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PubMed1977

Renin-angiotensin system and aldosterone secretion during aortic constriction in the rat.

Suprarenal aortic constriction sufficient to reduce renal perfusion pressure by approximately 50% increased aldosterone secretion in anesthetized rats pretreated with dexamethasone. Bilateral nephrectomy under the same experimental conditions blocked the aldosterone response. Additionally, [1-sarcosine, 8-alanine]angiotensin II blocked the response in aldosterone secretion to aortic constriction in dexamethasone-treated rats. Finally, in rats hypophysectomized to exclude the influence of ACTH, the aldosterone response to aortic constriction was blocked by [1-sarcosine, 8-alanine]angiotensin II. The results indicate that angiotensin II increased aldosterone secretion during aortic constriction in the rat. These observations, along with those reported previously in sodium-depleted rats, point to an important overall role for the renin-angiotensin system in the control of aldosterone secretion in the rat.

Adrenal Glands↗
PubMed1999

Elastic moduli of excised constricted rat lungs.

When airways constrict, the surrounding parenchyma undergoes stretch and distortion. Because of the mechanical interdependence between airways and parenchyma, the material properties of the parenchyma are important factors that modulate the degree of bronchoconstriction. The purpose of this study was to investigate the effect of changes in transpulmonary pressure (Ptp) and induced constriction on parenchymal bulk (k) and shear (mu) moduli. In excised rat lungs, pressure was measured at the airway opening, and pressure-volume curves were obtained by imposing step decreases in volume with a calibrated syringe from total lung inflation. Calculation was made of k during small-volume oscillations (1 Hz). Absolute lung volume at 0 cmH2O Ptp was obtained by saline displacement. To calculate mu, a lung-indentation test was performed. The lung surface was deformed with a cylindrical punch (diameter = 0.45 cm) in 0.25-mm increments, and the force required to effect this displacement was measured by a weight balance. Measurements of k and mu were obtained at 4 and 10 cmH2O Ptp, and again at 4 cmH2O Ptp, after delivery of methacholine aerosol (100 mg/ml) into the trachea. Values of k and mu in rat lungs were similar to those reported in other species. In addition, k and mu were dependent on Ptp. After induced constriction, k and mu increased significantly. That k and mu can increase after induced constriction has important implications vis a vis the factors modulating airway narrowing.

Aerosols↗
PubMed2005

Acute vibration increases alpha2C-adrenergic smooth muscle constriction and alters thermosensitivity of cutaneous arteries.

The vascular symptoms of hand-arm vibration syndrome, including cold-induced vasospasm, are in part mediated by increased sensitivity of cutaneous arteries to sympathetic stimulation. The goal of the present study was to use a rat tail model to analyze the effects of vibration on vascular function and alpha-adrenoceptor (AR) responsiveness. Rats were exposed to a single period of vibration (4 h, 125 Hz, constant acceleration 49 m/s2 root mean square). The physical or biodynamic response of the tail demonstrated increased transmissibility or resonance at this frequency, similar to that observed during vibration of human fingers. Morphological analysis demonstrated that vibration did not appear to cause structural injury to vascular cells. In vitro analysis of vascular function demonstrated that constriction to the alpha1-AR agonist phenylephrine was similar in vibrated and control arteries. In contrast, constriction to the alpha2-AR agonist UK14304 was increased in vibrated compared with control arteries, both in endothelium-containing or endothelium-denuded arteries. The alpha2C-AR antagonist MK912 (3 x 10(-10) M) inhibited constriction to UK14304 in vibrated but not control arteries, reversing the vibration-induced increase in alpha2-AR activity. Moderate cooling (to 28 degrees C) increased constriction to the alpha2-AR agonist in control and vibrated arteries, but the magnitude of the amplification was less in vibrated compared with control arteries. Endothelium-dependent relaxation to acetylcholine was similar in control and vibrated arteries. Based on these results, we conclude that a single exposure to vibration caused a persistent increase in alpha2C-AR-mediated vasoconstriction, which may contribute to the pathogenesis of vibration-induced vascular disease.

Adrenergic alpha-Agonists↗
PubMed2002

Diaphragm arterioles are less responsive to alpha1- adrenergic constriction than gastrocnemius arterioles.

The sympathetic nervous system has greater influence on vascular resistance in low-oxidative, fast-twitch skeletal muscle than in high-oxidative skeletal muscle (17). The purpose of this study was to test the hypothesis that arterioles isolated from low-oxidative, fast-twitch skeletal muscle [the white portion of gastrocnemius (WG)] possess greater responsiveness to adrenergic constriction than arterioles isolated from high-oxidative skeletal muscle [red portion of the gastrocnemius muscle (RG) and diaphragm (Dia)]. Second-order arterioles (2As) were isolated from WG, RG, and Dia of rats and reactivity examined in vitro. Results reveal that Dia 2As constrict less to norepinephrine (NE) (10(-9) to 10 (-4) M) than 2As from RG and WG, which exhibited similar NE-induced constrictions. This difference was not endothelium dependent, because responses of denuded 2As were similar to those of intact arterioles. The blunted NE-induced constrictor response of Dia 2As appears to be the result of differences in alpha1-receptor effects because 1) arterioles from Dia also responded less to selective alpha1-receptor stimulation with phenylephrine than RG and WG arterioles; 2) arterioles from Dia, RG, and WG dilated similarly to isoproterenol (10(-9) to 10(-4) M) and did not respond to selective alpha2-receptor stimulation with UK-14304; and 3) endothelin-1 produced similar constriction in 2As from Dia, RG, and WG. We conclude that differences in oxidative capacity and/or fiber type composition of muscle tissue do not explain different NE responsiveness of Dia 2As compared with 2As from gastrocnemius muscle. Differences in alpha1-adrenergic constrictor responsiveness among arterioles in skeletal muscle may contribute to nonuniform muscle blood flow responses observed during exercise and serve to maintain blood flow to Dia during exercise-induced increases in sympathetic nerve activity.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2003

Heartbeat control in leeches. I. Constriction pattern and neural modulation of blood pressure in intact animals.

Two tubular hearts propel blood through the closed circulatory system of the medicinal leech. The hearts are myogenic but are driven by a centrally generated motor pattern that controls heart rate and intersegmental coordination. In two consecutive papers, we address the question of how the motor pattern is translated into the pattern of diastole and systole of leech hearts. We imaged the constriction patterns of the hearts in quiescent intact animals. In one heart, systole progresses rear-to-front (peristaltic coordination mode), whereas systole occurs nearly simultaneously in the other heart (synchronous coordination mode) with regular switches between these two coordination modes. Intersegmental phase relations between heart segments do not vary with changes in the heartbeat period. The peristaltic heart drives blood forward through itself and then rearward through the other longitudinal vessels. The synchronous heart does not seem to contribute to rearward flow along the body axis and may support segmental circulation instead. Simultaneous monitoring of heart motor neuron discharge and the constriction of the corresponding heart segment in innervated, reduced preparations enabled us later to meld the constriction pattern with the fictive motor pattern described in the following paper. Current injections into one heart modulatory neuron while monitoring intravascular pressure from the corresponding heart showed that these neurons can acutely change diastolic and systolic pressure. However, they do not determine the different systolic pressure profiles associated with the two coordination modes, which appear to result from the constriction pattern.

Action Potentials↗
PubMed1982

Constriction of ear arteries from normotensive and renal hypertensive rabbits against different transmural pressures.

Isolated segments of rabbit ear arteries were made to constrict against normotensive and hypertensive transmural pressures by perfusion with submaximal concentrations of norepinephrine (NE). Changes in load (force/unit length of artery) and stress (force/wall cross-sectional area) during constriction against a constant pressure have been evaluated. Weak concentrations of NE constricted the arteries equally well against transmural pressures of 80 and 120 mm Hg and, in doing so, utilized much of the contractile capacity of the muscle. A stretch-mediated, co-operative interaction between muscle cells has been put forward to explain these observations. Ear arteries from renal hypertensive rabbits differed from those of normotensive rabbits in having a higher NE threshold concentration and in constricting better against 140 mm Hg. They did so because of the mechanical advantage provided by a smaller internal radius and a thicker wall which reduced the load and stress placed on the muscle by the pressure. No muscle hyperplasia or hypertrophy was detected.

Animals↗
PubMed1981

Endothelial cell damage and thrombus formation after partial arterial constriction: relevance to the role of coronary artery spasm in the pathogenesis of myocardial infarction.

The left anterior descending coronary artery of four dogs and the right common carotid artery of 15 rabbits were subjected to 40-60% reduction in transluminal diameter for 1 hour by partial ligation with suture thread. Scanning electron microscopic examination of the luminal surface of these vessels revealed endothelial craters and balloons, fragmentation and desquamation on the proximal slope of the constriction. Platelet attachment to exposed subendothelial tissues was clearly evident, and microthrombi were seen at the point of maximum constriction. Blood flow, as measured by electromagnetic flow probe, was virtually unchanged upon partial ligation. In control studies, where a second ligature was placed proximal to and before the first to reduce blood to the distal constriction site substantially or totally, endothelial desquamation was found in only one of 14 animals, and the number of craters and balloons was significantly reduced. We suggest that endothelial damage and thrombus formation may occur at the site of focal arterial constriction even when the reduction in transluminal diameter is insufficient to alter substantially the rate of flow.

Angina Pectoris↗
PubMed1988

Dilation of normal and constriction of atherosclerotic coronary arteries caused by the cold pressor test.

Increased vascular constriction has been observed at the site of atherosclerotic lesions, suggesting an association between atherosclerosis and altered vascular tone. While atherosclerosis may increase sensitivity to exogenous vasoconstrictors, little is known about the response of normal and atherosclerotic coronary arteries to an exogenous stimulus that excites the sympathetic nervous system. Therefore, we studied the response to cold pressor test (CPT) using quantitative angiography and Doppler flow velocity measurements in eight patients with angiographically normal coronary arteries (group I), nine patients with mild coronary atherosclerosis (less than 50% diameter narrowing) (group II), and 13 patients with advanced coronary stenoses (greater than 50% diameter narrowing) (group III). In 31 segments of angiographically smooth arteries in group I, the CPT produced vasodilation from a control mean diameter of 2.68 +/- 0.09 (mean +/- SE) to 2.99 +/- 0.09 mm at peak CPT (p less than 0.001), a 12 +/- 1% increase in diameter. In group II, 27 irregular segments constricted to peak CPT from a mean control diameter of 1.82 +/- 0.12 to 1.66 +/- 0.12 mm (p less than .001), a 9 +/- 1% decrease, while 10 smooth segments dilated from a mean control diameter of 1.98 +/- 0.11 mm to 2.34 +/- 0.15 mm (p less than .01), a 19 +/- 2% increase in diameter. Likewise, in group III, the 17 stenotic segments constricted from 1.16 +/- 0.09 to 0.89 +/- 0.09 mm (p less than .001), a 24 +/- 6% decrease; the irregular segments also constricted from 2.44 +/- 0.11 to 2.22 +/- 0.12 mm (p = .002), a 10 +/- 2% decrease. In contrast, two smooth segments dilated from 2.98 to 3.23 mm (mean), an 8% increase in diameter. Coronary blood flow increased 65 +/- 4% (mean) during CPT in group I, it increased 15 +/- 6% in group II, and it decreased 39 +/- 8% in group III. The vasodilator response in four normal patients was partly inhibited by the administration of intracoronary propranolol (17 +/- 3% increase during control, 10 +/- 2% increase after propranolol, 41% less dilation; p = .002). We conclude that the response of normal coronary arteries to the CPT test is dilation, in part related to beta-adrenoreceptor stimulation and possibly flow-mediated endothelial dilation or alpha 2-adrenergic activity. The paradoxical vasoconstrictor response induced by atherosclerosis may represent altered catecholamine sensitivity and/or a defect in endothelial vasodilator function. The presence of atherosclerosis impairs vasodilator responses and thus may contribute to the pathogenesis of myocardial ischemia.

Adult↗
PubMed1991

Inappropriate constriction of small coronary vessels as a possible cause of a positive exercise test early after successful coronary angioplasty.

BACKGROUND: The mechanism responsible for exercise-induced myocardial ischemia early after successful coronary angioplasty (PTCA) is poorly understood. METHODS AND RESULTS: Twelve patients who underwent one-vessel PTCA were studied. Exercise testing was performed before and on day 7 after PTCA, which was repeated after 10 mg sublingual isosorbide dinitrate if the test was positive. Quantitative coronary arteriography was also performed on day 8 after PTCA in the basal state, after intracoronary infusion of 0.9% saline, 1, 5, 10, and 20 micrograms ergonovine, and after 300 micrograms nitroglycerin. All patients had a positive exercise test before PTCA but on day 7, six patients had a positive exercise test (group 1) and six patients (group 2) had a negative exercise test. In group 1, all positive exercise tests on day 7 became negative when repeated after isosorbide dinitrate. Intracoronary ergonovine was associated with a dose-dependent constriction of the PTCA segment, a segment distal to it, and a control segment, with no significant difference in the magnitude of the response between the two groups; maximum constriction for group 1 was 19 +/- 3%, 23 +/- 2%, and 16 +/- 3% (p less than 0.001 versus basal), and in group 2 was 20 +/- 4%, 18 +/- 4%, and 9 +/- 2% (p less than 0.01 versus basal). No angina, ischemic ST segment changes, occlusive, or subocclusive spasm occurred in any patient of either group. CONCLUSIONS: We could find no evidence that exercise-induced myocardial ischemia early after PTCA is related to the presence of fixed angiographic restenosis or to dynamic constriction of any epicardial coronary segment. Therefore, inappropriate small coronary vessel constriction responsive to nitrates should be considered as a possible alternative explanation.

Adult↗
PubMed2004

Selective increase in renal arcuate innervation density and neurogenic constriction in chronic angiotensin II-infused rats.

This study investigated the effects of angiotensin II "slow pressor" hypertension on structure and function of nerves supplying the renal vasculature. Low-dose angiotensin II (10 ng/kg per minute, initially sub-pressor) or saline vehicle was infused intravenously for 21 days in rats, and the effects were compared in renal and mesenteric arteries. Mean arterial pressure averaged 12+/-2 mm Hg higher than in vehicle-infused rats at 21 days. Using electron microscopy, the innervation density of renal arcuate, but not mesenteric arteries of equivalent size, was significantly higher in angiotensin II-infused than in vehicle-infused rats. Functional testing on a pressure myograph revealed that constrictions evoked by nerve stimulation in arcuate arteries were 2.3+/-0.7-fold greater in vessels from angiotensin II-infused compared with vehicle-infused rats (P<0.0001), whereas there was no significant difference in nerve-induced constrictions in mesenteric arteries. Sensitivity to and maximum amplitude of constrictions evoked by phenylephrine were not different in renal or mesenteric arteries between groups, suggesting that the increased neurally evoked constriction in renal arcuate arteries was not caused by postsynaptic changes. Endothelium-dependent vasorelaxation and the vessel wall physical properties were not different between the two groups in either artery. Thus, angiotensin II infusion appeared to evoke renal-specific increases in vessel innervation and increased vasoconstriction to nerve stimulation. These changes appear early and occur before changes in renal endothelial function are apparent. Thus, "slow pressor" angiotensin II hypertension is associated with increased renal innervation, compatible with a pathogenetic role.

Angiotensin II↗
PubMed2005

Contribution of 20-HETE to augmented myogenic constriction in coronary arteries of endothelial NO synthase knockout mice.

Previous studies suggested an important role for 20-HETE in the regulation of myogenic responses. Thus, pressure-diameter relationships were investigated in isolated, cannulated coronary arteries (approximately 100 microm) from male endothelial NO synthase knockout (eNOS-KO) and wild-type (WT) mice. All arteries constricted in response to step increases in perfusate pressure from 20 to 100 mm Hg. This constriction was significantly enhanced from 40 to 100 mm Hg in arteries of eNOS-KO compared with those of WT mice. For example, at 60 and 100 mm Hg, respectively, the normalized diameter (expressed as a percentage of the corresponding passive diameter) of arteries of eNOS-KO mice was 10% and 12% smaller than that of WT mice. Removal of the endothelium did not significantly affect the responses of vessels from either strain of mice. However, N-methylsulfonyl-12,12-dibromododec-11-enamide (5x10(-6) M), an inhibitor of cytochrome P-450 (CYP)/omega-hydroxylase, significantly attenuated the greater myogenic constriction of arteries from eNOS-KO mice by approximately 12% at each pressure step but did not significantly affect responses of those from WT mice, leading to a comparable myogenic response in the 2 strains. Western blot analysis demonstrated a comparable CYP4A protein content in coronary arteries of the 2 strains of mice. However, production of 20-HETE, measured by fluorescent high-performance liquid chromatography assay was approximately 2.7-fold greater in eNOS-KO compared to WT mice. Thus, as a function of eNOS deficiency, the enhanced coronary artery constriction to pressure is attributable to an increased activity of omega-hydroxylase, which, consequently, increases the synthesis of 20-HETE in vascular smooth muscle.

Amides↗
PubMed1996

20-HETE requires increased vascular tone to constrict rabbit afferent arterioles.

Renal production of 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450-dependent arachidonate metabolite, increases during development of hypertension in spontaneously hypertensive rats, and inhibition of its production prevents hypertension. Since 20-HETE is a potent vasoconstrictor, these findings suggest that 20-HETE may contribute to the development of hypertension by elevating renal vascular resistance. In this study we examined the direct action of 20-HETE on the afferent arteriole, a vascular segment crucial to the control of renal vascular resistance. Rabbit afferent arterioles were microperfused at 60 mm Hg in vitro, and 20-HETE was added to the lumen. Although 20-HETE (10(-10) to 10(-6) mol/L) had no effect on the diameter of non-treated afferent arterioles (n=6), it caused dose-dependent constriction when vascular tone was increased with norepinephrine (0.3 micromol/L); 20-HETE at 10(-6) mol/L decreased diameter by 43 +/- 4% (n=6, P < .001). This constriction was abolished by disrupting the endothelium (n=5). Moreover, pretreatment with the cyclooxygenase inhibitor indomethacin (50 micromol/L) or the thromboxane/endoperoxide receptor antagonist SQ29548 (1 micromol/L) significantly (P < .03) attenuated 20-HETE-induced constriction: 20-HETE at 10(-6) mol/L constricted norepinephrine-treated afferent arterioles by 28 +/- 3% (n=6) and 25 +/- 4% (n=5), respectively. These results demonstrate that an increase in afferent arteriolar tone is required for the vasoconstrictor action of 20-HETE, which is partly mediated by the endothelial cyclooxygenase pathway. THus, increased production of 20-HETE in the kidney and increase in afferent arteriolar tone, both of which often precede the development of hypertension, may synergistically contribute to the development of hypertension by elevating renal vascular resistance.

Animals↗
PubMed2004

Rho kinase mediates cold-induced constriction of cutaneous arteries: role of alpha2C-adrenoceptor translocation.

Cold-induced vasoconstriction in cutaneous blood vessels is mediated in part by increased activity of vascular smooth muscle alpha2-adrenoceptors (VSM alpha2-ARs). In mouse cutaneous arteries, alpha2C-ARs are normally silent at 37 degrees C but mediate cold-induced augmentation of alpha2-AR responsiveness. In transfected HEK293 cells, this functional rescue is mediated by cold-induced translocation of alpha2C-ARs from the Golgi to the plasma membrane. Experiments were performed to determine the role of Rho/Rho kinase signaling in this process. Inhibition of Rho kinase (fasudil, Y27632 or H-1152) did not affect constriction of isolated mouse tail arteries to the alpha2-AR agonist UK 14 304 at 37 degrees C but dramatically reduced the augmented responses to the agonist at 28 degrees C. After Rho kinase inhibition, cooling no longer increased constriction evoked by alpha2-AR stimulation. Cooling (to 28 degrees C) activated Rho in VSM cells and increased the calcium sensitivity of constriction in alpha toxin-permeabilized arteries. Stimulation of alpha2-ARs in VSM cells had no effect on Rho activity or calcium sensitivity at 37 degrees C or 28 degrees C. In HEK293 cells transfected with alpha2C-ARs, cooling (to 28 degrees C) stimulated the translocation of alpha2C-ARs to the plasma membrane and this effect was prevented by inhibition of Rho kinase, using fasudil or RNA interference. Consistent with inhibition of the spatial rescue of alpha2C-ARs, fasudil inhibited alpha2-AR-mediated mobilization of calcium in tail arteries at 28 degrees C but not 37 degrees C. Therefore, cold-induced activation of Rho/Rho kinase can mediate cold-induced constriction in cutaneous arteries by enabling translocation of alpha2C-ARs to the plasma membrane and by increasing the calcium sensitivity of the contractile process.

Animals↗
PubMed1986

Coordination of mural elements and myofilaments during arteriolar constriction.

Arterioles undergo major morphological changes during vasoconstriction. We used transmission electron microscopy to study wall morphology in both dilated and constricted microvessels to understand the cellular basis of these changes. The relation between the orientation and density of myofilaments and the distribution of dense bodies was analyzed with respect to the level of microvessel tone. The data show a strong correlation between the degree of arteriolar constriction and both the orientation and density of myofilaments. In dilated arterioles, myofilament orientation was predominantly circumferential across the entire smooth muscle cell, averaging 84 +/- 2 degrees (SEM) relative to a radial reference line. In vessels constricted to 50% of their maximal diameter, myofilament orientation was dependent upon the location within the cell, being largely circumferential at the adventitial border (77 +/- 4 degrees) and shifting to a radial arrangement at the intimal border (36 +/- 5 degrees). The reorganization of myofilaments during constriction was associated with a decrease in myofilament density at the intimal-medial border of the smooth muscle cells. The decrease in myofilament density resulted from a selective withdrawal of myofilaments from periluminal areas where "ridges" had formed. Our observations suggest that an ordered distribution of membrane-associated dense bodies along the periluminal aspect of the smooth muscle cells is responsible for both the myofilament reorganization and ridge formation during vasoconstriction. Results of the present study are incorporated into a hypothetical model of arteriolar ultrastructure compatible with the mural reorganization observed during vasoconstriction.

Actin Cytoskeleton↗
PubMed2001

An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide.

Myogenic tone is an important determinant of vascular tone and blood flow in small resistance arteries of certain vascular beds. The role of the endothelium in myogenic responses is unclear. We hypothesized that endothelium-derived NO release modulates myogenic constriction in small resistance arteries and that mesenteric small arteries from mice with targeted disruption of the gene for endothelial NO synthase (eNOS) (knockout mice) demonstrate greater myogenic tone than do wild-type mice. Third-order mesenteric arteries (approximately 200 micrometer) were isolated and mounted in a pressure myograph. Internal diameter was recorded over a pressure range of 10 to 80 mm Hg. Removal of the endothelium significantly (P<0.05) enhanced the magnitude of myogenic constriction in wild-type mice. Similarly, pretreatment of arteries with N(G)-nitro-L-arginine methyl ester (L-NAME; 300 micromol/L) produced a comparable significant (P<0.05) increase in myogenic tone, whereas indomethacin (5 micromol/L) had no effect. eNOS knockout arteries also exhibited myogenic constriction. Neither L-NAME nor indomethacin had any effect on myogenic tone in the arteries of eNOS knockout mice. However, blockade of potential endothelium-derived hyperpolarizing factor-like mechanisms via inhibition of K(+) flux using either apamin (100 nmol/L) with charybdotoxin (100 nmol/L), Ba(2+) (30 micromol/L) with ouabain (1 mmol/L), or 18alpha-glycyrrhetinic acid (100 micromol/L) significantly (P<0.01) enhanced myogenic constriction. This study demonstrates that basal endothelium-derived NO modulates myogenic tone in mesenteric small arteries of wild-type mice. However, eNOS knockout arteries display normal myogenic responsiveness despite the absence of basal NO activity. The data suggest that this compensatory effect is due to the activity of an endothelium-derived hyperpolarizing factor to normalize vascular tone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

Aerosolized human neutrophil elastase induces airway constriction and hyperresponsiveness with protection by intravenous pretreatment with half-length secretory leukoprotease inhibitor.

This study was designed to determine the effects of inhaled human neutrophil elastase (HNE) on airway constriction and airway responsiveness, and to examine the protection by an intravenous recombinant half-length secretory leukoprotease inhibitor, r1/2SLPI in guinea pigs. Aerosol inhalation of HNE (250 microgram/ml, for 3 min) caused a transient but significant airway constriction, in which lung resistance (RL) increased from 194 +/- 18 (mean +/- SEM) to 461 +/- 42 cm H2O/L/s (p < 0.001). Thirty minutes after the end of HNE inhalation, airway responsiveness to intravenous 5-hydroxytryptamine (5-HT) was significantly increased. The provocative dose causing a 200% increase in RL (PD200) was significantly decreased from 10.0 +/- 1.2 to 6.5 +/- 0.8 microgram/kg (p < 0.001). Forty-five minutes after the end of HNE inhalation, total cells in bronchoalveolar lavage fluid (BALF) were significantly increased (p < 0.05). Histologic study of intrapulmonary bronchi demonstrated an acute inflammatory response characterized by damage to the epithelium, airway obstruction by mucus plugs, and recruitment of mononuclear and polymorphonuclear cells to the bronchial epithelium. r1/2SLPI (30 mg/kg) injected 5 min before the initiation of HNE inhalation significantly inhibited the airway constriction (p < 0.05), the airway hyperresponsiveness (p < 0.01), and the increase of cells in BALF (p < 0.05). The present data suggest that HNE plays a role in the induction of airway constriction and airway hyperresponsiveness in various inflammatory lung diseases with pulmonary neutrophil infiltration, such as chronic obstructive pulmonary diseases (COPD) and possibly bronchial asthma. r1/2SLPI may be useful as an antiprotease treatment.

Aerosols↗
PubMed1993

Pulmonary venous sphincter constriction is attenuated by alpha-adrenergic antagonism.

Pulmonary veins of rats have regular thin bands of constriction (sphincters) that deepen when the animals are given a blow to the head that is sufficient to cause pulmonary edema. Pulmonary edema caused by a stimulus to the brain is attenuated by alpha-adrenergic blockade. This study tested the hypothesis that alpha-adrenergic antagonism decreases this contraction in pulmonary veins. Male and female Sprague-Dawley rats were given prazosin, an alpha 1-specific antagonist, phentolamine, a combined alpha 1- and alpha 2-antagonist, or saline 10 min before their lungs were cast and they were given a blow on the head. The casts were fractured, causing the veins to break at the site of the constriction. Depth of contraction expressed as a percentage was 1 minus the ratio of the inner (constricted) and outer (total) diameters of the vein at the fracture. Resin that escaped the vascular space to cast alveoli and lymphatics was also measured. The average contraction of the veins at the site of the sphincters was 7.9 +/- 1.1% in the saline group, 5.4 +/- 0.7% in the phentolamine group, and 4.8 +/- 0.7% in the prazosin group (p < 0.05), although about a third of the constrictions were less than 2% in all groups. Arteries had no contraction. Contraction was greater in heavier and male animals, which were variables that interacted with the agent the animals were given in a multivariate analysis. Contrary to the hypothesis, lymphatic casts were greater in the animals receiving alpha-blockers (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effects of topically instilled bunazosin, an alpha1-adrenoceptor antagonist, on constrictions induced by phenylephrine and ET-1 in rabbit retinal arteries.

PURPOSE: To examine the inhibitory effects of topically instilled bunazosin hydrochloride (bunazosin), a selective alpha1-adrenoceptor antagonist, on the retinal artery constrictions induced by intravitreous phenylephrine hydrochloride (phenylephrine) and endothelin (ET)-1 in rabbits. METHODS: Phenylephrine or ET-1 (20 microL) was injected into the central part of the vitreous in both eyes in pigmented rabbits. Color fundus photographs were taken at 5 minutes before and 60 minutes after the injection. The average diameter of the major retinal arteries at the rim of the optic nerve head (ONH) was normalized with respect to ONH diameter. Bunazosin was instilled into one eye (chosen randomly) and vehicle into the fellow eye at 60 minutes before the intravitreous injection. To examine any interaction between the alpha1-adrenoceptor and ET receptor, phenylephrine and ET-1 were co-injected at individually ineffective doses. In addition, ET-1-induced vasoconstriction was examined after unilateral superior cervical ganglionectomy. The binding affinities of bunazosin for ETA and ETB receptors were also evaluated. The series of experiments was performed as masked tests. RESULTS: Retinal arteries were dose-dependently constricted by both intravitreous phenylephrine and intravitreous ET-1. Topically instilled bunazosin at 0.01% partly inhibited both of these vasoconstrictions on the ipsilateral side, but not on the contralateral side. Bunazosin did not bind to ET receptors. Co-injection of phenylephrine and ET-1 at individually ineffective doses constricted retinal arteries significantly. An adrenergic supersensitivity in retinal arteries was observed after superior cervical ganglionectomy only on the ganglionectomized eye. The ET-1-induced vasoconstriction was significantly weaker in cervical ganglionectomized eyes than in sham-surgery eyes. CONCLUSIONS: The present findings suggest that topically instilled bunazosin reaches the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine- or ET-1-induced constriction of retinal arteries in normal rabbit eyes, and that the inhibitory effect of bunazosin on the ET-1-induced vasoconstriction in this tissue may be partly attributable to an interaction between the alpha1-adrenoceptor and ET receptor.

Administration, Topical↗