Biomedical subjects

K S Lindeman

Publications and source records attributed to K S Lindeman.

26 records · Page 2Linked to original sources

PubMed1993

Lemakalim attenuates hypocapnia- and dry air-induced bronchoconstriction in canine peripheral airways.

To determine the effect of changes in potassium (K+) flux on airway constriction, we studied effects of lemakalim, a K+ channel opener, and glibenclamide, an ATP-sensitive K+ channel blocker. A wedged bronchoscope technique was used to measure peripheral airway resistance (Rp) in anesthetized dogs. Rp was measured before and after constriction of the airways by hypocapnic challenge, acetylcholine aerosol, or dry air hyperpnea. Lemakalim (5 micrograms/kg i.v.) was administered, and the challenge was repeated. Lemakalim attenuated responses to hypocapnia by 72 +/- 7% (n = 6, P = 0.0007) and to dry air challenge by 37 +/- 8% (n = 6, P = 0.005) but not to acetylcholine. On separate days, sublobar segments were pretreated with aerosolized glibenclamide (2 mg/ml), and responses to hypocapnic challenge were measured before and after lemakalim (5 micrograms/kg i.v.), nifedipine (20 micrograms/kg i.v.), or albuterol (1 microgram/kg i.v.). In the presence of glibenclamide, lemakalim had no significant effect on responses to hypocapnia; however, both nifedipine (n = 6, P = 0.0003) and albuterol (n = 6, P = 0.0001) attenuated responses to hypocapnic challenge. These findings suggest that lemakalim attenuated hypocapnic bronchoconstriction by promoting K+ efflux through ATP-sensitive K+ channels.

Acetylcholine↗

PubMed1993

Importance of prostanoids in calcium chelator-induced airway constriction.

To elucidate the mechanism of calcium chelator-induced airway constriction, we examined the relationship between prostanoids and histamine in bronchoalveolar lavage (BAL) fluid and the magnitude of airway constriction in peripheral airways of anesthetized Basenji-Greyhound dogs. A wedged bronchoscope technique was used to measure collateral system resistance (Rcs) before and after aerosol challenges. Sublobar segments were challenged either with acetylcholine or with Na2EDTA in the presence or absence of meclofenamate sodium (3 mg/kg iv) or methylprednisolone (2 mg.kg-1.day-1). After measurements of Rcs, BAL was performed, and the fluid was analyzed for prostanoids with the use of gas chromatography-mass spectrometry. Sublobar segments challenged with Na2EDTA showed increased concentrations of prostaglandin (PG) D2 but no increases in PGE2, PGF2 alpha, 9 alpha,11 beta-PGF2, 6-keto-PGF1 alpha, thromboxane B2, or histamine. There was a strong relationship (r = 0.84, P = 0.005) between changes in Rcs after Na2EDTA and concentrations of PGD2 in BAL fluid. Acetylcholine, which increased Rcs to a similar degree as Na2EDTA did, produced no significant increase in prostanoid concentrations. Changes in Rcs after Na2EDTA and concentrations of PGD2 were reduced in the presence of meclofenamate or methylprednisolone. These data support the idea that the mechanism of calcium chelator-induced bronchoconstriction involves the release of bronchoconstricting prostanoids.

Acetylcholine↗

PubMed1993

Corticosteroid withdrawal restores responses to calcium chelators and enhances cholinergic responsiveness.

To investigate the importance of the inflammatory response in acute peripheral airway constriction, we measured peripheral airway responses to calcium chelators and acetylcholine in anesthetized Basenji-Greyhound (BG) dogs before, during, and after chronic corticosteroid treatment. A wedged bronchoscope technique was used to measure peripheral airway resistance before and after aerosol challenge with 4% Na2EDTA or acetylcholine (10 micrograms/ml) in contralateral lungs. After the initial measurements, five BG dogs received long-term treatment with methylprednisolone (2 mg/kg/d, subcutaneously), and five dogs were not treated and served as controls. Four weeks of methylprednisolone treatment almost totally abolished responses to Na2EDTA, but responses to acetylcholine did not change significantly. After discontinuing corticosteroid therapy, responses to Na2EDTA returned to levels found before corticosteroid treatment; responses to acetylcholine were significantly enhanced. We conclude that chronic corticosteroid treatment reduces acute response to calcium chelators and that withdrawal of corticosteroid therapy is associated with enhanced cholinergic responsiveness.

Acetylcholine↗

PubMed1992

Mechanism of action of atracurium on airways.

Histamine-releasing drugs may produce significant effects on airways in high-risk populations. To determine if clinically relevant doses of atracurium produce adverse effects on airways, we measured changes in airway resistance in the lung periphery of anesthetized Basenji-Greyhound dogs before and after intravenous (iv) administration of atracurium. A wedged bronchoscope technique was used to measure collateral system resistance (Rcs). After a stable baseline was obtained, atracurium (1.2 or 0.5 mg/kg) or histamine (200 micrograms) were administered as an iv bolus, and percent increase in Rcs was calculated. On separate days dogs were pretreated with the histamine 1 receptor antagonist, chlorpheniramine (0.2 mg/kg iv), with or without atropine (0.2 mg/kg iv) and ranitidine (0.75 mg/kg iv) and the experiment repeated. Histamine (200 micrograms) increased Rcs 97 +/- 24% at 30 s (8 sublobar segments), whereas a second dose increased Rcs 77 +/- 15%. Pretreatment with chlorpheniramine (0.2 mg/kg iv) totally prevented increases in Rcs (9 sublobar segments). Atracurium (1.2 mg/kg) increased Rcs to 174 +/- 35% at 3 min (14 sublobar segments), whereas 0.5 mg/kg had little effect (10 sublobar segments). A second bolus of atracurium (1.2 mg/kg) increased Rcs to only 54 +/- 14% (P less than 0.01). Chlorpheniramine pretreatment (0.2 mg/kg iv) reduced the response to the initial dose of atracurium to only 26 +/- 14% (10 sublobar segments). Pretreatment with a combination of atropine and chlorpheniramine (4 sublobar segments), or ranitidine and chlorpheniramine (5 sublobar segments), did not attenuate the increase in Rcs significantly more than chlorpheniramine pretreatment alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

PubMed1991

Calcium channel blockers modulate airway constriction in the canine lung periphery.

We studied the effect of two voltage-sensitive calcium channel blockers on Na2EDTA-induced bronchoconstriction in the canine lung periphery. A wedged bronchoscope technique was used to measure collateral system resistance before and after challenges with aerosolized Na2EDTA, hypocapnia, aerosolized acetylcholine, and increased flow of dry air in anesthetized mongrel dogs. Nifedipine, a dihydropyridine calcium channel blocker, reduced hypocapnia-induced bronchoconstriction by 88 +/- 6% (SE) but did not alter Na2EDTA-induced constriction. Verapamil, a phenylalkylamine calcium channel blocker, attenuated hypocapnia- and Na2EDTA-induced bronchoconstriction by 69 +/- 6 and 44 +/- 7%, respectively, but did not significantly alter responses to either acetylcholine or dry air challenge. We conclude that calcium influx through voltage-sensitive calcium channels, perhaps of the T subtype, has a limited role in the initiation of Na2EDTA-induced bronchoconstriction in the canine lung periphery.

Acetylcholine↗

PubMed1991

Functional antagonism of airway constriction in the canine lung periphery.

We studied the ability of a beta-adrenergic agonist (albuterol) to attenuate calcium chelator- and acetylcholine-induced airway constriction in the lung periphery of anesthetized mongrel and Basenji-Greyhound (BG) dogs. A wedged bronchoscope technique was used to measure collateral system resistance before and after challenges with aerosolized Na2EDTA and acetylcholine. Time course of the response to Na2EDTA differed significantly between mongrel and BG dogs. Peak response to challenge with 4% Na2EDTA occurred within 2 min for mongrel dogs and at 5 min for BG dogs. Albuterol (1 microgram/kg iv) significantly attenuated Na2EDTA-induced bronchoconstriction in both groups of animals (P less than 0.01, each group). Albuterol (1 microgram/kg iv) significantly attenuated acetylcholine-induced bronchoconstriction in mongrel (P less than 0.01) but not in BG dogs. We conclude that a qualitative difference exists in the mechanism of Na2EDTA-induced constriction in the lung periphery of BG compared with mongrel dogs. In addition, the lung periphery of BG dogs demonstrates reduced beta-adrenergic sensitivity with respect to a cholinergic challenge compared with mongrels, suggesting enhanced cholinergic inhibition of the beta-adrenergic system.

Acetylcholine↗

PubMed1990

Calcium chelators induce bronchoconstriction in the canine lung periphery.

We studied the mechanism by which Na2EDTA, a divalent cation chelator, induces bronchoconstriction in the lung periphery of mongrel dogs as a model of nonspecific small airway hyperresponsiveness. Using a wedged bronchoscope technique, we measured collateral system resistance (Rcs) before and after challenges with aerosolized Na2EDTA. An isotonic solution (4% Na2EDTA, 0.28 osmol/kg) increased Rcs 91 +/- 21%. Na2EDTA increased Rcs in a dose-dependent fashion after challenges of increasing concentration (0, 1, 3, and 6%) or duration (15, 30, 60, and 90 s) with 6% Na2EDTA. Atropine (1 mg/kg iv) significantly (P = 0.01) attenuated the response to an aerosol challenge with distilled H2O. Atropine did not significantly (P = 0.35) alter the response to a challenge with 4% Na2EDTA. Challenge with 6% Na2EDTA (0.42 osmol/kg) increased Rcs to a significantly greater (P less than 0.01) extent than did challenge with 6% CaNa2EDTA (0.37 osmol/kg, 250 +/- 55 vs. 29 +/- 11%, respectively). We conclude that Na2EDTA induces bronchoconstriction in the canine lung periphery in a dose-dependent fashion. As suggested by the Na2EDTA-CaNa2EDTA comparison, hyperosmolality of the solution alone cannot explain this phenomenon. The mechanism does not depend on muscarinic activity and appears to involve chelation of calcium.

Airway Resistance↗

PubMed1989

Effect of magnesium sulfate on bronchoconstriction in the lung periphery.

Magnesium sulfate has been shown to be effective clinically as a bronchodilator, but its mechanism of action is unknown. We used a wedged bronchoscope technique to study the ability of MgSO4 at clinically relevant concentrations to attenuate hypocapnia-, acetylcholine- (ACh), and dry air-induced bronchoconstriction in the canine lung periphery. Control experiments demonstrated that consecutive challenges of either hypocapnia or ACh resulted in greater collateral system resistance (Rcs) after the second challenge compared with the first. Intravenous infusion of MgSO4 diminished the maximum response to a second hypocapnic challenge (Rcs = 1.59 +/- 0.29 cmH2O.ml-1.s prechallenge vs. 1.12 +/- 0.20 postchallenge) but had no effect on either ACh- or dry air-induced bronchoconstriction. Serum magnesium levels before MgSO4 administration were 1.59 +/- 0.04 meq/l and rose to 6.20 +/- 0.13 during the infusion. Previous studies demonstrated that nifedipine, like MgSO4 in this study, attenuates hypocapnia-induced bronchoconstriction in the canine lung periphery but has no effect on ACh- or dry air-induced bronchoconstriction. We conclude that these results are consistent with the idea that, like nifedipine, magnesium acts in the airway as a voltage-sensitive calcium channel blocker.

Acetylcholine↗