Contractile response of isoprenaline (IC50 = 13 nM)[1]

Cyclic somatostatin (0-10 μM; 15 min) dose-dependently suppresses the rat ventricular cardiomyocytes' contractile response to isoproterenol with an IC50 value 13 nM[1].

In ruminants, visceral metabolism is impacted by cyclic somatostatin (5 μg/kg; injected intravenously every hour for 18–22 hours) [3].

Somatostatin-14 elicits negative inotropic and chronotropic actions in atrial myocardium. Less is known about the effects of somatostatin-14 in ventricular myocardium. The direct contractile effects of somatostatin-14 were assessed using ventricular cardiomyocytes isolated from the hearts of adult rats. Cells were stimulated at 0.5 Hz with CaCl2 (2 mM) under basal conditions and in the presence of the beta-adrenoceptor agonist, isoprenaline (1 nM), or the selective inhibitor of the transient outward current (Ito), 4-aminopyridine (500 microM). Somatostatin-14 did not alter basal contractile response but it did inhibit (IC50 = 13 nM) the response to isoprenaline (1 nM). In the presence of 4-aminopyridine (500 microM), somatostatin-14 stimulated a positive contractile response (EC50 = 118 fM) that was attenuated markedly by diltiazem (100 nM). These data indicate that somatostatin-14 exerts dual effects directly in rat ventricular cardiomyocytes: (1) a negative contractile effect, observed in the presence of isoprenaline (1 nM), coupled to activation of Ito; and (2) a previously unreported and very potent positive contractile effect, unmasked by 4-aminopyridine (500 microM), coupled to the influx of calcium ions via L-type calcium channels. The greater potency of somatostatin-14 for producing the positive contractile effect indicates that the peptide may exert a predominantly stimulatory influence on the resting contractility of ventricular myocardium in vivo, whereas the negative contractile effect, observed at much higher concentrations, could indicate that localized elevations in the concentration of the peptide may serve as a negative regulatory influence to limit the detrimental effects of excessive stimulation of cardiomyocyte contractility[1].

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mRNA and protein expression of each receptor subtype were quantified by RT-PCR and immunoblotting respectively; for contraction studies, cells were stimulated at 0.5 Hz under basal conditions and in the presence of isoprenaline (ISO, 10(-8)M). Results: all five SRIF (SSTR) receptor subtypes were expressed in cardiomyocytes although SRIF1A (SSTR2) and SRIF2A (SSTR1) were less abundant than the other subtypes. L803087 (10(-8)M), a SRIF2B (SSTR4) agonist, attenuated ISO-stimulated peak contractile amplitude and prolonged relaxation time (T(50)). L796778 (10(-7)M), a SRIF1C (SSTR3) agonist, augmented basal and ISO-stimulated peak contractile amplitude; L779976 (10(-8)M) and L817818 (10(-9)M), agonists at SRIF1A (SSTR2) and SRIF1B (SSTR5) receptors, respectively, also augmented ISO-stimulated peak amplitude. Conclusion: These data support involvement of SRIF2B (SSTR4) receptors in the negative contractile effects of SRIF-14, while one or more of the three SRIF1 receptor subtypes (SSTR2, 3 or 5) may contribute to the positive contractile effects of SRIF-14.[2]

Animal/Disease Models: Polypay sheep [3]
Doses: 5 μg/kg
Route of Administration: intravenous (iv) (iv)injection; 5 μg/kg once an hour; lasts for 18-22 hrs (hrs (hours))
Experimental Results: Glucose, α-amino N, ammonia N, b-hydroxybutyric acid Net portal venous excretion of splanchnic release, oxygen consumption, hepatic oxygen consumption, and total splanchnic α-amino-N release and oxygen consumption were diminished. Increases lactate release and net hepatic glucose output.

[1]. Murray F, et al. Positive and negative contractile effects of somatostatin-14 on rat ventricular cardiomyocytes. J Cardiovasc Pharmacol. 2001 Mar;37(3):324-32.
[2]. Bell D, et al. SRIF receptor subtype expression and involvement in positive and negative contractile effects of somatostatin-14 (SRIF-14) in ventricular cardiomyocytes. Cell Physiol Biochem. 2008;22(5-6):653-64.
[3]. https://pubmed.ncbi.nlm.nih.gov/9374319/

Somatostatin is a 14-membered cyclic heterocyclic peptide composed of 14 amino acid residues, with the sequence Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys, formed by a disulfide bond between two cysteine residues at positions 3 and 14. It is a heterocyclic peptide and also a peptide hormone. Somatostatin, also known as growth hormone-inhibiting hormone, is a naturally occurring peptide hormone composed of 14 or 28 amino acid residues that regulates the endocrine system. It is secreted by pancreatic D cells, inhibiting the release of insulin and glucagon; it is also produced in the hypothalamus, inhibiting the release of growth hormone and thyroid-stimulating hormone from the anterior pituitary gland. Somatostatin is initially secreted as a 116-amino acid precursor—prosomatostatin—which is cleaved by an endonuclease to produce prosomatostatin. Prosostatin is further processed into two active forms: somatostatin-14 (SST-14) and somatostatin-28 (SST-28), the latter being an N-terminal extension of SST-14. The action of somatostatin is mediated through a G protein-coupled somatostatin receptor signaling pathway. The antitumor effects of somatostatin and its potential applications in various tumors, including pituitary adenomas, gastrointestinal and pancreatic neuroendocrine tumors, paragangliomas, carcinoid tumors, breast cancer, malignant lymphomas, and small cell lung cancer, have been extensively studied. Clinically, somatostatin has been used for the diagnosis of acromegaly and gastrointestinal tumors. Analogs have been developed to achieve more favorable pharmacokinetics, thus enabling more effective treatment of acute conditions such as esophageal varices. [DB00104] is a long-acting somatostatin analog that inhibits the release of multiple hormones and is clinically used to relieve symptoms of rare gastrointestinal and pancreatic endocrine tumors and to treat acromegaly. Recombinant somatostatin is a recombinant peptide with the same or similar chemical structure as endogenous somatostatin. Somatostatin is a cyclic fourteen-eighteen-amino acid peptide that regulates various endocrine and nervous system functions. Somatostatin inhibits the release of pituitary growth hormone, thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), insulin, glucagon, gastrin from the gastric mucosa, secretin from the intestinal mucosa, and renin by binding to a specific somatostatin receptor (SSTR). The somatostatin receptor is a cell surface G protein-coupled receptor expressed in a tissue-specific manner. Somatostatin is a 14-amino acid peptide named for its ability to inhibit the release of pituitary growth hormone; it is also known as somatostatin-releasing inhibitory factor (SRIF). It is expressed in the central and peripheral nervous systems, the intestines, and other organs. In addition to acting as a neurotransmitter and neuromodulator, SRIF also inhibits the release of TSH, prolactin, insulin, and glucagon. In many species, including humans, an additional form of somatostatin, SRIF-28, exists, with a 14-amino acid extension at the N-terminus.

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Drug Indications
For the treatment of symptoms of acute bleeding from esophageal varices. Once the condition is initially controlled, other long-term treatment options may be considered if necessary.

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Pharmacodynamics
Somatostatin is an endogenous peptide hormone secreted by neurons in the central nervous system, gastrointestinal tract, retina, peripheral neurons, and pancreatic D cells. It has a variety of biological functions, but its main role is to inhibit the secretion of other hormones and neurotransmitters. Although the distribution of the two active somatostatin subtypes is similar, SST-14 is more common in enteric neurons and peripheral nerves, while SST-28 is more prominent in retinal and intestinal mucosal cells. Anterior Pituitary Gland and Brain: It inhibits the release of growth hormone and thyroid-stimulating hormones, such as thyroid-stimulating hormone (TSH) and thyrotropin, from the anterior pituitary gland, while also inhibiting the release of dopamine from the midbrain, as well as the release of norepinephrine, thyrotropin-releasing hormone (TRH), and corticotropin-releasing hormone (CRH) from the brain. Pancreas: In the pancreas, somatostatin reduces the secretion of glucagon and insulin, as well as bicarbonate ions and other enzymes. Thyroid: Somatostatin reduces the secretion of T3, T4, and calcitonin. Somatostatin regulates thyroid function by reducing basal TSH release. Gastrointestinal Tract: It attenuates the release of most gastrointestinal hormones, such as gastrin, secretin, motilin, gastric acid, incretin, cholecystokinin (CCK), vasoactive intestinal peptide (VIP), gastric inhibitory peptide (GIP), intrinsic factor, pepsin, neurotensin, and the secretion of bile and colonic fluid. Adrenal glands: It inhibits angiotensin II-stimulated aldosterone secretion and acetylcholine-induced medullary catecholamine secretion. Eye/retina: Somatostatin inhibits the production of vascular endothelial growth factor. Inflammatory cells and sensory nerves: Studies have found that somatostatin is expressed in inflammatory cells such as lymphocytes, monocytes, macrophages, and endothelial cells, participating in local immune responses as an autocrine or paracrine regulator. Research results suggest that somatostatin may play a role in exerting local and systemic anti-inflammatory and analgesic effects. In primary afferent neurons, somatostatin reduces the response of C-type mechanothermal fibers to thermal stimulation in a dose-dependent manner and reduces the excitation and thermosensitization responses of C-type mechanothermal fibers induced by bradykinin. Intrathecal injection of somatostatin has been reported to produce analgesic effects; there is evidence that systemic application of somatostatin may also produce similar effects when treating endocrine disorders. Somatostatin is thought to reduce esophageal variceal bleeding by inducing visceral vasoconstriction. Somatostatin exerts antitumor effects against various tumors through direct or indirect action, or a combination of both.

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Absorption
This pharmacokinetic data is irrelevant.
Elimination Pathway
Somatostatin is a polypeptide chain primarily eliminated via peptidase metabolism.
Clearance
After intravenous injection of 3H-labeled endogenous somatostatin, the systemic clearance is approximately 50 mL/min. In humans, this value is calculated to be as high as 3000 mL/min, far exceeding hepatic blood flow. This indicates that rapid enzymatic degradation in the circulatory system and other tissues is an important clearance pathway.

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Metabolism/Metabolites
Somatostatin is rapidly degraded by peptidases present in cells and plasma.
Biological Half-Life
Due to rapid degradation by peptidases present in plasma and tissues, the half-life of endogenous somatostatin is 1–3 minutes.

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Mechanism of Action
Somatostatin binds to five somatostatin receptor (SSTR) subtypes, all of which are Gi protein-coupled transmembrane receptors that, upon activation, inhibit adenylate cyclase. SSTRs block cellular secretion by inhibiting intracellular cyclic adenosine monophosphate (cAMP) and calcium ions (Ca2+), as well as by suppressing exocytosis via receptor-mediated distal effects. The signaling pathways shared by these receptors involve activation of phosphotyrosine phosphatase (PTP) and regulation of mitogen-activated protein kinase (MAPK). Except for SSTR3, activation of SSTRs leads to activation of voltage-gated potassium channels, accompanied by an increase in K+ current. This results in membrane hyperpolarization and inhibits depolarization-induced Ca2+ influx through voltage-sensitive Ca2+ channels. Depending on the receptor subtype, the signaling cascade also involves activation of other downstream targets, such as Na+/H+ exchangers, Rho GTPases, and nitric oxide synthase (NOS). SSTRs 1 through 4 exhibit nanomolar binding affinities with both somatostatin subtypes, while SSTR5 shows a 5- to 10-fold higher affinity for SST-28. Functions of SSTR1: Upon binding and activation of somatostatin, SSTR1 mediates the inhibition of growth hormone, prolactin, and calcitonin secretion. Functions of SSTR2: The SSTR2 subtype is dominant in endocrine tissues. Somatostatin exerts paracrine inhibition through binding to the SSTR2 receptor, affecting gastrin release from G cells, histamine release from ECL cells, and parietal acid secretion. The SSTR2 receptor signaling pathway also inhibits the secretion of growth hormone, adrenocorticotropic hormone, glucagon, insulin, and interferon-γ. Functions of SSTR3: Activation of these receptors leads to reduced cell proliferation. SSTR3 triggers PTP-dependent apoptosis, accompanied by activation of p53 and the pro-apoptotic protein Bax. Studies using the matrix gel sponge assay suggest that somatostatin may exert its anti-tumor effect by inhibiting tumor angiogenesis through SSTR3-mediated inhibition of NOS and MAPK activity. Functions of SSTR4: The function of SSTR4 is not fully understood. Functions of SSTR5: Similar to SSTR2, the SSTR5 subtype is primarily found in endocrine tissues. Upon activation, SSTR5 signaling pathways inhibit the secretion of growth hormone, adrenocorticotropic hormone (ACTH), insulin, glucagon-like peptide-1 (GLP-1), and amylase. Somatostatin receptors have been detected in most neuroendocrine tumors, gastrointestinal pancreatic (GEP) tumors, paragangliomas, pheochromocytomas, medullary thyroid carcinoma (MTC), and small cell lung cancer. Somatostatin's antitumor effects are also effective against various malignant lymphomas and breast tumors. Gastrointestinal hormones, such as gastrin, secretin, and cholecystokinin (CCK), as well as growth hormone and growth factors, are elevated in gastrointestinal and neuroendocrine tumors, and somatostatin can inhibit the secretion of these hormones. In vitro experiments have shown that somatostatin can inhibit epidermal growth factor (EGF)-induced DNA synthesis and replication, suggesting that somatostatin may exert a direct antiproliferative effect through the SSTR signaling pathway. Acromegaly is an endocrine disorder caused by functional tumors of the anterior pituitary gland that secrete growth hormone. Somatostatin analogue therapy can normalize elevated growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels and inhibit tumor growth. In the vascular system, somatostatin may induce vasoconstriction by inhibiting adenylate cyclase, leading to a decrease in cyclic adenosine monophosphate (cAMP) concentration in endothelial cells, ultimately blocking vasodilation along this pathway. This vasoconstriction is thought to reduce blood flow to the esophageal tissue, thereby reducing esophageal variceal bleeding. Somatostatin exerts its analgesic effect by reducing inflammatory vasculature and nociceptive components. Studies have shown that somatostatin may be present in nociceptive dorsal root ganglion (DRG) neurons and primary afferent neurons with C-fibers to inhibit the release of neurotransmitters at presynaptic junctions of sensory-efferent nerve endings. Exogenous somatostatin has been shown to inhibit the release of substance P from central and peripheral nerve endings.

C78H108N18O21S2

1697.947

1696.737

54472-66-1

54472-66-1 (acetate);38916-34-6;

86278199

Typically exists as solid at room temperature

-4.25

23

26

26

119

3270

15

S1C[C@@H](C(N[C@H](C(N[C@@H](CC(N)=O)C(N[C@@H](CC2C=CC=CC=2)C(N[C@@H](CC2C=CC=CC=2)C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(=O)O)CS1)=O)CO)=O)[C@@H](C)O)=O)CC1C=CC=CC=1)=O)[C@@H](C)O)=O)CCCCN)=O)CC1=CNC2C=CC=CC1=2)=O)=O)=O)=O)CCCCN)=O)NC(CNC([C@H](C)N)=O)=O.OC(C)=O

GFYNCDIZASLOMM-HMAILDBGSA-N

InChI=1S/C76H104N18O19S2.C2H4O2/c1-41(79)64(100)82-37-61(99)83-58-39-114-115-40-59(76(112)113)92-72(108)57(38-95)91-75(111)63(43(3)97)94-71(107)54(33-46-23-11-6-12-24-46)90-74(110)62(42(2)96)93-66(102)51(28-16-18-30-78)84-69(105)55(34-47-36-81-49-26-14-13-25-48(47)49)88-68(104)53(32-45-21-9-5-10-22-45)86-67(103)52(31-44-19-7-4-8-20-44)87-70(106)56(35-60(80)98)89-65(101)50(85-73(58)109)27-15-17-29-77;1-2(3)4/h4-14,19-26,36,41-43,50-59,62-63,81,95-97H,15-18,27-35,37-40,77-79H2,1-3H3,(H2,80,98)(H,82,100)(H,83,99)(H,84,105)(H,85,109)(H,86,103)(H,87,106)(H,88,104)(H,89,101)(H,90,110)(H,91,111)(H,92,108)(H,93,102)(H,94,107)(H,112,113);1H3,(H,3,4)/t41-,42+,43+,50-,51-,52-,53-,54-,55-,56-,57-,58-,59-,62-,63-;/m0./s1

Ala-gly-cys-lys-asn-phe-phe-trp-lys-thr-phe-thr-ser-cys acetate (Disulfide bond)

Somatostatin Acetate growth hormone–inhibiting hormoneGHIH

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)