Antagonistic Effect Of Dipfluzine On KCL And Endothelin-1-evoked Contraction In Isolated Rat Basilar Artery And Underlying Mechanisms

When cerebral ischemia happened ,the ion balance inside and outside of cells is broken, and the concentration of K+ outside of cells increased from 3mmol to 50~80mmol in short time. The high [K+] outside of cells can make vessels contracted.Endothelin (ET) is one of the most potent cerebrovascular contractors. The powerful contractive effect of ET is considered to be involved in vasospasm after cerebral ischemia and subarachoid homorrhage. The contractile effect of ET-1 is associated with Ca2+.Dipfluzine (Dip), a new diphenylpiperazine compound, was developed by Hebei Medical University, according to the characteristics of molecular formula of cinnarizine (Cin) and droperidol. Our previous studies have shown that Dip possesses the protective effect on cerebral ischemia. One of the most possible mechanisms of the protective effect on cerebral ischemia is that Dip can dilate vessels in ischemic regions and attenuate vasospasm. We found that Dip can inhibit the contraction of isolated rabbit's aorta rings evoked by KCL and norepinephrine (NA) and the contraction of isolated pig's basilar artery evoked by KCL and 5-hydroxytrptamine (5-HT). In anesthetic dogs, Dip could also decrease the vascular resistance of vertebral artery, coronary artery and femoral artery, and had a high selectivity to vertebral artery. The present study mainly explores the effect of Dip on the contraction in the isolated rat's basilar artery evoked by KCL and endothelin-1 (ET-1), and it's mechanisms. Objective: To study the effect of Dip on the contraction in the isolated rat's basilar artery evoked by KCL and ET-1 and compared with the effect of flunarizine (Flu).Method: The isolated basilar artery was placed in cold (4℃)PSS solution that contained (mmol/L: NaCl 119, KCl 4.7, CaCl2 2.5, MgSO4·7H2O 1.17, NaHCO3 25, KH2PO4 1.18, EDTA 0.027, Glucose 5.5). Isolated basilar arteries was cut into rings (2-mm in length) and mounted on 40-μm stainless steel wires in the chambers of Multi Myograph System-610M (Danish Myo Technology A/S) for measurement of isometric tension; they were bathed in PSS solution (37℃) gassed with 95% O2 and 5% CO2 mixture. Isometric tension is expressed as millinewtons per millimeter of vessel length. Then record the isometric tension of vessels' responsiveness to KCL and ET-1 in the presence and absence of Dip or Flu, and make the concentration-response curves. Flu was chosen as positive control medicine.Result: 1) Both Dip and Flu inhibited totally the contraction of isolated basilar artery rings evoked by KCL, and the effects of them were similar. The inhibitory potencies (IC50) of them are 26580nmol/L and 20161nmol/L respectively. 2) Both Dip and Flu inhibited the contraction of basilar artery rings evoked by ET-1, but the effects of them were different obviously. The inhibitory effect of Dip was more potent than Flu (p<0.01). The IC50 of them are 1611829nmol/L and 1789519nmol/L respectively.Conclusions: 1) Dip can act on VDCC of the vascular smooth muscle cells, block Ca2+ flowing into cells and inhibit vessels contracting evoked by KCL. 2) The effect of Dip on cerebral vasopasm evoked by ET-1 maybe involve both blocking Ca2+ outside of cells flowing into cells and restraining the intracellular Ca2+ pools released Ca2+.