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Mechanism of reduced maximum expiratory flow in methacholine-induced bronchoconstriction in dogs.

Airway sites of flow limitation ["choke points" (CP)] were identified during forced deflation in open-chest dogs before (C) and after (B) bronchoconstriction was produced by nebulizing a solution of methacholine chloride into their airways. CP were identified in two respective groups. In group I (n = 8) a retrograde catheter was used to locate CP and in the other a Pitot static tube (group II, n = 5), CP were identified at multiple lung volumes (VL) over the lower one-half of total lung capacity. Both groups showed similar findings at each condition. At B, corresponding values of maximum expiratory flow (Vmax) at each VL decreased to about 10% of those at C. Movement of CP relative to their original location varied at each VL and, especially at the lower VL, showed little peripheral movement. In group I, equal pressure points were also measured and were found to move peripherally at all the measured VL. In group II, cross-sectional area (A*) and airway compliance (K) at CP were estimated. During bronchoconstriction, A* decreased at the respective VL, and airways became less compliant. The reduction in Vmax could be explained in terms of changes in A* and K as described by wave-speed theory, and Vmax decreased because A* decreased. The decrease in A* was related in part to an increase in viscous pressure losses that reduced total pressure at CP and also in part to a change in the pressure-area behavior of bronchi at CP. Their relative effects on reducing A* and Vmax were examined.

Airway Obstruction↗

Inflation of antishock trousers increases bronchial response to methacholine in healthy subjects.

We studied changes in lung volumes and in bronchial response to methacholine chloride (MC) challenge when antishock trousers (AST) were inflated at venous occlusion pressure in healthy subjects in the standing posture, a maneuver known to shift blood toward lung vessels. On inflation of bladders isolated to lower limbs, lung volumes did not change but bronchial response to MC increased, as evidenced by a greater fall in the forced expiratory volume in 1 s (FEV1) at the highest dose of MC used compared with control without AST inflation (delta FEV1 = 0.94 +/- 0.40 vs. 0.66 +/- 0.46 liter, P less than 0.001). Full inflation of AST, i.e., lower limb and abdominal bladder inflated, significantly reduced vital capacity (P less than 0.001), functional residual capacity (P less than 0.01), and FEV1 (P less than 0.01) and enhanced the bronchial response to MC challenge compared with partial AST inflation (delta FEV1 = 1.28 +/- 0.47 liter, P less than 0.05). Because there was no significant reduction of lung volumes on partial AST inflation, the enhanced bronchial response to MC cannot be explained solely by changes in base-line lung volumes. An alternative explanation might be a congestion and/or edema of the airway wall on AST inflation. Therefore, to investigate further the mechanism of the increased bronchial response to MC, we pretreated the subjects with the inhaled alpha 1-adrenergic agonist methoxamine, which has both direct bronchoconstrictor and bronchial vasoconstrictor effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Effect of methacholine on Na+ pump activity and ion content of dispersed avian salt gland cells.

The effects of the cholinergic agonist methacholine chloride (MCh) on cellular ion content and Na+ pump activity of dissociated duck salt gland cells were studied. Dispersed salt gland cells regulate intracellular ion levels in a ouabain-sensitive manner. MCh (0.5 mM) caused no detectable change in cell Na+ levels over the first 10 min of exposure of cells to the agonist but elicited decreases of 23 and 13%, respectively, in intracellular Cl- and K+ content. The rate of turnover of salt gland cell plasmalemmal Na+ pumps, as measured by [3H]ouabain binding to the dissociated cells, was markedly stimulated by 0.5 mM MCh, although the total number of binding sites at equilibrium remained unchanged. Replacement of medium Na+ with choline abolished the MCh-stimulated increase in ouabain binding but had no effect on the rate of glycoside binding in the absence of the agonist. Substitution of Cl- in the medium by NO3-, SO42-, or benzene sulfonate- reduced the stimulated component of Na+ pump turnover by 85-90%. Addition of 1 mM furosemide to the medium abolished the increase in ouabain binding and ouabain-sensitive oxygen consumption observed after exposure of salt gland cells to MCh. These data are consistent with the hypothesis that cholinergic stimulation of salt gland cells triggers a Cl--dependent uptake of Na+, which elicits a compensatory increase in Na+ pump turnover. In addition, the decrease in cellular Cl- content caused by MCh suggests that the agonist either directly or indirectly mediates an efflux of Cl- from the cells.

Animals↗

Selective impairment of endothelium-mediated vasodilation in liver transplant recipients with cyclosporin A-induced hypertension.

Arterial hypertension is commonly observed in orthotopic liver transplantation (OLT) recipients receiving cyclosporin A (CsA), but the precise pathogenetic mechanisms remain partially unknown. The aim of this study was to investigate endothelium-dependent and -independent dilation and adrenergic constriction of resistance vessels of OLT recipients treated with CsA. Vascular reactivity was examined in 22 OLT patients, 10 with and 12 without arterial hypertension, and in 10 control subjects by assessing the forearm blood flow response to the brachial artery infusion of increasing concentrations of methacholine chloride, sodium nitroprusside, and phenylephrine. In 10 OLT patients, the response to methacholine was also examined after acetylsalicylate. The ratio of serum nitrite and nitrate to serum creatinine was lower (P < .05) in OLT patients with hypertension than in nonhypertensive patients and controls. Basal forearm flow was similar in the three groups. Methacholine vasodilation was impaired in the hypertensive patients as shown by a lower maximum forearm vasodilator response and a shift in the dose response curve to methacholine to the right compared with the nonhypertensive OLT patients and the controls. The response to methacholine was not modified after salicylate. Forearm flow response to nitroprusside was similar in the three groups. No differences between the patients and the controls were found in the maximum forearm flow contraction in response to phenylephrine. An impairment in endothelium-dependent vasodilation could mediate arterial hypertension in OLT patients immunosuppressed with CsA.

Adult↗

Occupational exposure to inhalative irritants and methacholine responsiveness.

OBJECTIVES: Occupational exposures to inhalative irritants have been associated with an increased reporting of respiratory symptoms in previous studies. Methacholine responsiveness represents a continuous measure of airway responsiveness. As such, it may be less subject to recall bias and more sensitive to detecting effects of occupational exposure on airways. Such effects may be stronger among atopic persons. The objective of the study was to examine the relationship between self-reports of occupational exposure to dusts, gases, vapors, aerosols, and fumes and methacholine responsiveness. METHODS: A sample was studied of never smokers (N=3044) chosen randomly from 8 areas in Switzerland. Atopy was defined as any positive skin test to 8 inhalative allergens. Nonspecific bronchial reactivity was tested using methacholine chloride and quantified by calculating the slope of the dose-response. RESULTS: The methacholine slopes were 19% [95% confidence interval (95% CI) 6-32] higher for never smokers with exposure to dusts, fumes, vapors, gases, or aerosols than for the unexposed group. When only atopic never smokers were examined. the increase was larger (37%, 95% CI 7-75), and for persons with >2 positive skin prick tests the effect was still higher (42%, 95% CI -1.5-104). Exposure to vapors and aerosols was strongly associated with increased methacholine slopes among the atopic subjects. CONCLUSIONS: Occupational exposure, particularly to dusts and fumes, was associated with increased bronchial reactivity in never smokers in this study. The magnitude of the effect was larger among atopic subjects.

Adolescent↗

Comparison of nasal responsiveness to histamine, methacholine and phentolamine in allergic rhinitis patients and controls.

In a selected group of rhinitis patients with an IgE-mediated allergy to house dust mites the nasal response to insufflation of histamine chloride, methacholine and phentolamine was demonstrated to be higher than in a control group. With the methods used histamine chloride was better at discriminating between healthy subjects and patients than methacholine or phentolamine. This discrimination was shown by assessing the severity of reflex-mediated symptoms such as the number of sneezes and the amount of secretion, and not by differences in nasal airway resistance.

Adult↗

Inhibition of protein kinase Cbeta prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans.

The bioavailability of nitric oxide is decreased in animal models and humans with diabetes mellitus. Hyperglycemia, in particular, attenuates endothelium-dependent vasodilation in healthy subjects. In vitro and in vivo animal studies implicate activation of protein kinase Cbeta as an important mechanism whereby hyperglycemia decreases endothelium-derived nitric oxide. Accordingly, this study tested the hypothesis that inhibition of protein kinase Cbeta would prevent impairment of endothelium-dependent vasodilation in healthy humans exposed to hyperglycemia. This study was a randomized, double-blind, placebo-controlled, crossover trial. Healthy subjects were treated with an orally active, selective, protein kinase Cbeta inhibitor, LY333531, or matching placebo once a day for 7 days before vascular function testing. Forearm blood flow was measured using venous-occlusion, strain-gauge plethysmography. Endothelium-dependent vasodilation was measured via incremental brachial artery administration of methacholine chloride (0.3 to 10 microg/min) during euglycemia and after 6 hours of hyperglycemic clamp. The forearm blood flow dose-response curve to methacholine was significantly attenuated by hyperglycemia after placebo treatment (P=0.009 by ANOVA, euglycemia versus hyperglycemia) but not after treatment with LY333531. Inhibition of protein kinase Cbeta prevents the reduction in endothelium-dependent vasodilation induced by acute hyperglycemia in healthy humans in vivo. These findings suggest that hyperglycemia impairs endothelial function, in part, via protein kinase Cbeta activation.

Adult↗

Effects of smoked substance abuse on nonspecific airway hyperresponsiveness.

Previous data suggest that regular tobacco smoking may lead to nonspecific airway hyperresponsiveness (AHR) independent of airway obstruction, possibly because of effects on bronchial inflammation or mucosal permeability. Little is known concerning the effects on AHR of other widely smoked substances besides tobacco such as marijuana or cocaine. The smoke of both marijuana and cocaine contains respiratory irritants that elicit cough and produce abnormalities in airway dynamics and bronchial mucosal histopathology in habitual smokers. Therefore, regular smoking of one or both of these illicit substances could cause AHR or augment the AHR associated with tobacco smoking. The present study examined the influence of habitual smoking of marijuana, cocaine, and/or tobacco on nonspecific AHR in 542 (456 male) healthy participants (mean age, 34.8 +/- 6.8 SD yr) in an ongoing cohort study of the pulmonary effects of habitual smoking of illicit substances. Subjects with a history of intravenous drug abuse, significant occupational exposures, asthma, or recent upper respiratory tract infection were excluded. Inhalation challenge studies were performed using solutions of diluent and methacholine chloride (1.25 to 25 mg/ml) aerosolized by a DeVilbiss no. 646 nebulizer attached to a breath-activated dosimeter inhaled by three to five inspiratory capacity breaths. Positive responses to methacholine were defined by > or = 20% or > or = 10% declines in FEV1 from the postdiluent control value after inhalation of each concentration of methacholine. Participants were categorized by smoking status (nonsmoking and smoking of marijuana, cocaine, and/or tobacco alone and in combination); most analyses were performed in men and women separately.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans.

Endothelium-dependent vasodilation is impaired in hypercholesterolemia, even before the development of atherosclerosis. The purpose of this study was to determine whether infusion of L-arginine, the precursor of the endothelium-derived relaxing factor, nitric oxide, improves endothelium-dependent vasodilation in hypercholesterolemic humans. Vascular reactivity was measured in the forearm resistance vessels of 11 normal subjects (serum LDL cholesterol = 2.76 +/- 0.10 mmol/liter) and 14 age-matched patients with hypercholesterolemia (serum LDL cholesterol = 4.65 +/- 0.36 mmol/liter, P < 0.05). The vasodilative response to the endothelium-dependent vasodilator, methacholine chloride, was depressed in the hypercholesterolemic group, whereas endothelium-independent vasodilation, induced by nitroprusside, was similar in each group. Intravenous administration of L-arginine augmented the forearm blood flow response to methacholine in the hypercholesterolemic individuals, but not in the normal subjects. L-arginine did not alter the effect of nitroprusside in either group. D-arginine had no effect on forearm vascular reactivity in either group. It is concluded that endothelium-dependent vasodilation is impaired in hypercholesterolemic humans. This abnormality can be improved acutely by administration of L-arginine, possibly by increasing the synthesis of endothelium-derived relaxing factor.

Adult↗

Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo.

BACKGROUND: Endothelial function is impaired in patients with diabetes mellitus. However, the factors contributing to this defect are currently unknown. Hyperglycemia attenuates endothelium-dependent relaxation in normal rabbit arteries in vitro and rat arterioles in vivo. Accordingly, this study examined the effect of acute hyperglycemia on endothelium-dependent vasodilation in nondiabetic humans in vivo. METHODS AND RESULTS: Endothelium-dependent vasodilation was assessed through brachial artery infusion of methacholine chloride both before and during 6 hours of local hyperglycemia (300 mg/dL) achieved by intra-arterial infusion of 50% dextrose. Forearm blood flow was determined by plethysmography. In a group of 10 subjects, there was a trend toward attenuated methacholine-mediated vasodilation during hyperglycemia compared with euglycemia (P=.07 by ANOVA; maximal response, 13.3+/-2.8 versus 14.7+/-1.5 mL x min(-1) x 100 mL(-1), respectively). In these subjects, the systemic serum insulin levels increased significantly during the dextrose infusion (P<.001). To eliminate the confounding vasoactive effects of insulin, the protocol was repeated during systemic infusion of octreotide (30 ng x kg(-1) x min(-1)) to inhibit pancreatic secretion of insulin. In these subjects (n=10), hyperglycemia significantly attenuated the forearm blood flow response to methacholine (P<.01 by ANOVA; maximal response, 16.9+/-2.5 before versus 12.7+/-1.8 mL x min(-1) x 100 mL(-1) during hyperglycemia). Methacholine-mediated vasodilation was not attenuated by an equimolar infusion of mannitol (P>.40), nor did hyperglycemia reduce endothelium-independent vasodilation to verapamil (P>.50). CONCLUSIONS: Acute hyperglycemia impairs endothelium-dependent vasodilation in healthy humans in vivo. This finding suggests that elevated glucose may contribute to the endothelial dysfunction observed in patients with diabetes mellitus.

Acute Disease↗

Airway hyperreactivity: assessment with helical thin-section CT.

PURPOSE: To determine the accuracy of helical computed tomography (CT) for assessing reversible changes in bronchial size and air trapping due to airway hyperreactivity. MATERIALS AND METHODS: Spirometry and helical CT were performed in 15 patients with mild asthma and six healthy control subjects before and after bronchial provocation with methacholine chloride and after reversal of provocation with albuterol. CT was performed at suspended functional residual capacity and at residual volume in two lung regions (above and below the carina). Bronchial area and lung attenuation measurements were compared. RESULTS: At baseline, lung attenuation frequency distribution curves were similar between the control and asthma groups. After methacholine, control subjects showed a decrease of less than 10% in the forced expiratory volume at 1 second (FEV1) and no significant differences in lung attenuation curves. Patients with asthma showed a 20%-36% decrease in FEV1, with significant decreases in the median and lowest 10th percentile regions of the attenuation curves and in the cross-sectional area of small (< 5-mm2) airways (P < .001 for all comparisons). After albuterol, control subjects showed no change in spirometric measurements, lung attenuation, or bronchial size, whereas all such parameters returned to baseline levels in patients with asthma. CONCLUSION: Functional helical CT can accurately demonstrate reversible airflow obstruction resulting from airway hyperreactivity.

Adolescent↗

Effects of loratadine and terfenadine on the induced nasal allergic reaction.

OBJECTIVE: To evaluate the effect of terfenadine and loratadine on the early nasal allergic response to challenge and the subsequent cellular influx and hyperresponsiveness. DESIGN: Double-blind, placebo-controlled, triple-crossover study. SUBJECTS: Fourteen, asymptomatic, allergic volunteers. INTERVENTIONS: After an initial challenge with methacholine chloride, subjects received treatment with placebo, loratadine (10 mg by mouth daily), or terfenadine (60 mg by mouth twice daily) for 1 week, followed by a nasal allergen challenge with lavages; 24 hours later, while the subjects were still receiving medication, the quantity of cells in the nasal lavage was determined, and another challenge with methacholine was done. Mediator levels were quantified in the nasal lavages after the allergen c hallenge, and the weight of the methacholine-induced nasal secretions was measured. RESULTS: Both loratadine and terfenadine treatment resulted in significant reductions in allergen-induced sneezing and the levels of histamine, kinins, albumin, and N-alpha-tosyl-L-arginine methyl ester-esterase activity in recovered nasal lavages compared with the reductions that resulted from placebo treatment, with no significant difference among the treatments. Treatment had no effect on the levels of tryptase, prostaglandin D2 or leukotriene C4. A significant eosinophil influx into nasal secretions 24 hours after the allergen challenge in patients who were receiving placebo (P=.006) was not affected by loratidine or terfenadine treatment. Comparing methacholine-induced secretions between screening challenges and challenges with the patients who were being treated with either loratadine or terfenadine, there was a significant decrease in secretions after the use of these antihistamines (P<.05). CONCLUSION: Both loratadine and terfenadine partially inhibit the early nasal response to allergen challenge and the subsequent reactivity to a challenge with methacholine without affecting the influx of eosinophils into nasal secretions.

Adult↗

Enhanced endothelium-dependent vasodilation in patients with cirrhosis.

Experimental evidence indicates that an increased production of nitric oxide could play a role in the peripheral vasodilation of portal hypertension. To test this hypothesis in humans, we studied basal serum NO(2-) + NO3- levels and the response of forearm resistance vessels to increasing concentrations of methacholine chloride, sodium nitroprusside, and phenylephrine infused into the brachial artery of 12 cirrhotic patients and 10 controls. Forearm vascular resistance (FVR) was calculated from mean arterial pressure and forearm blood flow (FBF). Cirrhotics showed higher NO(2-) + NO3- levels (P < 0.05), higher FBF (P < 0.01), and lower FVR (P < 0.01) than controls. The reduction of FVR in response to every dose of methacholine was greater in cirrhotics than in controls; this was significant (P < 0.05) at the 3 and 10 micrograms/min doses. This response to methacholine was not modified by blockade of vascular prostacyclin. The response to nitroprusside was similar in both groups. The increase in FVR in response to every dose of phenylephrine was significantly (P < 0.01) lower in cirrhotics than in controls. In cirrhotics, a significant correlation (r = -0.81, P < 0.01) was found between the FVR response to the highest doses of methacholine and phenylephrine. In conclusion, cirrhotic patients show an enhanced endothelium-mediated vasodilation, which suggests an increased synthesis of nitric oxide. This defect may mediate the peripheral vasodilation and hyporeactivity to vasopressors of these patients.

Adult↗

Effect of salbutamol on pulmonary responsiveness in chronic pulmonary allergic inflammation in guinea pigs.

Beta-2-agonists have been widely used by asthmatic subjects to relieve their obstructive symptoms. However, there are reports that continuous use could lead to loss of bronchial protection and exacerbation of asthma symptoms. We evaluated the effect of two regimens of salbutamol administration (twice and five times a week) in a model of chronic airway inflammation in male Hartley guinea pigs (protocol starting weight: 286 +/- 30 g) induced by repeated exposures to aerosols of ovalbumin (OVA). After sensitization, guinea pigs were exposed to aerosols of 0.1 mg/ml salbutamol solution twice a week (OVA + S2x, N = 7) or five times a week (OVA + S5x, N = 8). We studied allergen-specific (OVA inhalation time) and -nonspecific (response to methacholine) respiratory system responsiveness. Seventy-two hours after the last OVA challenge, guinea pigs were anesthetized and tracheostomized, respiratory system resistance and elastance were measured and a dose-response curve to inhaled methacholine chloride was obtained. Specific IgG1 was also quantified by the passive cutaneous anaphylactic technique. OVA-sensitized guinea pigs (N = 8) showed reduction of the time of OVA exposure before the onset of respiratory distress, at the 5th, 6th and 7th exposures (P < 0.001). The OVA + S2x group (but not the OVA + S5x group) showed a significant increase in OVA inhalation time. There were no significant differences in pulmonary responsiveness to methacholine among the experimental groups. OVA + S2x (but not OVA + S5x) animals showed a decrease in the levels of IgG(1)-specific anaphylactic antibodies compared to the OVA group (P < 0.05). Our results suggest that, in this experimental model, frequent administration of beta(2)-agonists results in a loss of some of their protective effects against the allergen.

Adrenergic beta-Agonists↗

Modulation by L-type Ca2+ channels and apamin-sensitive K+ channels of muscarinic responses in cat chromaffin cells.

In the perfused cat adrenal gland stimulated with the muscarinic agonist methacholine chloride (100 microM for 3 min), two components were detected in the catecholamine secretory response: 1) an early phasic component that peaked at 300 ng/5 s catecholamine release and 2) a tonic component whose peak was transient and declined to a plateau of about 140 ng/5 s. Apamin (0.1 microM) increased the phasic component to 1,200 ng/5 s and the tonic component to approximately 350 ng/5 s. In single fura 2-loaded cat adrenal chromaffin cells, the cytosolic Ca2+ concentration ([Ca2+]i) also followed a biphasic pattern after stimulation with methacholine. Depletion of extracellular Ca2+ reduced the phasic [Ca2+]i peak by > 50% and the phasic secretory peak by approximately 90%; both the tonic components of [Ca2+]i and secretion were abolished. Depletion of intracellular Ca2+ pools decreased the phasic and tonic components of [Ca2+]i and secretion with respect to control values; however, the phasic components diminished more than the tonic components of [Ca2+]i and secretion. Although 3 microM furnidipine (a dihydropyridine L-type Ca2+ channel blocker) inhibited the phasic component of [Ca2+]i and secretion, its effects were more pronounced on the tonic component. omega-Conotoxin GVIA (1 microM, an N-type Ca2+ channel blocker) did not affect the [Ca2+]i or the methacholine secretory responses. The secretion peak seems to depend on both extracellular free Ca2+ (Cao2+) entry through L-type Ca2+ channels as well as on the mobilization of Ca2+ from intracellular stores; the plateau depends only on Cao2+ entry through L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗

Effect of captopril and enalapril on endothelial function in hypertensive patients.

Endothelium-dependent vasodilation is impaired in patients with essential hypertension. The objective of this study was to determine whether long-term treatment with angiotensin-converting enzyme inhibitors improves endothelium-dependent vasodilation in forearm resistance vessels of patients with hypertension. Furthermore, since tissue thiols may be relevant to nitric oxide-mediated vasodilation, we queried whether an angiotensin-converting enzyme inhibitor with a sulfhydryl group preferentially augments endothelium-dependent vasodilation in these individuals. The study included 24 patients with essential hypertension (mean age, 45 +/- 2 years) and 20 normotensive subjects (mean age, 47 +/- 1 years). Methacholine chloride (0.3 to 10 micrograms/min) was infused via the brachial artery to assess endothelium-dependent vasodilation in forearm resistance vessels. Nitroglycerin (1 to 30 micrograms/min) was administered to evaluate endothelium-independent vasodilation. Forearm blood flow was determined by venous occlusion strain-gauge plethysmography. Forearm vascular function studies were performed in hypertensive patients before and 7 to 8 weeks after randomization to either captopril or enalapril, angiotensin-converting enzyme inhibitors with and without a sulfhydryl moiety, respectively. Normotensive subjects were studied on only one occasion. Before treatment, the forearm vasodilative response to methacholine was attenuated in hypertensive compared with normotensive subjects (P < .01). The effects of nitroglycerin on forearm blood flow did not differ significantly between the two groups. Both captopril and enalapril reduced mean blood pressure in the hypertensive subjects (12 +/- 2 versus 15 +/- 3 mm Hg, respectively; P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered- dose inhalers.

BACKGROUND: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation. OBJECTIVE: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations. METHODS: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV(1) was measured after each methacholine dose until a 20 % decrease in FEV(1) (PD(20)) was achieved. RESULTS: Mean PD(20) values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD(20) values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 microg) of albuterol MDI were within the sensitive region of the dose- response curve. The mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was 119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage coefficient of variation of 69.0 %. CONCLUSIONS: The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products.

Administration, Inhalation↗

Baroreflex depression persists in the early phase after hypertension reversal.

The baroreflex control of heart rate (HR) was evaluated in conscious chronic renal hypertensive rats (RHR; 1K-1C, 2 mo) under control conditions and after reversal of hypertension by unclipping the renal artery or sodium nitroprusside infusion. Unclipping and nitroprusside infusion were both followed by significant decreases in the mean arterial pressure (unclipping: from 199 +/- 4 to 153 +/- 8 mmHg; nitroprusside infusion: from 197 +/- 9 to 166 +/- 6 mmHg) as well as slight and significant increases, respectively, in the baroreflex bradycardic response index (unclipping: from 0.2 +/- 0.04 to 0.6 +/- 0.1 beats x min(-1) x mmHg(-1); nitroprusside infusion: from 0.1 +/- 0.04 to 0.5 +/- 0.1 beats x min(-1) x mmHg(-1)). However, this index was still depressed compared with that for normotensive control rats (2.1 +/- 0.2 beats x min(-1) x mmHg(-1)). The index for the baroreflex tachycardic response was also depressed under control conditions and remained unchanged after hypertension reversal. RHR possessed markedly attenuated vagal tone as demonstrated by pharmacological blockade of parasympathetic and sympathetic control of HR with methylatropine and propranolol, respectively. A reduced bradycardic response was also observed in anesthetized RHR during electrical stimulation of the vagus nerve or methacholine chloride injection, indicating impairment of efferent vagal influence over the HR. Together, these data indicate that 2 h after hypertension reversal in RHR, the previously described normalization of baroreceptor gain occurs independent of the minimal or lack of recovery of baroreflex control over HR.

Animals↗