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PubMed1987

Effects of sympathectomy on heart size and function in aortic-constricted rats.

Effects of chemical sympathectomy with 6-hydroxydopamine on left ventricular mass, norepinephrine content, and performance in aortic-constricted and sham-constricted rats were examined. Sympathectomy did not affect mean arterial pressure but it led to lower final body weights in aortic-constricted rats. Of the hypertensive aortic-constricted rats, those that had also been sympathectomized showed greater increases in left ventricular weight-to-body weight, right ventricular weight-to-body weight, and lung weight-to-body weight ratios. Left ventricular norepinephrine content was depressed by either sympathectomy or aortic constriction and was severely depleted by their combination. Sympathectomy had no effect on maximal cardiac output or left ventricular stroke work during rapid saline infusion. In aortic-constricted rats, however, it lowered heart rate during the infusion and increased left ventricular end-diastolic pressure at peak stroke work. This evidence suggests that elimination of the adrenergic nervous system's chronotropic influence promotes greater left ventricular filling, and the resultant increase in preload may importantly contribute to the stimulation of cardiac hypertrophy.

Animals↗
PubMed1990

Leukocyte and platelet-derived factors augment canine coronary constriction to serotonin.

In open-chest anesthetized dogs acute hypertension causes neutrophil and platelet adhesion to vascular endothelium and selectively potentiates constriction to serotonin in proximal coronary arteries. To examine underlying mechanisms, canine left anterior descending coronary arteries subjected to 15 min hypertension (LAD-HYP) and control left circumflex coronary arteries (CX) perfused at normal pressure were studied in organ chambers. In endothelium-intact LAD-HYP rings, constriction to serotonin was potentiated fourfold compared with control CX rings but was similar in denuded LAD-HYP and CX vessels. Endothelium-dependent relaxation to acetylcholine was not affected by acute hypertension. In LAD-HYP rings 10 microM LY 83583 (which depletes guanosine 3',5'-cyclic monophosphate and inhibits effects of endothelium-derived relaxing factor) augmented constriction to serotonin twofold. LY 83583 did not affect the serotonin response in hypertensive rings whose endothelium was mechanically removed. Blockade of either leukotriene D4 (LTD4) receptors (either with LY 171883 or SKF 102992) or thromboxane A2 (TxA2) receptors (with SQ 29548) partially blunted constriction to serotonin. Combined LTD4- and TxA2-receptor blockade completely normalized serotonin-induced constriction in LAD-HYP rings. In preconstricted LAD-HYP rings, relaxations to serotonin were markedly impaired but were restored by addition of ketanserin. Normalization of relaxation to serotonin in hypertensive vessels by ketanserin is likely due to inhibition of 5-hydroxytryptamine2 (5-HT2) receptors on platelet membranes. In conclusion, augmented constriction to serotonin in canine epicardial vessels exposed to acute hypertension is not due to an impairment of endothelium-dependent relaxation to the amine but to concomitant release of leukotrienes and TxA2 from leukocytes and platelets adhering to damaged endothelium. Activation of 5-HT2 serotonergic receptors on platelet membranes could be a possible trigger mechanism.

Acetylcholine↗
PubMed1992

Reversal by increased CSF [H+] and [K+] of phorbol ester-induced arteriolar constriction in piglets.

We determined whether several dilator stimuli could counteract phorbol ester-induced constriction of pial arterioles. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy in newborn pigs. Diameter of one pial arteriole was determined during baseline conditions and topical application of 10(-5) M phorbol 12, 13-dibutyrate (PDB) and during subsequent application of one of the following: arterial hypercapnia (inhalation of 10% CO2), topical application of cerebrospinal fluid with 12 mM K+, or topical application of 10(-5) M isoproterenol in cerebrospinal fluid. PDB constricted the arterioles from 101 +/- 5 to 70 +/- 5 microns (27 +/- 4%; n = 28). During this period of constriction which lasted longer than subsequent interventions (> 90 min), arterial hypercapnia dilated the arterioles by 85 +/- 19% (n = 12), and topical 12 mM K+ dilated the arterioles by 59 +/- 12% and caused vasomotion (n = 7). Despite blockade of direct dilator effects of arterial hypercapnia by indomethacin, arterial hypercapnia still reversed phorbol ester-induced constriction, suggesting that acidosis by itself is sufficient to cause this effect. In contrast, topical isoproterenol did not dilate PDB-constricted arterioles (n = 9); however, topical forskolin (2.4 x 10(-7) M) did reverse constriction, implying that protein kinase C activation may interfere with proper functioning of the beta-adrenoceptor. Therefore, increased extracellular fluid levels of K+ and H+, but not isoproterenol, are able to interfere with cerebrovascular consequences of protein kinase C activation.

Animals↗
PubMed1997

Endothelium-derived nitric oxide limits sympathetic neurogenic constriction in intestinal microcirculation.

We have recently shown that endogenous nitric oxide (NO) activity can attenuate the sympathetic neurogenic constriction of intestinal arterioles. The purpose of this study was to determine whether the microvascular endothelium is an important site of NO production under these conditions. In the superfused small intestine of the rat, intravital microscopy was used to study the responses of first-order arterioles (1A) to perivascular sympathetic nerve stimulation and directly applied norepinephrine before and then after passage of a CO2 embolus through the 1A lumen to inhibit endothelial function. CO2 embolization did not significantly alter resting arteriolar diameter (50 +/- 4 microns before vs. 51 +/- 4 microns after embolization) but abolished the dilator response to acetylcholine without altering the dilator response to sodium nitroprusside. Stimulation at 3, 8, and 16 Hz caused respective constrictions of 4 +/- 1, 11 +/- 1, and 18 +/- 2 microns, and after CO2 these responses were significantly increased to 9 +/- 1, 18 +/- 1, and 29 +/- 3 microns, respectively. Exposure to the nitric oxide synthase inhibitor NG-monomethyl-L-arginine(10(-4) M in superfusate) after CO2 embolization had no further effect on the magnitude of neurogenic constriction. Similar results were seen when embolization was achieved with N2, and CO2 embolization had the same effect on norepinephrine-induced constriction as it did on neurogenic constriction. These results suggest that nitric oxide of endothelial origin can attenuate sympathetic neurogenic constriction in the intestinal microvasculature.

Animals↗
PubMed1999

Endothelin antagonists block alpha1-adrenergic constriction of coronary arterioles.

We have previously observed that intracoronary administration of the alpha1-adrenergic agonist phenylephrine (PE) over a period of minutes induced both an immediate and long-lasting (2 h) vasoconstriction of epicardial coronary arterioles. Because it is unlikely that alpha1-adrenergic constriction would persist for hours after removal of the agonist, this observation supports the view that another constrictor(s) is released during alpha1-adrenergic activation and induces the prolonged vasoconstriction. Therefore, we hypothesized that the prolonged microvascular constriction after PE is due to the production of endothelin (ET). We focused on ET not only because this peptide produces potent vasoconstriction but also because its vasoconstrictor action is characterized by a long duration. To test this hypothesis, the diameters of coronary arterioles (<222 micrometers) in the beating heart of pentobarbital-anesthetized dogs with stroboscopic intravital microscopy were measured during a 15-min intracoronary infusion of PE (1 microgram. kg-1 . min-1) and at 15-min intervals for a total of 120 min. All experiments were performed in the presence of beta-adrenergic blockade with propranolol. At 120 min, arterioles in the PE group were constricted (-23 +/- 9% change in diameter vs. baseline). Pretreatment with the ET-converting enzyme inhibitor phosphoramidon or the ETA-receptor antagonist FR-139317 prevented the PE-induced constriction at 120 min (-1 +/- 3 and -6 +/- 3%, respectively, P < 0.01 vs. PE). Pretreatment with the selective alpha1-adrenergic antagonist prazosin (Prz) also prevented the sustained constriction (0 +/- 2%, P < 0.01 vs. PE) but Prz given 60 min after PE infusion did not (-13 +/- 3%). In the aggregate, these results show that vasoconstriction of epicardial coronary arterioles via alpha1-adrenergic activation is blocked by an ET antagonist and an inhibitor of its production. From these data, we conclude that alpha1-adrenergic activation promotes the production and/or release of ET, which produces or facilitates microvascular constriction of epicardial canine coronary arterioles.

Adrenergic alpha-Agonists↗
PubMed2005

Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus.

After birth, constriction of the full-term ductus arteriosus induces oxygen, glucose and ATP depletion, cell death, and anatomic remodeling of the ductus wall. The immature ductus frequently fails to develop the same degree of constriction or anatomic remodeling after birth. In addition, the immature ductus loses its ability to respond to vasoconstrictive agents, like oxygen or indomethacin, with increasing postnatal age. We examined the effects of premature delivery and postnatal constriction on the immature baboon ductus arteriosus. By 6 days after birth, surrogate markers of hypoxia (HIF1alpha/VEGF mRNA) and cell death [dUTP nick-end labeling (TUNEL)-staining] increased, while glucose and ATP concentrations (bioluminescence imaging) decreased in the immature ductus. TUNEL-staining was significantly related to the degree of glucose and ATP depletion. Glucose and ATP depletion were directly related to the degree of ductus constriction; while TUNEL-staining was logarithmically related to the degree of ductus constriction. Extensive cell death (>15% TUNEL-positive cells) occurred only when there was no Doppler flow through the ductus lumen. In contrast, HIF1alpha/VEGF expression and ATP concentrations were significantly altered even when the immature ductus remained open after birth. Decreased ATP concentrations produced decreased oxygen-induced contractile responses in the immature ductus. We hypothesize that ATP depletion in the persistently patent immature newborn ductus is insufficient to induce cell death and remodeling but sufficient to decrease its ability to constrict after birth. This may explain its decreasing contractile response to oxygen, indomethacin, and other contractile agents with increasing postnatal age.

Adenosine Triphosphate↗
PubMed2003

How does airway inflammation modulate asthmatic airway constriction? An antigen challenge study.

During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.

Adult↗
PubMed2003

Modeling airflow-related shear stress during heterogeneous constriction and mechanical ventilation.

Ventilator-induced lung injury has been proposed as being caused by overdistention and closure and reopening of small airways and alveoli. Here we investigate the possibility that heterogeneous constriction increases airflow-related shear stress to a dangerously high level that may be sufficient to cause injury to the epithelial cells during mechanical ventilation. We employed an anatomically consistent model of the respiratory system, based on Horsfield morphometric data, and solved for the time evolution of pressure and flow along the airway tree during mechanical ventilation. We simulated constant-flow ventilation with passive expiration in two different conditions: baseline and highly heterogeneous constriction. The constriction was applied with two strategies: establishing a simple diameter reduction or adding also a length shortening. The shear stress distribution on airway walls was analyzed for airways ranging from the trachea to the acini. Our results indicate that 1). heterogeneous constriction can amplify the maximal values of shear stress up to 50-fold, with peak values higher than 0.6 cmH2O; 2). the highest shear stress is found in pathways constricted by 60-80%; 3). simultaneous diameter reduction and shortening amplifies the shear stresses by three- to fourfold, with shear stresses reaching 2 cmH2O; and 4). there is a range of airways (diameters from 0.6 to 0.3 mm at baseline) that appear to be at risk of very high stresses. We conclude that elevated airflow-related shear stress on the epithelial cell layer can occur during heterogeneous constriction and conjecture that this may constitute a mechanism contributing to ventilator-induced lung injury.

Air Pressure↗
PubMed1979

A tdic(5;15)(p31;p11) chromosome showing variation for constriction in the centromeric regions in a patient with the cri du chat syndrome.

Some dicentric chromosomes show only one primary constriction at metaphase and behave in cell division as if they are monocentric. The few previous reports of tdic (translocation dicentric) chromosomes showing one morphologic indicate that among the cells of an individual the same centromere consistently shows the primary constriction. The present case deals with a tdic(5;15)(p13;p11) chromosome that is an exception to this pattern. Scoring 98 GTG-, C-, and QFQ-banded metaphases specifically for primary constrictions revealed 15 (15%) containing a tdic chromosome with a single primary constriction. Among these chromosomes, 8 (8%) were at the chromosome 15 centromere and 7 (7%) were at the chromosome 5 centromere. The remaining 83 (85%) tdic chromosomes showed two primary constrictions. We analyzed a total of 172 metaphases from peripheral blood, and all except 3 (1.7%) contained the tdic chromosome. Among these three cells, the tdic chromosome was broken in two and absent in one, which indicates that there was some unstable separation of this dicentric in cell division. In two metaphases, there was a chromatid gap at the site of one centromere. Possibly, the absence of certain primary constrictions was associated with deletion of centromeres. This mechanism may be a continual source for additional centromere inactivation during the life of this patient. This case demonstrates that for some dicentrics either centromere may become nonfunctional and inactivation can occur more than once within an individual. The karyotype of this patient was 45,XX,tdic(5;15)(p31;p11). Thus, she was monosomic for about 3/4 of the chromosome 5 short arm. Clinically, this infant had a shrill catlike cry and facies of the cri du chat syndrome.

Centromere↗
PubMed1998

Requisite role of cardiac myocytes in coronary alpha1-adrenergic constriction.

BACKGROUND: Alpha-adrenergic activation in vivo causes constriction of coronary arterioles, but, paradoxically, in vitro these microvessels do not contract to this stimulus. We hypothesized that cardiac myocytes have a requisite role in alpha1-adrenergic coronary arteriolar constriction through the release of myocyte-derived contractile factor(s). METHODS AND RESULTS: Administration of the alpha1-adrenergic agonist phenylephrine did not constrict isolated coronary arterioles, but constriction was observed to supernatant obtained from phenylephrine-treated cardiac myocytes. Constriction to the supernatant was blocked by administration of an endothelin-A antagonist to the microvessel preparation or an alpha-adrenergic antagonist to the myocytes and was augmented after administration of an adenosine antagonist. Administration of phenylephrine to the myocytes increased endothelin-1 levels in the supernatant, but only to subthreshold concentrations. CONCLUSIONS: Cardiac myocytes have a requisite role in constriction of coronary resistance vessels to alpha1-adrenergic stimuli, which may be mediated by endothelin-1 and other unidentified myocyte-derived vasoconstrictors.

Adenosine↗
PubMed1996

Differential sensitivity of venular and arteriolar alpha-adrenergic receptor constriction to inhibition by hypoxia. Role of receptor subtype and coupling heterogeneity.

Reflex adrenergic constriction of the venous circulation is considerably less sensitive than the arterial circulation to local metabolic inhibition, but the basis for this difference remains unclear. The purpose of the present study was to determine whether alpha-adrenergic receptor (AR) constriction of venular smooth muscle is in fact protected against inhibition by hypoxia, per se, and to examine possible mechanisms for this protection. An intermediate level of alpha 1-AR (norepinephrine + rauwolscine) or alpha 2-AR (UK 14,304 + prazosin) tone was induced in rat cremaster skeletal muscle arterioles and venules (control lumen diameter, 134 and 194 micron respectively), and tissue bath PO2 was lowered from the control value (30 mm Hg). Arteriolar alpha 2-AR tone was inhibited by 29% at 5 mm Hg PO2 (P < .05), whereas arteriolar alpha 1-, venular alpha 1, and venular alpha 2-AR constrictions were unaffected. Like these findings obtained for in situ vessels with normal blood flow, alpha 1-AR tone induced in vascularly "isolated" venules and basal diameter were again unaffected by hypoxia, whereas alpha 2-AR tone was actually enhanced by 19% (P < .05). This constriction was prevented by indomethacin but not by endothelin or nitric oxide blockade; importantly, however, venular alpha 2- and alpha 1-AR tone still remained insensitive to inhibition by hypoxia. ATP-sensitive K+ (KATP) channels, which are known to participate in hypoxic inhibition of arteriolar smooth muscle, were examined for a role in this differential arteriolar versus venular sensitivity to hypoxia. Use of the KATP antagonists glibenclamide and U-37883A and the KATP channel opener cromakalim suggested that venular, unlike arteriolar, smooth muscle had no detectable basal or inducible KATP activity. Also, unlike arteriolar alpha 2-AR constriction, venular alpha 2-AR tone did not depend on KATP activity. Finally, venular alpha 2-AR tone was unaffected by nifedipine (0.06 to 3 mumol/L), whereas venular alpha 1-AR tone was inhibited by 50% (P < .05), findings opposite those found for arteriolar alpha 1 and alpha 2 tone. These data demonstrate that venular alpha 1- and alpha 2-AR constrictions are insensitive to inhibition by hypoxia and suggest that this may be due to a paucity of KATP channels on venular smooth muscle. In addition, venular alpha 1- but not alpha 2-ARs appear to couple to dihydropyridine-sensitive voltage-operated Ca2+ channels.

Animals↗
PubMed2002

Xanthine oxidase-derived reactive oxygen species convert flow-induced arteriolar dilation to constriction in hyperhomocysteinemia: possible role of peroxynitrite.

We hypothesized that in hyperhomocysteinemia (HHcy), flow-induced arteriolar constriction is due to an enhanced generation of reactive oxygen and/or nitrogen species, causing an impairment of nitric oxide (NO) and prostaglandin mediation of the response. Changes in diameter of isolated, pressurized (at 80 mm Hg) gracilis muscle arterioles (diameter approximately 170 microm) from control and methionine diet-induced HHcy rats were measured by videomicroscopy. Increases in intraluminal flow (from 0 to 25 microL/min) resulted in NO- and prostaglandin-mediated dilations of control arterioles (maximum, control, 30+/-4 microm) but elicited significant constrictions of HHcy arterioles (maximum, HHcy, -32+/-3 microm), which were abolished by the thromboxane A(2) receptor blocker SQ 29,548. Intraluminal administration of superoxide dismutase plus catalase did not affect flow-mediated dilations of control arterioles, but in HHcy arterioles, it reversed the flow-induced constrictions to dilations (maximum 18+/-4 microm), which were abolished by an NO synthase inhibitor. Flow-induced constrictions of HHcy arterioles were prevented by the presence of the xanthine oxidase inhibitor oxypurinol [but not by the NAD(P)H-oxidase inhibitor diphenyleneiodonium] and by urate, a known peroxynitrite scavenger. Also, authentic peroxynitrite elicited arteriolar constrictions (-31+/-8 microm) that were eliminated by urate and SQ 29,548. Thus, we suggest that in HHcy, xanthine oxidase-derived superoxide scavenges NO released to flow, forming peroxynitrite, which promotes release of thromboxane A(2), resulting in arteriolar constriction.

Animals↗
PubMed2001

Airway constriction pattern is a central component of asthma severity: the role of deep inspirations.

Measurements of lung resistance and elastance (RL and EL) from 0.1 to 8 Hz reflect both the mean level and pattern of lung constriction. The goal of this study was to establish a relation between a deep inspiration (DI) and the heterogeneity of constriction in healthy versus asthmatic subjects. Constriction pattern was assessed from measurements of the RL and EL from 0.1 to 8 Hz in seven healthy subjects and in 12 asthmatics. These data were acquired before and after a DI and before and after a standard methacholine challenge versus a modified challenge in which a DI is prohibited. Generally, avoidance of a DI increased responsiveness. In healthy subjects and in those with mild-to-moderate baseline asthma a bronchial challenge, especially during self-inhibited DI, produced a heterogenous pattern of constriction inclusive of randomly distributed airway closures or near closures. Nevertheless, such subjects were able to reopen their airways via a DI. In contrast, in subjects with severe baseline asthma, there is a more extreme heterogeneous constriction pattern with random airway closures even at baseline. Further, there is no residual bronchodilatory effect of a DI either before or after bronchial challenge. We conjecture that inflammation and wall-remodeling facilitate a dangerous degree of heterogeneous constriction inclusive of airway closures or near closures, and contribute to the prevention of a DI from having a residual bronchodilatory effect.

Adolescent↗
PubMed1987

In vivo constriction of the ductus arteriosus by nonsteroidal antiinflammatory drugs in near-term and preterm fetal rats.

Herein we report age differences of in vivo constriction of the fetal ductus arteriosus by nonsteroidal antiinflammatory drugs in near-term and preterm rats. Two potent nonsteroidal antiinflammatory drugs, indomethacin and flurbiprofen, were studied in preterm (19th and 20th day) and near-term (21st day) rats, whose gestational period was 21.5 days. The time course of fetal ductus constriction was studied on the 20th (preterm fetus) and the 21st (near-term fetus) days of gestation with indomethacin (1 mg/kg, 10 mg/kg) and flurbiprofen (10 mg/kg). In addition, 5 mg/kg of indomethacin was used on the 21st day. Maximal ductal constriction was noticed 8 h after administration. Constriction of the ductus was significantly weaker on the 20th day than on the 21st day in all three studies including indomethacin 1 mg/kg, 10 mg/kg, and flurbiprofen, 10 mg/kg. Dose-response curves were studied at 4 h following administration of indomethacin on the 19th, 20th, and 21st days, and flurbiprofen on the 20th and 21st days. With both drugs, the ductus constricted more vigorously on the 21st day than on the 20th or 19th day. These studies showed a weaker constrictive response of the ductus to nonsteroidal antiinflammatory drugs in the preterm fetus than in the near-term fetus. Twenty-four h after administration of indomethacin on the 20th day, the fetal ductus was dilated, although its plasma indomethacin concentration was high and comparable with that obtained 4 h after administration. These results show that the response of the fetal ductus to indomethacin decreased further at 24 h after administration to preterm rats.

Animals↗
PubMed1990

Involvement of alpha 2-adrenergic receptors in the vagal reflex-induced tracheal constriction.

The effects of clonidine on the vagal reflex-induced tracheal constriction have been investigated in anesthetized, paralyzed, and artificially ventilated mongrel dogs. The cervical trachea was transected in situ into two parts. Responses of the tracheal musculature were measured as changes in the intratracheal pressure on an air-filled balloon introduced into the rostral side of the transected trachea. Reflex tracheal constriction was induced by afferent electrical stimulation at the central cut end of the vagus nerve. Drugs were injected or infused close intraarterially (i.a.) into the bilateral cranial thyroid arteries in such a way that each drug was applied just to the rostral trachea. The reflex tracheal constriction was abolished by a close i.a. infusion of 3 microM atropine. The magnitude of the reflex tracheal constriction was slightly reduced by a close i.a. infusion of 10 microM clonidine and was significantly reduced by the infusion of clonidine at a concentration of 100 and 300 microM. The response to 100 microM clonidine was antagonized by a close i.a. infusion of 1 microM yohimbine. The tracheal constriction induced by i.a. injection of 5.5 nmol acetylcholine was unaffected by infusion of 10, 100 and 300 microM clonidine. The vagal reflex-induced tracheal constriction seems to be inhibited by stimulation of prejunctional alpha 2-adrenoceptors.

Acetylcholine↗
PubMed1994

Spontaneous airways constrict during breath holding studied by high-resolution computed tomography.

Airway constriction during a breath hold could not be examined previously using standard methods. We used high-resolution computed tomography (HRCT) in vivo to assess the temporal changes in airway area and the effects of a deep inspiration with and without vagal suppression. Five dogs were anesthetized, intubated, and their lungs ventilated with 100 percent oxygen. Fifteen HRCT slices were obtained at functional residual capacity (FRC) either immediately after stopping ventilation at end expiration after either a tidal volume breath or three deep inspirations. Subsequently the dogs were given atropine, 0.2 mg/kg, and the scans were repeated. The cross-sectional areas of 33 airways ranging in size from 1.6 to 9.7 mm in diameter were measured. Airways were separated in three groups based on size: small (< 3 mm in diameter); medium (3 to 6-mm in diameter); and large (> 6 mm in diameter). The small, medium, and large airways showed a spontaneous constriction over time to 49 +/- 8 percent, 83 +/- 4 percent, and 82 +/- 4 percent of initial airway size, respectively (p < 0.01), (p < 0.0001). The deep inspiration caused an initial dilation only in the smallest airways to 133.3 +/- 4 percent. The subsequent constrictions were even greater than after the tidal volume breath averaging 67 +/- 15 percent, 61 +/- 6 percent, and 60 +/- 9 percent of initial airway area in the small, medium, and large airways, respectively (p = 0.001). Atropine caused an average increase in baseline airway area of 115 +/- 5 percent and 121 +/- 6 percent after a tidal volume breath and deep inspiration, respectively, compared with the preatropine controls, with no difference between the three groups. Atropine also completely abolished the spontaneous airway constriction observed after either a tidal volume breath or a deep inspiration in all three groups equally. In conclusion, using direct airway imaging in vivo, we found that airways spontaneously constrict during a prolonged expiratory pause, and a deep inspiration significantly augments this airway constriction. These responses are mediated via vagal afferent pathways, likely arising from progressively decreasing slow-adapting receptor activity.

Analysis of Variance↗
PubMed1997

Direct evidence that thromboxane mimetic U44069 preferentially constricts the afferent arteriole.

The thromboxane A2 (TXA2) mimetic U44069 has been demonstrated to reduce the GFR and filtration fraction of the normal isolated perfused rat kidney markedly, suggesting a predominant constriction of preglomerular vessels. To assess this possibility directly, effects of U44069 on the renal microvessels of the isolated perfused hydronephrotic kidney were examined. At 10(-6) mol/L, U44069 elicited a 27 +/- 2% decrease in afferent arteriolar (AA) diameter (from 18.8 +/- 0.3 to 13.7 +/- 0.3 micron, P < 0.001). In contrast, efferent arteriolar (EA) diameter decreased by only 9 +/- 1% (from 16.4 +/- 0.5 to 15.0 +/- 0.5 micron, P < 0.001). These effects on both AA and EA were completely reversed by the TXA2 receptor antagonist SQ29548. The calcium antagonist diltiazem reversed U44069-induced AA constriction by 83 +/- 5%. The U44069-induced EA constriction was insensitive to the vasodilator action of diltiazem at concentrations from 10(-8) to 10(-6) mol/L, but at 10(-5) mol/L, diltiazem increased the EA diameter significantly, albeit modestly. Nifedipine also reversed the U44069-induced AA constriction (81 +/- 7%), but failed to inhibit the EA constriction at concentrations from 10(-9) to 10(-6) mol/L. These findings constitute the first direct evidence that a TXA2 agonist preferentially constricts the afferent arteriole. Furthermore, the ability of both the calcium antagonist and SQ29548 to reverse the renal microvascular actions of TXA2 agonists suggests a potential utility of these agents in ameliorating TXA2-induced renal hemodynamic abnormalities.

Animals↗
PubMed2002

Endothelin-1 in citric acid aerosol inhalation-induced airway constriction of guinea pigs.

Endotheline-1 (ET-1) has been shown to enhance tachykinin-induced airway constriction. This study was designed to test whether ET-1 is involved in citric acid-induced bronchoconstriction. Forty-eight anesthetized-paralyzed guinea pigs were divided into six groups of 8 animals each: saline control; citric acid; ET-1; ET-1 + citric acid; BQ123 + ET-1 + citric acid; and BQ788 + ET-1 + citric acid. BQ123 and BQ788 are specific ETA and ETB receptor antagonists, respectively. Each animal in the saline control group received 50 breaths of 4 ml saline aerosol and in all citric acid-treated groups was given 50 breaths of 4 ml aerosol generated from 0.6 M citric acid. In all ET-1-treated groups, each animal was exposed to aerosol generated from 10(-8) M ET-1. The animal in the ET-1 + citric acid group was exposed to ET-1 5 min prior to the citric acid. For the last two groups, each animal was first exposed to aerosol generated from either 10(-5) M BQ123 or 10(-5) M BQ788. Five min later, the animal was exposed to ET-1; and then 5 min later was followed by citric acid. Dynamic respiratory compliance (Crs), forced expiratory volume in 0.1 sec (FEV(0.1)), and maximal expiratory flow at 30% total lung capacity (Vmax 30) were obtained before and 3-15 min after citric acid. Either citric acid or ET-1 inhalation caused significant decreases in Crs, FEV(0.1), and Vmax 30, indicating airway constriction. Citric acid-induced airway constriction, for most cases, was not significantly augmented by ET-1. However, either BQ123 or BQ 788 significantly attenuated the airway constriction induced by the combination of ET-1 and citric acid. Also, in an additional study, either BQ123 or BQ788 significantly attenuated citric acid-induced airway constriction. These data suggest that endogenous ET-1 plays an important role in citric acid aerosol-induced airway constriction in guinea pigs.

Administration, Inhalation↗