Functional anticholinergic activity of drugs classified as strong and moderate on the anticholinergic burden scale on bladder and ileum.

Several medications are commonly administered to older Japanese patients. Since some of them have not been included in previously developed scales to estimate the anticholinergic burden, we have developed a new muscarinic receptor binding-based anticholinergic burden scale. This study aimed to investigate the functional inhibitory effects of 60 medications, classified as anticholinergic burden scales 3 and 2 by the anticholinergic burden scale, on muscarinic receptor-mediated contractions in the bladder and ileum. The relaxation response induced by these drugs on isolated rat bladders and ileum smooth muscles constricted by carbachol was assessed using the organ bath method. All drugs inhibited smooth muscle contractile responses induced by the muscarinic receptor activation in a concentration-dependent manner in the rat bladder and ileum. Notably, variations were observed in the relaxation responses of the drugs, and the function EC50 values were positively correlated with the binding IC50 values in the bladder and ileum. The results of this study provide functional pharmacological evidence for the muscarinic receptor binding-based anticholinergic burden scale. Implementation of this scale may help reduce the risk of constipation and urinary retention, which are common side effects associated with anticholinergic drugs.

Development of a pharmacological evidence-based anticholinergic burden scale for medications commonly used in older adults.

AIM: The present study aimed to develop a pharmacological evidence-based anticholinergic burden scale (ABS) through a direct assessment of muscarinic receptor-binding activities of 260 medications commonly used in older adults. METHODS: The muscarinic receptor-binding activities of 260 drugs were assessed by the displacement of specific [N-methyl-3 H]scopolamine methyl chloride binding in the rat brain. The maximum blood concentrations (Cmax ) of drugs after their administration to subjects were cited from their interview forms. RESULTS: In total, 96 of 260 drugs displayed concentration-dependent muscarinic receptor binding in rat brain. Based on muscarinic receptor-binding activity (IC50 ) and Cmax after the administration at clinical doses in humans, we rated ABS 3 (strong) for 33 drugs and ABS 2 (moderate) for 37 drugs. There was an approximate similarity between muscarinic receptor-binding activities (IC50 ) and Cmax of 33 drugs (ABS 3) after their administration at clinical doses in humans. Furthermore, 26 drugs were defined as ABS 1 (weak) by muscarinic receptor-binding activity. The remaining 164 drugs exhibited slight or no significant muscarinic receptor-binding activities at high concentration of 100 µM, and they were defined as ABS 0. There was a marked similarity for 28 drugs (ABS 3) between the present ABS data and their previous scoring data in the literature. CONCLUSIONS: To our knowledge, the present study developed the first comprehensive pharmacological evidence-based ABS of drugs based on muscarinic receptor-binding activity, which provides guidance as to which drugs may be discontinued to reduce anticholinergic burden. Geriatr Gerontol Int 2023; 23: 558-564.

Modulation of Vasomotor Function by Perivascular Adipose Tissue of Renal Artery Depends on Severity of Arterial Dysfunction to Nitric Oxide and Severity of Metabolic Parameters.

Perivascular adipose tissue (PVAT) enhances vascular relaxation of mesenteric arteries in SHRSP.Z-Leprfa/IzmDmcr rats (SPZF), a metabolic syndrome model. We investigated and compared the effects of PVAT on the renal artery in SPZF with those on SHR/NDmcr-cp rats (CP). Renal arteries with and without PVAT were isolated from 23-week-old SPZF and CP. The effects of PVAT on acetylcholine- and nitroprusside-induced relaxation were examined using bioassays with phenylephrine-contracted arterial rings. Acetylcholine-induced relaxations without PVAT in SPZF and CP were 0.7- and 0.5-times lower in females than in males, respectively. In the presence of PVAT, acetylcholine-induced relaxations increased 1.4- and 2-times in male and female CP, respectively, but did not differ in SPZF. Nitroprusside-induced relaxation with and without PVAT was 0.7-times lower in female than in male SPZF but did not differ in CP. Angiotensin-II type-1 receptor (AT1R)/AT1R-associated protein mRNA ratios were lower in CP than in the SPZF and negatively correlated with the difference in arterial relaxation with and without PVAT. The effects of renal artery PVAT differed between the SPZF and CP groups. Higher levels of enhanced AT1R activity in SPZF PVAT may drive these differences by impairing the vascular smooth muscle responses to nitric oxide.

Perivascular Adipose Tissue Compensation for Endothelial Dysfunction in the Superior Mesenteric Artery of Female SHRSP.Z-Leprfa/IzmDmcr Rats.

Regulation of arterial tone by perivascular adipose tissue (PVAT) differs between sexes. In male SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF), PVAT exerts a compensatory relaxation effect for the loss of endothelium-mediated vasorelaxation, which occurs during the early stages of metabolic syndrome. However, this effect deteriorates by 23 weeks of age. Here, therefore, we compared the effects of PVAT in female and male SHRSP.ZF. Acetylcholine-induced relaxation in superior mesenteric artery without PVAT did not differ between 23-week-old females and males. However, the presence of PVAT enhanced relaxation in 23-week-old females, but not in males. The mRNA levels of angiotensin II type 1 receptor (AT1R) in PVAT did not differ between sexes, but AT1R-associated protein (ATRAP) and apelin levels were higher in females than in males. We observed a positive relationship between differences in artery relaxation with and without PVAT and ATRAP or apelin mRNA levels. In 30-week-old females, PVAT-enhanced relaxation disappeared, and mRNA levels of AT1R increased, while apelin levels decreased compared to 23-week-old females. These results demonstrated that in SHRSP.ZF, PVAT compensation for endothelium dysfunction extended to older ages in females than in males. Apelin and AT1R/ATRAP expression in PVAT may be predictors of favorable effects.

Lipoxin A4 Receptor Stimulation Attenuates Neuroinflammation in a Mouse Model of Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is caused by the rupture of blood vessels in the brain. The excessive activation of glial cells and the infiltration of numerous inflammatory cells are observed during bleeding. Thrombin is a key molecule that triggers neuroinflammation in the ICH brain. In this study, we focused on lipoxin A4 (LXA4), an arachidonic acid metabolite that has been reported to suppress inflammation and cell migration. LXA4 and BML-111, an agonist of the LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2), suppressed microglial activation; LXA4 strongly inhibited the migration of neutrophil-like cells in vitro. ALX/FPR2 was expressed on neutrophils in the ICH mouse brain and the daily administration of BML-111 attenuated the motor coordination dysfunction and suppressed the production of proinflammatory cytokines in the ICH mouse brain. On the other hand, BML-111 did not show a significant reduction in the number of microglia and neutrophils. These results suggest that systemic administration of ALX/FPR2 agonists may suppress the neuroinflammatory response of microglia and neutrophils without a change in cell numbers. Additionally, their combination with molecules that reduce cell numbers, such as modulators of leukotriene B4 signaling, may be required in future studies.

Microglia-released leukotriene B4 promotes neutrophil infiltration and microglial activation following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) from blood vessel rupture results in parenchymal hematoma formation and neuroinflammation, ultimately leading to neurodegeneration. Several lines of evidence suggest that the severity of ICH-induced neural damage is exacerbated by infiltration of T-cells, monocytes, and especially neutrophils into the hematoma. Neutrophil migration is regulated by chemokines, formyl peptides, and leukotriene B4 (LTB4), a metabolite of arachidonic acid. In this study, we demonstrate that LTB4 is a key signaling factor promoting microglial activity and leukocyte infiltration into hematoma and thus a potentially critical determinant of ICH pathogenesis and clinical outcome. Lipidomic analysis revealed markedly increased LTB4 concentration in the hematoma-containing brain tissues 6-24 h after experimental ICH in mice. Expression of 5-lipoxygenase, a rate-limiting enzyme for LTB4 production, was upregulated in activated microglia and neutrophils within the hematoma following ICH. Treatment of cultured BV-2 microglia with thrombin, which is abundant in hematoma, promoted activation, proinflammatory cytokine expression, and LTB4 secretion. Further, conditioned medium from thrombin-stimulated BV-2 cells potentiated the transwell migration of neutrophil-like cells, a response blocked by a LTB4 receptor antagonist. These results suggest that arachidonic acid conversion to LTB4 following ICH contributes to neuroinflammation and ensuing neural tissue damage by inducing microglial activation and neutrophil recruitment.