oxadiazoles and Carotid-Stenosis

Angiotensin II type 2 (AT(2)) receptor activation has been reported to play a role in cognitive function, although its detailed mechanisms and pathologic significance are not fully understood. We examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) could prevent cognitive decline associated with hypoperfusion in the brain.We employed a bilateral common carotid artery stenosis (BCAS) model in mice as a model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. Azilsartan (0.1 mg/kg/day) or C21 (10 μg/kg/day) was administered from 1 week before BCAS. Cerebral blood flow (CBF) and inflammatory cytokine levels were also determined. Wild-type (WT) mice showed significant prolongation of escape latency after BCAS, and this cognitive impairment was attenuated by pretreatment with azilsartan. Cognitive impairment was more marked in AT(2) receptor knockout (AT(2)KO) mice, and the preventive effect of azilsartan on cognitive decline was weaker in AT(2)KO mice than in WT mice, suggesting that the improvement of cognitive decline by azilsartan may involve stimulation of the AT(2) receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C21 treatment. The decrease in CBF in the BCAS-treated group was blunted by C21 treatment, and the increase in TNF-α and MCP-1 mRNA expression after BCAS was attenuated by C21 treatment. These findings indicate that direct AT(2) receptor stimulation attenuates ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and a reduction of inflammation.

Topics: Animals; Benzimidazoles; Brain; Carotid Stenosis; Cerebral Cortex; Chemokine CCL2; Dementia, Vascular; Disease Models, Animal; Drug Evaluation, Preclinical; Maze Learning; Mice, Inbred C57BL; Oxadiazoles; Receptor, Angiotensin, Type 2; Regional Blood Flow; RNA, Messenger; Sulfonamides; Thiophenes; Tumor Necrosis Factor-alpha

Experiments performed in 226 pentobarbitone-anesthetized rabbits were designed to investigate the involvement of thromboxane/prostanoid and 5-hydroxytryptamine (5-HT)2A/C receptors during arterial thrombus formation in distinct low- and high-shear rate thrombosis models. Antithrombotic activities of the thromboxane/prostanoid receptor antagonist SQ 29,548 and two chemically distinct 5-HT2A/C receptor antagonists, ritanserin and ketanserin, were assessed first in low-shear rate (approximately 600 sec(-1)) arterial thrombosis, produced by insertion of a silk thread as thrombogenic substrate into the central section of an extracorporeal arteriovenous shunt established between the left carotid artery and the right jugular vein (n = 77), and second in high-shear rate (approximately 40,000 sec(-1)) arterial thrombosis, produced by critical stenosis and local endothelial injury of a carotid artery, characterized by cyclic flow reductions (CFRs) due to recurrent platelet aggregation and subsequent dislodgement of the thrombus (n = 149). Under low shear rate, SQ 29,548 (10-2500 microg/kg plus 10-2500 microg/kg/hr i.v.), but not ritanserin or ketanserin (both at 2500 microg/kg i.v.), dose-dependently inhibited thrombus formation. In contrast, under high shear rate, SQ 29,548 (10-160 microg/kg plus 10-160 microg/kg/hr i.v.) and both ritanserin and ketanserin (both at 10-2500 microg/kg i.v.) dose-dependently reduced CFR frequency, with ID50 values of 35 microg/kg (95% confidence limits, 24-58 microg/kg), 77 microg/kg (95% confidence limits, 40-132 microg/kg) and 89 microg/kg (95% confidence limits, 36-285 microg/kg) i.v., respectively. Furthermore, local infusion of the stable thromboxane A2 analog U-46619 (0.63 microg/kg/min) or 5-HT (20.8 microg/kg/min) proximal to the site of injury and stenosis in rabbits pretreated with either SQ 29,548 (40 microg/kg plus 40 microg/kg/hr i.v.) or ritanserin (160 microg/kg i.v.), respectively, restored CFR frequency to vehicle group levels in animals whose CFR frequency was previously reduced. The inhibitory activity of ketanserin and ritanserin on CFRs could not be attributed to 5-HT1B/D or alpha-1 adrenoceptor antagonist properties or to any hypotensive activity. These results provide firm evidence that thromboxane/prostanoid receptors are involved in arterial thrombosis in rabbits independently of the shear rate, whereas 5-HT2A/C receptors play a major role only in high-shear rate thrombus formation.

Topics: Animals; Arteriovenous Shunt, Surgical; Aspirin; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Carotid Arteries; Carotid Stenosis; Endothelium, Vascular; Fatty Acids, Unsaturated; Heart Rate; Hemodynamics; Hydrazines; Jugular Veins; Ketanserin; Male; Oxadiazoles; Piperazines; Platelet Aggregation; Prazosin; Rabbits; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Receptors, Prostaglandin; Receptors, Serotonin; Receptors, Thromboxane; Ritanserin; Serotonin Antagonists; Stress, Mechanical