB receptor. to aldosterone also in humans. However, the effectiveness of the ETA-specific Whether the ET-1 in the adrenal tissue modifies antagonist in blocking aldosterone secretion also the aldosterone secretion is the next question. We indicates the involvement of the ETA receptor. The examined the effects of BQ-123 on aldosterone se- results of the in situ hybridization study cretion from bovine zona glomerulosa cells. The demonstrating the presence of ETA mRNA at the ETA receptor antagonist showed a slight but sig- corticomedullary junction and the diffuse nificant suppression of basal aldosterone secretion, localization of ETB mRNA in both the cortex and suggesting that adrenal ET is involved in the regu- the medulla [101] indicate different roles of each lation of basal secretion of aldosterone [96]. Al- receptor, although it is not yet possible to correlate though ET was reported to potentiate the aldoster- the biological action and the localization. one production by ACTH [92] or Ang II [94] in To elucidate the role of adrenal ET in the re- cultured bovine zona glomerulosa cells, BQ-123 sponse to the systemic changes in body fluid ho- did not affect the ACTH- and Ang II-induced al- meostasis, the effects of DOCA/salt or low salt dosterone secretion in our study. These findings treatments on adrenal ET content were studied. suggest that the effects of ACTH and Ang II on Contrary to our expectations, adrenal ET-1 and ET- aldosterone secretion are not mediated by adrenal 3 contents showed a significant increase and de- ET. crease after one-week of DOCA/salt and low salt Specific binding sites for ET-1 were initially treatments, respectively. In contrast to the changes demonstrated by autoradiography [4, 5, 97]. in the adrenal, no significant change was seen in Although the receptor initially identified by the the liver, indicating that the changes in the adrenal binding study has a higher affinity with ET-1 and are organ specific (Fig. 5). The plasma renin-angio- ET-2 than ET-3 [90, 94, 98], thus corresponding to tensin-aldosterone system is suppressed in the ETA receptor, another receptor with similar DOCA/salt treatment, while it is stimulated in low affinity with all the ET family peptides, thus salt treatment. The reciprocal changes in the adre- corresponding to the ETB receptor, was found [91]. nal ET content and the plasma aldosterone levels Recent studies with Northern blot analysis on the allow of alternative explanations: 1) decreased se- expression of ET receptor mRNA showed that the cretion of ET and 2) accelerated production of ad-

Fig. 5. Effects of DOCA/salt and low salt treatments on ET contents in rat adrenal (a) it-1 1ivar /hl REVIEW: RECENT PROGRESS IN ENDOTHELIN RESEARCH 499

renal ET to counterregulate the decreased aldosterone secretion. To address this question, we determined the changes in the preproET-1 mRNA in the adrenal tissue with RT-PCR. The PCR products showed a significant increase after DOCA/salt treatment and a decrease after low salt treatment, respectively (Fig. 6). ET in the adrenal may be regulated to compensate for the changes in aldosterone production in response to systemic stimuli. Fig. 7 illustrates the role of ET in the adrenal gland taking all these findings together. Aldosterone secretion is mainly regulated by systemic factors including ACTH, Ang II, and potassium as stimulatory factors and natriuretic peptides as inhibitory factors [102]. ET may serve as one of the local factors such as the adrenal renin-angiotensin system [103] and IGF-1 [104]. How these systemic and local factors interact and cooperate with each other remains to be elucidated. In addition, details of the physiological and pathophysiological significance of adrenal ET are not yet known, but a higher content of ET-1 in the adenoma portion than in the adjacent tissue in primary aldosteronism (Fig. 3) suggests a pathological role in the excess production of Fig. 6. Southern blot analysis of RT-PCR amplified aldosterone. The reduced responsiveness to product of preproET-1 transcript in rat adrenal: exogenous ET-1 [95] could be explained by prior effects of DOCA/salt treatment and low salt diet. exposure to an increased amount of endogenous ET leading to receptor occupancy, receptor down regulation, or tachyphylaxis. Adrenal ET may also be involved in disproportionately increased plasma aldosterone compared to plasma renin during the recovery period from malignant hypertension [105]. The remarkable increase in adrenal ET content in a patient with acute myocardial infarction suggests that adrenal ET is involved in the stress-mediated response, a speculation requiring further investigation.

2. Hypothalamo-Pituitary Axis

1) Anterior Pituitary Gland ET exists in a high concentration in the pituitary (Fig. 1). It is noteworthy that the anterior pituitary gland is one of the exceptional tissues where the ET-3 content is higher than that of ET-1 [22]. The expression of ET mRNA in the tissue [106] indicates its local synthesis. The rank order of the binding affinity of the isopeptides [107], the po- Fig. 7. Systemic and possible local regulators of tency of the effects on the hormone secretion [108- aldosterone secretion. 500 NARUSE et al.

111], and in situ hybridization of ET mRNA [101], local modulation. In addition, the gonadotrophs all indicate that ETA is the predominant ET recep- produce renin, Ang II [122], activin, ANP [123], tor in the pituitary, whereas the presence of the and ET-3 [120] as well as gonadotropins. Since ETs receptor is suggested in some studies [106, Ang II, activin, and ET-3 affect the secretion of go- 112]. Whatever the subtype of the ET receptor, lo- nadotropins, the gonadotrophs could be another cal production of ET and the receptors in the same candidate cells modulating locally the anterior pi- tissue suggest the role of ET as a paracrine/ tuitary functions. Close anatomical localization of autocrine factor in the pituitary. gonadotrophs and lactotrophs provides further The functional interrelation between ET and the evidence to support the functional significance of anterior pituitary was first described by Stojilkovic ET-3-mediated paracrine regulation of PRL secre- et al. [113]. ET was shown to increase the intracel- tion. lular Ca2+ concentration and to stimulate the secretion of both LH and FSH in rats. Acute admin- 2) Posterior Pituitary Gland istration of rather higher doses of ET was subse- ET content is highest in the posterior pituitary. quently demonstrated to stimulate the secretion of The interrelation between ET and posterior pitu- LH, FSH, GH, TSH, and PRL, while lower doses of itary function was first described by Yoshizawa et ET for a longer period inhibited the secretion of al. [124]. ET was found immunohistochemically in PRL [110, 111, 114]. The biphasic effects of ET on the paraventricular and supraoptic nuclei of the PRL secretion, especially the inhibitory action of hypothalamus and the axon terminals in the poste- the later phase, coincide with other studies [108, rior pituitary. ET mRNA was also visualized in 109, 112, 115]. The effect is influenced by specific the paraventricular nucleus. After water depriva- ETA receptor antagonists [109, 111], but not by tion for 4 days, ET in the posterior pituitary disap- dopamine receptor antagonists [112, 116]. The peared, suggesting a functional linkage between PRL-inhibitory factor (PIF) found in the intermedi- ET and vasopressin secretion. Since ET-1 stimu- ate lobe was ET-like [117]. Therefore, the pituitary lates the release of vasopressin from the perfused ET may be a PIF other than dopamine. Although rat hypothalamus [125] and intracerebroventricular the effects on the secretion of gonadotropin were administration of ET-1 increases the plasma vaso- demonstrated also in a gonadotroph-rich culture study [118], the effects on the pituitary hormones other than the PRL [108, 110, 111, 114, 116, 119] need further characterization. The exact localization of ET in the pituitary is expected to provide information on the physiological role of ET. Samson et al. [117] showed intense immunohistochemical staining in the intermediate lobe and weak staining disseminated in the anterior pituitary of rats, suggesting paracrine control of anterior pituitary functions by ET from the intermediate lobe. By contrast, we found immunohistochemical staining of ET-3 in the cytoplasm of large ovoid cells of the human anterior pituitary. These cells were identified as gonadotrophs by means of a double staining technique and staining in the adjacent sections [120]. Despite of a possible interspecies difference, it is still fascinating to hypothesize the functional significance of the pituitary ET as illustrated in Fig. 8. Pituitary functions could be regulated by local factors in a paracrine/autocrine fashion. Of various Fig. 8. ET-3 in gonadotrophs as a possible center of types of pituitary cells, the folliculostellate cells paracrine/autocrine regulation of anterior pituitary [121] are quite intriguing as a possible center of the functions. REVIEW: RECENT PROGRESS IN ENDOTHELIN RESEARCH 501

Table 2. Effects of dehydration for 2 days on hematocrit, serum osmolarity, plasma levels of it-VP, plasma and neurohypophyseal levels of it-ET-1, density of NSG, and density of it-ET-1 in NSG

pressin levels in conscious rabbits [126], ET-1 may 130]. ET-1 inhibits vasopressin-evoked osmotic act at the hypothalamic level on the perikarya of water permeability and cAMP accumulation in the the magnocellular neurons. ET was also shown to cortical and medullary collecting ducts [35]. ET potentiate the depolarization-induced vasopressin may therefore antagonize vasopressin action to in- release from nerve endings in the posterior pitu- crease urine volume despite the decrease in renal itary [127], suggesting that ET modulates vaso- blood flow. pressin release at the pituitary level also. The ET The interactions between ET and vasopressin in receptor involved in this action is likely to be the the hypothalamo-neurohypophyseal system and in ETA type [127], the same subtype as in the anterior the kidney seem to be independent of each other, pituitary. since it is generally believed that ET acts locally Although a considerable number of neuro- rather than in an endocrine fashion. Both ET secretory granules in both types of axons were mRNA and ET receptor mRNA are expressed in immunolabeled with antiserum to ET-1, the these tissues. The fact that the plasma ET levels vasopressin-containing granules were more heavily are unchanged after water deprivation also sup- labeled with anti-ET-1 antiserum than oxytocin- ports this view, but intravenous administration of containing granules [128]. Double immunogold ET provokes an increase in plasma vasopressin in labeling clearly demonstrated intragranular dogs [131]. In addition, systemic ET acts at the colocalization of ET -1 and vasopressin or oxytocin. subfornical organ which lacks the blood-brain bar- In addition, the posterior pituitary levels of ET-1, rier to have an excitatory action on vasopressin density of the neurosecretory granules, and the and oxytocin-secreting neurons in rats [132]. The number of immunogold particles for ET-1 per possible involvement of circulating ET in the regu- neurosecretory granule, all showed a significant lation of vasopressin secretion and/or vasopressin decrease after water deprivation (Table 2). Plasma action can therefore not be completely excluded. vasopressin increased significantly after water The volume regulation by vasopressin may be un- deprivation, while plasma ET-1 was unchanged. der the dual control of the ET system-one in the All these findings support the notion that the ET-1 brain and the other in the kidney. in the neurohypophyseal system is involved in the regulation of body fluid homeostasis by locally modulating the secretion of vasopressin at the Summary level of the hypothalamus and/or the posterior pituitary. Recent advances in ET research on the cardio- Relevant to this issue, interaction between ET vascular and endocrine systems were reviewed. and vasopressin at the kidney level is noteworthy. Considering the potent vasculotropic actions, stra- ET increases urinary flow despite a decrease in re- tegically advantageous localization, and recent nal blood flow and glomerular filtration rate [129, findings with the specific receptor antagonist, ET is 502 NARUSE et al. potentially involved in the regulation of hemody- K. Tsuchiya, A. Ohono, K. Nitta, H. Nihei, N. Sugino namic homeostasis and in the pathogenesis of es- (Kidney Center), R. Demura (Dept. of Medicine), T. sential and secondary hypertension. The mitoge- Obara, Y. Ito (Endocrine Surgery), M. Kawamura, H. nic action on the vascular smooth muscle cells sug- Ohgawara, T. Wasada, Y. Omori (Diabetes Center), gests its more chronic effect on the vascular struc- T. Nishikawa, T. Kasajima (Dept. of Pathology) in ture. In addition to the hypertensinogenic aspects, the Tokyo Women's Medical College, H. Uemura, S. the role of ET in maintaining blood pressure in a Nakamura (Kanagawa Dental College), M. hypotensive condition should not be overlooked. Yamakado (Mitsui Memorial Hospital), S. Hifumi The development of specific antagonists which (Kanazawa Junkanki Hospital), N. Suzuki (Takeda block the action of locally operating ET in vivo will Pharmaceutical Industry), K. Ohosumi, Y. Watanabe, be a powerful tool in elucidating the pathophysi- F. Kurimoto (Mitsubishiyuka Bioclinical Labora- ological significance of ET and will provide a new tory), K. Yamada, Y. Matsuda (Kyowa Hakko therapeutic approach for hypertension. The roles Kogyo, Co., Ltd.) for their support in our studies of ET in the endocrine system are also fascinating. mentioned in the present review. We also would Accumulating evidence supports the notion that like to thank Ms. Y. Kato, Ms. C. Monzen, Ms. Y. ET modulates the secretion of pituitary and adre- Fujimaki, and Ms. M. Kawai for their technical and nal hormones. The mode of action is likely to be secretarial assistance. paracrine/autocrine rather than endocrine, al- This work was supported in part by research though a possible role of circulating ET cannot be grants from the Japanese Ministry of Health and ruled out. The pathophysiological role of ET in the Welfare "Disorders of Adrenal Hormones" Re- endocrine tissues remains to be clarified. The di- search Committee, Hisako Yamakawa Memorial versity of the action of ET on the blood pressure Research Award, and Hiroto Yoshioka Memorial and endocrine functions provides further evidence Medical Research Award of Tokyo Women's of the complexity of the homeostatic mechanisms, Medical College. leaving us an intriguing subject for future study. Note added in proof. After we submitted our manuscript in April 1994, an article by Shimada et Acknowledgments al. describing cloning of endothelin-converting enzyme appeared in the J Biol Chem (269: 18275- The authors thank Drs. K. Takagi, K. Hashiguchi 18278). (Maternal Center), M. Kawana (Dept. of Cardiology),

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