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PubMed2001

Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors.

We have tested the role of various protein kinases in noradrenaline-induced, alpha1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Effects of the tripeptide substance P antagonist, FR113680, on airway constriction and airway edema induced by neurokinins in guinea-pigs.

FR113680 is a newly developed tripeptide substance P (SP) receptor antagonist. The effects of FR113680 on airway constriction and airway edema induced by neurokinins were investigated in guinea-pigs. In in vitro experiments, FR113680 inhibited the contraction of isolated guinea-pig trachea induced by SP and neurokinin A (NKA) in a dose-dependent manner with IC50 values of 2.3 x 10(-6) and 1.5 x 10(-5) M, respectively. The tracheal contraction induced by histamine and acetylcholine was not affected by FR113680. FR113680 (5 x 10(-5) M) also significantly inhibited the atropine-resistant contraction of isolated guinea-pig bronchi induced by electrical field stimulation. In in vivo experiments, FR113680 given i.v. inhibited SP-induced airway constriction in guinea-pigs at doses of 1 and 10 mg kg-1. However, FR113680 only inhibited NKA- and capsaicin-induced airway constriction by 40-50% even at a dose of 10 mg kg-1. FR113680 also inhibited SP-induced airway edema in guinea-pigs with the same potency as it inhibited SP-induced airway constriction. Histamine-induced airway constriction and airway edema were not affected at a dose of 10 mg kg-1. These results suggest that FR113680 preferentially inhibits responses induced by NK1 receptor activation (SP-induced airway constriction and airway edema), but is less effective on a NK2 receptor-induced response (airway constriction by NKA and neurogenic stimulation).

Amino Acid Sequence↗

PubMed2006

Acetylcholine stimulated dilatation and stretch induced myogenic constriction in mesenteric artery of rats with chronic heart failure.

Rats with chronic heart failure (CHF) develop increased myogenic constriction in mesenteric resistance arteries. Here we investigated increased myogenic constriction in relation to alterations in EDHF- and NO-mediated dilatation in CHF-rats. Male Spraque-Dawley rats were subjected to myocardial-infarction or sham-surgery. At 9-10 weeks after surgery, isolated mesenteric artery ring preparations were studied in a wire-myograph. Stretch-induced myogenic constriction was obtained by stepwise increase of the internal circumference diameter (0.5-1.2 L100). Cyclooxygenase- and eNOS-inhibitors were employed to study NO- and EDHF-mediated dilatation in response to acetylcholine. Rats with CHF (n=8), but not sham-rats (n=6), developed significant myogenic constriction. In addition, the contribution of endothelial dilator mediators was significantly altered in CHF-rats, with increased dependency on NO and decreased EDHF-mediated dilatation. Moreover, EDHF-mediated dilatation was inversely correlated with myogenic constriction in individual CHF-rats (r=-0.74, p=0.04). These data demonstrate increased myogenic constriction in mesenteric arteries of rats with CHF post-MI to be correlated to decreased EDHF-mediated dilatation. These findings extend the previous observation that myogenic constriction antagonizes EDHF-mediated dilatation in rat coronary artery under normal conditions, and suggests this relationship also to become functional in mesenteric arteries under pathophysiological conditions of CHF.

Acetylcholine↗

PubMed2005

Mast cell mediators in citric acid-induced airway constriction of guinea pigs.

We demonstrated previously that mast cells play an important role in citric acid (CA)-induced airway constriction. In this study, we further investigated the underlying mediator(s) for this type of airway constriction. At first, to examine effects caused by blocking agents, 67 young Hartley guinea pigs were divided into 7 groups: saline + CA; methysergide (serotonin receptor antagonist) + CA; MK-886 (leukotriene synthesis inhibitor) + CA; mepyramine (histamine H1 receptor antagonist) + CA; indomethacin (cyclooxygenase inhibitor) + CA; cromolyn sodium (mast cell stabilizer) + CA; and compound 48/80 (mast cell degranulating agent) + CA. Then, we tested whether leukotriene C4 (LTC4) or histamine enhances CA-induced airway constriction in compound 48/80-pretreated guinea pigs. We measured dynamic respiratory compliance (Crs) and forced expiratory volume in 0.1 s (FEV0.1) during either baseline or recovery period. In addition, we detected histamine level, an index of pulmonary mast cell degranulation, in bronchoalveolar lavage (BAL) samples. Citric acid aerosol inhalation caused decreases in Crs and FEV0.1, indicating airway constriction in the control group. This airway constriction was significantly attenuated by MK-886, mepyramine, cromolyn sodium, and compound 48/80, but not by either methysergide or indomethacin. Both LTC4 and histamine infusion significantly increased the magnitude of CA-induced airway constriction in compound 48/80-pretreated guinea pigs. Citric acid inhalation caused significant increase in histamine level in the BAL sample, which was significantly suppressed by compound 48/80. These results suggest that leukotrienes and histamine originating from mast cells play an important role in CA inhalation-induced noncholinergic airway constriction.

Administration, Inhalation↗

PubMed1987

Exogenous norepinephrine constricts cerebral arterioles via alpha 2-adrenoceptors in newborn pigs.

The purpose of this study was to determine whether exogenous norepinephrine mediates cerebrovascular constriction via alpha 1- or alpha 2-adrenoceptors in anesthetized neonatal pigs. Diameters of pial arterioles in anesthetized piglets, 1--6 days old, were investigated using a "closed" cranial window. We examined constrictor effects of norepinephrine on pial arterioles in the absence and presence of relatively selective alpha 1-(prazosin) and alpha 2-(yohimbine) adrenoceptor antagonists (1 mg/kg i.v.). Yohimbine and prazosin inhibited pial arteriolar constriction induced by topical application of clonidine and phenylephrine (10(-6) and 10(-4) M, respectively), and yohimbine did not affect the response to topical phenylephrine. In one group diameter was 188 +/- 13 (mean +/- SEM) micron during control and 146 +/- 12 micron during 10(-5) M norepinephrine (22 +/- 5% constriction). Following yohimbine the same vessels did not constrict significantly. In another group 10(-5) M norepinephrine constricted arterioles by 22 +/- 5%, and this response was unaffected by prazosin (24 +/- 5% constriction). We conclude that pial arterioles are responsive to both alpha 1- and alpha 2-adrenoceptor agonists, that intravenous administration of prazosin and yohimbine results in these drugs crossing the blood-brain barrier and inhibiting constrictor effects of agonists, and that norepinephrine constricts pial arterioles predominantly via alpha 2-adrenoceptors.

Animals↗

PubMed2004

EP1- and EP3-receptors mediate prostaglandin E2-induced constriction of porcine large cerebral arteries.

Prostaglandin E2 (PGE2) has been shown to dilate and constrict the systemic vascular beds, including cerebral vessels. The exact mechanism of PGE2-induced cerebral vasoconstriction, however, is less clarified. The authors' preliminary studies showed that PGE2 exclusively constricted the adult porcine basilar arteries. The present study, therefore, was designed to examine the receptor mechanisms involved in PGE2-induced constriction of large cerebral arteries in the adult pig. Results from an in vitro tissue-bath study indicated that PGE2 and its agonists 17-phenyl trinor PGE2 (17-PGE2), sulprostone (EP1/EP3 receptor agonists), and 11-deoxy-16,16-dimethyl PGE2 (11-PGE2, an EP2/EP3-receptor agonist) induced exclusive constriction, which was not affected by endothelium denudation or cold-storage denervation of perivascular nerves. The constriction induced by PGE2, 17-PGE2, and sulprostone, but not by potassium chloride, was blocked by SC-19220 (a selective EP1-receptor antagonist), AH-6809 (an EP1/EP2-receptor antagonist), and U-73122 and neomycin (phospholipase C inhibitors). AH-6809, however, did not affect 11-PGE2-induced contraction. These results suggest that the contraction was not mediated by the EP2-receptor, but was mediated by EP1- and EP3-receptors. Furthermore, EP1-receptor immunoreactivities were found across the entire medial smooth muscle layers, whereas EP3-receptor immunoreactivities were limited to the outer smooth muscle layer toward the adventitia. Western blotting also showed the presence of EP1- and EP3-receptor proteins in cultured primary cerebral vascular smooth muscle cells. In conclusion, PGE2 exclusively constricts the adult porcine large cerebral arteries. This constriction is mediated by phosphatidyl-inositol pathway via activation of EP1- and EP3-receptors located on the smooth muscle cells. These two receptor subtypes may play important roles in physiologic and pathophysiologic control of cerebral vascular tone.

Animals↗

PubMed1995

Effects of halothane and isoflurane on antigen- and leukotriene-D4-induced constriction of guinea pig trachea.

We investigated the mechanism of the action of volatile anesthetics on the airway smooth muscle constricted by an antigen and leukotriene-D4 (LTD4). Excised tracheal rings from ovalbumin-sensitized guinea pigs were suspended in eight tissue baths. Halothane or isoflurane was aerated into four tissue baths, while the remaining four served as time controls. To assess the antispasmogenic activity of halothane and isoflurane, concentration-response curves for antigen and LTD, were constructed exposed to anesthetics and compared to controls. The spasmolytic activity of halothane and isoflurane was measured in the tracheal rings constricted by a single antigen challenge or by EC50 of LTD. Both halothane and isoflurane produced significant rightward shifts of ovalbumin and LTD, concentration-response curve with corresponding increases in the EC50 values. Halothane increased the EC50 value for LTD, from 5.38 +/- 0.43 x 10-9 M to 1.2 +/- 0.18 x 10-8 M, and for ovalbumin from 1.2 +/- 0.06 x 10-4 mg/ml to 3.03 +/- 0.28 x 10-4 mg/ml. Isoflurane increased the EC50 value for LTD, from 5.17 +/- 0.64 x 10-9 M to 8.98 +/- 1.01 x 10-9 M, and for ovalbumin from 1.21 +/- 0.09 x 10-4 mg/ml to 2.61 +/- 0.19 x 10-4 mg/ml. Furthermore, halothane and isoflurane significantly reduced the magnitude of the antigen-and LTD4-induced constriction. In 30 min intervals, 1% and 2% halothane reduced the magnitude of the ovalbumin-induced constriction by 32% and 50%, respectively, while isoflurane (2% and 4%) caused relaxation of 16% and 35%, respectively. The magnitude of LTD4-induced constriction was reduced by 17% and 24%, with 1% and 2% halothane, respectively. Isoflurane (2% and 4%) reduced this constriction by 25% and 25% respectively. In conclusion, halothane and isoflurane attenuate and prevent the constrictive response of airway smooth muscle to allergen and LTD. A direct, nonspecific dilating effect is suggested as the mechanism responsible for the observed effects.

Anesthetics, Inhalation↗

PubMed1992

Acoustic and perceptual effects of changes in vocal tract constrictions for vowels.

The purpose of this study was to use vocal tract simulation and synthesis as means to determine the acoustic and perceptual effects of changing both the cross-sectional area and location of vocal tract constrictions for six different vowels: Area functions at and near vocal tract constrictions are considered critical to the acoustic output and are also the central point of hypotheses concerning speech targets. Area functions for the six vowels, [symbol: see text] were perturbed by changing the cross-sectional area of the constriction (Ac) and the location of the constriction (Xc). Perturbations for Ac were performed for different values of Xc, producing several series of acoustic continua for the different vowels. Acoustic simulations for the different area functions were made using a frequency domain model of the vocal tract. Each simulated vowel was then synthesized as a 1-s duration steady-state segment. The phoneme boundaries of the perturbed synthesized vowels were determined by formal perception tests. Results of the perturbation analyses showed that formants for each of the vowels were more sensitive to changes in constriction cross-sectional area than changes in constriction location. Vowel perception, however, was highly resistant to both types of changes. Results are discussed in terms of articulatory precision and constriction-related speech production strategies.

Adult↗

PubMed2002

Different roles of PKC and MAP kinases in arteriolar constrictions to pressure and agonists.

Protein kinase C (PKC) and mitogen-activated protein (MAP) kinases have been implicated in the modulation of agonist-induced contractions of large vessels. However, their role in pressure- and agonist-induced constrictions of skeletal muscle arterioles, which have a major role in regulating peripheral resistance, is not clearly elucidated. Thus constrictions of isolated rat gracilis muscle arterioles (approximately 80 microm in diameter) to increases in intraluminal pressure and to norepinephrine (NE) or angiotensin II (ANG II) were assessed in the absence or presence of chelerythrine, PD-98058, and SB-203580 (inhibitors of PKC, p42/44 and p38 MAP kinase pathways, respectively). Arteriolar constriction to NE and ANG II were significantly reduced by chelerythrine (by approximately 90%) and unaffected by SB-203580, whereas PD-98058 decreased only ANG II-induced constrictions (by approximately 60%). Pressure-induced increases in wall tension (from 0.1 to 0.7 N/m) resulted in significant arteriolar constrictions (50% maximum) that were abolished by chelerythrine without altering smooth muscle intracellular Ca(2+) concentration ([Ca(2+)](i)) (fura 2 microfluorimetry). PD-98058 and SB-203580 significantly decreased the magnitude of myogenic tone (by 20% and 60%, respectively) and reduced the sensitivity of the myogenic mechanism to wall tension, causing a significant rightward shift in the wall tension-myogenic tone relationship without affecting smooth muscle [Ca(2+)i]. MAP kinases were demonstrated with Western blotting. Thus in skeletal muscle arterioles 1) PKC is involved in both myogenic and agonist-induced constrictions, 2) PD-98058-sensitive p42/44 MAP kinases modulate both wall tension-dependent and ANG II-induced constrictions, whereas 3) a SB-203580-sensitive p38 MAP kinase pathway seems to be specifically involved in the mechanotransduction of wall tension.

Angiotensin II↗

PubMed1992

Skeletal muscle arteriolar constriction to ANG II: evaluation of a myogenic component.

This study addressed the hypothesis that an increase in blood pressure contributes to the overall constrictive response of skeletal muscle arterioles to angiotensin II (ANG II). Diameters of second-order arterioles (2A) and third-order arterioles (3A) in the rat cremaster muscle were quantitated after intravenous administration of ANG II. Hindquarter blood pressure was either allowed to increase or was maintained at normal levels. Constriction of 3A to bolus injection of ANG II was the same whether hindquarter pressure increased or not. However, the total vascular constrictive response of the cremaster muscle (based on 2A blood flow) and of the entire hindquarter (based on iliac arterial blood flow) to bolus ANG II was greater when hindquarter pressure was held constant. During slow infusion of ANG II, 3A constriction was unaffected by an abrupt decrease or increase in hindquarter pressure. However, an abrupt reduction of hindquarter pressure caused a significant decline in hindquarter vascular resistance. Thus an increase in blood pressure, whether rapid or gradual, does not influence 3A constriction to ANG II. However, in the entire hindquarter, a rapid rise in blood pressure opposes constriction to ANG II, whereas a gradual pressure rise evokes a mechanism that enhances constrictive response to the peptide.

Angiotensin II↗

PubMed1997

Pial arteriolar constriction to alpha 2-adrenergic agonist dexmedetomidine in the rat.

Dexmedetomidine (Dex) is an alpha 2-adrenergic agonist that decreases cerebral blood flow (CBF) when administered systemically. It is unclear whether cerebral vasoconstriction is mediated by a local effect on cerebral vessels or by a remote neural mechanism. In the present study, we compared the pial arteriole responses to locally and systemically administered Dex with and without local application of the specific alpha 2-adrenergic antagonist atipamezole. Six groups of male rats (n = 7 each) were anesthetized with isoflurane and prepared for measurements of small (20-39 microns), medium (40-59 microns), and large (60-79 microns) pial arteriole diameter by intravital microscopy or for regional CBF measurement by the radiolabeled-microsphere method. Local application of Dex caused dose-dependent constriction that was significant starting at 10(-8) M for small and medium-sized arterioles and at 10(-7) M for large arterioles. Constriction to 10(-5) M in small [21 +/- 2% (SE)], medium (21 +/- 2%), and large (15 +/- 1%) arterioles was almost completely blocked by local application of 10(-4) M atipamezole. Intravenous administration of Dex at 1 microgram/kg decreased CBF and caused modest arteriolar constriction that began to resolve 8 min after administration. A dose of 10 micrograms/kg constricted arterioles of all sizes with constriction beginning to resolve after approximately 10 min. Local application of atipamezole (10(-4) M) slightly blunted the response to 1 micrograms/kg of intravenous Dex but did not substantially limit constriction after 10 micrograms/kg. These data demonstrate that pial arterioles are capable of substantial constriction to Dex by a local alpha 2-adrenergic mechanism. However, the inability of locally applied atipamezole to substantially inhibit the vasoconstrictor response to systemically administered Dex suggests that Dex might also cause vasoconstriction indirectly through actions at other sites in the central nervous system.

Adrenergic alpha-Agonists↗

PubMed1983

Inappropriate drinking and secretion of vasopressin after caval constriction in dogs.

The object of this study was to determine if chronic thoracic vena caval constriction affected mechanisms regulating water balance, independent of known changes in sodium metabolism in the dog. Fluid and electrolyte balances were determined for 5 days before and 14 days after constriction of the vena cava (n = 5) and in a separate population of time controls (n = 4). Cardiac output was reduced and heart rate was increased in response to chronic caval constriction although blood pressure was maintained at control levels. Water intake and plasma arginine vasopressin (AVP) increased from 31 +/- 4 ml/kg and 1.3 +/- 0.2 pg/ml during the control period to 81 +/- 6 ml/kg and 3.4 +/- 0.6 pg/ml during the period of caval constriction. The caval dogs developed a positive water balance, which preceded the development of a positive sodium balance. This led to a significant fall in plasma osmolality from a control mean of 296 +/- 1 to 284 +/- 4 mosmol/kg during caval constriction and dilutional hyponatremia. Plasma and blood volume increased significantly in response to constriction and were accompanied by formation of 123 +/- 10 ml/kg of ascitic fluid. These results show that water intake and plasma levels of AVP were increased in spite of a fall in plasma osmolality and an increase in vascular volume. These responses cannot be secondary to sodium retention because water was retained in excess of sodium hence hyponatremia. Therefore, chronic caval constriction causes a profound primary disturbance in mechanisms regulating water balance, which may contribute to the formation of edema fluid.

Adrenocorticotropic Hormone↗

PubMed2004

Mast cells and reactive oxygen species in citric acid-induced airway constriction.

The noncholinergic airway constriction is mediated by tachykinins, mainly neurokinin A and substance P, and this bronchoconstriction is usually enhanced during inflammatory episodes. We demonstrated previously that reactive oxygen species play an important role in capsaicin-, hyperventilation-, and citric acid (CA) inhalation-induced noncholinergic airway constriction. For understanding cellular involvement, we further investigated the relationship between mast cells, bradykinin (BK), reactive oxygen species, and noncholinergic airway constriction. Sixty-five guinea pigs were divided into seven groups: saline control; CA; BK + CA; cromolyn sodium (CS) + CA; BK + CS + CA; compound 48/80 + CA; and compound 48/80 + BK + CA. CS was used to stabilize mast cells, whereas a secretagogue, compound 48/80, was for the depletion of mast cells. Each animal was anesthetized, cannulated, paralyzed, and ventilated artificially. In control animals, CA aerosol inhalation caused decreases in dynamic compliance and forced expiratory parameters, indicating CA-induced noncholinergic airway constriction. Either CS or compound 48/80 significantly attenuated the CA-induced airway constriction. Also, we detected a significant increase in lucigenin-initiated chemiluminescence counts of the bronchoalveolar lavage sample in the BK + CA group. Furthermore, CA exposure caused an increase in bronchoalveolar lavage substance P level. Either CS or compound 48/80 prevented the above CA-induced increases in chemiluminescence and substance P. These results suggest that mast cells play an important role in CA aerosol inhalation-induced airway constriction via perhaps releasing constricting factors.

Acridines↗

PubMed1988

Identification of constriction in large versus small vessels using the arterial-venous and the double-occlusion techniques in isolated canine lungs.

By applying the arterial and venous occlusion technique and the double-occlusion technique in the isolated perfused dog left lower lobe, the total pressure gradient across the pulmonary vasculature can be partitioned into four segments: upstream arterial (delta Pa), precapillary (delta Pa'), postcapillary (delta Pv') and downstream venous (delta Pv). Changes in delta Pa and in delta Pv would result from constriction of the large arteries and veins, respectively, while changes in delta Pa' and delta Pv' would result from constriction of the smallest muscular arteries and veins. The results revealed that at the dosages used, serotonin and angiotensin II constricted the large arteries only. Histamine constricted the large and small veins, whereas norepinephrine constricted the large arteries and large veins. Hypoxia constricted primarily the precapillary vessels, and slightly the postcapillary vessels. Elevation of alveolar pressure relative to vascular pressure increased primarily the pressure gradient across the postcapillary vessels (delta Pv'), and to some extent, increased the pressure gradient across the precapillary vessels (delta Pa'). Thus the two techniques when applied together in the isolated lung can differentiate between constriction in large versus small vessels. Caution is recommended when extrapolating these results to other animal species, because the site of vasoconstriction may be different for a given substance.

Animals↗

PubMed1990

Histamine elicits competing endothelium-dependent constriction and endothelium-independent dilation in vivo in mouse cerebral arterioles.

We used television microscopy and an image-splitting technique to monitor the changes in diameter produced by histamine applied locally to mouse pial arterioles in vivo. A high dose (50 micrograms/ml, 3 X 10(-4) M) of histamine constricted the arterioles, whereas lower doses (20 and 10 micrograms/ml) relaxed them. Constriction was blocked and dilation occurred when selective injury of the endothelium was produced by light from a helium-neon laser in the presence of intravascular Evans blue. From this we conclude that the constriction was endothelium-dependent and was caused by the release of an endothelium-derived constricting factor. Constriction was also blocked by each of two antagonists of the H1 histamine receptor and by pretreatment of the arterioles with indomethacin. H1 blockade unmasked a dilating action of 1 micrograms/ml histamine, a dose too low to affect the diameter of arterioles not treated with the H1 blocker. An H2 blocker interfered with the relaxation by low-dose (10 micrograms/ml, 6 X 10(-5) M) histamine. These data indicate that for mouse pial arterioles, histamine can interact with H1 receptors on the endothelium to release an endothelium-derived constricting factor that causes constriction of the underlying muscle while simultaneously interacting with H2 receptors in the muscle that mediate relaxation of the vessel.

Animals↗

PubMed1989

Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats.

To find a better treatment for patient ductus arteriosus of preterm infants, we studied the combined effect of indomethacin and betamethasone on the fetal ductus in rats. We used a rapid whole-body freezing technique, and the ratio of the inner diameter of the ductus to the main pulmonary artery, which was 1.0 in controls, was used as an index of constriction. Indices of ductal constriction 4 h after administration of indomethacin (1 mg/kg) alone, betamethasone (1 mg/kg) alone or in combination in near-term rats were 0.56 +/- 0.05 (mean +/- SEM), 0.76 +/- 0.06, and 0.17 +/- 0.03, respectively. In preterm rats too, a marked increase in fetal ductus constriction was observed with the combined administration of these two drugs. Study of the dose effect of betamethasone revealed that maximal effects were obtained with 1 mg/kg of betamethasone combined with indomethacin in both preterm and near-term fetal rats. Increased constriction of the fetal ductus with combination treatment persisted from 1 to 8 h after administration. Administration of betamethasone 24 h before the rat was killed did not augment constriction of the fetal ductus by indomethacin administered 4 h before they were killed. Fetal ductus constriction by sulindac, another nonsteroidal antiinflammatory drug with little inhibitory effect on renal function, also was augmented by combined use with betamethasone (1 mg/kg). In conclusion, ductal constriction was markedly increased by combined administration of indomethacin and betamethasone in near-term and preterm fetal rats.

Animals↗

PubMed2005

In vivo constriction of the fetal and neonatal ductus arteriosus by a prostanoid EP4-receptor antagonist in rats.

Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 microg/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 microg/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants.

Animals↗

PubMed1989

Inhibition of the vagal reflex-induced tracheal constriction by psychotropic drugs.

We investigated the effects of psychotropic drugs on reflex tracheal constriction in anesthetized, paralyzed, and artificially ventilated mongrel dogs. The tracheal constriction induced by the electrical stimulation of the central cut end of the right vagus nerve was abolished by sectioning both the left superior laryngeal and recurrent laryngeal nerves, and was reduced by a low dose of pentobarbital (3 mg/kg, i.v.). This indicates that the tracheal constriction is mediated by a vagal reflex. Chlorpromazine (3 mg/kg, i.v.) and imipramine (1-3 mg/kg) reduced the reflex tracheal constriction. Chlorpromazine and imipramine had no effect on the tracheal constriction induced by the efferent electrical stimulation of the recurrent laryngeal nerve. This suggests that the higher centers may affect the reflex airway constriction and that the present preparation may be useful for investigating the effect of psychotropic drugs on the reflex airway constriction during asthmatic attacks.

Airway Resistance↗