Abstract
Previous studies suggest that middle cerebral arteries (MCAs) of Fawn Hooded Hypertensive (FHH) rats exhibit impaired myogenic response and introgression of a small region of Brown Norway chromosome 1 containing 15 genes restored the response in FHH.1BN congenic rat. The impaired myogenic response in FHH rats is associated with an increase in the activity of the large conductance potassium (BK) channel in vascular smooth muscle cells (VSMCs). The present study examined whether the increased BK channel function in FHH rat alters vasoconstrictor response to serotonin (5-HT). Basal myogenic tone and spontaneous myogenic response of the MCA was attenuated by about twofold and about fivefold, respectively in FHH compared with FHH.1BN rats. 5-HT (0.1 μM)-mediated vasoconstriction was about twofold lower, and inhibition of the BK channel increased the vasoconstrictor response by about threefold in FHH compared with FHH.1BN rats. 5-HT (3 μM) decreased BK channel and spontaneous transient outward currents in VSMCs isolated from FHH.1BN but had no effect in FHH rats. 5-HT significantly depolarized the membrane potential in MCAs of FHH.1BN than FHH rats. Blockade of the BK channel normalized 5-HT-induced depolarization in MCAs of FHH rats. The 5-HT-mediated increase in cytosolic calcium concentration was significantly reduced in plateau phase in the VSMCs of FHH relative to FHH.1BN rats. These findings suggest that sequence variants in the genes located in the small region of FHH rat chromosome 1 impairs 5-HT-mediated vasoconstriction by decreasing its ability to inhibit BK channel activity, depolarize the membrane and blunt the rise in cytosolic calcium concentration.
Highlights
The results of the present study indicate that the vasoconstrictor response to 5-HT is markedly reduced in MCAs isolated from FHH relative to FHH.1BN rats
Evaluation of the dose response curves indicates that the maximal response to 5-HT was attenuated in FHH rats compared with FHH.1BN rats, but there were no significant difference in the EC50 values
Izes the membrane that opposes Ca2ϩ influx through voltagegated calcium channels (VGCC) and diminishes the vasoconstrictor response to 5-HT. Consistent with this interpretation, we found that the peak increase in [Ca2ϩ]i was similar in VSMCs isolated from both FHH.1BN and FHH rats, but the
Summary
Experiments were performed on 72 nine- to 12-week-old male FHH and FHH.1BN congenic rats that were obtained from inbred colonies maintained at the University Of Mississippi Medical Center (UMMC). An unbranched segment of the MCA with an inner diameter of 100 –200 m was dissected They were mounted on glass micropipettes, tied with 8-0 nylon in a myograph containing physiological salt solution (PSS) (in mM): 119 NaCl, 4.7 KCl, 1.17 MgSO4, 1.8 CaCl2, 18 NaHCO3, 5 HEPES, 1.18 NaH2PO4, and 10 glucose, pH 7.4. MCAs were microdissected and digested in a low-calcium dissociation solution containing (in mM): 145 NaCl, 4 KCl, 1 MgCl2, 10 HEPES, 0.05 CaCl2, and 10 glucose (pH 7.4). An Axopatch 200B amplifier (Axon Instruments, Foster City, CA) was used to clamp the pipette potential and to record whole cell currents. The cells were bathed in physiological salt solution (PSS) containing (in mM): 130 NaCl, 5 KCl, 1.8 CaCl2, 1 MgCl2, 10 HEPES, and 10 glucose (pH 7.4). A P value Ͻ0.05 was considered to be significant
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