Effects of barbiturates on ATP-sensitive K channels in rat substantia nigra.

ATP-sensitive K channels are widely expressed in cytoplasmic membranes of neurons, and they couple cell metabolism to excitability. They are thought to be involved in neuroprotection against cell damage during hypoxia, ischemia and excitotoxicity by hyperpolarizing neurons and reducing excitability. Although barbiturates are often used in patients with brain ischemia, the effects of these agents on neuronal ATP-sensitive K channels have not been clarified. We studied the effects of thiopental and pentobarbital on surface ATP-sensitive K channels in principal neurons of rat substantia nigra pars compacta. Whole cell voltage- and current-clamp recordings were made using rat midbrain slices. ATP-sensitive K channels were activated by intracellular dialysis with an ATP-free pipette solution during perfusion with a glucose-free solution. When the pipette solution contained 4mM ATP and the perfusing solution contained 25 mM glucose, the membrane current at -60 mV remained stable. When intracellular ATP was depleted, hyperpolarization and an outward current developed slowly. Although thiopental did not affect the membrane current in the presence of ATP and glucose, it reversibly inhibited the hyperpolarization and outward current induced by intracellular ATP depletion at 100 and 300 microM. Thiopental reduced the ATP depletion-induced outward current by 4.7%, 36.7% and 87% at 30, 100 and 300 microM, respectively. The high dose of pentobarbital also exhibited similar effects on ATP-sensitive K channels. These results suggest that barbiturates at high concentrations but not at clinically relevant concentrations inhibit ATP-sensitive K channels activated by intracellular ATP depletion in rat substantia nigra.

Clinically safe dosage of felypressin for patients with essential hypertension.

Hemodynamic changes were evaluated in patients with essential hypertension when felypressin of various concentrations was administered. The parameters studied were systolic pressure, diastolic pressure, heart rate, left ventricular systolic phase, and endocardial viability ratio. Results showed that blood pressure tended to increase, and the value of 1/pre-ejection period2 (PEP2) tended to decrease, upon administration of 3 ml of 2% propitocaine containing 0.06 international units/ml (IU/ml) of felypressin. Significant increase of blood pressure and decrease in 1/PEP2 was noted upon administration of 3 ml of anesthetic solution containing 0.13 IU/ml of felypressin. No ischemic change of the myocardium was detected even with the highest felypressin concentration (3 ml of 2% propitocaine containing 0.25 IU/ml of felypressin). These results suggest that the clinically safe dosage of felypressin for patients with essential hypertension is approximately 0.18 IU. This amount is equivalent to 6 ml of 3% propitocaine with 0.03 IU/ml of felypressin, which is a commercially available local anesthetic for dental use. It seems that the decrease in 1/PEP2 that occurred during blood pressure increase was due to the increase in afterload caused by contraction of the arterioles. Although in the present study no ischemic change was noted, special care should be taken to prevent myocardial ischemia in patients with severe hypertension.