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L C Wagerle

Publications and source records attributed to L C Wagerle.

At least 19 recordsLinked to original sources
PubMed2001

Phosphorylation in coronary artery cold-induced contraction in the newborn lamb.

Myocardial dysfunction after hypothermic protection has been linked to various mechanisms. Coronary vasospasm in particular may be responsible for ischemic injury during reperfusion. Herein we hypothesized that coronary arteries (CA) sustain a cold-induced contraction during hypothermia mediated by a protein tyrosine kinase (PTK)-/protein tyrosine phosphatase (PTP)-dependent pathway. Isolated newborn lamb CA rings were studied in a tissue bath for isometric contraction during 2-h profound (17 degrees C) or ultra-profound (7 degrees C) hypothermia. In parallel, protein tyrosine phosphorylation was evaluated by use of the Western blot technique. Na-orthovanadate (SOV) and genestein (GEN) were used separately and in combination to evaluate the effect of PTK/PTP activation on CA contraction and tyrosine phosphorylation during cooling (17 or 7 degrees C) vs 37 degrees C. Cooling from 37 to 7 degrees C induced transient contraction at approximately 17 degrees C (29% KCl response), which was more prominent during rewarming to 37 degrees C (36% KCl). Cooling to 17 degrees C resulted in sustained contraction (7-10% KCl), which was reversible upon rewarming. Cold-induced contraction was significantly enhanced by SOV (7- to 10-fold at 17 degrees C; 2-fold at 7 degrees C) and abolished by GEN. Concurrently, tyrosine phosphorylation of 33-, 45-, and 104-kDa proteins increased during cooling (35-100% at 17 degrees C; 46-66% at 7 degrees C). Tyrosine phosphorylation was similarly enhanced by SOV (1.7- to 2.3-fold at 17 degrees C; 2.9- to 3.9-fold at 7 degrees C) and abolished by GEN in the presence or absence of SOV. These results support a prominent role for the PTK/PTP signal transduction pathway in the coronary artery cold-induced contraction. This information provides one possible biomolecular mechanism linked to ischemia/reperfusion pathophysiology of CA in neonatal hearts exposed to hypothermic myocardial protection.

Animals↗
PubMed1999

Effects of hypothermosol, an experimental acellular solution for tissue preservation and cardiopulmonary bypass, on isolated newborn lamb coronary vessels subjected to ultra profound hypothermia and anoxia.

Ultra profound hypothermia (4 to 10 degrees C) is an experimental method aiming at safely prolonging organ and total body preservation. For this purpose, Hypothermosol (HTS), an investigational acellular solution for blood substitution, was demonstrated to be beneficial in animal models undergoing cardiopulmonary bypass. We investigated the beneficial versus deleterious effects of cold preservation and the role of HTS on isolated coronary arteries (CA) during cold exposure, rewarming, and post-rewarming exposure to anoxia. Newborn lamb CA rings were studied using a tissue bath technique. CA were subjected to cold (7 degrees C for 3 h) and treated with either Krebs' buffer (Krebs/hypothermia) or HTS (HTS/hypothermia) (n = 15 each). A third group maintained at 37 degrees C (Krebs/normothermia) (n = 18) served as a time control. After rewarming (37 degrees C), precontracted CA were exposed to anoxia. In Krebs/hypothermia a substantial hypercontraction (g) occurred during rewarming (1.21+/-0.07) (mean +/- SEM) but not in HTS/hypothermia (0.79+/-0.03); P<0.05. Precontraction force generated by indomethacin/U46619 was identical in all three groups. However, Krebs/hypothermia vessels demonstrated a significantly higher relative vasoconstriction (percentage) in the early (approximately 10 min) and late (30 min) anoxia exposure than the HTS/hypothermia and time control (119.5%+/- 3.7 vs. 109.5%+/-4.4 and 101.5%+/-3, and 71%+/-7.6 vs. 38.9%+/-7 and 51.5%+/-5.9, respectively; P<0.05). In conclusion, Ultra profound hypothermia promotes coronary vasoconstriction upon rewarming, which is detrimental to relaxant response to hypoxia. Both phenomena are alleviated by performing ultra profound hypothermia under HTS protection.

Animals↗
PubMed1998

Endothelial dysfunction in cerebral microcirculation during hypothermic cardiopulmonary bypass in newborn lambs.

OBJECTIVES: Inflammatory stimuli or mechanical stresses associated with hypothermic cardiopulmonary bypass could potentially impair cerebrovascular function, resulting in inadequate cerebral perfusion. We hypothesize that hypothermic cardiopulmonary bypass is associated with endothelial or vascular smooth muscle dysfunction and associated cerebral hypoperfusion. Therefore we studied the cerebrovascular response to endothelium-dependent vasodilator, acetylcholine, endothelium-independent nitric oxide donor, sodium nitroprusside, and vasoactive amine, serotonin, in newborn lambs undergoing hypothermic cardiopulmonary bypass (nasopharygeal temperature = 18 degrees C). METHODS: Studies were performed on 13 newborn lambs equipped with a closed cranial window, allowing for direct visualization of surface pial arterioles. Six animals were studied while undergoing hypothermic cardiopulmonary bypass, whereas seven served as nonbypass, warm (37 degrees C) controls. Pial arteriolar caliber (range = 111 to 316 microm diameter) was monitored using video microscopy. RESULTS: Topical application of acetylcholine caused a dose-dependent increase in arteriolar diameter in the control group that was absent in animals undergoing hypothermic cardiopulmonary bypass. Hypothermic cardiopulmonary bypass did not alter the vasodilation in response to sodium nitroprusside. Furthermore, the contractile response to serotonin was fully expressed during hypothermic cardiopulmonary bypass. CONCLUSIONS: The specific loss of acetylcholine-induced vasodilation suggests endothelial cell dysfunction rather than impaired ability of vascular smooth muscle to respond to nitric oxide. It is speculated that loss of endothelium-dependent regulatory factors in the cerebral microcirculation during hypothermic cardiopulmonary bypass may enhance vasoconstriction, and impaired cerebrovascular function may be a basis for associated neurologic injury during or after hypothermic cardiopulmonary bypass.

Acetylcholine↗
PubMed1996

Protein tyrosine kinase signaling in cold-stimulated contraction of newborn lamb cerebral arteries.

We recently reported a contraction of middle cerebral artery (MCA) preparations isolated from newborn lambs in response to tissue cooling. However, the mechanism(s) by which cold stimulus modifies the contractile properties of MCA is not known. We hypothesize that cold stimulus-triggered contraction may be mediated by a signal transduction pathway associated with protein tyrosine kinase (PTK)-dependent machinery. In the present study the tissue bath technique was used to evaluate the effect of select inhibitors of PTK and protein tyrosine phosphatase (PTP) on the temperature-dependent contractile behavior of isolated MCA from new-born lambs. Reduction of tissue bath temperature from 37 to 21 degrees C stimulated contraction (55 +/- 3% of the response to 120 mM KCl). Two distinct inhibitors of PTK, genistein and tyrphostin 47, completely reversed the cold-stimulated contraction, whereas staurosporine, an inhibitor of protein kinase C, was without effect. Sodium orthovanadate (50 microM) potentiated the cold-stimulated contraction, augmenting the slope of the temperature-force relationship over twofold. Two Ser/Thr phosphatase inhibitors (okadaic acid and calyculin A) had no effect on the temperature-force relationship. These results offer experimental evidence to support a novel hypothesis where PTK/PTP-dependent signal transduction pathways may be preferably targeted by cold stimulus and thus provide a biochemical basis for cold-stimulated modification of cerebral vascular contractile properties.

Animals↗
PubMed1995

Effects of halothane on the immature lamb heart.

The choice of anesthesia during pregnancy and fetal operations is controversial. Halothane frequently is used, but its direct effects on fetal cardiac performance are unknown. The effects of halothane on fetal cardiac mechanics were studied in 8 fetal lamb hearts (135 days' gestation) using a modified Langendorff model connected to a membrane oxygenator. The perfusate consisted of oxygenated maternal blood at a constant flow temperature, hematocrit value, and glucose level. Coronary blood flow, left ventricular systolic pressure, left ventricular end-diastolic pressure, and the developed left ventricular pressure at a fixed volume were evaluated at baseline and after the addition of incremental concentrations of halothane to the perfusate through the oxygenator. Perfusate halothane levels were maintained in a clinical range. Systolic and diastolic cardiac function were adversely affected by the administration of even low doses of halothane, despite a concomitant increase in coronary blood flow. Because of the immaturity of their calcium transport system, fetal hearts may be particularly sensitive to the known calcium channel-blocking properties of halothane.

Animals↗
PubMed1995

Nitric oxide and beta-adrenergic mechanisms modify contractile responses to norepinephrine in ovine fetal and newborn cerebral arteries.

Ovine fetal cerebral arteries exhibit an enhanced contractile response to norepinephrine (NE) compared with newborns and adults. It is possible that beta-adrenergic receptors and/or nitric oxide (NO), a putative endothelium-dependent relaxing factor, differentially modulate cerebrovascular responsiveness to NE as a function of development. The present study evaluated the effect of the beta-adrenoceptor antagonist, propranolol, and the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (LNAME), on the contractile response of isolated middle cerebral artery (MCA) and basilar artery (BA) to NE during fetal development. MCAs isolated from four preterm fetal lambs (105 d of gestation), seven near-term fetal lambs (125-130 d of gestation), and eight newborn lambs (2-7 d of age) were evaluated using organ baths. BAs isolated from the near-term fetal and newborn lambs were also evaluated. Contractile reactivity of MCAs to NE decreased significantly during fetal maturation as manifested by a marked decrease in Fmax (maximal relative contractile force generated) and an increase in EC50 (Fmax = 100 +/- 7, 41 +/- 7, and 28 +/- 8% of KCl contraction; EC50 = 0.14 +/- 0.03, 1.09 +/- 0.36, and 1.07 +/- 0.22 microM for preterm fetus, near-term fetus, and newborn lamb MCAs, respectively, p < or = 0.05). Propranolol treatment (10(-5) M) increased Fmax (2-fold) only for newborn lamb MCAs. Pretreatment with LNAME (10(-4) M) markedly enhanced the contractile response to NE (7-fold decrease in EC50 and 2-fold increase in Fmax, p < 0.05) for near-term fetus MCAs, whereas preterm fetus and newborn lamb MCAs were unaffected by the inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1994

Hypothermia enhances contractility in cerebral arteries of newborn lambs.

Hypothermia is the major factor influencing autoregulatory properties of the cerebral circulation in human infants undergoing hypothermic cardiopulmonary bypass. The present investigation evaluated the effect of decreased temperature on the contractility of isolated middle cerebral arteries obtained from newborn lambs. Reducing bath temperature from 37 to 21 degrees C caused a temperature-dependent increase in contractile tension, achieving 1.32 +/- 0.09 g above resting tension (0.75 g). Pretreatment with nonselective (alpha 1 and alpha 2) alpha-adrenoceptor antagonist, phentolamine (10(-5) M), with an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester hydrochloride (10(-4) M), and with a cyclooxygenase inhibitor, indomethacin (10(-5) M), did not affect the contractile response to a decrease in bath temperature from 37 to 21 degrees C. Furthermore, cerebral arteries were responsive to both norepinephrine (constriction) and sodium nitroprusside (relaxation) and the sensitivity of cerebral arteries to the sympathetic neurotransmitter norepinephrine appears to be enhanced at low temperatures. We postulate that direct cerebral vasoconstriction and enhanced adrenergic contractility may be responsible for increased cerebrovascular resistance during and after hypothermic cardiopulmonary bypass with possible ischemic cerebral injury and neurological sequelae.

Animals↗
PubMed1994

Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin.

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Cerebrovascular reactivity to adenosine analogues in 0.6-0.7 gestation and near-term fetal sheep.

During acute hypoxia, fetal sheep less than 0.7 gestation increase cerebral blood flow (CBF) relatively less than fetal sheep near term. We hypothesized that cerebrovascular reactivity to a hypoxic vasodilator metabolite such as adenosine might be diminished in immature fetuses. This study examined cerebral vasoreactivity to adenosine analogues in nine sheep fetuses less than 0.7 gestation (90-103 days) and nine near term (129-143 days). Fetuses were equipped in utero with a closed cranial window, and pial arterioles were studied by intravital microscopy. 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-9)-10(-5) M) and N6-cyclopentyladenosine (CPA; 10(-9)-10(-4) M) each caused a dose-dependent increase in arteriolar diameter that was attenuated in the presence of the adenosine receptor antagonist 8-phenyltheophylline (8-PT; 5 x 10(-6) M). Dose-response curves to the agonists were similar for both age groups. NECA was a more potent vasodilator than CPA, in keeping with their affinity for the A2 receptor. Suffusion of 8-PT alone at less than 10(-5) M had no effect on arteriolar diameter. We conclude that adenosine is able to dilate fetal cerebral arterioles as young as 0.6 gestation by acting at an A2 receptor, although resting tone is not influenced by adenosine. The immature fetal sheep CBF response to hypoxia is not attributable to undeveloped vasoreactivity to adenosine.

Adenosine↗
PubMed1992

Cholinergic reactivity of cerebral arteries in the developing fetal and newborn lamb.

Cerebral arteries of newborn pigs and baboons constrict to acetylcholine, suggesting that endothelium-dependent dilator mechanisms may be lacking in immature cerebral arteries. The present study tested this possibility in the immature sheep by examining the response of cerebral arterioles in fetal and newborn sheep to endothelium-dependent dilator, acetylcholine. Pial arteriolar diameter was measured in 9 anaesthetized foetuses in utero (4 preterm, 90-111 days gestation and 5 term, 128-143 days gestation) and in 5 anaesthetized, newborn lambs (14 days) using a closed cranial window with intravital microscopy. Application of acetylcholine to the pial surface induced dose-dependent increase in pial arteriolar diameter in all age groups; EC50 for acetylcholine was 0.10 +/- 0.03, 0.28 +/- 0.08 and 0.26 +/- 0.17 microM for preterm fetal, term fetal, and newborn lambs, respectively. The data demonstrate a sensitive dilator response to acetylcholine in immature fetuses as well as newborn lambs suggesting that cholinergic-mediated release of endothelium-dependent relaxing factor is functional early in gestation. The contractile response to acetylcholine observed in newborn pigs and premature baboons may reflect a species difference rather than maturational lack of endothelium-dependent dilator mechanisms.

Acetylcholine↗
PubMed1991

Effect of dexamethasone on cerebral prostanoid formation and pial arteriolar reactivity to CO2 in newborn pigs.

This study investigates the effect of glucocorticoid treatment on the relationship between arteriolar PCO2 and cortical prostanoid production and on cerebrovascular responsiveness to elevated CO2 in newborn piglets. The response of pial arteries to hypercapnia (fractional inspired CO2 = 0.035 and 0.07) was studied in 18 anesthetized newborn piglets, 9 of which were pretreated with dexamethasone (2 mg.kg-1.day-1 for 36-48 h). Pial arterioles (77-122 microns diam) were monitored using a closed cranial window and intravital microscopy. Perivascular cerebrospinal fluid (CSF) was sampled from the cortical surface and analyzed for 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) using radioimmunoassay. In the dexamethasone-treated animals the increase in arteriolar diameter to CO2 was diminished by approximately 50% for each respective CO2 concentration vs. the control group. Acute sympathetic denervation did not restore the CO2 dilator response. Dexamethasone did not alter baseline cortical CSF prostanoid concentrations but abolished the CO2-induced increase in CSF prostanoids. The dilator response to exogenously applied prostaglandin E2 was inhibited in dexamethasone-treated animals. However, the dilator response to exogenous adenosine and the contractile response to prostaglandin F2 alpha were not altered in the dexamethasone-treated piglets. The data support the concept that metabolites of arachidonic acid participate in the cerebrovascular response to CO2 and suggest that glucocorticoid treatment may influence cerebrovascular tone via this mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Sympathetic nerve modulation of regional cerebral blood flow during asphyxia in newborn piglets.

Regional cerebral blood flow (rCBF) during asphyxia suggests a reflex vasoconstrictor mechanism active principally in brain cortex. Present studies in newborn piglets investigate sympathetic modulation of the cerebrovasculature both during and after acute asphyxia. Unilateral superior cervical sympathetic ganglionectomy (SCSG) was performed in 13 newborn piglets, after which asphyxia was produced by discontinuing ventilation. In 8 animals, blood flow was measured during control and sequentially 1, 2, and 3 min after ventilation was stopped. In 5 piglets with unilateral SCSG, cortical flow decreased in the innervated hemisphere, -34 +/- 14% after 2 min, and -25 +/- 9% at 3 min of asphyxia compared with control (104 +/- 22 ml.min-1.100 g-1; mean +/- SE). In contrast, the sympathetically denervated hemisphere showed -13 +/- 17% at 2 min and +7 +/- 23% at 3 min, representing 45 +/- 6% and 30 +/- 9% left-right (L-R) flow differences, respectively. Bilateral SCSG (3 piglets) similarly attenuated the cortical CBF vasoconstrictor response to asphyxia, +6 +/- 21% at 2 min and -8 +/- 5% at 3 min. Significant innervated-denervated rCBF differences were present during asphyxia in cerebral gray (55% +/- 24), cerebral white (41% +/- 16), caudate (25% +/- 7), hippocampus (36% +/- 12), and choroid plexus (145% +/- 42), indicating sympathetic nerve modulation. Brain stem structures showed increasing rCBF throughout asphyxia and no L-R differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Lipid peroxidation as the mechanism of modification of brain 5'-nucleotidase activity in vitro.

The effect of lipid peroxidation on the Mg2(+)-independent and Mg2(+)-dependent activity of brain cell membrane 5'-nucleotidase was determined and the affinity of the active sites of Mg2(+)-dependent enzyme for 5'-AMP (substrate) and Mg2+ (activator) was examined. Brain cell membranes were peroxidized at 37 degrees C in the presence of 100 microM ascorbate and 25 microM FeCl2 (resultant) for 10 min. The activity of 5'-nucleotidase and lipid peroxidation products (thiobarbituric acid reactive substances) were determined. At 10 min, the level of lipid peroxidation products increased from 0.20 +/- 0.10 to 17.5 +/- 1.5 nmoles malonaldehyde/mg membrane protein. The activity of Mg2(+)-independent 5'-nucleotidase increased from 0.201 +/- 0.020 in controls to 0.305 +/- 0.028 mumol Pi/mg protein/hr in peroxidized membranes. In the presence of 10 mM Mg2+, the activity increased by 5.8-fold in the peroxidized membrane preparation in comparison to 14-fold in control. In peroxidized preparation, the affinity of active site of Mg2(+)-dependent 5'-nucleotidase for 5'-AMP tripled, as indicated by a significant decrease in Km (Km = 95 +/- 2 microM AMP for control; Km = 32 +/- 2 microM AMP for peroxidized). Vmax was significantly reduced from 3.35 +/- 0.16 in control to 1.70 +/- 0.9 mumoles Pi/mg protein in peroxidized membranes. The affinity of the active site for Mg2+ significantly increased (Km = 6.17 +/- 0.37 mM Mg2+ for control; Km = 4.0 +/- 0.31 peroxidized).(ABSTRACT TRUNCATED AT 250 WORDS)

5'-Nucleotidase↗
PubMed1990

Anti-oxidant enzymes in the brain of newborn piglets during ischemia followed by reperfusion.

The activity of anti-oxidant enzymes in the brains of newborn piglets were studied under the condition of ischemic hypoxia followed by reperfusion. The activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase, was determined in the brain tissue of control animals and animals exposed to 60 min of hypoxia followed by 30 min of normoxia. The results showed that the activities of these enzymes were not significantly affected by hypoxia and subsequent reperfusion, suggesting that under these conditions the anti-oxidant system is not a target for, nor is its inhibition a cause of, cellular damage. It is proposed that the anti-oxidant enzyme system in the brain is non-responsive to and may not play a role during hypoxia/ischemia and subsequent reperfusion.

Animals↗
PubMed1990

Sympathetic reactivity of cerebral arteries in developing fetal lamb and adult sheep.

The response of cerebral arteries to norepinephrine was examined in vivo in six dated preterm fetal (94-121 days gestation), eight term fetal (127-141 days gestation), five newborn (7-14 days), and five adult sheep, anesthetized and equipped with a closed cranial window. Norepinephrine (10(-8)-10(-4) M in cerebrospinal fluid) caused a dose-dependent decrease in pial arteriolar diameter in fetal and newborn lambs; however, preterm fetuses were 7- and 14-fold more sensitive to norepinephrine than term fetuses and newborn lambs, respectively. The effective concentration of norepinephrine inducing a 15% decrease in diameter (EC15) was 4.6 +/- 1.8, 33 +/- 11, and 64 +/- 23 microM, for the respective ages. Adult cerebral arterioles did not contract to norepinephrine. In preterm and term fetuses, the contractile response to norepinephrine was blocked by alpha 1-antagonist, prazosin (3 mg iv), and was enhanced by cocaine (10(-5) M; EC15 = 0.086 +/- 0.04 and 1.84 +/- 1.20 microM, respectively) indicating that alpha 1-adrenoceptors mediate the response and that the decrease in sensitivity is not caused by development of neuronal uptake processes. In seven fetuses (111-141 days; mean 123 days gestation), electrical stimulation of the superior cervical sympathetic ganglion constricted pial arterioles by 21 +/- 5%; this contractile response was also blocked by prazosin. The cerebral arterioles of the fetus in utero possess a functional sympathetic innervation capable of influencing cerebrovascular resistance. There is a loss of responsiveness of cerebral arterioles to norepinephrine during fetal and postnatal development, suggesting that the contribution of neuroadrenergic mechanisms to cerebrovascular regulation may be relatively unique to the immature brain.

Aging↗
PubMed1990

Effect of thromboxane A2/endoperoxide antagonist SQ29548 on the contractile response to acetylcholine in newborn piglet cerebral arteries.

Previous studies have shown that cholinergic stimulation results in a prostanoid-dependent cerebral vasoconstriction in piglets. The present study specifically investigated the contribution of thromboxane A2 (TXA2)/prostaglandin endoperoxide and prostaglandin F2 alpha (PGF2 alpha) to the cerebral vascular response to exogenous acetylcholine (ACh). Effects of TXA2/prostaglandin endoperoxide-receptor antagonist SQ29548 on responsiveness of pial arterioles to ACh (10(-7) and 10(-4) M), PGF2 alpha (10(-7)-10(-5) M), TXA2 mimetic 9,11-methanoepoxy prostaglandin H2 (U46619, 5 and 10 ng/ml), and norepinephrine (10(-6)-10(-4) M) were studied by use of a closed cranial window in 37 anesthetized mechanically ventilated newborn piglets. Pial arteriolar diameter was measured by intravital microscopy. Topical application of exogenous PGF2 alpha and U46619 resulted in dose-dependent cerebral vasoconstriction, and the dose-response curve for each agonist was shifted to the right by the increasing concentrations of SQ29548 (10(-6)-10(-8) M). Topical application of high concentration of ACh (10(-4) M) caused a transient 34 +/- 4% decrease in pial arteriolar diameter from 98 +/- 6 to 65 +/- 5 microns (p less than 0.05). This constriction was attenuated (16 +/- 3%) in the presence of 10(-8) M SQ29548 and abolished with 10(-6) or 10(-4) M SQ29548. SQ29548 (10(-6) M) was without effect on the vasoconstrictor response to exogenous norepinephrine. Low concentration of ACh (10(-7) M) had no consistent effect on pial arterioles in the absence or presence of TXA2/prostaglandin endoperoxide-receptor blockade. The data suggest that vascular prostaglandin/endoperoxide receptors mediate cerebral vasoconstriction upon muscarinic-receptor stimulation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Mono-L-arginine-containing compounds dilate piglet pial arterioles via an endothelium-derived relaxing factor-like substance.

We determined the effects of mono-L-arginine-containing compounds on pial arterioles of anesthetized piglets. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy. Diameter was determined during application of artificial cerebrospinal fluid containing no drugs and during application of 10(-5), 10(-4), 10(-3), and 10(-2) M L-arginine (ARG), L-arginine ethyl ester (AEE), N alpha-benzoyl-L-arginine (NBA), N alpha-benzoyl-L-arginine ester ethyl (BAEE), and L-citrulline (CIT). Initial diameters were 100-200 microns. All of these compounds dilated arterioles, but the threshold concentration needed to elicit dilation varied: 10(-5) M for NBA (n = 5), 10(-3) M for AEE (n = 9) and BAEE (n = 6), and 10(-2) M for ARG (n = 6) and CIT (n = 4). Maximal responses were 15 +/- 8% for CIT, 17 +/- 4% for ARG, 19 +/- 8% for BAEE, 28 +/- 5% for NBA, and 27 +/- 6% for AEE. Indomethacin pretreatment (5 mg/kg i.v.) did not change arteriolar responses to AEE, NBA, and BAEE. However, coadministration of methylene blue (0.5 x 10(-4) M or 0.5 x 10(-3) M) abolished dilation to 10(-3) M AEE or BAEE and attenuated dilation to 10(-5) M NBA. In addition, coadministration of hemoglobin (0.4 x 10(-4) M) abolished dilation to AEE, BAEE, or NBA. Last, intravenous (5 mg/kg) and coadministration (10(-3) M) of NG-methyl-L-arginine blocked dilation to NBA or AEE. We conclude that mono-L-arginine-containing compounds produce pial arteriolar dilation in piglets, possibly involving an endothelium-derived relaxing factor.

Animals↗