Study Of Cardiovascular Effects Of Cgmp Pathway Activation On Experimental Rat Model Of Metabolic Syndrome
JOURNAL OF HYPERTENSION(2019)
摘要
Objective: Metabolic syndrome is a fast growing problem associated with an increased risk of cardiovascular death. This association has been shown to be multifactorial where endothelial dysfunction acts as a major contributor. However, few studies have explored the effects of cyclic guanosine monophosphate (cGMP) pathway activation on cardiovascular dysfunction related to metabolic syndrome. The aim was to investigate the effects of a long-term administration of BAY 41–2272, a cGMP pathway activator on cardiovascular reactivity in spontaneously hypertensive rats (SHR) with an experimentally-induced metabolic syndrome. Design and method: Thirty-six 9-week-old rats were randomly divided into 3 groups: Standard diet-fed rats (control group), Cafeteria diet (CAF)-fed rats and CAF diet-fed rats treated with BAY 41–2272 (5 mg/kg) daily for 12 weeks. CAF consisted of allowing rats free access to energy dense human foods during 12 weeks. Body weight, abdominal circumference, arterial pressure and glucose tolerance test were monitored. Cumulative concentration-response curves to isoproterenol (0.1 nM – 1 μM), phenylephrine (1 nM – 10 μM), acetylcholine (1 nM – 10 μM), insulin (1 nM – 3 μM) and sodium nitroprusside (SNP) (0.1 nM – 0.1 μM) were performed on isolated persfused heart and thoracic aorta. A significance level of 0.05 was used for statistical comparison purposes. Results: 12 weeks of CAF feeding induced obesity, arterial hypertension and glucose intolerance. Compared to the control group, there was a significant decrease in the positive inotropic effect of isoproterenol and in the α1-adrenergic response in CAF fed-group. Long-term BAY 41–2272 treatment significantly improved the metabolic abnormalities, restored the cardiac inotropy and the α1-adrenergic response. CAF fed-rats showed also an altered insulin-induced vasorelaxation which was significantly improved after BQ-123 preincubation (1 μM), a selective endothelin 1 receptor antagonist. However, BAY 41–2272 did not improve the insulin-induced vasorelaxation. No difference in acetylcholine and SNP-induced vasorelaxations was observed between all groups. Conclusions: In this study, we demonstrated the positive effects of BAY 41–2272 on metabolic alterations and cardiovascular reactivity in SHR with metabolic syndrome. These results suggest that cGMP pathway modulation may be a promising therapeutic target in the management of the metabolic syndrome.
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关键词
cgmp pathway activation,metabolic syndrome,cardiovascular effects,experimental rat model
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