Citations

Cerebral blood flow (CBF) was measured during 28 carotid endarterectomies in 25 patients, by injection of 133 Xe into the exposed internal carotid artery (ICA). Twenty-three patients had episodic cerebral or retinal ischemia and five had neurologic deficits before operation. Initial CBF values were variable. Increases of Pa Co Co2 caused CBF to increase in four of six patients, to increase slightly in one, and to decrease in one. In each of 19 procedures, CBF decreased during surgical occlusion of the ICA, 11 times to less than 30 ml/100 g/min, but absence of postoperative worsening indicated that decreased ICA blood flow is not a major risk of the procedure; embolization from the site of operation may be a greater threat to the patient. CBF increased after 14 endarterectomies, perhaps due to failure of autoregulation or to reactive hyperemia. Measurements of jugular PV o o2 and lactate concentration were of little value.

Background— Na V 1.5 is a mechanosensitive voltage-gated sodium-selective ion channel responsible for the depolarizing current and maintenance of the action potential plateau in the heart. Ranolazine is a Na V 1.5 antagonist with antianginal and antiarrhythmic properties. Methods and Results— Mechanosensitivity of Na V 1.5 was tested in voltage-clamped whole cells and cell-attached patches by bath flow and patch pressure, respectively. In whole cells, bath flow increased peak inward current in both murine ventricular cardiac myocytes (24±8%) and human embryonic kidney 293 cells heterologously expressing Na V 1.5 (18±3%). The flow-induced increases in peak current were blocked by ranolazine. In cell-attached patches from cardiac myocytes and Na V 1.5-expressing human embryonic kidney 293 cells, negative pressure increased Na V peak currents by 27±18% and 18±4% and hyperpolarized voltage dependence of activation by −11 mV and −10 mV, respectively. In human embryonic kidney 293 cells, negative pressure also increased the window current (250%) and increased late open channel events (250%). Ranolazine decreased pressure-induced shift in the voltage dependence (IC 50 54 μmol/L) and eliminated the pressure-induced increases in window current and late current event numbers. Block of Na V 1.5 mechanosensitivity by ranolazine was not due to the known binding site on DIVS6 (F1760). The effect of ranolazine on mechanosensitivity of Na V 1.5 was approximated by lidocaine. However, ionized ranolazine and charged lidocaine analog (QX-314) failed to block mechanosensitivity. Conclusions— Ranolazine effectively inhibits mechanosensitivity of Na V 1.5. The block of Na V 1.5 mechanosensitivity by ranolazine does not utilize the established binding site and may require bilayer partitioning. Ranolazine block of Na V 1.5 mechanosensitivity may be relevant in disorders of mechanoelectric dysfunction.