Is There Loss of a Protective Muscarinic Receptor Mechanism in Asthma: Methacholine-induced Bronchoconstriction

Effect of Prior Muscarinic Receptor Stimulation on Histamine and Methacholine-induced Bronchoconstriction
In the normal group, prior muscarinic receptor stimulation with methacholine caused a rightward shift in the histamine dose-response curve in most of the subjects and a significant increase in histamine PD.50 (Fig 1 and 2). The mean ± SE histamine PD^ on a control day was 13.7 ± 3.1 breath units; the histamine PD50 increased to 28.4 ±7.2 breath units when histamine challenge was performed after muscarinic stimulation (p<0.05) (Fig 2). In the asthmatic group, muscarinic receptor stimulation failed to change the PD50 of histamine (Fig 2 and 3). Mean±SE PDgo of histamine on control day was 3.6 ±2.5 breath units, which was not different from PD*, of 4.1 ±3.5 breath units, when histamine challenge was performed after muscarinic stimulation (p = NS) (Fig 2). The suppression of histamine-induced bronchoconstriction by prior muscarinic stimulation in normal subjects was unrelated to the dose of methacholine used; as prior exposure to a lower dose of methacholine (5 breath units vs 19 breath units) in five subjects caused an equivalent increase in PD^ of histamine (Fig 4).

Prior methacholine inhalation did not cause any change in the bronchoconstrictor response to a second methacholine challenge in both normal subjects and asthmatic groups. In the normal group, mean± SE PD.50 values of methacholine were 13.9 ±2.8 breath units and 13.8 ±2.4 breath units for the first and second methacholine challenges, respectively, (p = NS) (Fig 1 and Table 2). In the asthmatic group PD^,, values of methacholine were 4.9 ± 3.3 breath units and 2.5 ± 1.9 breath units for the first and second methacholine challenges, respectively, (p = NS) (Fig 3 and Table 2).
Effect of Prior Histamine-Beceptor Stimulation on Methacholine or Histamine-induced Bronchoconstriction
Prior challenge with aerosolized histamine did not stimulation of airway muscarinic receptors by inhaled methacholine causes a suppression of bronchoconstrictor response to histamine. Suppression of bronchoconstrictor response to histamine by prior muscarinic receptor stimulation was only observed in normals and not in subjects with bronchial asthma. Our study also demonstrates that suppression of histamine responses was specific and only observed after prior muscarinic receptor stimulation. This was demonstrated by the absence of any change in the bronchoconstrictor response to methacholine by prior exposure to methacholine or histamine.

Figure 1. Individual dose response curves to histamine and methacholine in a normal subject. Bost-methacholine there is a rightward shift in the histamine dose-response curve (panel A).

Figure 1. Individual dose response curves to histamine and methacholine in a normal subject. Bost-methacholine there is a rightward shift in the histamine dose-response curve (panel A).

Figure 2. Modification of bronchoconstrictor response to histamine by prior muscarinic stimulation with methacholine in normal subjects (n = 9) and subjects with bronchial asthma (n = 6). Data are expressed as mean ± SE PD*, of histamine (cumulative provocative dose of histamine which caused a 50 percent decrease in SCaw).

 

Figure 2. Modification of bronchoconstrictor response to histamine by prior muscarinic stimulation with methacholine in normal subjects (n = 9) and subjects with bronchial asthma (n = 6). Data are expressed as mean ± SE PD*, of histamine (cumulative provocative dose of histamine which caused a 50 percent decrease in SCaw).

Figure 3. Individual dose-response curves to histamine and methacholine in an asthmatic subject. Prior muscarinic stimulation did not cause a rightward shift in the histamine dose-response curve.

Figure 3. Individual dose-response curves to histamine and methacholine in an asthmatic subject. Prior muscarinic stimulation did not cause a rightward shift in the histamine dose-response curve.

Figure 4. Effects of prior muscarinic stimulation with high (19 breath units) and low (5 breath units) doses of methacholine on bronchoconstrictor responses to histamine in normal subjects (n = 5). Data are shown as mean± SE PD* of histamine (cumulative provocative dose of histamine which caused a 50 percent decrease in SGaw). *p<.05 significantly different from control.

Figure 4. Effects of prior muscarinic stimulation with high (19 breath units) and low (5 breath units) doses of methacholine on bronchoconstrictor responses to histamine in normal subjects (n = 5). Data are shown as mean± SE PD* of histamine (cumulative provocative dose of histamine which caused a 50 percent decrease in SGaw). *p<.05 significantly different from control.

Figure 5. Modification of histamine-induced bronchoconstriction by pretreatment with ipratropium bromide (36pig) in normal subjects (n = 5). Data are expressed as mean ± SE PD*, of histamine (cumulative provocative dose of histamine which caused a 50 percent decrease in SGaw. *p<.Q5 significantly different from control.

Figure 5. Modification of histamine-induced bronchoconstriction by pretreatment with ipratropium bromide (36pig) in normal subjects (n = 5). Data are expressed as mean ± SE PD*, of histamine (cumulative provocative dose of histamine which caused a 50 percent decrease in SGaw. *p<.Q5 significantly different from control.

Table 2—Effects of Prior Histamine Stimulation (A) and Muscarinic Stimulation (B) on Bronchoconstrictor Besponses to Methacholine in Normal (n=9) and Asthmatic (n=6) Subjects

(A) Methacholine PD*
Methacholine(control) Methacholine(post-histamine)
Normal
Subjects 16.9 ±3.6 p = NS 14.6 ±2.8
Asthmatic
Patients 4.3±2.5 p = NS 4.1±3.3
(B) Methacholine PD*,
Methacholine (1st Challenge) Methacholine (2nd Challenge)
Normal
Subjects 13.9 ±2.8 p = NS 13.8 ±2.4
Asthmatic
Patients 4.9 ±3.3 p = NS 2.5±1.9

Category: Asthma

Tags: Asthma, Methacholine, muscarinic receptor