OBJECTIVES: Extracellular signal-regulated kinases (ERK1/2) modulate vascular smooth muscle cell (VSMC) growth and contractility, important factors in blood pressure regulation. In the present in vivo study, we investigated whether short-term inhibition of ERK1/2-dependent signaling pathways influences vascular function and blood pressure (BP) in spontaneously hypertensive rats (SHR). METHODS: SHR and Wistar-Kyoto (WKY) rats were injected subcutaneously with either PD98059, selective MEK1/2 inhibitor (20 mg/kg), or vehicle. BP was measured by telemetry. Rats were killed 24 h after injection and small mesenteric arteries mounted as pressurized systems for morphometric analysis and assessment of endothelial function and angiotensin II (Ang II)-induced contractility. ERK1/2 phosphorylation was measured by Western blots, using protein extracts from mesenteric arteries, aorta, heart and kidneys. RESULTS: BP was higher (P < 0.01) in SHR than in WKY rats. PD98059 did not influence BP in either group. Endothelial-dependent relaxation (acetylcholine-induced), which was impaired in SHR, was improved by PD98059 (P < 0.05). Ang II increased contraction, with greater responses in SHR (Emax = 25 +/- 4%) than WKY (Emax = 9 +/- 3%) (P < 0.01). PD98059 reduced Ang II-induced contraction in SHR (Emax = 5.8 +/- 0.4%) and WKY (Emax = 4 +/- 0.4%). Vascular structure was unaltered by PD98059. Vascular and renal ERK1/2 phosphorylation, which was higher in SHR than WKY, was decreased by PD98059 in SHR. CONCLUSION: Short-term treatment with PD98059 improves endothelial function and vascular contractility without influencing BP in SHR. These findings provide evidence that vascular ERK1/2 activity is upregulated and that MEK1/2-sensitive signaling pathways play an important role in the regulation of vascular function in SHR. Acute inhibition of MEK1/2 does not alter blood pressure despite improved endothelial function and reduced arterial reactivity to Ang II.
OBJECTIVES: Extracellular signal-regulated kinases (ERK1/2) modulate vascular smooth muscle cell (VSMC) growth and contractility, important factors in blood pressure regulation. In the present in vivo study, we investigated whether short-term inhibition of ERK1/2-dependent signaling pathways influences vascular function and blood pressure (BP) in spontaneously hypertensiverats (SHR). METHODS: SHR and Wistar-Kyoto (WKY) rats were injected subcutaneously with either PD98059, selective MEK1/2 inhibitor (20 mg/kg), or vehicle. BP was measured by telemetry. Rats were killed 24 h after injection and small mesenteric arteries mounted as pressurized systems for morphometric analysis and assessment of endothelial function and angiotensin II (Ang II)-induced contractility. ERK1/2 phosphorylation was measured by Western blots, using protein extracts from mesenteric arteries, aorta, heart and kidneys. RESULTS: BP was higher (P < 0.01) in SHR than in WKY rats. PD98059 did not influence BP in either group. Endothelial-dependent relaxation (acetylcholine-induced), which was impaired in SHR, was improved by PD98059 (P < 0.05). Ang II increased contraction, with greater responses in SHR (Emax = 25 +/- 4%) than WKY (Emax = 9 +/- 3%) (P < 0.01). PD98059 reduced Ang II-induced contraction in SHR (Emax = 5.8 +/- 0.4%) and WKY (Emax = 4 +/- 0.4%). Vascular structure was unaltered by PD98059. Vascular and renal ERK1/2 phosphorylation, which was higher in SHR than WKY, was decreased by PD98059 in SHR. CONCLUSION: Short-term treatment with PD98059 improves endothelial function and vascular contractility without influencing BP in SHR. These findings provide evidence that vascular ERK1/2 activity is upregulated and that MEK1/2-sensitive signaling pathways play an important role in the regulation of vascular function in SHR. Acute inhibition of MEK1/2 does not alter blood pressure despite improved endothelial function and reduced arterial reactivity to Ang II.
Authors: Surabhi Chandra; David J R Fulton; Ruth B Caldwell; R William Caldwell; Haroldo A Toque Journal: Eur J Pharmacol Date: 2018-11-28 Impact factor: 4.432
Authors: Haroldo A Toque; Maritza J Romero; Rita C Tostes; Alia Shatanawi; Surabhi Chandra; Zidonia N Carneiro; Edward W Inscho; Robert Clinton Webb; Ruth B Caldwell; Robert William Caldwell Journal: J Sex Med Date: 2010-08-30 Impact factor: 3.802