Blockade of cardiac nicotinic responses by anticholinesterases.

1. Tacrine (10 microM) and physostigmine (10 microM) completely inhibited the positive chronotropic and inotropic actions of acetylcholine (ACh) or nicotine in the atropinized guinea pig right atria. 2. Edrophonium (6 microM) and soman (0.1 microM) completely inhibited these nicotinic responses, as well as the associated increase in pyridine nucleotide fluorescence and vasodilation induced by ACh in the atropinized guinea pig perfused heart. 3. The 200-fold increase in noradrenaline release induced by ACh in the perfused heart was blocked by 10 microM tacrine and 6 microM edrophonium. 4. Tacrine (10 microM) significantly (16-32%) reduced the basal heart rate of both preparations. 5. Edrophonium (6 microM) induced a five- to sixfold increase in basal 3,4-dihydroxyphenyl-(ethylene) glycol (DOPEG) release. 6. The inhibition of nicotinic receptor activation in the atria by the anticholinesterases appears mainly non-competitive. IC50 values range from 0.1 to 10 microM in the perfused heart to 1 to 100 microM in atria (in either case tacrine about 2 microM). 7. The possibility that these compounds have a direct action at nicotinic receptors is discussed.

Simple high-performance liquid chromatographic method for assessing the deterioration of atropine-oxime mixtures employed as antidotes in the treatment of nerve agent poisoning.

A set of reversed-phase HPLC conditions for determining the degradation of atropine and the oxime (pralidoxime, obidoxime, or HI-6) in autoinjectors designed for use against nerve agent poisoning is described. The assay conditions for atropine do not require its prior separation from the large molar excess of oxime since both the atropine and tropic acid peaks elute well clear of the oxime and its degradation products and the phenolic preservatives. Further dilution of the sample and simple changes to the mobile phase then provide conditions for the oxime and its major degradation products to be quantitated.

Age-dependent pattern of autonomic heart rate control during hypoxia in fetal and newborn lambs.

Autonomic nervous control of heart rate (HR) during hypoxia was studied longitudinally using 9 chronically catheterized fetal lambs (109 day to term) and 10 newborn lambs (2--28 days old). Changes in heart rate (deltaHR) during hypoxia were age-dependent. Before 120 days of gestation deltaHR was insignificant, but between 120 days to term bradycardia occurred. The newborn response was marked tachycardia. Autonomic influences on HR were quantified using atropine and propranolol blockade. In fetal lambs, antagonistic increases in parasympathetic and sympathetic outflows were evident during hypoxia. In hypoxic lambs 120 days to term, net bradycardia reflected predominant parasympathetic cardio-deceleration; before 120 days of gestation both the parasympathetic and sympathetic outflows increased, but no net deltaHR occurred. In hypoxic newborn lambs, sympathetic and parasympathetic changes contributed synergistically to the net tachycardia. Thus the pattern of autonomic control of HR during hypoxia differs in fetal and newborn lambs. Changes in sympathetic and parasympathetic influences are antagonistic in the fetus, but synergistic in the newborn.

Sympathetic and parasympathetic control of heart rate in unanaesthetized fetal and newborn lambs.

Development of autonomic nervous control of basal heart rate was studied in unanesthetized fetal lambs (93 days to term) and newborn lambs (2--29 days), using atropine and/or propranolol blockade. Fetal lambs showed a progressive increase in parasympathetic restraint of heart rate; vagal influence in the newborn lamb was similar to the term fetus. Sympathetic stimulation of fetal heart rate declined toward term, possibly due to the strongly increasing parasympathetic influence. Sympathetic influence in the newborn was similar to the early-gestation fetus. Intrinsic heart rate was about 185 beats/min throughout the fetal and newborn life span studied. Thus changes in basal heart rate resulted from a different balance of the sympathetic and parasympathetic components of the autonomic nervous outflow.

Baroreflex activity in conscious fetal and newborn lambs.

The immediate transient baroreceptor sensitivity was measured in 9 conscious fetal and 7 conscious newborn lambs for periods of at least 35 days following bolus injections of phenylephrine (20-50 mug/kg). Mean sensitivities were unchanged throughout gestation from 105 days at 6.7 +/- 0.4 msec/cm H2O (n = 45) and were insignificantly different from those in the newborn period, 5.9 +/- 0.4 msec/cm H2O (n = 78). In contrast, baroreflex sensitivities were less in 2 fetuses and 2 newborn lambs when pressures were increased by chronically implanted thoracic aortic balloon cuff; they were 3.03 +/- 0.11 (n = 127) and 0.91 +/- 0.11 msec/cm H2O (n =61), respectively. "Steady-state" heart period-arterial pressure curves indicate that the baroreflex operates down to levels of 40 cm H2O in the fetus which is lower than that achieved in the adult of other species, rabbit and man.

Modification of respiratory center output in the unanesthetized fetal sheep "in utero".

Diaphragmatic electromyographic activity, tracheal and amniotic fluid pressures, lung liquid flow, and carotid and jugular venous pressures were measured on eight fetal lambs who survived for periods of 9-43 days postoperatively. The fetal gestational age ranged from 98 to 113 days at operation. Respiratory center output of the fetus as indicated by electromyographic activity was modified by the following stimuli. It was suppressed by anesthesia and fetal hypoxia (Pao2 = 12 mmHg), tonically reduced by lung inflation, and stimulated by cyanide injections (150-600 mug) into the fetal jugular vein. Neuromuscular transmission to the diaphragm was blocked with d-tubocurarine (0.2-0.6 mg). These experiments indicate that central and motor pathways to the diaphragm are sufficiently mature by 101 days in the fetal sheep to permit their output to be modified by chemical and mechanical stimuli.