The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 1981
Renal function during consciousness and anesthesia in sheep: effects of renal vasodilation by papaverine and acetylcholine.
Adult ewes were studied to determine the effects of barbiturate anesthesia on renal function and the natriuretic response to renal vasodilation by papaverine and acetylcholine. During a period of consciousness, renal blood flow, glomerular filtration rate, urinary Na excretion (UNaV) and arterial blood pressure were monitored. Renal blood flow was maximally increased by renal arterial infusion of papaverine or acetylcholine and changes in renal function were observed. ⋯ During consciousness, maximal renal vasodilation by papaverine or acetylcholine did not increase UNaV or fractional Na excretion. During anesthesia, both papaverine and acetylcholine produced large increases in both UNaV and fractional Na excretion. These data indicate that renal vasodilation per se is not a sufficient condition to increase UNaV and suggest that barbiturate anesthetics can alter renal function in such a manner as to render drugs, which are not natriuretic during consciousness, effective natriuretic agents during anesthesia.
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J. Pharmacol. Exp. Ther. · Jul 1981
Barbiturates: active form and site of action at node of Ranvier sodium channels.
Barbiturate sodium channel block was investigated in the voltage-clamped amphibian node of Ranvier. Internal pH was manipulated by diffusion of buffers from the cut internodes. Like local anesthetics and volatile general anesthetics, barbiturates shift the voltage dependence of inactivation in the hyperpolarizing direction. ⋯ Unlike local anesthetics, however, phenobarbital exerts a frequency-dependent block which is modified by changes in internal pH and is not affected by changes in external pH. In addition, barbiturate frequency dependence is apparently more exclusively involved with channel inactivation. The results suggest a barbiturate sodium channel binding site closer to the axoplasm than the local anesthetic binding site is and also suggest that there is a proton barrier between the two sites.
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J. Pharmacol. Exp. Ther. · Jul 1981
Fixed-ratio responding under second-order schedules of food presentation or cocaine injection.
Squirrel monkeys pressed a key under second-order schedules in which every nth response resulted in a 2-sec visual stimulus (n-response fixed ratio; n = 10, 20 or 30); after a minimum fixed-interval of time elapsed (second-order t-min fixed-interval; t = 5 or 60), the completion of a fixed-ratio resulted in both the brief stimulus and either presentation of food or i.v. injection of cocaine. Under a second-order 5-min fixed-interval schedule with 15 intervals per session, rates of responding increased to a maximum and then decreased with increases in the amount of food (from 250 to 4000 mg/presentation) or cocaine (from 25 to 400 micrograms/kg/injection). Cocaine injections maintained higher maximal rates of responding than food presentation. ⋯ Under a second-order 60-min fixed-interval with one interval per session, both food and cocaine maintained relatively high rates of responding even with large amounts of food (7.5-14 g/presentation) or cocaine (375-1500 micrograms/kg/injection). When the brief stimuli were omitted during the 60-min interval, rates of responding maintained by either food or cocaine decreased. Thus, the brief-stimulus presentations were essential for maintaining performance under the second-order 60-min fixed-interval schedule.
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J. Pharmacol. Exp. Ther. · Apr 1980
Structure-activity relations for frequency-dependent sodium channel block in nerve by local anesthetics.
Different local anesthetic drug structures differ significantly in their capabilities for producing frequency (f)-dependent sodium channel block. Voltage-clamped frog myelinated nerve preparations have been utilized in order to investigate structure-activity relations for several modes of local anesthetic drug action, including the kinetics of f-dependent excitability block. ⋯ In addition, f-dependent block increments are greater for drugs of lower lipid solubility, supporting the "modulated drug receptor" hypothesis that intracellular drug forms participate in the open channel binding involved in f-dependent blocking. Finally, molecular size has been shown to be a very important determinant of closed channel block escape rates with smaller drug structures showing faster escape rates from f-dependent increments in channel block.
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J. Pharmacol. Exp. Ther. · Apr 1980
Phenytoin pharmacokinetics in burned rats and plasma protein binding of phenytoin in burned patients.
Unexpectedly low serum phenytoin levels occurred in burned epileptic patients, suggesting the possibility of altered phenytoin disposition. Subsequently, phenytoin log-linear elimination kinetics after a 10 mg/kg i.v. single dose was examined in a burned rat model. Clearance increased from 1.08 +/- 0.28 liters/hr/kg in control rats to 1.50 +/- 0.38 liters/hr/kg in burned rats (P less than .05). ⋯ The free fraction in plasma increased from 27.1% +/- 1.2 in controls to 33.4% +/- 1.6 in burned rats (P less than .0005). The change in binding was consistent with a decrease in serum albumin from 2.64 +/- 0.33 g/dl in controls to 1.98 +/- 0.16 g/dl in burned rats (P less than .0005). Plasma samples of four burned human subjects revealed low serum albumin and markedly decreased plasma protein binding of phenytoin (2- to 3-fold increase in free fraction in plasma).