Biomedical subjects

A Shulkes

Publications and source records attributed to A Shulkes.

At least 91 records · Page 5Linked to original sources

PubMed1988

The cardiovascular effects of human calcitonin gene-related peptide in conscious sheep.

Calcitonin gene-related peptide (CGRP) is localized in nerve fibres in close association with the vasculature. The in vivo effect of human CGRP upon the cardiovascular system was investigated by intravenous infusion of CGRP into seven conscious sheep at doses of 1.5 and 10-pmol/kg per min for 75 min. CGRP at the 5- and 10-pmol/kg per min infusions decreased mean arterial pressure (maximal decrease of 10 mmHg) and stroke volume (maximal decrease of 42 ml/min), and increased heart rate by 60 beats/min. No changes in cardiac output were observed and total peripheral resistance only fell with the 5-pmol/kg per min infusion. Increases in both plasma arginine vasopressin and plasma renin concentration and a decrease in total and ionized plasma calcium were also observed. CGRP appears to be a potent vasodilator acting upon both arterioles and capacitance vessels in vivo.

Animals↗

PubMed1988

Altered levels of neuropeptides in the medulla and spinal cord of spontaneously hypertensive rats.

1. Spontaneously hypertensive rats (SHR) are useful for investigating the possible pathophysiological and neurochemical basis of human essential hypertension. 2. The accepted pathogenic mechanism of hypertension in SHR is an increased central sympathetic drive which results in an increased peripheral resistance. 3. The neurochemical basis of the increased sympathetic drive is unknown. The observation that there are reduced levels of neuropeptides (vasoactive intestinal peptide, neuropeptide Y, cholecystokinin octapeptide, neurotensin and calcitonin gene related peptide) in the spinal cord in SHR rats compared with age and gender matched Wistar-Kyoto normotensive rats could provide a basis for understanding the mechanism of hypertension in SHR.

Animals↗

PubMed1988

Effects of the vagus nerves on gastric motility and release of vasoactive intestinal polypeptide in the anaesthetized lamb.

1. Effects of the vagus nerves on the activity of the reticulo-omasal orifice (ROO) and the abomasum and the concentration of vasoactive intestinal polypeptide (VIP) in gastric and intestinal venous effluent were studied in anaesthetized lambs. 2. Both excitatory and inhibitory effects of the vagus on the ROO and abomasum were demonstrated. Excitation of activity of the ROO was dominant with stimulation at lower frequencies (less than or equal to 20 Hz) whereas higher frequencies (50-70 Hz) caused inhibition. 3. Inhibition but not stimulation of the ROO and abomasum were obtained with vagal stimulation after administration of atropine (200-500 micrograms kg-1 I.V.). 4. The concentration of VIP in gastric venous effluent blood rose by 41 +/- 10 pmol l-1 (n = 13) within 90 s of the start of stimulation (10 Hz, 5 ms pulse duration, 10 V for 180 s) of a vagus nerve and fell within 60 s of its cessation to or near basal levels. The effects of vagal stimulation in changing the concentration of VIP were not altered by administration of atropine. 5. The concentration of VIP in the intestinal venous effluent increased during stimulation (10 Hz, 5 ms pulse duration, 10 V, for 180 s) of a vagus nerve by 15 +/- 5 pmol l-1 (n = 11) and remained elevated for more than 10 min after the stimulus had ceased. 6. The changes in gastric motility and in concentration of VIP in gastric and intestinal venous blood with stimulation of the vagus nerves have been discussed in relation to similar alterations which occur in lambs during sucking of milk.

Anesthesia, Intravenous↗

PubMed1988

The effects of vasoactive intestinal polypeptide on gastric motility in the lamb.

1. Intra-arterial infusions of vasoactive intestinal polypeptide (VIP) were made in anaesthetized lambs in which activity of the reticulo-omasal orifice (ROO) was recorded manometrically and in conscious lambs in which activity of the reticulum, ROO and abomasum were recorded by electromyographic (EMG) techniques. 2. Spontaneous rhythmic opening and closing movements of the ROO occurred in anaesthetized lambs at 3-5 min-1. Infusions of VIP into the left gastric artery at rates of 0.5-3.0 nmol min-1 produced changes in activity of the ROO. Within 120 s of commencement of the infusions there was an increase in frequency and magnitude of the movements of the ROO for up to 120 s. This was followed with infusion of VIP at the lower levels (0.5-1.0 nmol min-1), by a marked reduction and sometimes complete loss of the rhythmic movements. There was always complete cessation of activity of the ROO with infusion of VIP at 1.5-3.0 nmol min-1. 3. In conscious lambs the frequency of the diphasic reticular EMG bursts which recur at intervals of ca. 1 min was not affected by infusions of VIP at 3.0 nmol min-1 for 10 min. 4. Between each diphasic reticular EMG burst in the conscious lamb there was normally phasic activity of the ROO consisting of EMG bursts of long (ca. 4 s) and short (ca. 1 s) duration. Within 90 s of commencement of infusion of VIP at 3.0 nmol min-1 short-burst EMG activity disappeared with the remaining long bursts being of greater duration (5.4 +/- 1.2 s) than before infusion. After a series of four to fifteen such more prolonged long bursts there was quiescence of the EMG of the ROO. After infusion of VIP EMG activity recommenced first as a series of eight to fourteen long bursts which was followed by the reappearance also of short-burst activity. Infusions of VIP at 8-10 nmol min-1 produced a more prompt cessation of EMG activity of the ROO. Of other peptides which were infused only PHI (a peptide with N-terminal histidine and C-terminal isoleucine amide) produced cessation of the EMG activity of the ROO. However, on a molar basis VIP was 2-3 times more potent than PHI in causing cessation of activity of the ROO. 5. Infusion of VIP at 3.0 nmol min-1 produced a cessation or diminution of EMG activity of the body, antrum and pylorus of the abomasum.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1988

Effect of 'weekend therapy' with omeprazole on basal and stimulated acid secretion and fasting plasma gastrin in duodenal ulcer patients.

The effect of intermittent dosage with omeprazole on basal and pentagastrin stimulated gastric acid secretion and fasting plasma gastrin was assessed in eight duodenal ulcer subjects who were in remission. Omeprazole (20 mg daily) was given for a three day 'weekend' each week for two months. Twenty four hours after the first and eighth weekend, basal and peak acid output were still markedly suppressed (greater than 50%) compared with pretreatment. After the treatment free four days, however (just before the eighth weekend), peak acid output had returned to pretreatment values; basal acid output was still somewhat reduced (mean 3.6 mmol/l) but the difference from baseline was not statistically significant. Fasting plasma gastrin concentration increased slightly but significantly, from a baseline median of 17 pmol/l to 25 and 31 pmol/l respectively, 24 hours after the first and eighth weekends. All but two values (of 16) remained within the reference range. Before the fourth and eighth weekends, and again at 12 days and three months after treatment, gastrin values were not significantly different from baseline. Thus a 'weekend therapy' regimen with this long acting antisecretory compound produces substantial acid suppression, but for only part of the week, with modest and reversible changes in fasting plasma gastrin. It should therefore be suitable for efficacy testing for prevention of recurrence of peptic ulcer or reflux oesophagitis.

Adult↗

PubMed1988

Effect of vaso-active intestinal polypeptide on systemic and splanchnic haemodynamics: role in vasodilation following mesenteric ischaemia.

Vaso-active intestinal polypeptide (VIP) and the related peptide, peptide histidine isoleucine, were infused intravenously in anaesthetized sheep. The VIP doses were designed to reproduce plasma concentrations seen after mesenteric ischaemia. The vasodilator action of VIP varied between different segments of the circulation and these differences in sensitivity were observed for both the degree and duration of the vaso-active action. A sustained vasodilation was detected in the coeliac artery and portal vein vascular beds during a 30-min VIP infusion. VIP is likely to be a contributory factor involved in the development of circulatory collapse during reperfusion after experimental mesenteric ischaemia.

Animals↗

PubMed1988

Pharmacokinetics and organ-specific metabolism of calcitonin gene-related peptide in sheep.

Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism. The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain. The metabolic clearance rate at steady state was 22.6 +/- 2.1 (S.E.M.) and 15.0 +/- 17 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3.6 +/- 0.3 min for the first phase and 13.6 +/- 1.0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1-37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial-renal vein gradient of 14%, and the liver, with a portal-hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Role of vagal hyperactivity in gastric stress ulceration after acute injury to the cervical cord.

The role of vagal hyperactivity in the pathogenesis of gastric stress ulceration that occurs after acute trauma to the cervical cord is controversial. We have used a rat model of transection of the cervical cord to induce gastric stress ulceration and to examine the cause of the ulcers. Cervical cord transection did not increase gastric acid output or plasma levels of gastrin or pancreatic polypeptide, either immediately or up to eight hours later. However, gastric stress ulceration showed a time-related increase in ulceration. Vagal stimulation with 2-deoxy-glucose enhanced the gastric acid output in rats with cervical cord transection but failed to change the quantity or characteristics of the gastric ulceration. We conclude that there is no evidence to support the vagal hyperactivity hypothesis in the pathogenesis of gastric stress ulceration after acute cervical cord injury.

Acute Disease↗

PubMed1987

Strain differences in central nervous system neurotensin content between normotensive and spontaneously hypertensive rats.

Regional brain concentrations of neurotensin (NT) were measured in age-matched normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The relative distribution of NT was similar in the two strains with the hypothalamus having the highest concentration (55-75 pmol/g) and the cerebellum the lowest (3-6 pmol/g). In comparison to the WKY rats, the SH rats had significantly lower NT levels in the hypothalamus (-17%), medulla oblongata-pons (-18%), pituitary (-52%) and spinal cord (-44%). In view of the putative role of NT as a neurotransmitter and its cardiovascular effects following central and peripheral administration, the reduced levels of this peptide may be of importance in the higher blood pressure of the SH rat.

Animals↗

PubMed1987

Effect of omeprazole on acute gastric stress ulceration in cervical cord transected rats.

Patients with acute paraplegia from trauma have an increased frequency of developing gastric stress ulceration and subsequent hemorrhage. Current treatment of gastric stress ulcer is by antacids or H2 antagonists, but despite such therapy stress ulceration still occurs, probably because these agents are unable to maintain gastric pH above 4. Omeprazole, which blocks the terminal step of acid secretion--the proton pump, can produce long-lasting achlorhydria. This study examined the efficacy of omeprazole in preventing stress ulcer in rats with acute cervical cord transection. Omeprazole was administered intraduodenally at 1.725, 2.625, 3.5, and 17.5 mg/kg, and the ulcer incidence and gastric acid output were measured. Omeprazole produced a dose-dependent inhibition of gastric acid output in the cervical cord transected rat. At the highest dose, complete achlorhydria was achieved. The quantity of gastric ulceration was inversely proportional to the omeprazole dosage with nearly complete prevention of ulceration at the highest dose. In conclusion, omeprazole is very effective in preventing gastric stress ulcers in the spinal cord transected rat. This appears to be related to its potent long-lasting inhibitory effect on gastric acidity.

Achlorhydria↗

PubMed1987

Fetal metabolism and placental transfer of vasoactive intestinal peptide in sheep.

Vasoactive Intestinal Peptide (VIP) is a 28-amino-acid putative neurotransmitter that may have a role in the regulation of myometrial blood flow and uterine contractility. The chronically cannulated fetal sheep preparation was used to examine the fetal clearance and placental transfer of VIP. Metabolic Clearance Rate (MCR) and placental transfer of VIP were measured by alternate steady-state infusion of VIP into the mother and fetus. Plasma concentrations of VIP were measured by radioimmunoassay. MCR was similar in the pregnant (45 +/- 10 ml/kg/min) and nonpregnant ewes (35 +/- 5 ml/kg/min). However, compared to both pregnant and nonpregnant ewes, fetal MCR was significantly increased at 77 +/- 15 ml/kg/min, indicating highly developed clearance mechanisms in the fetus. VIP did not cross the placenta in either direction. Both the placenta and fetal liver metabolized VIP and contributed to the elevated fetal clearance of VIP. The results show that VIP in fetal tissue is unlikely to influence maternal uterine activity with any VIP-mediated effects emanating from maternal and/or placental sources.

Animals↗

PubMed1987

Nature of the gastric acid-gastrin feedback loop in the fetal sheep.

1. The neonates of sheep and other species have a decreased gastric acid secretion but an elevated plasma gastrin concentration. 2. Since low gastric acid secretion is a stimulus for gastrin release in mature animals the present study examined whether the relative hypochlorhydria in the sheep fetus was sustaining the hypergastrinaemia. 3. Fetal plasma gastrin was measured following fetal gastric acidification (pentagastrin infusion) and gastric neutralization (parietal cell blockade with the proton pump inhibitor omeprazole) in chronically cannulated fetal sheep from 101 days until term (145 days). 4. Acutely raising gastric pH with omeprazole increased plasma gastrin in the mature sheep. However, in the fetus increasing the pH with omeprazole or decreasing pH with pentagastrin had no effect on fetal plasma gastrin. This was true for fetuses from all age groups. 5. The results indicate that the gastric acid-gastrin feedback loop is not functional in the fetus and that the hypergastrinaemia at birth is therefore not the result of the relative hypochlorhydria. 6. The time after birth when the gastric acid-gastrin feedback loop matures remains to be determined.

Animals↗

PubMed1987

Extraction of neurotensin by the liver.

1. Neurotensin is released from the intestine into the portal circulation and to exert a systemic effect it must traverse the liver intact. 2. The role of the liver in neurotensin clearance was examined using the isolated perfused rat liver preparation. Two concentrations of neurotensin were used to determine the extraction capacity of the liver. 3. Approximately 10% of the added neurotensin (with either dose) was extracted in a single pass through the liver. This extraction rate was low when compared to previous studies with cholecystokinin (60% extraction in a single pass) and vasoactive intestinal peptide (100%). 4. It is concluded that there is a small but high capacity for direct extraction of neurotensin. This low direct extraction percentage supports our previous contention that the major influence of the liver on the metabolism of neurotensin is by the release of neurotensin degrading peptidases into the circulation.

Animals↗

PubMed1987

The vagus and neurotensin release in duodenal ulcer--clinical and experimental studies.

Although meal-stimulated neurotensin release from the small intestine is inhibited by cholinergic blockade, it is uncertain whether this cholinergic mechanism involves the vagus. This study examines the role of the vagus in neurotensin release by first determining the effect of vagotomy on meal-stimulated plasma neurotensin in man and second, the effect on plasma neurotensin of electrical stimulation of the vagus in sheep. Six volunteers were studied 6-8 weeks after truncal vagotomy and pyloroplasty. Basal plasma neurotensin at 32(15-67) pmol/l (median, range) was greater than in normal controls at 17 (9-52) pmol/l (P less than 0.05). Following a standard meal, plasma neurotensin rose significantly (P less than 0.05), but similarly in both post-vagotomy and control groups to maxima of 74 (43-76) pmol/l and 52 (35-65) pmol/l, respectively. Basal plasma neurotensin in the six sheep was below the detection limit of the assay and remained undetectable during electrical stimulation of the vagus. Significant rises in plasma pancreatic polypeptide and gastrin confirmed the efficacy of the electrical stimulation. It is concluded that although the vagus might have a tonic inhibitory effect on basal plasma neurotensin, meal-stimulated neurotensin release is vagally independent. The inhibitory cholinergic influence on meal-stimulated release is most likely therefore to be mediated by cholinergic nerves of the enteric nervous system.

Adolescent↗

PubMed1987

Hepatic metabolism of neurotensin.

Neurotensin is released from the intestinal mucosa into the portal circulation and, to exert a systemic effect, it must traverse the liver intact. We examined the potential role of the liver in neurotensin clearance using the isolated perfused rat liver model. With N-terminal and C-terminal directed RIAs and HPLC, we demonstrated rapid metabolism of intact neurotensin to inactive N-terminal fragments in the isolated rat liver system. The disappearance half-lives of C-terminal and N-terminal immunoreactivity were 20.4 +/- 6.0 min and 82.7 +/- 7.7 min, respectively, (P less than 0.002). To assess whether this neurotensin disappearance might be due to metabolism within the perfusate itself by a peptidase released from liver, we further incubated neurotensin in perfusate previously circulated through liver. A rapid and progressive breakdown of intact neurotensin to N-terminal fragments was again shown. These data demonstrate that a substantial proportion of the hepatic clearance of neurotensin is attributable to release of a peptidase by the liver into the circulation.

Animals↗

PubMed1987

Regional brain concentrations of several putative peptide neurotransmitters in normotensive and spontaneously hypertensive rats: effects of continuous (10-day) clonidine infusion.

In the present study, the mean arterial pressures (MAP) and heart rates (HR) were measured in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that had received a 10-day continuous subcutaneous infusion of either saline or the centrally acting alpha-adrenoceptor agonist clonidine (10 micrograms/kg/h). In separate groups of similarly treated rats, the concentrations of neurotensin (NT), vasoactive intestinal polypeptide (VIP), cholecystokinin octapeptide (CCK-8), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were measured in the cortex (COR), hypothalamus (HYP), medulla oblongata/pons (MO/P), and cervical (CSC) and thoracic (TSC) spinal cord. In comparison to the WKY rats, the SHR had significantly lower neuropeptide concentrations within the COR (NPY, CCK-8), HYP (NT), MO/P (NPY, NT, and CCK-8), CSC (all neuropeptides), and TSC (NPY, NT, CCK-8, and VIP). The infusion of clonidine lowered the MAP of the WKY and SHR rats (-10 and -35 mm Hg, as compared with respective saline controls) and HR in the WKY rats (-45 beats/min). In general, the infusion of clonidine produced decreases in neuropeptide levels within the CNS of the WKY rather than the SHR strain. When there was a strain difference (i.e., SHR less than WKY), it was evident, particularly within the spinal cord, that clonidine reduced the levels of the neuropeptides in the WKY rats to those levels in the SHR. These findings suggest that the reduced neuropeptide concentrations of the SHR (particularly those within the CSC) and TSC may be a result of, rather than a causal factor in, hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Regional brain concentrations of vasoactive intestinal polypeptide in normotensive Wistar-Kyoto and spontaneously hypertensive rats.

The regional brain and spinal cord concentrations of vasoactive intestinal polypeptide immunoreactivity (VIP) were measured in age-matched normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats. The relative order of distribution of VIP in the WKY strain was cortex (44 pmol/g) greater than hippocampus = striatum greater than midbrain = hypothalamus greater than medulla oblongata/pons = lumbar spinal cord (SC) greater than cervical SC greater than thoracic SC (2.5 pmol/g) whereas in the SH strain this order was cortex (35 pmol/g) greater than striatum = midbrain greater than hippocampus = hypothalamus greater than medulla oblongata/pons = lumbar SC greater than cervical SC greater than thoracic SC (1 pmol/g). The VIP concentrations of the thalamus, cerebellum and pituitary were at the level of assay sensitivity (0.5 pmol/g) in both strains. In comparison to the WKY, the SH rats had significantly lower VIP levels in the hippocampus (-42%) and cervical (-46%) and thoracic (-56%) spinal cord but significantly higher levels in the midbrain (+64%).

Animals↗

PubMed1986

Basal and stimulated release of calcitonin gene-related peptide (CGRP) in patients with medullary thyroid carcinoma.

Calcitonin gene-related peptide (CGRP) is a recently discovered peptide whose existence was first predicted following sequence analysis of the rat calcitonin gene. In the present study, plasma levels of CGRP were measured in patients with medullary thyroid carcinoma, both basally and following calcium or pentagastrin stimulation. Using a sensitive radioimmunoassay for CGRP, 19 of 21 patients with medullary thyroid carcinoma had elevated plasma levels of immunoreactive CGRP (median value 114 pmol/l) while 23 normal subjects had plasma CGRP levels below the detection limit of the assay (less than 10 pmol/l). Calcium or pentagastrin infusion in medullary thyroid carcinoma patients were potent stimuli to CGRP release, increasing plasma levels two- to five-fold. Chromatographic characterization using high pressure liquid chromatography of the CGRP immunoreactivity in plasma from two patients with medullary carcinoma of the thyroid demonstrated the presence of two molecular forms, neither of which co-eluted with synthetic human CGRP. The role of CGRP in the pathophysiology of medullary thyroid carcinoma is not clear but it may contribute to some of the clinical features associated with the disease. Furthermore, measurement of CGRP in conjunction with calcitonin could help in determining the prognosis of these patients.

Calcitonin↗