Shigeru Itabashi

Inhibitory actions of prostaglandin E1 on non-adrenergic non-cholinergic contraction in guinea-pig bronchi.

We have investigated the effect of prostaglandin E1 (PGE1) on non‐adrenergic, non‐cholinergic (NANC) contraction in guinea‐pig bronchial strips. PGE1 (10 nM to 10 μm) did not alter baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration‐dependent fashion (‐log EC50 was 6.60 ± 0.10M and maximum inhibition was 88.7 ± 2.9%). PGE1 (>0.3 μm) also reduced the contraction induced by substance P (1 μm). Removal of epithelium did not alter the effects of PGE1 on NANC contraction. These results suggest that PGE1 exerts both pre‐ and post‐junctional inhibitory actions on NANC contraction.

Absence of Association of α1-Antichymotrypsin Polymorphisms with Alzheimer's Disease: A Report on Autopsy-Confirmed Cases

alpha1-Antichymotrypsin (ACT) polymorphisms were examined in 79 cases with autopsy-confirmed Alzheimers disease (AD) as well as in 28 cases with autopsy-confirmed nonneurological diseases to test the hypothesis that ACT polymorphisms confer a risk to an individual to develop AD. Neither ACT genotype frequency nor ACT allele frequency in the AD group was significantly different from the control group. The ACT polymorphic pattern was essentially the same among apolipoprotein E (apoE) epsilon4 carriers and noncarriers. The age at onset of AD was not significantly affected by the inherited dose of ACT/A allele. Taking together, our observations do not confirm the effect of the ACT/A allele as a risk factor for developing AD in addition to the ApoE epsilon4 allele.

Evidence that an atypical β-adrenoceptor mediates the prejunctional inhibition of non-adrenergic non-cholinergic contraction in guinea-pig bronchi

We investigated the effect of the putative beta 3 agonist BRL 35135 on non-adrenergic non-cholinergic (NANC) contractions in guinea-pig bronchial strips. BRL 35135 (10(-9) to 10(-6) M) did not alter the baseline tension but reduced NANC contractions induced by electrical field stimulation (EFS) in a concentration-dependent fashion without having a significant effect on the contraction induced by substance P (10(-6) M). BRL 35135 (10(-6) M) also reduced the contraction induced by capsaicin (10(-7) M). Likewise, BRL 37344 (10(-9) to 10(-6) M) reduced NANC contractions induced by EFS in a concentration-dependent fashion. While BRL 37344 up to concentrations of 10(-8) M did not alter the contraction induced by SP (10(-6) M), BRL 37344 (10(-8) M) significantly inhibited NANC contractions induced by EFS and capsaicin (10(-7) M), (P less than 0.01). The inhibitory effect of BRL 35135 (10(-6) M) on NANC contractions induced by EFS was not significantly altered by the non-selective beta-adrenoceptor antagonists, propranolol and pindolol (P greater than 0.10), by the beta 1-selective antagonists, atenolol and metoprolol (P greater than 0.20) (10(-8) to 10(-6) M), or by the alpha-adrenoceptor antagonist, phentolamine (10(-7) to 10(-5) M) (P greater than 0.50). These results suggest that beta 3 agonists exert a prejunctional inhibitory action on NANC contractions.

ELEVATED CEREBROSPINAL FLUID TAU LEVELS: IMPLICATIONS FOR THE EARLY DIAGNOSIS OF ALZHEIMER'S DISEASE

Hiroyuki Arai, MD, PhD

The role of cyclic AMP in non‐adrenergic non‐cholinergic contraction in guinea‐pig bronchi

1 We investigated the role of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) in non‐adrenergic non‐cholinergic (NANC) contraction in guinea‐pig bronchial strips. 2 Forskolin (3 nm to 1 μm) reduced NANC contraction induced by electrical field stimulation (EFS) in a concentration‐dependent fashion (–log EC50 was 7.22 ± 0.12 m and maximum inhibition was 100 ± 0.01%). However, forskolin (< 1 μm) did not alter the contraction induced by substance P (SP, 1 μm). 3 Dibutyryl cyclic AMP (1 mm) also reduced NANC contractions induced by EFS (100 ± 0.01%) without significant effect on SP (1 μm)‐induced contractions. In contrast, dibutyryl cyclic GMP (1 mm) was without effect against either NANC or SP‐induced contractions. 4 Both the β2‐adrenoceptor agonist, procaterol (0.1 nm to 3 nm) and theophylline (100 nm to 1 mm) concentration‐dependently reduced EFS‐induced NANC contractions without significant effect on SP (1 μm)‐induced contractions. 5 In contrast to forskolin, procaterol and theophylline, both sodium nitroprusside and cromakalim inhibited the EFS‐induced contractions only at those concentrations that similarly reduced the contractions induced by SP (1 μm). 6 These results suggest that cyclic AMP may mediate pre‐junctional inhibition of NANC contractions in guinea‐pig bronchi.

APOE ε4 allele in Alzheimer's and non-Alzheimer's dementias

ApoE4 cases for whom SPECT data are available, three show bilateral frontal reduction, one unilateral frontal reduction, and the other diffuse unilateral atrophy (this patient is also thought to have vascular disease). From our study it would appear that in a cohort of subjects at risk of developing AD the 2-year incident cases are predominantly non-ApoE4-related. Non-ApoE4 cases of AD show some tendency, at least in this early stage of the disease, to manifest frontal lobe rather than temporoparietal pathology. Is non-ApoE4 AD a separate disease entity? Are cholinesterase inhibitors more efficient in ApoE4 AD because temporal rather than frontal areas are involved? The following shortcomings in our observations must be taken into account: (1) Weiner et al have observed frontal lobe reduction in 24% of cases of AD so our results could be due to chance; (2) in our series the diagnosis of AD has not been confirmed by necropsy; and (3) cases of non-ApoE4 AD with temporoparietal pathology (or conversely cases of ApoE4 AD with frontal pathology) may have died before clinical examination.

Peripheral airway hyperresponsiveness in the choline-deficiently fed rat

Rats fed with choline-deficient diets are known as a model of aging and learning impairments due to acetylcholine (ACh) deficiency in the brain which may be associated with a decrease in acetylcholinesterase (AChE; EC 3.1.1.7). To determine the role of AChE in bronchial responsiveness, we examined the contractile response of isolated lung parenchymal strips to ACh in control rats and rats fed with choline-deficient diets. Concentration-response curves to ACh shifted to the lower concentrations and the maximum response to ACh was greater in rats fed with choline-deficient diets than in control rats (P < 0.01). Physostigmine (10(-6) M) mimicked effects of choline-deficient diets on the contractile response to ACh. However, concentration response curves to carbachol and 5-hydroxytryptamine did not differ between control rats and rats fed with choline-deficient diets. Choline-deficient diets significantly decreased the AChE activity from homogenates of lung parenchymal tissues (P < 0.01). These results suggest that a decrease in AChE activity of lung tissues may relate to airway hyperresponsiveness to ACh.

Allergic Sensitization in Elderly Patients with Chronic Obstructive Pulmonary Disease

To study whether allergic sensitization occurs in elderly patients with chronic pulmonary obstructive disease (COPD), we examined serum IgE and skin test reactivity to allergens in three age-matched groups of normal subjects, and in patients with COPD and bronchial asthma (BA). Serum IgE was significantly higher in patients with COPD and BA than in normal subjects (p less than 0.05), and patients with COPD showed serum IgE levels as high as those of patients with BA. However, the skin test scores were significantly higher in patients with BA than in normal subjects and patients with COPD (p less than 0.05). Neither serum IgE nor skin test score significantly correlated with FEV1%, PaO2, PaCO2 or Brinkmans Index in any group (p greater than 0.20). These results suggest that allergic sensitization occurs in elderly patients with COPD and that symptoms associated with COPD may be partly due to allergic inflammation.

Late Asthmatic Response Causes Peripheral Airway Hyperresponsiveness in Dogs Treated with Metopirone

To determine if late asthmatic response (LAR) is associated with hyperresponsiveness of airway smooth muscle itself, we performed antigen challenge in dogs treated with Metopirone. We studied the contractile response to acetylcholine (ACh) in isolated bronchial and bronchiolar segments 8 h after either saline inhalation (the control group) or antigen challenge in dogs demonstrating immediate asthmatic response (IAR) alone and in dogs demonstrating both IAR and LAR. Airway responses to Ascaris suum antigen were assessed by changes in respiratory resistance measured with the forced oscillation technique at 3 Hz. Concentration-response curves of bronchial preparations to ACh did not differ significantly among three groups consisting of the control, IAR and LAR. However, the contractile response of bronchiolar preparations to ACh was significantly greater in the LAR group when compared to the control and IAR groups at the concentrations of ACh ranging from 10(-6) to 3 x 10(-4) M (p < 0.01). SQ 29548, a receptor antagonist of thromboxane A2 and prostaglandin D2 (PGD2), inhibited LAR-induced hyperresponsiveness to ACh in a concentration-dependent fashion. The bronchiolar preparations obtained from dogs showing LAR contained a significantly higher amount of PGD2 than those obtained from dogs showing IAR alone (p < 0.01, n = 6). These results suggest that LAR is associated with hyperresponsiveness of peripheral airway smooth muscle to ACh, and this augmented response to ACh mediates via PGD2 released during LAR.