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Y C Patel

Publications and source records attributed to Y C Patel.

At least 109 records · Page 6Linked to original sources
PubMed1984

Impaired hepatic metabolism of somatostatin-14 and somatostatin-28 in spontaneously diabetic BB rats.

Somatostatin-14 (S-14) and somatostatin-28 (S-28) circulate in normal portal plasma and are rapidly metabolized by the liver. In the present study we have investigated the hepatic clearance of the two peptides in insulinopenic diabetes using as a model spontaneously diabetic BB rats. Isolated livers from three groups of five nondiabetic, untreated diabetic, or insulin-treated diabetic animals were perfused with synthetic S-14 or S-28. The metabolism of the two peptides was monitored as S-14-like immunoreactivity by RIA using antibody R149 specific for the central segment of S-14, which detects S-14 and S-28 equally. The t1/2 and hepatic extraction of S-14 in untreated diabetic rats (25.9 +/- 2.6 min and 27.1 +/- 4.6%, respectively) were significantly different (P less than 0.01) compared with nondiabetic control values (13.3 +/- 1.1 min and 42.8 +/- 2.5%) and were normalized with insulin treatment (13.1 +/- 1.0 min and 42.0 +/- 2.3%). Similarly, the t1/2 of S-28 disappearance and the hepatic extraction of the peptide in untreated diabetic rats (62.1 +/- 1.8 min and 9.8 +/- 0.6%) were also significantly different (P less than 0.05) from nondiabetic control values (44.0 +/- 1.9 min and 13.7 +/- 1.6%) and were normalized with insulin treatment (47.2 +/- 2.0 min and 13.1 +/- 1.8%). Sephadex G-50 gel chromatography of media after S-28 perfusion showed two peaks of S-14-like immunoreactivity corresponding to S-28 and S-14. The extent of S-28 to S-14 conversion varied from 10% in 10-min perfusion samples to 30% in 60-min samples and was identical in normal and untreated diabetic rats. We conclude that 1) S-14 is metabolized more rapidly than S-28 by livers of both normal and diabetic rats; 2) the hepatic extraction of S-14 and S-28 is significantly impaired in insulin-deficient diabetic rats and normalized with insulin treatment; and 3) S-28 is significantly converted to S-14 equally in normal and diabetic rats.

Animals↗
PubMed1984

Cysteamine-induced depletion of brain somatostatin is associated with up-regulation of cerebrocortical somatostatin receptors.

Cysteamine (CSH) administered as a single sc injection to rats produced rapid depletion of cerebrocortical Somatostatin-14 like immunoreactivity (S-14 LI) with a significant 48% reduction occurring within 5 min and maximum (72%) decrease at 4 h. The depletion of S-14 LI was associated with a 1.7 fold increase in Bmax of the cerebrocortical S-14 receptors 5 min after CSH administration and a concomitant but slower increase in the affinity of these receptors [dissociation constant (Kd) being 1.8- and 1.6-fold lower than the control at 30 and 60 min, respectively, post CSH]. Incubation of intact synaptosomes with 1 mM CSH at 37 C in vitro for 60 min also caused a rapid depletion of S-14 LI, but in contrast to the in vivo data, there was no change in the Bmax or Kd of the S-14 receptors for up to 30 min beyond which time a 2.8-fold decrease in the affinity of S-14 receptors was observed. Higher concentrations of CSH (greater than or equal to 10 mM) added during the incubation of synaptosomes in vitro completely abolished the specific binding of these receptors. The pituitary S-14 receptors were studied 30 min after CSH administration and unlike the cerebrocortical S-14 receptors at this time did not exhibit any change in Bmax or affinity. When added at the time of the binding assay CSH (1 mM) was without a direct effect on cerebrocortical as well as pituitary membrane S-14 receptors. Furthermore, addition of CSH at the time of binding assay did not destroy the integrity of [125I-Tyr11]S-14. It is concluded that administration of CSH to rats in vivo depletes brain S-14 LI and up-regulates synaptosomal S-14 receptors. Exposure of synaptosomes to CSH in vitro for 30 min also depletes S-14 LI but has no effect on S-14 receptors suggesting that S-14 receptor regulation by S-14 is an in vivo phenomenon or requires the intact cell. CSH has a direct inhibitory effect on S-14 receptor binding after prolonged in vitro incubation. Pituitary S-14 receptors unlike those in the brain are unaffected by S-14 LI depletion at least acutely.

Animals↗
PubMed1983

Processing of somatostatin-28 to somatostatin-14 by rat hypothalamic synaptosomal membranes.

The conversion of synthetic somatostatin-28 (S-28) to somatostatin-14 (S-14, SRIF) by subcellular fractions of rat hypothalamus has been investigated. The conversion products were identified by two techniques: (1) two separate RIAs using antibodies directed toward the central (RIA R149) or the N-terminal (RIA S39) region of the S-14 molecule, (2) gel chromatography of the reaction mixture followed by analysis of the column fractions by RIA R149. Maximal S-28 to S-14 converting activity was observed with the particulate fraction of the lysed synaptosomal pellet sedimenting at the density interface 8-16% Ficoll in 0.32 M sucrose in a discontinuous sucrose/Ficoll gradient. Concomitant with conversion, degradation of total somatostatin-like immunoreactivity (SLI) was also observed with this fraction (t1/2 approximately 24 min). Relatively little converting activity was found in the remaining subcellular fractions. These data suggest that hypothalamic synaptosomes contain membrane bound enzymes which are able to catalyze the conversion of S-28 to S-14. Tissue specific differences in this converting activity may account for the reported variability in the S-28:S-14 ratios in different tissues.

Animals↗
PubMed1983

Position 4 substituted somatostatin analogs: increased binding to somatostatin receptors in pituitary and brain.

Somatostatin (S-14) analogs with Phe4 substitutions bound to pituitary and cerebrocortical S-14 receptors more avidly than did S-14. The 2-4 fold greater affinities of the Phe4 S-14 as well as analogs with structural modification of the Phe4 residue for binding to pituitary S-14 receptors showed good correlation with their reported potencies for in vivo Gh inhibition. In the cerebral cortex, [Phe4] S-14, [Phe4, D-Trp8] S-14 and [F5-Phe4] S14 were 2-3 times more potent while [p-NH2-Phe4] S-14 was 6 times more potent compared to S-14 in binding to S-14 receptors. The increased binding affinities of the Phe4 analogs in these two tissues does not appear to be due to differential stability of the analogs compared to S-14 under the experimental conditions used. [Thr4] S-14 exhibited very low binding in both these tissues. Thus structural modification of the position 4 moiety of the S-14 molecule does not result in dissociated affinities for binding to S-14 receptors in the brain and the pituitary. The increased receptor binding affinities of the Phe4 analogs in the cerebral cortex suggest that they may be more potent than S-14 in the CNS.

Animals↗
PubMed1983

Alterations in somatostatin and other islet cell functions in the spontaneously diabetic BB Wistar rat: biochemical and morphological characterization.

In the present study we have attempted to assess the functional status of somatostatin cells in relation to the function of the other islet cell types (B, A, and PP cells) in the BB Wistar rat. Somatostatin-like immunoreactivity (SLI), glucagon, and insulin were measured in extracted plasma obtained from the hepatic portal vein (PV) and inferior vena cava (IVC) of acutely diabetic untreated rats, insulin-treated diabetic rats and nondiabetic controls. Extracts of the pancreas were assayed for SLI, glucagon, and insulin, and the pancreatic populations of A, B, D, and PP cells were evaluated by morphometry. Extrapancreatic somatostatin changes were assessed by measurement of SLI in extracts of the whole gut, hypothalamus, and retina. Direct studies of SLI, glucagon, and insulin secretion in response to glucose, arginine, and theophylline were carried out using the isolated perfused pancreases of two separate groups of untreated diabetic and nondiabetic rats. Our results showed that in the severely insulin deficient BB Wistar rat (1) pancreatic concentrations of SLI, glucagon, and insulin were reduced; (2) the B cells are virtually eliminated and the D cells severely reduced early in diabetes; A and PP cells are resistant initially but eventually sustain major losses as observed in terminal islets; (3) retinal SLI is reduced, but SLI in gut and brain appears unchanged; (4) the secretion of SLI, glucagon, and insulin from the perfused pancreas is diminished 60%, 36%, and 99%, respectively; (5) PV and IVC blood levels of SLI and glucagon are elevated despite decreased pancreatic secretion; (6) The trans-hepatic gradient of SLI is reduced; and (7) Insulin treatment normalizes the elevated PV and IVC levels of SLI and glucagon. It is concluded that the elevated PV and IVC levels of SLI are secondary to insulin deficiency and result from increased SLI secretion most probably from the gut and from diminished hepatic metabolism. The origin of the hyperglucagonemia is less certain, but as in the case of SLI, important contributions from extra-pancreatic secretion appears likely.

Animals↗
PubMed1983

A high molecular weight form of somatostatin-28 (1-12)-like immunoreactive substance without somatostatin-14 immunoreactivity in the rat pancreas. Evidence that somatostatin-14 synthesis can occur independently of somatostatin-28.

Synthesis of somatostatin-14 (S-14) could occur through direct enzymatic processing of precursor somatostatin (prosomatostatin) or via sequential breakdown of prosomatostatin leads to somatostatin-28 (S-28) leads to S-14. If direct processing is important, it should theoretically generate S-14 and a molecule equivalent to prosomatostatin without the S-14 sequence. In an attempt to identify such a molecule, I characterized the molecular forms of S-28(1-12)-like immunoreactivity (S-28(1-12) LI) in the rat pancreas and compared the relative amounts of these forms with those of S-14-like immunoreactivity (S-14 LI). Pancreatic extracts were chromatographed on Sephadex G-50 and Sephadex G-75 columns (Pharmacia Fine Chemicals Inc., Piscataway, NJ) under denaturing conditions and immunoreactivity in the eluting fractions was analyzed by region-specific radioimmunoassays (RIAs). For RIA of S-28(1-12) LI we used a newly developed rabbit antibody R 21 B, 125I-Tyr12 S-28(1-14), and S-28(1-12) standards. This system detects S-28, S-28(1-12), high molecular weight forms of S-28(1-12), but not S-14. S-14 LI was measured using antibody R149, which detects S-14, S-28, and higher molecular weight S-14-like substances, but not S-28(1-12). Three forms of S-28(1-12) LI were identified: Mr 9,000-11,000, Mr 1,200 (corresponding to S-28(1-12), and Mr less than 1,000, comprising, respectively, 35, 53, and 12% of total immunoreactivity. The relative abundance of the 9,000-11,000 mol wt S-28(1-12) LI material was unchanged following removal of S-14 LI from pancreatic extracts by affinity chromatography before gel filtration. Serial dilutions of fractions containing 9-11,000 and 1,200 mol wt materials exhibited parallelism with synthetic S-28(1-12). The total pancreatic concentration of S-28(1-12) LI was 1.56 pmol/mg protein, of which S-28(1-12) accounted for 0.83 pmol/mg protein and 9-11,000 S-28(1-12) LI comprised 0.55 pmol/mg protein. Pancreatic S-14 LI concentration was 2.07 pmol/mg protein, of which 98% corresponded to S-14. S-28-related peaks accounted for <1% of immunoreactivity in both RIAs. I concluded that (a) S-14 is the main form of pancreatic S-14 LI; (b) S-28 is present in very small quantities, in the pancreas; (c) S-28(1-12) LI consist mainly of S-28(1-12) and 9-11,000 mol wt S-28(1-12) LI; (d) 9-11,000 l wt S-28(1-12) LI could represent prosomatostatin without the S-14 sequence; (e) the finding of high concentrations of 9-11,000 mol wt S-28(1-12) LI suggests that S-14 synthesis can occur independently of S-28 and that direct processing of prosomatostatin is an important pathway for S-14 synthesis in the pancreas.

Animals↗
PubMed1983

Pancreatic somatostatinoma: abundance of somatostatin-28(1-12)-like immunoreactivity in tumor and plasma.

UNLABELLED: In the present study we characterized and compared the relative amounts of the different molecular forms of somatostatin-14 like immunoreactivity (S-14 LI) and of somatostatin-28(1-12) like immunoreactivity (S-28(1-12) LI) in extracts of tumor and peripheral plasma of a patient with a pancreatic somatostatinoma. Tissue and plasma were chromatographed on Sephadex G-50 columns equilibrated with 6 M urea. Immunoreactivity in the eluting fractions was assayed with two separate, region specific RIAs using antibodies R149 (S-14 LI) and S309 (S-28(1-12)LI). RIA R149 recognizes the 6-8 and 14 regions of the S-14 sequence and detects S-14, S-28, and prosomatostatin, an approximately 14,000 mol wt precursor for the two peptides. RIA S309 recognizes the 2-11 segment of S-28 and reacts with S-28, S-28(1-12), and higher mol wt S-28(1-12) LI but not S-14. Total tumor S-14 LI was 190 pmol/mg protein and consisted of three peaks of immunoreactivity of apparent 14,000 mol wt (14K S-14 LI), 3,200 mol wt (3.2K corresponding to S-28) and 1,600 mol wt (1.6K corresponding to S-14). The three peaks comprised, respectively, 7%, 57%, and 36% of total S-14 LI. Total tumor S-28(1-12) LI was 594 pmol/mg protein and eluted as four major peaks of immunoreactivity as follows: peak I (mol wt 15,000, 10% of total S-28(1-12) LI); peak II (mol wt 8,000, 20% of S-28(1-12) LI), peak III (corresponding to S-28, 19% of S-28(1-12) LI); peak IV (corresponding to S-28(1-12), approximately 50% of total S-28(1-12) LI). Total plasma concentration of S-14 LI was 714 pM, being made up of the three peaks found in tumor but in the following relative amounts (14K S-14 LI, 22%; 3.2K, 29%; 1.6 K, 49%). Plasma S-28(1-12) LI was 4 times higher (2879 pM) than S-14 LI and contained immunoreactivity corresponding to each of the four peaks found in the tumor. CONCLUSIONS: 1) The tumor and plasma concentrations of S-28(1-12) LI were greater than that of S-14 LI. 2) Both tumor and plasma S-14 LI and S-28 LI were heterogeneous and comprised species corresponding not only to S-14 but also S-28, S-28(1-12), prosomatostatin, and other higher mol wt forms of S-28.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenoma, Islet Cell↗
PubMed1983

Blood pressure response and plasma fentanyl concentrations during high- and very high-dose fentanyl anesthesia for coronary artery surgery.

We examined whether different plasma fentanyl concentrations could maintain hemodynamic stability during coronary artery surgery. Two randomly selected groups of 10 patients were studied. Patients in group 1 received a single 75-micrograms/kg intravenous dose of fentanyl; patients in group 2 received the same dose but it was followed by an infusion of fentanyl at a rate of 0.75 micrograms/kg/min. The total dose of fentanyl in group 2 was 162 +/- 6.5 micrograms/kg (mean +/- SEM). At some point during surgery, all 10 patients in group 1 and 7 of 10 patients in group 2 had a hypertensive response. Plasma fentanyl concentrations in the two groups were not significantly different in the period 10-45 min after induction of anesthesia. At 60 min, corresponding to the time of aortic root dissection, mean plasma fentanyl concentration was statistically significantly lower in group 1 than in group 2 (13.5 +/- 1.4 ng/ml and 24 +/- 2.3 ng/ml, respectively, P less than 0.01). However, no significant difference was observed in the frequency of hypertensive response between the two groups in the period before cardiopulmonary bypass. During cardiopulmonary bypass, plasma fentanyl concentrations in group 1 were 2-3 times lower than those in group 2, and hypertension was observed in all 10 patients in group 1 but in only 2 patients in group 2 (P less than 0.05). Patients in group 1 were ventilated for 16.6 +/- 1.5 h, and those in group 2 for 19.1 +/- 1.8 h, postoperatively (P greater than 0.05). Six patients in group 1 required vasodilating drugs, whereas eight patients in group 2 required alpha-adrenergic agonists. Although the plasma fentanyl concentrations achieved were not successful in totally suppressing a hypertensive response, this study suggests that a plasma fentanyl concentration might be attainable to effect this.

Anesthesia, Intravenous↗
PubMed1982

Quantitative electron microscopic autoradiography of insulin, glucagon, and somatostatin binding sites on islets.

After monolayer cultures of rat islets were exposed to [(125)I]insulin,[(125)I]glucagon, and [(125)I]tyrosinyl somatostatin, specific autoradiographic grains associated with each radioactively labeled ligand were found on B, A, and D cells. The density of labeling of the B, A, and D cells with each labeled ligand correlated well with the known actions of the three hormones on each of the islet cells.

Animals↗
PubMed1982

Processing of synthetic somatostatin-28 and a related endogenous rat hypothalamic somatostatin-like molecule by hypothalamic enzymes.

Synthetic somatostatin-28 (S-28) as well as a related endogenous rat hypothalamic somatostatin-like compound (3K SLI) were incubated with hypothalamic extracts from which endogenous somatostatin-like immunoreactivity (SLI) had been removed by immunoabsorption. The reaction products were analyzed by gel chromatography, HPLC as well as two different radioimmunoassay for tetradecapeptide somatostatin (S-14) in which S-28 crossreacted either 100% (RIA R149) or less than 0.001% (RIA S39). The results indicate that incubation of S-28 with SLI free hypothalamic extracts results in a rapid decrease of total immunoreactivity measured with RIA R149 (t 1/2 = 14 min). By contrast, with RIA S39 a rise from zero to a peak value at 8 min was measured suggesting the formation of S-14. This was confirmed by subsequent analysis by gel chromatography and HPLC. Using endogenous 3K SLI a decrease of total R149-immunoreactivity with a similar time course (t 1/2 = 17 min) was observed simultaneously with the emergence of material that corresponded to S-14. This converting activity seems to be specific for SLI-containing tissues since similar rates of conversion were observed with extracts from cerebral cortex and cerebellum but not with lung and liver extracts. It is concluded that (1) S-28 is converted to S-14 by hypothalamic enzymes; (2) the processing of 3K SLI is similar, suggesting the two molecules are closely related, if not identical, and (3) the regulation of S-28 to S-14 conversion could represent an important mechanism for controlling the functional activity of somatostatinergic cells.

Animals↗
PubMed1982

Biosynthesis of immunoreactive somatostatin by hypothalamic neurons in culture.

The neuronal biosynthesis of somatostatin-like immunoreactivity (SLI) was investigated using mechanically dispersed neonatal rat hypothalamic cells kept in culture for up to 6 wk. Immunohistochemically, SLI was specifically localized to a small subpopulation of parvicellular neurons and their cell processes. By radioimmunoassay the cellular SLI content declined steadily during the first 2 wk in culture (nadir value of 60 fmol/dish at day 15) but then increased progressively to reach a maximum value of 381 fmol/dish at day 46. Gel chromatographic analysis showed this immunoreactivity to consist of forms corresponding to tetradecapeptide somatostatin (S-14), somatostatin-28 (S-28), and a 15,000-mol-wt molecule. After incubation of the cells with [3H]phenylalanine, the cellular extracts, purified by adsorption to C18 silica, contained material that bound specifically to an immobilized antisomatostatin antibody. Analysis by gel chromatography and high performance liquid chromatography of the specifically bound label provided evidence for the presence of labeled S-14, S-28, and the 15,000-mol-wt molecule. Pulse-chase experiments (20-min pulse, 20-min chase) demonstrated a transfer of radioactivity from the 15,000-mol-wt form to material corresponding to S-14 as well as to S-28. These studies demonstrate that cultured hypothalamic neurons are capable of synthesizing three somatostatin-like peptides (15,000-mol-wt SLI, S-28, S-14), one of which (15,000-mol-wt SLI) serve as a biosynthetic precursor for both S-28 and S-14. This in vitro system should provide a powerful tool for further investigation of the biosynthesis and regulation of biosynthesis of somatostatin in the hypothalamus.

Animals↗
PubMed1982

Characterization of pituitary membrane receptors for somatostatin in the rat.

We have demonstrated the presence of specific receptors for somatostatin (SRIF) in normal rat pituitary membranes using ([125I]Tyr11]SRIF) as the radioligand. These receptors bind SRIF with high affinity (Ka approximately 0.47 X 10(10) M-1) and have a maximal binding capacity of 0.095 pmol/mg membrane protein. Two other radioiodinated SRIF analogs which contain N-terminally situated radiolabel, [125I-Tyr1]SRIF and [125I-N-Tyr] SRIF, were found unsuitable for receptor binding studies due to loss of the radiolabel from the ligand molecule under the experimental conditions employed. Binding of [125I]Tyr11]SRIF to these receptors was specific and was not influenced by a variety of other neuropeptides. The specificity of SRIF receptors was also examined using 10 synthetic SRIF analogs as well as catfish somatostatin I. Catfish somatostatin I was 8.3 times less potent than SRIF in binding to SRIF receptors, although it has been reported to be equipotent in terms of in vitro GH inhibition. Analogs which exhibit greater potency for GH inhibition in vitro bound to these receptors with greater affinities than SRIF, whereas biologically inactive analogs showed markedly reduced binding, suggesting that the in vitro GH inhibitory actions of SRIF analogs are related to their ability to interact with SRIF receptors.

Animals↗
PubMed1982

Fentanyl infusion anesthesia for aortocoronary bypass surgery: plasma levels and hemodynamic response.

Plasma fentanyl concentrations were measured by radioimmunoassay in patients during aortocoronary bypass surgery and correlated with hemodynamic responses to surgical stimulation. Thirty patients scheduled for aortocoronary bypass surgery were divided into three groups of 10. Patients in group 1 received fentanyl, 30 micrograms/kg, as a loading dose followed by an infusion of 0.3 microgram/kg/min; those in group 2 received 40 micrograms/kg as a loading dose followed by an infusion of 0.4 microgram/kg/min; and those in group 3 received 50 micrograms/kg as the loading dose followed by an infusion of 0.5 microgram/kg/min. The total dose of fentanyl administered to each group up to the time of rewarming on cardiopulmonary bypass was 60 micrograms/kg, 90 micrograms/kg, respectively. Each of the dose regimens produced stable plasma concentrations starting approximately 20 minutes after induction and continuing until the infusion was discontinued. Patients in group 1 had a mean plasma concentration of 10 to 12 ng/ml in the stable period compared with 12 to 14 ng/ml in group 2 and 15 to 18 ng/ml in group 3. Fewer patients in group 3 responded to intubation and surgical stimulation than in the other groups, although the differences between groups were not statistically significant. Response to stimulation was treated by the administration of droperidol or volatile anesthetic agents. At a plasma concentration of 15 ng/ml, 50% of patients had an increase in systolic blood pressure which required treatment. This minimal intra-arterial concentration, analogous to MAC, can be achieved by the administration of fentanyl as a loading dose of 50 micrograms/kg followed by an infusion of 0.5 microgram/kg/min.

Anesthesia, Intravenous↗
PubMed1981

Somatostatin receptors: identification and characterization in rat brain membranes.

We have identified and characterized specific receptors for tetradecapeptide somatostatin (SRIF; somatotropin release-inhibiting factor) in rat brain using [125I]Tyr11]SRIF as the radioligand. These receptors are present in membranes obtained from a subfraction of synaptosomes. Membranes derived from cerebral cortex bind SRIF with high affinity (Ka = 1.25 X 10(10) M-1) and have a maximum binding capacity (Bmax) of 0.155 X 10(-12) mol/mg. Neither opiates nor other neuropeptides appear to influence the binding of SRIF to brain membranes. Synthetic analogs with greater biological potency than SRIF--[D-Trp8]SRIF, [D-Cys14]SRIF, and [D-Trp8, D-Cys14]SRIF--bind to the receptors with greater avidity than SRIF, whereas inactive analogs [(2H)Ala3]SRIF and [Ala6]SRIF exhibit low binding. The ratio of receptor density to endogenous somatostatin is high in the cortex, thalamus, and striatum, low in the hypothalamus, and extremely low in the brain stem and cerebellum. Thus, SRIF receptors in the brain appear to be a distinct, new class of receptors with a regional distribution different from that of endogenous somatostatin.

Animals↗