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Peptide and Protein Hormones----5. Blood Pressure Regulating Peptides 1

Author:N/A    | Post time:2012-05-26

5. Blood Pressure Regulating Peptides
Top of page
1. Introduction
2. Gonadoliberin, Thyroliberin, Gonadotropins, Thyrotropin, Inhibin, and Related Hormones
3. Parathyroid Hormone and the Calcitonin Family
4. Corticoliberin – Proopiomelanocortin Cascade
5. Blood Pressure Regulating Peptides
6. Cholecystokinin and Gastrin
7. Secretin Family
8. Neurotensin [1971]
9. Motilin [2005]
10. Pancreatic Spasmolytic Peptide
This chapter deals with the angiotensin–kinin system, the neurokinins and tachykinins, vasopressin and the structurally related peptides, oxytocin and vasotocin, the endothelins, the atrial natriuretic factor (ANF), and neuropeptide Y (NPY). These peptide hormones influence blood pressure and function as modulators of the reproductive hormones (Chap. Gonadoliberin, Thyroliberin, Gonadotropins, Thyrotropin, Inhibin, and Related Hormones) and of the stress-induced proopiomelanocortin (POMC) cascade (Chap. Corticoliberin – Proopiomelanocortin Cascade). AT II and, above all, the kinins appear to be involved in ovulation and the formation of semen. AT II stimulates the POMC cascade, presumably via CRH, and the formation of gluco- and mineralocorticoids; it also raises the level of luteotropin (LH) when applied centrally. Vasopressin has a peripheral stimulating effect and inhibits the POMC cascade when administered centrally. Oxytocin plays a role during mating as well as during and after birth. Endothelin releases LH from the pituitary; ANF, which can be released by endothelin, inhibits the formation of the stress hormone cascade and the synthesis of aldosterone. NPY also exerts an effect on the secretion of LH through the release of LHRH from the hypothalamus.

  5.1. The Angiotensin – Kinin System
The kinins and angiotensins are formed in biological fluids by the enzymatic cleavage of protein precursors. Kallikreins cleave kininogens (KG) to yield kinins, which are blood pressure lowering peptides. The species-specific enzyme renin can also be generated by kallikrein from inactive prorenin and is responsible for the formation of the decapeptide angiotensin I (AT I) from the N-terminus of the -globulin angiotensinogen (ATG). The structures of r-prepro-ATG and h-prepro-ATG have been elucidated [731]. Glucocorticoids stimulate the formation of ATG [732], [733], IL-6 potentiates the glucocorticoid-stimulated synthesis of ATG [733], and AT II or [Sar1]AT II inhibits the production of ATG in hepatocytes [734].

Although AT I has no effect on blood pressure, it is acted upon by the membrane-bound angiotensin converting enzyme (ACE or kininase II), a zinc-containing carboxydipeptidase, to form the octapeptide angiotensin II (AT II), a vasopressor (i.e., blood pressure increasing agent). The hypotensive kinins are, however, degraded by ACE. Therefore, the inhibition of ACE has a double hypotensive effect because both the formation of the blood pressure increasing AT II as well as the degradation of blood pressure lowering kinins are inhibited. The first inhibitors of ACE were isolated from snake venom and called bradykinin potentiating peptides. Examples of orally active ACE inhibitors are captopril, enalapril, and ramipril. Inhibitors of renin also exert a hypotensive effect. Potent inhibitors of renin are ATG analogues in which the peptide bond between positions 10 and 11 is reduced or replaced by statin, an amino acid occurring in pepstatin, or by similar compounds.

5.1.1. Angiotensins
  Occurrence. Angiotensins (ATs) are found both in the periphery and in the brain. Plasma AT II is formed primarily in the lungs. AT II and AT III are also synthesized in the juxtaglomerula cells of the kidney [735], the adrenal cortex [736], the gonadotropic cells of the pituitary [737], the hypothalamus [738], the ovarian follicle [739], and the Leydig cells of the testes. Roughly equimolar amounts of AT II-(1 – 7), AT II, and AT I have been found in the rat hypothalamus [738]. The sequences of human and rat angiotensins are as follows:  


  Release. See Figure 4. AT I [9041-90-1], Mr 1296.5, is formed by the action of renin on -globulin angiotensinogen (ATG). AT I is in turn cleaved by the angiotensin converting enzyme (ACE), also known as kininase II, or carboxypeptidases to form AT II [11128-99-7], Mr 1046.2 [740]. AT III [12687-51-3], Mr 931.1, is formed from AT II (aminopeptidase A) or de-Asp1-AT I (ACE or carboxypeptidases). Large amounts of aminopeptidase A are found in the adrenal cortex.  Figure 4. Formation of angiotensins (AT) from angiotensinogen (ATG)

Estradiol or a combination of estradiol and progesterone increases the plasma level of AT I and II in rats, whereas progesterone alone exerts no such effect [741]. A low-NaCl diet raises and a high-NaCl diet lowers the serum level of AT II [742]. The intracerebroventricular application of sodium chloride appears to result in a pressor effect through secretion of AT II [743]. The plasma AT II level is increased in thirst [744], dehydration, loss of blood [745], and endotoxin shock [746].

Receptors. Two AT II receptors occur in the adrenal gland: The AT 1 receptor (adrenal cortex) is sensitive to DuP-753 (Du Pont) [747], the AT 2 receptor (adrenal medulla) is sensitive to PD 123 319 (Parke Davis), Exp-655 (Merck MSD/Du Pont) [747], and WL-19 (Werner Lambert) [748].

AT III has its own subclass of receptors in the vascular smooth muscles: [Sar1,Ile7]-AT III is a selective antagonist for AT III [749].

The density of the AT II receptors can be increased by dehydration [750], stress [751], or IGF-I [752]. Treatment with AT II leads to the down regulation of the receptors in rat hepatocytes [753]. The density of the AT II receptors on the glomeruli in the kidney is reduced by a low intake of sodium chloride [744], diabetes mellitus [754], and by ACTH-(1 – 24) [755]. Chronic treatment with estrogen reduces the AT II receptor density in the hypophysis, adrenal cortex [756], and the rat placenta [741].

  Biological Effects. AT II and AT III increase intracellular levels of calcium, phosphatidic acid, phosphoinositides [757], and cGMP [758], and increase the formation of PGE2 and PGI2 by activating phospholipase A2 [759].

In the kidney, AT II inhibits the activity of renin [760] and the synthesis of messenger RNA for renin by a negative feedback effect through a lipoxygenase product [761].

AT II causes contraction of the vascular smooth muscles of the uterus, intestine, aorta, myocardium, and kidney, resulting in a potent vasoconstricting and blood pressor activity. Prostaglandins counteract the activity of AT II in the kidney [762].

AT II has many other effects. It increases plasma vasopressin levels [763] and exerts a positive inotropic effect on the myocardium [764]; in the kidney it reduces the glomerular filtration rate and, in physiological doses, the excretion of sodium ions and water [765], but it exerts a natriuretic and diuretic effect when given in high doses [766]. It reduces water absorption by the jejunum via the synthesis of prostaglandins [767] and stimulates the formation of aldosterone and corticosterone in the adrenal glands after short-term administration [768]. It may play a role in ovulation [769]: it stimulates the secretion of androgen and estrogen from rat ovaries [739] and reduces the LH-stimulated synthesis of progesterone in bovine luteal cells [770]. Like AT II, AT III stimulates the release of aldosterone and prostaglandin.

Structure – Activity Relationships. The C-terminal carboxyl group and the aromatic amino acids are important for the activity of AT II [771]. The N-terminal sequence is responsible for the specificity, intensity, and duration of its biological activity. However AT II-(1 – 7), like AT II, releases vasopressin and probably plays a physiological role in its formation [772].

h-[Sar1]AT II, h-[Aib1]AT II, and [d-Ser1]AT II [773] are more stable to aminopeptidases and thus more potent than AT II. The activity is lowered if Asn occupies position 1 [774].

Although the N-terminal amino group is not important for the pressor activity of AT II, acylation decreases the myotropic and aldosterone-stimulating effects.

Tyr4 is very important for biological activity: fragments without Tyr4 are devoid of activity [771]. The activity depends on the electronegativity of the aromatic ring in position 4. Increasingly electronegative substituents lower activity. [Sar1,3-NH2-Tyr4]AT II [775] and monoiodo-AT II [776] are, however, more active than [Sar1]AT II and AT II. A -branched amino acid in position 5 is important for agonistic activity. O-Methylthreonine is more effective than Ile in position 5 [777].

If Pro7 in AT I or AT II is replaced by Ala, cardioselective substances are obtained which have a positive inotropic activity and lower pressor effect [764]. [Cys3,Cys5]AT II is a cyclic analogue with about the same activity as AT II [778].

  AT II Antagonists. Positions 4 and 8 are responsible for the agonistic or antagonistic action of AT II. Competitive antagonists result when the side chain of Phe8 is extended or shortened by a methylene group or when aliphatic or branched aromatic [779] amino acids are substituted for Phe8. One of the most active antagonists of this series is [Sar1,Bip8]AT II [779] (Bip = biphenylalanine). The presence of d-amino acids, such as d-phenylglycine (d-Phg) or d-phenethylglycine (d-Peg), in position 8 gives active antagonists, which are not degraded by carboxypeptidases [780]. [Sar1,Val5,Ala8]AT II (saralasin) and [Sar1,Ile5,Thr8]AT II (DE-3489, sarthran) have been examined more closely. [Sar1,Thr(Me)5,8]AT II and [Sar1,Chg5,Lac8] AT II [781] (Chg = l-cyclohexylglycine, Lac = l-lactic acid) are more active than saralasin. Unlike the agonists, the antagonists do not require a -branched amino acid in position 5. For instance, [Sar1,Tyr5,Ile8]AT II has three times the antagonistic activity of [Sar1,Ile5,8]AT II [777].

Alkylation of the phenolic hydroxyl group of Tyr4 [782] or the substitution of Phe [783] or 4-ClPhe [784] for Tyr4 also gives AT II antagonists. However, [Sar1,Tyr(Me)4]AT II (sarmesin) is less active than saralasin.

Shortening the molecule at the C-terminus also yields AT II antagonists. Saralasin and sarmesin are about six times as active as [Sar1] AT II-(1 – 7)amide [785]. The latter compound has no agonistic properties and does not inhibit the central dipsogenic activity of AT II [786].

Nonpeptide AT II receptor antagonists are imidazole derivatives and are described in [747], [787], [788].

  AT III Analogues. Substitution of d-N-methylalanine for Arg1 in AT III produces a more potent analogue. [d-N-MeAla1,Ile7]AT III is a selective AT III antagonist [789]. [Sar1, Ile7]AT III is a selective vascular AT III antagonist. [Ile7]AT III inhibits both AT III and AT II [749].

  Uses. [Asn1,Val5]AT II (angiotensin amide [53-73-6], Hypertensin CIBA, Ciba), an AT II agonist, is administered in states of shock and collapse when normal blood pressure should be restored as quickly as possible.

The AT II antagonist saralasin [34273-10-4] (Sarenin, Röhm Pharma) is used in the diagnosis of AT II-dependent forms of hypertonia and in the preliminary treatment of donor kidneys before transplantation to minimize loss of functions of the transplanted kidney caused by ischemia.

5.1.2. Kinins [790]
  Occurrence. Kininogens (KG) are cleaved by kallikrein to give kinins. This system is widely distributed, e.g., in the liver, in acinar cells of the rat submandibular gland, in the human kidney, in platelets, endothelial cells, rat vascular smooth muscle cells (important for the regulation of the local vascular tone) [791], in the brain [792], Leydig cells, ovaries, and in milk [793]. The amino acid sequences of mammalian kinins follow:


Bradykinin (BK) [58-82-2],                      
    Mr 1060   R P P G F S P F R  
[Hyp3]BK   R P Ph G F S P F R  
Kallidin [342-10-9]                      
    , Mr 1188
  K R P P G F S P F R  
[Hyp3]Lys-BK  K R P Ph G F S P F R  
Met-Lys-BK M K R P P G F S P F R  
T-Kinin [86030-63-9],                      
    Mr 1260 I S R P P G F S P F R  
T-Kinin-Leu I S R P P G F S P F R L


Large amounts of BK, kallidin, [Hyp3]Lys-BK, and [Hyp3]BK were found in human urine [794], plasma [795], and in ascites of patients suffering from stomach cancer [796].

T-Kininogens have also been found in the rat [797]. These precursors are cleaved by T-kininogenase [798] (endopeptidase K [799]) or high concentrations of trypsin to give T-kinin (Ile-Ser-BK).

Structural similarities have been observed between kinins and various hormones of insects and crustaceans [800], [801].

  Release. Injury lowers tissue respiration and thus the pH [802] which activates the Hagemann factor (the blood clotting factor XII) resulting in the release of bradykinin (BK) [803]. Kallekrein in the plasma cleaves kininogen to produce BK, whereas tissue kallikrein cleaves kininogen to form kallidin (KD = Lys-BK), which can in turn be converted to BK by aminopeptidases.

Kinins are released during muscular work [804], PMSG/h-CG induced ovulation [805], and inflammation.

Prostaglandins inhibit the formation of kinins. Inhibitors of prostaglandin synthesis therefore potentiate BK synthesis [806]. Aspirin, for instance, potentiates the antihypertensive effect of Captopril in spontaneously hypertensive rats [807].

Inhibitors of kallikrein retard the release of kinins. Endogeneous kallikrein inhibitors include -macroglobulin and aprotinin (Trasylol, Bayer; Antagosan, Behring Werke). Synthetic inhibitors are substrate analogues of the kininogens, an example is d-Chg-l-Chg-l-Arg-4-nitroanilide, a structural analogue of the C-terminal cleavage sequence, Pro-Phe-Arg-Ser [808]. The bradykinin B2-receptor antagonists also inhibit kallikrein [809].

BK is deactivated primarily in the lungs by the dipeptidase kininase II, which is identical to ACE. Inhibitors of ACE (e.g., Captopril, Squibb; Enalapril, Merck; Ramipril, Hoechst) potentiate BK [810][811][812]. Other endopeptidases, carboxypeptidases (kininase I activity), and aminopeptidase degrade BK [813][814][815].

In patients suffering from hypertension, the concentrations of kallikrein, prekallikrein, and kinin in the urine are significantly lower than in persons with normal blood pressure [816]. Captopril decreases blood pressure in hypertensive patients with a normal urine kallikrein content, but not in patients who have a low urine kallikrein content [817]. Kallikrein activity decreases in old age.

An increased level of kinin or kallikrein is found in diabetics with orthostatic hypotension [818], allergic persons [819], and patients suffering from inflammatory stomach diseases, ulcerative colitis, pancreatitis, rheumatic inflammation, or myocardial infarction.

Only in rats, do prepro-T-kininogen messenger RNA [820] and T-kininogen [821] appear to be formed primarily in response to inflammatory stimulants. Expression of the T-kininogen gene increases with age [822].

Receptors. The B1- and B2-receptors for BK have been studied intensively. The B1-receptors bind de-Arg9-BK more strongly than BK, while the B2-receptors have a greater affinity for BK. Studies with agonists and antagonists on different tissues have led to the assumption that there are multiple B2-receptors for kinins [823]. The vasorelaxing effects of BK exerted via B2-receptors in isolated large vessels require intact vascular endothelial cells. The vasoconstricting effects of BK do not require an intact endothelium. The BK-receptor complex is internalized, causing temporary down regulation of the BK-receptor [824].

  Biological Effects [825].
  B1-receptor-mediated effects. The most important B1-receptor-mediated effects [826] are contraction of rat duodenum, relaxation of rabbit coeliac artery [827], capsaicin-induced inflammation in mice [828], and release of IL-1 and TNF- in macrophages.

  B2-receptor-mediated effects [826] include release of EDRF and calcium from intracellular stores, leading to activation of PLA2 and increase in PGE2 production; the PGE2-dependent activation of adenylate cyclase in arterial smooth muscle cells [829]; hypotensive activity: reduces blood pressure increased by AT II [830], adrenaline [831], and vasopressin [790]; increase of vascular permeability and pain [832] in rat skin; improvement of heart function [833]; and increase in human sperm motility.

  Other effects of the kinins include stimulation of ovulation [805], [834], rhinitis [790], release of SP- and CGRP-like materials in neurons sensitive to capsaicin [835], and glucose uptake in working skeletal muscle via prostaglandins and phosphofructokinase [836].

Structure – Activity Relationships. De-Arg9-BK and de-Arg10-Met-kallidin (stronger) are ligands for B1-receptors. The C-terminal arginine residue is very important for binding to the B2-receptors. De-Arg9-[d-Phe8]BK has four times and Sar-[d-Phe8]de-Arg9-BK ten times the effect of de-Arg9-BK on B1-receptors [837].

De-Arg9-[Leu8]BK, the corresponding KD derivative, de-Arg9-[Gly7]BK, and de-Arg9-[d-Ala7]BK [838] are powerful B1-receptor antagonists.

The action of KD on B2-receptors is greater than that of BK. The guanido groups of Arg1 and Arg9 and the proline residue in positions 2 and 3 of BK are important for biological activity at the B2-receptors. Strong agonists are obtained by the substitution of -(2-thienyl)-Ala (Thi) or dehydro-Phe (-Phe) for Phe5 and Phe8, Hyp for Pro3, -aminoisobutyric acid for Pro7, Tyr(Me) for Phe8, or by reduction of the peptide bonds between positions 8 and 9 [839] and 6 and 7 [840]. The effect of [Hyp3,Tyr(OMe)8]BK on B2-receptors is about three times that of BK [837]. [Phe8--(CH2-NH)-Arg9]BK is a selective B2-receptor agonist, which is five times as active as BK [839]. The effect of [-Phe5]BK on the uterus and ileum is twice that of BK and the effect on blood pressure is 23 times that of BK.

The replacement of Pro7 in BK by d-Phe, d-Nal, d-Pal, or d-tetrahydroisoquinolinecarboxylic acid (d-Tic) [841], and the substitution of octahydroindolecarboxylic acid (Oic) [841] for the Phe8 gives strong B2-receptor antagonists. Depending on the test, d-Arg-[Hyp3,Thi5, d-Tic7,Oic8]BK (Hoe 140) [841] is a 100 – 1000 times stronger BK antagonist than the standard peptide, d-Arg-[Hyp3,Thi5,8,d-Phe7]BK [842].

Modification of the BK antagonists at positions 1, 2, 3, 8, and 9, alters tissue selectivity; extension with d-Arg at the N-terminus improves affinity and inhibits enzymatic degradation [843].

BK-receptor antagonists with Phe8 or Thi8 also act as B1-receptor blockers [844] because carboxypeptidases convert these peptides to biologically active B1-receptor antagonists by cleaving the C-terminal arginine [845]. The histamine-releasing effect of BK antagonists can be lowered by acetylating the N-terminal amino group [846].

  Uses. BK antagonists may find application for treating inflammation, pain, rheumatoid arthritis, osteoarthritis, inflammatory stomach diseases, rhinitis, asthma, and gout [790].

  5.2. Substance P, Neurokinins, and Tachykinins [847]  
5.2.1. Introduction
  Occurrence. The neurokinins include substance P (SP) [516-47-2], neurokinin A (NKA) [86933-74-6], and neurokinin B (NKB) [86933-75-7]. Similar compounds which occur in cold-blooded animals are called tachykinins.  


Substance P was the first of a large number of peptides that were found in the gastrointestinal tract and the brain. Substance P and the neurokinins are produced in the form of preproneurokinins. Three preproneurokinins (, , and ) have been characterized in the cow and the rat [848]. There is a very great similarity between h--prepro neurokinin and b--prepro neurokinin [849]. Neuropeptide K (NPK) is neurokinin A that is extended by 26 amino acids at the N-terminus [850]. NPK, NKA [851], NKA-(3 – 10), and NKA-(4 – 10) [852] occur in the plasma and tumor tissue of carcinoid patients and in the bronchi. Apart from NKA, NKB (neuromedin K) has also been isolated from the spinal cord of the pig.

Substance P occurs in the spinal cord, the sensory nuclei of the brain stem, and the sensory nerve terminals in the gastrointestinal tract, urogenital tract, bile duct, bronchi, skin [853], and thymus [854]. Neurokinin A has been isolated from the rabbit iris [855].

Tachykinins are found in the salivary glands of the octopus, the skin of amphibians [856], and the locust [857]. Scyliorhinin I and II are the tachykinins of the mud fish, Scyliorhinus caniculus [856]. There are indications that tachykinin-like substances also occur in mammals [852]. There is a structural similarity between the tachykinins and the neurotoxic -amyloid protein-(25 – 35) [858].

  Release. Substance P is released after stimulation of the sensory neurons. It is assumed to be a pain transmitter, especially since the level of SP in the spinal cord is increased by mechanical pressure or hot water applied to the extremities [859], and analgesics inhibit the release of SP from sensory nerve ends [859].

Substance P and NKA are released by capsaicin, bombesin [860], CCK-8 [861], and by cholinergic [862], serotoninrgic [863], and dopaminergic [864] agents.

A high NKA- and SP-like immunoreactivity is found in tumor tissue and plasma NKA immunoreactivity can be used as tumor marker. “Flushing” episodes and diarrhoea correlate positively with plasma NKA [865]. The neurokinin level is also elevated in the joint fluid of patients with rheumatic inflammatory diseases [866].

In the brain, SP is preferentially cleaved by metalloendopeptidase E.C. (also called enkephalinase or neutral endopeptidase) to form the N-terminal heptapeptide SP-(1 – 7). The C-terminal heptapeptide SP-(5 – 11) is, however, also formed in the brain after cleavage with the post-proline-cleaving enzyme [867].

Digestion in the plasma occurs preferentially through a post-proline-cleaving enzyme to give dipeptides [868]. SP is also a substrate for the angiotensin converting enzyme (ACE). Levels of SP are increased by smoking (inhibition of the neutral endopeptidase) [869] and by ACE inhibitors [870].

Receptors. Three neurokinin receptors have been found: NK1 for SP, NK2 for NKA, and NK3 for NKB [871]. The r-NK1 receptor, the r-NK2 receptor [872], and the b-NK2 receptor [873] have been characterized via their cDNA. They occur in a wide variety of tissues [874].

Selective ligands of neurokinin receptors are described in the literature [874]:


NK1 receptor agonists [871], [877][878][879]
NK2 receptor agonists [878], [880][881][882]
NK3 receptor agonists [871], [876], [883]
NK1 receptor antagonists [884][885][886]
NK2 receptor antagonists [875], [887][888][889]
NK3 receptor antagonists [859], [890]



  Biological Effects [874].
  NK1-receptor-mediated effects The most important NK1-receptor-mediated effects are hyperalgesia, hypotension, salivary secretion, and increase of capillary permeability.

  NK2-receptor-mediated effects include bronchoconstriction [850], [891], [892], activation of guinea pig alveolar macrophages [893], protection against gastric lesions in rats [894], and tachycardia.

  NK3-receptor-mediated effects are analgesia [895], bradycardia, and increase in capillary permeability.

  Other effects of SP include activation of phospholipase C and D [896], stimulation of the proliferation of synoviocytes and the release of PGE2 and collagenase (rheumatoid arthritis) [897], modulation of gastrointestinal motility [898], [899], and immunostimulating activity [900], [901].

Structure – Activity Relationships. In the brain, SP-(5 – 11) is a pain neurotransmitter. It causes aggressive, stress-induced behavior, impairs memory, and increases blood pressure when applied centrally. SP-(1 – 7) exerts an analgesic effect, increases learning capacity, improves memory, and lowers blood pressure [867], [902], [903]. Based on the opposing effects of the N- and C-terminal peptides of SP, Stewart postulated the existence of SP-N and SP-C receptors [867]. The regeneration of nerve fibers is stimulated by N-terminal fragments of SP [904].

SP Agonists. The shortest active SP analogues are acylated SP-(7 – 11) derivatives [905], some are more active than SP. The most effective compound in the guinea pig ileum test is SP-(7 – 11) with a 4-hydroxyphenylacetic acid residue at its N-terminus.

The C-terminal amide group, a neutral lipophilic amino acid in position 11 [906], Leu10, and Gly9 are important for biological activity. Phe8 can be replaced by Tyr(OMe), cyclohexylalanine, or Ile without loss of activity, whereas substitution of these residues for Phe7 produces only slightly active compounds. The remaining N-terminal amino acids are not essential for biological activity.

pGlu-Gln-Phe-MePhe-Sar-Leu-Met-amide is an SP analogue with a long-lasting effect. It has only 10 % of the spasmogenic activity, but all of the aggressive CNS activity of SP and is resistant to the proteolytic enzymes of the hypothalamus.

A derivative that is dimerized with succinic acid via the N-terminal amino groups of SP-(3 – 11) has 2.4 times the receptor affinity and 75 times the saliva-producing effect of SP [907].

NKA-(4 – 10) is equally as active as NKA. Asp4, Phe6, and Val7 are important for the biological activity of NKA and NKB [908].

SP Antagonists. The standard antagonist is spantide I which binds primarily to the NK1 and NK2 receptors.


Spantide I [d-Arg1,d-Trp7,9,Leu11]SP
Spantide II [d-Lys(Nic)1,Pal3,d-Phe(Cl2)5,Asn6,d-Trp7,9,


d-Phe(Cl2) = 3,4-d-dichlorophenylalanine

d-Lys(Nic) = N-nicotinoyl-d-lysine

The activity of SP antagonists is enhanced by the replacement of Gln6 by Asn6 [909]. As a result of the substitution of d-Lys(Nic) for d-Arg1, spantide II, unlike spantide I, has no neurotoxic properties [910] and a reduced histamine-releasing activity [911]. Spantide I acts as a bombesin antagonist but spantide II has no effect on bombesin-induced contractions. Spantide II binds to all three neurokinin receptors [911] and exerts a short antinociceptive effect when applied intrathecally [912].

Reduction of peptide bonds also gives SP antagonists which have been evaluated by the displacement of SP from SP receptors in guinea pig acinar cells [913].

SP antagonists with basic N-terminal amino acids release histamine, whereas shortened antagonists (e.g., [d-Pro4,d-Trp7,910]SP-(4 – 11) can inhibit the SP-induced release of histamine in vitro.

[d-Arg1,d-Phe5,d-Trp7,9,Leu11]SP was the most suitable peptide for inhibiting the bombesin- and vasopressin induced mitogenesis in small cell lung cancer cells. It has the same affinity for the bombesin and SP receptors and is ten times more active than spantide I on the bombesin receptor [914]. Under comparable conditions, spantide I and other N-terminal-shortened SP antagonists did not inhibit the bombesin- or vasopressin-induced growth of Swiss 3T3 cells.

5.2.2. Amyloid A4 Protein [915]
  Occurrence. In Alzheimer\'s disease and in Down\'s syndrome (Mongolism), fibrillary amyloid is found within the cortical neurons as neurofibrillary tangles and extracellulary in meningeal and intracortical blood vessels as amyloid plaques. These deposits also occur in the skin, subcutaneous tissue, and in the intestine of Alzheimer patients and healthy elderly persons [916].

The plaques mainly consist of an insoluble peptide called the amyloid A4 protein (A4) [12627-51-9], Mr 4514 [917], or amyloid- protein [918]. It contains 42 amino acids [919]. The gene that codes for A4 produces at least three messenger RNAs for amyloid precursor protein, they form the APP695, APP751, and APP770 proteins [920].

APP695 consists of 695 amino acids and contains A4 in positions 597 – 638. APP751 is identical to APP695 apart from an insert of 56 amino acids (HL 124i) C-terminal from Arg288 and the substitution of Ile for Val289. Apart from an insert of 19 amino acids C-terminal from HL 124i and the substitution of Leu for Ile289, APP770 is identical to APP751. The HL 124i insert has the structure of a Kunitz inhibitor, which specifically inhibits serine proteases, such as trypsin, chymotrypsin, elastase, plasmin, and cathepsin G. In Alzheimer\'s disease, the total increase in the messenger RNA for APP in neurons from the locus ceruleus and nucleus basalis is due solely to an increase in APP695 that lacks this inhibitor domain. Therefore, it is assumed that A4 is readily formed from this precursor by the action of cerebral proteases [920]. These A4 precursors are transmembrane proteins and receptors for neuronal adherons [921]. Adherons are extracellular, adhesion-mediating particles (mostly glycoproteins) found in the extracellular matrix.

The gene for APP is expressed in certain neurons, some glia cells, and in brain macrophages. The A4 formed in the glia cells and macrophages is responsible for the extracellular formation of the amyloid plaques [919]. Human platelets contain APP751 in high concentrations [922].

The A4 of patients suffering from Alzheimer\'s disease and Down\'s syndrome is identical to the intraneural amyloid of the Parkinson dementia of Guam and the vascular amyloid of sporadic cerebral amyloid angiopathy. The amyloid protein of patients with leptomeningiosis haemorrhagica interna is shorter by three amino acids at the C-terminus [923].

  Release of APP and A 4. The APP gene is localized on chromosome 21 and amplified in Down\'s syndrome but not in Alzheimer\'s disease. It is assumed that the A4 protein is formed by increased proteolytic activity in Alzheimer\'s disease [924]. Proteolysis of APP in membranes at the C-terminus of A4 does not change the aggregation properties. However, enzymatic cleavage at the extracellular N-terminus of A4 is of great importance for plaque formation. Proteinase K cleaves a pro-A4 fragment to peptides of the size of A4 [925]. Platelets also release APP during degranulation [926].

  Biological Effects. APP is widely distributed in the neurons of the rat brain and appears to play a role in cell – cell contact, which is required for memory [917]. APP released from cells has an autocrine effect on growth regulation [927].

Low concentrations of A4 and A4-(25 – 35), which is structurally similar to the tachykinins, have a neurotrophic and at higher concentrations a neurotoxic effect on mature neurons. This neurotoxic activity is also exhibited by some tachykinin antagonists and can be abolished by tachykinin agonists [928].

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