Jugular Venous Plasma Research Articles

Effects of guanidino acetic acid and betaine supplementation on growth, dietary nutrient digestion and intestinal creatine metabolism in sheep.

The intestine of young ruminants is in the developmental stage and has weaker resistance to the changes of external environment. Improving intestinal health is vital to promoting growth of young ruminants. This study investigated effects of guanidino acetic acid (GAA) and rumen-protected betaine (RPB) supplementation on growth, dietary nutrient digestion and GAA metabolism in the small intestine of sheep. Eighteen healthy Kazakh rams (27.46±0.10kg of body weight and 3-month old) were categorized into control, test group I and test group II, which were fed a basal diet, 1500mg/kg GAA and 1500mg/kg GAA+600mg/kg RPB, respectively. Compared with control group, test group II had increased (p<0.05) average daily gain, plasma creatine level, ether extract (EE) and phosphorus digestibility on day 30. On day 60, the EE apparent digestibility, jugular venous plasma GAA, GAA content in the duodenal mucosa and GAA content in the jejunal and ileal mucosa of test group II were higher (p<0.05) than other groups. Transcriptome analysis revealed that the differentially expressed genes (DEGs) involved in the duodenal pathways of oxidative phosphorylation and non-alcoholic fatty liver disease were significantly altered in test group II versus test group I (p<0.05). Moreover, in the jejunum, the MAPK signalling pathway, complement and coagulation cascade and B-cell receptor signalling pathway were significantly enriched, with ATPase, solute carrier transporter protein, DHFR, SI, GCK, ACACA and FASN being the significantly DEGs (p<0.05). Dietary supplementation of RPB on top of GAA in sheep diets may promote sheep growth and development by improving the body's energy, amino acid, glucose and lipid metabolism capacity.

Lung-protective ventilation increases cerebral metabolism and non-inflammatory brain injury in porcine experimental sepsis

BackgroundProtective ventilation with lower tidal volumes reduces systemic and organ-specific inflammation. In sepsis-induced encephalopathy or acute brain injury the use of protective ventilation has not been widely investigated (experimentally or clinically). We hypothesized that protective ventilation would attenuate cerebral inflammation in a porcine endotoxemic sepsis model. The aim of the study was to study the effect of tidal volume on cerebral inflammatory response, cerebral metabolism and brain injury. Nine animals received protective mechanical ventilation with a tidal volume of 6 mL × kg−1 and nine animals were ventilated with a tidal volume of 10 mL × kg−1. During a 6-h experiment, the pigs received an endotoxin intravenous infusion of 0.25 µg × kg−1 × h−1. Systemic, superior sagittal sinus and jugular vein blood samples were analysed for inflammatory cytokines and S100B. Intracranial pressure, brain tissue oxygenation and brain microdialysis were sampled every hour.ResultsNo differences in systemic or sagittal sinus levels of TNF-α or IL-6 were seen between the groups. The low tidal volume group had increased cerebral blood flow (p < 0.001) and cerebral oxygen delivery (p < 0.001), lower cerebral vascular resistance (p < 0.05), higher cerebral metabolic rate (p < 0.05) along with higher cerebral glucose consumption (p < 0.05) and lactate production (p < 0.05). Moreover, low tidal volume ventilation increased the levels of glutamate (p < 0.01), glycerol (p < 0.05) and showed a trend towards higher lactate to pyruvate ratio (p = 0.08) in cerebral microdialysate as well as higher levels of S-100B (p < 0.05) in jugular venous plasma compared with medium–high tidal volume ventilation.ConclusionsContrary to the hypothesis, protective ventilation did not affect inflammatory cytokines. The low tidal volume group had increased cerebral blood flow, cerebral oxygen delivery and cerebral metabolism together with increased levels of markers of brain injury compared with medium–high tidal volume ventilation.

Stimulation of rat cranial dura mater with potassium chloride causes CGRP release into the cerebrospinal fluid and increases medullary blood flow

Primary headaches may be accompanied by increased intracranial blood flow induced by the release of the potent vasodilator calcitonin gene-related peptide (CGRP) from activated meningeal afferents. We aimed to record meningeal and medullary blood flow simultaneously and to localize the sites of CGRP release in rodent preparations in vivo and ex vivo.Blood flow in the exposed rat parietal dura mater and the medulla oblongata was recorded by laser Doppler flowmetry, while the dura was stimulated by topical application of 60mM potassium chloride (KCl). Samples of jugular venous plasma and cerebrospinal fluid (CSF) collected from the cisterna magna were analysed for CGRP concentrations using an enzyme immunoassay. In a hemisected rat skull preparation lined with dura mater the CGRP releasing effect of KCl superfusion was examined.Superfusion of the dura mater with KCl decreased meningeal blood flow unless alpha-adrenoceptors were blocked by phentolamine, whereas the medullary blood flow was increased. The same treatment caused increased CGRP concentrations in jugular plasma and CSF and induced significant CGRP release in the hemisected rat skull preparation. Anaesthesia of the trigeminal ganglion by injection of lidocaine reduced increases in medullary blood flow and CGRP concentration in the CSF upon meningeal KCl application.CGRP release evoked by depolarisation of meningeal afferents is accompanied by increased blood flow in the medulla oblongata but not the dura mater. This discrepancy can be explained by the smooth muscle depolarising effect of KCl and the activation of sympathetic vasoconstrictor mechanisms. The medullary blood flow response is most likely mediated by CGRP released from activated central terminals of trigeminal afferents. Increased blood supply of the medulla oblongata and CGRP release into the CSF may also occur in headaches accompanying vigorous activation of meningeal afferents.

RAAS and stress markers in acute ischemic stroke: preliminary findings.

Angiotensin II type 1 receptor blockade has neuroprotective effects in animal stroke models, but no effects in clinical stroke trials. We evaluated cerebral and peripheral changes in the renin angiotensin aldosterone system (RAAS) and stress responses in acute ischemic stroke patients. Blood from a jugular and cubital vein was collected within 48 h of stroke onset, after 24 and 48 h, and renin, angiotensin I, angiotensin II, aldosterone, norepinephrine, epinephrine, and cortisol were measured. Post-stroke cubital vein samples were collected after 8 (4.7-10) months. The acute systolic blood pressure was significantly increased, 148 (141-168) vs 140 (130-147) mmHg post-stroke. Angiotensin I, renin and aldosterone levels were significantly lower, angiotensin II was unchanged, and ACE activity was higher in the acute phase compared to post-stroke. No differences in RAAS were detected between jugular and cubital plasma levels. Jugular venous plasma levels of epinephrine and cortisol were elevated in the acute phase compared to cubital levels (P < 0.05). Increased epinephrine and cortisol levels in the jugular vein blood may reflect a higher peripheral turnover. The observed changes in RAAS in the acute stroke phase are consistent with responses to increased blood pressure.

Jugular venous reflux and plasma endothelin-1 are associated with cough syncope: a case control pilot study

BackgroundJugular venous reflux (JVR) has been reported to cause cough syncope via retrograde-transmitted venous hypertension and consequently decreased cerebral blood flow (CBF). Unmatched frequencies of JVR and cough syncope led us to postulate that there should be additional factors combined with JVR to exaggerate CBF decrement during cough, leading to syncope. The present pilot study tested the hypothesis that JVR, in addition to an increased level of plasma endothelin-1 (ET-1), a potent vasoconstrictor, is involved in the pathophysiology of cough syncope.MethodsSeventeen patients with cough syncope or pre-syncope (Mean[SD] = 74.63(12.37) years; 15 males) and 51 age/gender-matched controls received color-coded duplex ultrasonography for JVR determination and plasma ET-1 level measurements.ResultsMultivariate logistic analysis showed that the presence of both-side JVR (odds ratio [OR] = 10.77, 95% confident interval [CI] = 2.40-48.35, p = 0.0019) and plasma ET-1 > 3.43 pg/ml (OR = 14.57, 95% CI = 2.95-71.59, p = 0.001) were independently associated with the presence of cough syncope/ pre-syncope respectively. There was less incidence of cough syncope/ pre-syncope in subjects with the absence of both-side JVR and a plasma ET-1 ≦3.43 pg/ml. Presence of both side JVR and plasma ET-1 level of > 3.43 pg/ml, increased risk for cough syncope/pre-syncope (p < 0.001).ConclusionsJVR and higher plasma levels of ET-1 are associated with cough syncope/ pre-syncope. Although sample size of this study was small, we showed a synergistic effect between JVR and plasma ET-1 levels on the occurrence of cough syncope/pre-syncope. Future studies should confirm our pilot findings.

CGRP and NO in the Trigeminal System: Mechanisms and Role in Headache Generation

Calcitonin gene-related peptide (CGRP) and metabolic products of nitric oxide (NO) are increased in jugular venous plasma during migraine attacks and other primary headaches. Patients suffering from primary headaches are particularly sensitive to CGRP and NO donors responding with delayed headaches to an infusion of either of these substances. Accordingly, both CGRP and NO are considered as key mediators in migraine, and clinical trials have shown that inhibitors of CGRP receptors and NO synthase are effective in treating migraine. There is an implicit understanding that CGRP and NO systems interact, and here, we review the body of preclinical work on these systems focusing on the trigeminovascular system in migraine. NO derives from various cell types via 3 isoforms of NO synthase, whereas CGRP is produced from a subset of trigeminal afferents. In rodents, NO donors cause activity alterations on different levels of the trigeminal system including enhancement of CGRP release, which in turn results in arterial vasodilatation and possibly mast cell degranulation in the meninges. The activity of spinal trigeminal neurons, which is a sensitive integrative measure for trigeminal activity, is partly under the control of CGRP and NO. Both mediators facilitate nociceptive transmission, possibly via presynaptic mechanisms. These functions are supported by immunolocalization of CGRP receptor components on 3 trigeminovascular levels: cranial dura mater, trigeminal ganglion, and spinal trigeminal nucleus. Current data support a relationship of CGRP and NO actions on all levels of the trigeminovascular system and emphasize central CGRP receptors as possible therapeutic targets.

Brain and skin do not contribute to the systemic rise in erythropoietin during acute hypoxia in humans

Erythropoietin (EPO) preserves arterial oxygen content by controlling red blood cell and plasma volumes. Synthesis of EPO was long thought to relate inversely to renal oxygenation, but in knockout mice, brain and skin have been identified as essential for the acute hypoxic EPO response. Whether these findings apply to humans remains unknown. We exposed healthy young subjects to hypoxia (equivalent to 3800 m) and measured EPO in arterial and jugular venous plasma and in cerebrospinal fluid. To examine the role of the skin for EPO production during hypoxia, subjects were exposed to 8 h of hypobaric hypoxia with or without breathing oxygen-enriched air to ensure systemic normoxemia. With 9 h of hypoxia, arterial EPO increased (from 6.0±2.2 to 22.0±6.0 mU/ml, n=11, P<0.0001) and jugular venous EPO displayed a similar response (to 22.2±6.0 mU/ml, n=11). Thus, the arterio-jugular venous EPO difference was unaffected by hypoxia and also in cerebrospinal fluid EPO remained stable following hypoxic exposure (0.33±0.15 mU/ml, n=9 in normoxia vs. 0.41±0.20 mU/ml, n=9 in hypoxia, P=0.40). No change in plasma EPO was observed when only skin was exposed to hypobaric hypoxia (n=8). Thus, neither dermal oxygen exposure nor cerebral EPO production appears to be important for the systemic EPO response to acute hypoxia in healthy humans.

Changes in plasma phenylalanine, isoleucine, leucine, and valine are associated with significant changes in intracranial pressure and jugular venous oxygen saturation in patients with severe traumatic brain injury

Changes in plasma aromatic amino acids (AAA=phenylalanine, tryptophan, tyrosine) and branched chain amino acids (BCAA=isoleucine, leucine, valine) levels possibly influencing intracranial pressure (ICP) and cerebral oxygen consumption (SjvO(2)) were investigated in 19 sedated patients up to 14days following severe traumatic brain injury (TBI). Compared to 44 healthy volunteers, jugular venous plasma BCAA were significantly decreased by 35% (p<0.001) while AAA were markedly increased in TBI patients by 19% (p<0.001). The BCAA to AAA ratio was significantly decreased by 55% (p<0.001) which persisted during the entire study period. Elevated plasma phenylalanine was associated with decreased ICP and increased SjvO(2), while higher plasma isoleucine and leucine levels were associated with increased ICP and higher plasma leucine and valine were linked to decreased SjvO(2). The amount of enterally administered amino acids was associated with significantly increased plasma levels with the exception of phenylalanine. Contrary to the initial assumption that elevated AAA and decreased BCAA levels are detrimental, increased plasma phenylalanine levels were associated with beneficial signs in terms of decreased ICP and reduced cerebral oxygen consumption reflected by increased SjvO(2); concomitantly, elevated plasma isoleucine and leucine levels were associated with increased ICP while leucine and valine were associated with decreased SjvO(2) following severe TBI, respectively. The impact of enteral nutrition on this observed pattern must be examined prospectively to determine if higher amounts of phenylalanine should be administered to promote beneficial effects on brain metabolism and if normalization of plasma BCAA levels is without cerebral side effects.

Plasma oestrogen changes in adult male cats after orchiectomy, body-weight gain and low-dosage oestradiol administration

The physiological relevance of oestradiol (E2) on post-orchiectomy (OX) food intake control was evaluated in six adult, male, domestic, short-hair cats. Jugular venous plasma E2 and oestrone (E1) concentrations were determined weekly before OX and immediately after OX in a cross-over trial of two 3-week periods in which E2 (0.5 μg) or vehicle (0.1 ml/kg) was subcutaneously injected daily and blood was sampled 4 h later. Plasma E1 and E2 concentrations before OX were 32 (SE 8.3) and 4.3 (SE 1.0) pg/ml, respectively. Following OX, plasma concentrations of E2 were decreased (P = 0.04) while those of E1 were unchanged. Injections of E2 increased (P = 0.02) plasma E2 towards pre-OX concentrations. In a second cross-over trial, plasma E1 and E2 were determined weekly during the last 3 weeks of two 8-week periods in which food was continuously presented or restricted to 110 % of pre-OX amounts. Continuous food presentation compared with restricted food presentation resulted in greater body weight (6.4 (SE 0.4) v. 5.4 (SE 0.4) kg, P = 0.02) and body fat percentage (29 (SE 3) v. 23 (SE 2) %, P = 0.09) but no significant changes were observed in plasma E1 and E2 concentrations. Hence, circulating E2 appears to be reduced by OX, while it is not significantly changed by body-fat gain. The amount of E2 injected after OX was not supraphysiological; it restored plasma E2 to pre-OX concentrations and reduced food intake in five of the six cats by a mean of 14 (SE 3) %.

Neuropeptide Effects in the Trigeminal System: Pathophysiology and Clinical Relevance in Migraine

The neuropeptides substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) have been considered as important mediators in migraine and other primary headaches. CGRP and VIP have been found at increased concentrations in jugular venous plasma during attacks of migraine or cluster headache, and CGRP receptor antagonists have recently been shown to be effective in migraine therapy. Substance P and CGRP are produced from a subset of trigeminal afferents, whereas VIP derives from parasympathetic efferents. Release of these neuropeptides in the meninges can cause arterial vasodilatation, mast cell degranulation and plasma extravasation in animal experiments, but only CGRP seems to be relevant in migraine. Animal models have confirmed the important role of CGRP in meningeal nociception. The activity of spinal trigeminal neurons is a sensitive integrative measure of trigeminal activity and is partly under the control of CGRP, most likely via central mechanisms. CGRP released from central terminals of trigeminal afferents in the spinal trigeminal nucleus seems to facilitate nociceptive transmission via presynaptic mechanisms. The central effect of CGRP is substantiated by suppression of nociceptive c-fos activation and neuronal activity in the spinal trigeminal nucleus following CGRP receptor inhibition. These proposed functions are supported by the localization of CGRP receptor components in the rat cranial dura mater, trigeminal ganglion and spinal trigeminal nucleus. The currently available data indicate multiple sites of CGRP action in trigeminal nociception and the pathogenesis of migraine; however, central CGRP receptors are likely to be the essential targets in the treatment of migraine using CGRP receptor antagonists.

Is endothelin-1 luteolytic or antiluteolytic in ewes?

Endothelin-1 (ET-1) has been reported to mediate prostaglandin (PG) F 2α (PGF 2α)-induced luteolysis. Prostaglandins E (PGE; PGE 1 + PGE 2) are associated with implantation, maternal recognition of pregnancy, and are antiluteolytic and luteotropic in vitro and in vivo. ET-1 increased PGE secretion by bovine luteal tissue in vitro from cows where estrus was not synchronized or when estrus was synchronized with lutalyse and did not affect luteal PGF 2α or progesterone secretion, which does not support the concept that ET-1 is luteolytic or mediates PGF 2α luteolysis. Therefore, the objective of this experiment was to determine whether ET-1 infused every 6 h from 2400 h on day 10–1800 h on day 18 of the ovine estrous cycle either into the interstitial tissue of the ovarian vascular pedicle (IP) or intrauterine (IU) adjacent to the luteal-containing ovary was luteolytic in ewes. Treatments were: Vehicle-IP; Vehicle-IU; ET-1-IP; or ET-1-IU. Weights of corpora lutea differed ( P ≤ 0.05) among treatment groups. Weights of corpora lutea at 1800 h on day 18 were: VEH-IP—247 ± 38 mg; VEH-IU—195 ± 31 mg; ET-1-IP—626 ± 74 mg; and ET-1-IU—542 ± 69 mg. Luteal weights on day 18 in ET-1-IP or ET-1-IU-treated ewes did not differ ( P ≥ 0.05), but were heavier ( P ≤ 0.05) than in the Vehicle-IP or Vehicle-IU treatment groups which did not differ ( P ≥ 0.05). Profiles of progesterone in jugular venous plasma of both control groups treated with Vehicle-IP or Vehicle-IU were lower ( P ≤ 0.05) than in ewes treated with ET-1-IP or ET-1-IU, which did not differ ( P ≥ 0.05) between ET-1-IP or ET-1-IU treatment groups. Treatment with ET-1-IP or ET-1-IU increased ( P ≤ 0.05) the PGE:PGF 2α ratio when compared to the Vehicle-IP or Vehicle-IU treatment groups, which did not differ ( P ≥ 0.05) between each other. In summary, ET-1 prevented the decrease in luteal weights and the decline in progesterone, but increased the PGE:PGF 2α ratio when compared to controls. Therefore, it is concluded that ET-1 is not luteolytic in ewes, but instead may be luteotropic or antiluteolytic by altering uterine secretion of the PGE:PGF 2α ratio, since PGE 1 or PGE 2 are luteotropic in vitro and in vivo, PGE 1 or PGE 2 prevent PGF 2α-induced luteolysis in vitro and in vivo, and PGE 1 and PGE 2 increase two-fold in ewe endometrium to prevent luteolysis during early pregnancy.

Influence of administration route on the biotransformation of amoxicillin in the pig

A comparison was made in the plasma concentration of the major metabolites of amoxicillin (AMO), i.e. amoxicilloic acid (AMA) and amoxicillin diketopiperazine-2',5'-dione (DIKETO) in portal and jugular venous plasma after oral (p.o.) and intravenous (i.v.) AMO administration to pigs, in order to study a possible presystemic degradation of AMO in the gastro-intestinal tract and liver. Almost identical plasma concentration-time curves were obtained for AMO and its metabolites in portal and jugular venous plasma, both after p.o. and i.v. AMO administration. Almost immediately after i.v. AMO administration, high AMA and DIKETO concentrations were measured in plasma, while after p.o. dosing, the metabolites appeared in plasma after almost complete absorption of AMO. No significant differences in pharmacokinetic parameters of AMO, AMA and DIKETO, derived from the concentration-time profiles in portal and jugular venous plasma were calculated, both after i.v. and p.o. AMO administration (P > 0.05). After p.o. administration, the half-life of elimination (t(1/2(el))) for AMA is at least two or three times the t(1/2(el)) of AMO (0.75 h for AMO vs. 2.69 h for AMA), indicating the slower clearance of the metabolite. It could be hypothesized that AMA is only eliminated by glomerular filtration, as its open beta-lactam structure might not be recognized by the transport carrier in the proximal tubule of the kidney. The results of the study indicate that AMO is not substantially metabolized presystemically in the gut and liver. Therefore, it may be assumed that the kidney may be the major organ for AMO biotransformation. Future in vivo and in vitro experiments should be performed to state this hypothesis.

Effect of luteinizing hormone (LH), pregnancy-specific protein B (PSPB), or arachidonic acid (AA) on secretion of progesterone and prostaglandins (PG) E (PGE; PGE 1 and PGE 2) and F 2α (PGF 2α) by ovine corpora lutea of the estrous cycle or pregnancy in vitro

LH regulates luteal progesterone secretion during the estrous cycle in ewes and cows [1]. However, PGE, not LH, stimulated ovine luteal progesterone secretion in vitro at day 90 of pregnancy [2] and at day 200 in cows [3–5]. The hypophysis is not obligatory after day 50 [6] nor the ovaries [7] after day 55 to maintain pregnancy in ewes. LH has been reported to regulate ovine placental PGE secretion up to day 50 of pregnancy and by pregnancy-specific protein B (PSPB) after day 50 of pregnancy [4,6,8]. The objective of this experiment was to determine if and when a switch from LH to PGE occurred as the luteotropin regulating luteal progesterone secretion during pregnancy in ewes. Ovine luteal tissue slices of the estrous cycle (days 8, 11, 13, and 15) or pregnancy (days 8, 11, 13, 15, 20, 30, 40, 50, 60, and 90) were incubated in vitro with vehicle, LH, AA (precursor to PGE 2 and PGF 2α synthesis; [9]), or PSPB in M199 for 4 h and 8 h. Concentrations of progesterone in jugular venous plasma of bred ewes increased ( P ≤ 0.05) after day 50 and continued to increase through day 90. Secretion of progesterone by luteal tissue of non-bred ewes on days 8, 11, 13 and 15 and by bred ewes on days 8, 11, 13, 15, 20, 30, 40, and 50 was increased ( P ≤ 0.05) by LH, but not by luteal tissue from pregnant ewes after day 50 ( P ≥ 0.05). LH-stimulated progesterone secretion by luteal tissue from day 15 bred ewes was greater ( P ≤ 0.05) than day 15 luteal tissue from non-bred ewes. Concentrations of progesterone in media were increased ( P ≤ 0.05) when luteal tissue from pregnant ewes on day 50, 60, or 90 were incubated with AA or PSPB. Concentrations of PGE in media of non-bred ewes on days 8, 11, 13, or 15 and bred ewes on days 8 and 11 did not differ ( P ≥ 0.05). Concentrations of PGE were increased ( P ≤ 0.05) in media by luteal slices from bred ewes on days 13, 15, 20, 30, 40, 50, 60, and 90 of vehicle, LH, AA or PSPB-treated ewes. In addition, PSPB increased ( P ≤ 0.05) PGE in media by luteal slices from pregnant ewes only on days 40, 50, 60, and 90. Concentrations of PGF 2α were increased in media ( P < 0.05) of vehicle, AA, LH, or PSPB-treated luteal tissue from non-bred ewes and bred ewes on day 15 and by luteal tissue from bred ewes on days 20 and 30 after which concentrations of PGF 2α in media declined ( P ≤ 0.05) and did not differ ( P ≥ 0.05) from non-bred or bred ewes on days 8, 11, or 13. It is concluded that LH regulates luteal progesterone secretion during the estrous cycle of non-bred ewes and up to day 50 of pregnancy, while only PGE regulates luteal progresterone secretion by ovine corpora lutea from days 50 to 90 of pregnancy. In addition, PSPB appears to regulate luteal secretion of progesterone from days 50 to 90 of pregnancy through stimulation of PGE secretion by ovine luteal tissue.

In Vivo Evidence that Local Cortisol Production Increases in the Preovulatory Follicle of the Cow

The aim of the present in vivo study was to monitor real-time fluctuations of cortisol (Cr) in the wall of preovulatory follicles using a microdialysis system (MDS) implanted in the theca layer as well as changes in ovarian venous plasma (OVP) and jugular venous plasma (JVP). Seven cows were superovulated using FSH and prostaglandin F2alpha injections. Dialysis capillary membranes were surgically implanted into the theca layer of mature follicles and connected to a microdialysis system. Fractions of the perfusates were collected from Day -1 (Day 0=LH surge) to Day 3. No difference in the concentrations of Cr between JVP and OVP was detected throughout the experiment. Circulating concentrations of Cr ranged from 20 to 35 ng/ml 8 h after surgery in ovulatory and anovulatory cows. In five ovulatory cows, the Cr concentration decreased to basal levels (<10 ng/ml) between 12 and 24 h after surgery, however, two anovulatory cows retained high Cr levels (>10 ng/ml) up to 42 h after surgery. There was a clear increase in the local concentration of Cr from 13.3+/-2.1 pg/ml at -24 h to 27.5+/-1.7 pg/ml at 0 h (peak of the LH surge) within the wall of ovulatory follicles. This increase was not detected in anovulatory follicles. This transient increase in Cr occurred only in the follicle wall, but not in the OVP or JVP, indicating that the presence of a local regulatory mechanism for Cr production/conversion in ovulatory follicles, and this mechanism may modulate the inflammatory-like reaction induced by LH surge in the follicle wall. The present results demonstrate that the glucocorticoid environment in the follicular wall adjusts at the local level in bovine ovulatory follicles. This mechanism may protect follicles from the adverse effects of glucocorticoid, and it may prevent excess inflammatory reactions associated with ovulation by temporarily increasing local concentrations of glucocorticoid, thus forming an integral part of the regulatory mechanism in ovarian physiology.

Effects of sumatriptan on capsaicin-induced carotid haemodynamic changes and CGRP release in anaesthetized pigs.

It is suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Hence, inhibition of trigeminal CGRP release may prevent the above vasodilatation and, accordingly, abort migraine headache. Therefore, this study investigated the effects of sumatriptan (100 and 300 microg/kg, i.v.) on capsaicin-induced carotid haemodynamic changes and on CGRP release. Intracarotid (i.c.) infusions of capsaicin (10 microg/kg/min, i.c.) increased total carotid, arteriovenous anastomotic and capillary conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. Except for some attenuation of arteriovenous anastomotic changes, the capsaicin-induced responses were not affected by sumatriptan. Moreover, i.c. infusions of capsaicin (0.3, 1, 3 and 10 microg/kg/min, i.c.) dose-dependently increased the jugular venous plasma concentrations of CGRP, which also remained unaffected by sumatriptan. The above results support the contention that the therapeutic action of sumatriptan is mainly due to cranial vasoconstriction rather than trigeminal (CGRP release) inhibition.

Real-time dynamics of prostaglandin F2alpha release from uterus and corpus luteum during spontaneous luteolysis in the cow.

Prostaglandin (PG) F2alpha released from the uterus in a pulsatile fashion is essential to induce regression of the corpus luteum (CL) in the cow. In addition to the uterus, the CL has also been recognized as a site of PGF(2alpha) production. Therefore, this study aimed to determine the detailed dynamics of the releasing profile of CL-derived PGF2alpha together with uterus-derived PGF2alpha during spontaneous luteolysis in the cow. Non-lactating Holstein cows (n = 6) were surgically implanted with a microdialysis system (MDS) on day 15 (oestrus = day 0) of the oestrous cycle. Simultaneously, catheters were implanted to collect ovarian venous plasma ipsilateral to the CL as well as jugular venous plasma. The concentrations of PGF2alpha, 13,14-dihydro-15-keto-PGF2alpha (PGFM) and progesterone in the MDS and plasma samples were determined by enzyme immunoassays. The intra-luteal PGF2alpha secretion slightly increased after the onset of luteolysis (0 h) and drastically increased from 24 h, and was maintained at high levels towards the following oestrus. Furthermore, PGF2alpha was released from the CL into the ovarian vein in a pulsatile manner during spontaneous luteolysis. Also, the fact that intra-luteal secretion of PGF2alpha and PGFM showed a positive correlation indicates the existence of a local metabolic pathway for PGF2alpha in the CL. In conclusion, the present study clarified the real-time dynamics of uterus-derived PGF2alpha and CL-derived PGF2alpha during spontaneous luteolysis in the cow, and gives the first in vivo evidence that the CL releases PGF2alpha during spontaneous luteolysis in the cow. Although the physiological relevance of CL-derived PGF2alpha appears to be restricted to a local role as an autocrine/paracrine factor in the CL, overall results support the concept that the local release of PGF2alpha within the regressing CL amplifies the luteolytic action of PGF2alpha from the uterus.

Do calcium-mediated cellular signalling pathways, prostaglandin E 2 (PGE 2), estrogen or progesterone receptor antagonists, or bacterial endotoxins affect bovine placental function in vitro?

The major objective of this experiment was to determine whether the bovine placenta could be stimulated to secrete progesterone, since the bovine placenta secretes little progesterone when the corpus luteum is functional. Secondly, we wanted to determine whether reported abortifacients or progesterone or estrogen receptor antagonists affected bovine placental prostaglandin secretion. The ovine placenta secretes half of the circulating progesterone at day 90 of pregnancy and PGE 2 appears to regulate ovine placental progesterone secretion. Calcium has been reported to regulate placental progesterone secretion in cattle. Diced 186–245-day placental slice explants from six Brahman and six Angus cows were incubated in vitro at 39.5 °C under 95% air: 5% CO 2 at pH 7.2 in 5 ml of M-199 for 1 h in the absence of treatments and for 4 and 8 h in the presence of treatments. Treatments were: vehicle; R24571; compound 48/80; IP 3; PGE 2; CaCl 2; cyclosporin A; lipopolysaccharide (endotoxin) from Salmonella abortus equi., enteriditis, and typhimurium; monensin; ionomycin; arachidonic acid; mimosine; palmitic acid; progesterone, androstenedione; estradiol-17β; A23187; RU-486; or MER-25. Jugular and uterine venous plasma and culture media were analyzed for progesterone, PGE 2 and PGF 2α by radioimmunoassay (RIA). Plasma hormone data were analyzed by a One-Way Analysis of Variance (ANOVA). Hormone data in culture media were analyzed for breed and treatment effects by a Factorial Design (2 breeds, 2-range of days, 21 treatments) for ANOVA (2 × 2 × 21). Since hormone data secreted by placental tissue in vitro did not differ ( P≥0.05) by breed or range of days of pregnancy, data were pooled and analyzed by a One-Way ANOVA. Concentrations of PGE 2 in uterine venous blood were two-fold greater ( P≤0.05) in Angus than Brahman cows. PGE 2 and PGF 2α in vehicle controls increased from 4 to 8 h ( P≤0.05), but not progesterone ( P≥0.05). Progesterone in culture media treated with RU-486 increased ( P≤0.05) at 4 and 8 h compared to vehicle controls and was not affected by other treatments ( P≥0.05). Concentrations of PGE 2 in media at 4 and 8 h were lower ( P≤0.05) when compared to controls except treatment with PGE 2 at 4 and 8 h and RU-486 at 8 h ( P≥0.05). PGF 2α was increased ( P≤0.05) by RU-486 at 8 h and no other treatment affected PGF 2α at 4 or 8 h ( P≤0.05). In conclusion, modulators of cellular calcium signalling pathways given alone do not affect bovine placental progesterone secretion at the days studied and progesterone receptor-mediated events appear to suppress placental progesterone, PGF 2α, and PGE 2 secretion in cattle. In addition, PGE 2 does not appear to regulate bovine placental progesterone secretion when the corpus luteum is functional and bacterial endotoxin does not appear to affect bovine placental secretion of PGF 2α or PGE 2.

Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs.

1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.

Changes in prostaglandin secretion by the regressing bovine corpus luteum

Secretion of prostaglandins (PGs) by the regressing corpus luteum (CL) was investigated in the cow. Six cows were implanted with microcapillary dialysis membranes of a microdialysis system (MDS) into the CL during Days 8–9 (Day 0=estrus), and a prostaglandin (PG) F 2α analogue (Estrumate) was injected intramuscularly (i.m.) to induce luteolysis. Acute increases in intraluteal release of PGF 2α and PGE 2 were observed during the first 4 h, followed by decreases over the next 8 h. Intraluteal release of both PGs gradually increased again during the period 48–72 h. Concentrations of PGF 2α in ovarian venous plasma (OVP) were 4–13 times higher than those of jugular venous plasma (JVP) ( P<0.001) during the period of the experiment, and increased from 24 h after treatment with Estrumate ( P<0.05). Cyclooxygenase (COX)-2 mRNA expression increased ( P<0.05) at 2 and 24 h after treatment with Estrumate. The results indicated that local release of PGF 2α and PGE 2, and COX-2 mRNA expression were increased by Estrumate in the regressing CL at the later stages of luteolysis. Thus, luteal secretion of PGs may be involved in the local mechanism for structural rather than functional luteolysis.

Intraluteal release of angiotensin II and progesterone in vivo during corpora lutea development in the cow: effect of vasoactive peptides.

The newly formed corpus luteum (CL) develops rapidly and has the features of active vascularization and mitosis of steroidogenic cells. Such local mechanisms must be strictly regulated by the complex relationship between angiogenic growth factors and vasoactive peptides such as angiotensin (Ang) II, atrial natriuretic peptide (ANP), and endothelin (ET)-1. Thus, the objective of the present study was to determine 1) the changes in vasoactive peptides and progesterone (P) concentrations within the developing CL, along with the changes in concentration in ovarian venous plasma (OVP) and jugular venous plasma (JVP) in the cow, 2) the effects of CL exposure to vasoactive peptides on Ang II and P secretion, and 3) the expression of mRNA for ANP type C receptor in the bovine CL and endothelial cells (ETC) from bovine developing CL. A microdialysis system (MDS) was surgically implanted into multiple CL of six cows on Day 3 after a GnRH injection that induced superovulation, and a catheter was simultaneously inserted into the ovarian vein. The Ang II concentration in OVP was higher than that in JVP throughout the experiment, while the intraluteal release of Ang II was stable. During the experimental period, the concentrations of other vasoactive peptides (ANP and ET-1) showed no clear changes in plasma and were below detectable levels in the MDS perfusate. Exposure of CL to Ang II using the MDS stimulated P release, while exposure to ANP enhanced Ang II release within the developing CL. However, ET-1 had no effect on either P or Ang II release. The expression of mRNA for ANP type C receptor was mainly observed in early CL and ETC. The results suggest that the ET-Ang-ANP system in the preovulatory follicle switches to an Ang-ANP system to enhance both the angiogenesis and steroidogenesis that are actively occurring in developing CL.