Increased sensitivity of the isometric contraction of the neonatal isolated rat atria to halothane, isoflurane, and enflurane.

Isolated atria from neonatal (0-5 day old) and adult (50 +/- 5 day old) rats were perifused in oxygenated Kreb's Henseleit solution at 30 +/- 0.5 degrees C and exposed to four different concentrations of halothane, isoflurane, or enflurane while isometric contractile tension was recorded and compared with control atria. ED50 values (mM of anesthetic required to produce 50% reduction in contractile tension) of neonates for halothane (0.18 +/- 0.01), isoflurane (0.41 +/- 0.05), and enflurane (0.41 +/- 0.04) were significantly lower than those of adults (0.35 +/- 0.02, 0.80 +/- 0.05, and 1.15 +/- 0.05, respectively). Furthermore, neonatal ED50 calculated as per cent of adult ED50 was significantly less for enflurane (35%) than for halothane (54%) or isoflurane (51%).

Dopamine reverses cardiovascular depression of toxic doses of pentobarbitone in dogs.

Pentobarbitone, 20 mg X kg-1 IV followed by infusion of 25 mg X kg-1 X hr-1, produced a progressive decrease in mean arterial pressure in dogs from 113 +/- 17 mmHg (SD) after one hour of infusion to 82 +/- 21 mmHg after 3.5 hours and to 49 +/- 22 mmHg after 5.5 hours. EEG silence occurred at 3.6 +/- 0.6 hours. In dogs similarly treated with pentobarbitone, a two hour infusion of dopamine 5 micrograms X kg-1 X min-1 beginning at the time of EEG silence prevented the further decrease in pressure and restored pressure to 87 +/- 18 mmHg. The mechanism for this effect of dopamine was an increase in cardiac output as systemic vascular resistance was unaffected by dopamine. The cardiac output increase was mainly the result of an increase in stroke volume as heart rate increased only slightly. Since reduced stroke volume was the main reason why pentobarbitone lowered blood pressure, the effect of dopamine on stroke volume and thus on blood pressure makes it an appropriate antagonist to the cardiovascular effects of toxic doses of pentobarbitone.

Measurement of cardiac output in adult and newborn animals by ascorbic acid dilution.

We have developed an ascorbic acid-dilution method for measuring cardiac output which requires minimal blood withdrawal. Ascorbate is injected into a central venous catheter. The indicator-dilution curve is obtained by drawing blood from an arterial catheter through an amperometric cell at 0.96 ml/min for 35 s. The current is measured by a picoammeter . A calibration curve is obtained in 15 s prior to each indicator-dilution curve. An on-line digital computer measures the curve areas and calculates the cardiac output. Cardiac outputs of heparinized dogs anesthetized with pentobarbital and halothane measured by this method (AA) compared closely to cardiac outputs measured by the dye-dilution method (CG) (AA = 0.96 CG + 20 ml/min, r = 0.98). Both the cardiac output and the arterial blood pressure remained stable during replicate measurements of the cardiac output of 1-day-old piglets. This system allows cardiac output determinations of neonatal subjects without excessive blood removal and, with further development, should be practical in human neonates.

Effect of age on epinephrine-induced arrhythmias during halothane anaesthesia in pigs.

The effect of age on the arrhythmogenicity of epinephrine during halothane anaesthesia was studied in pigs of two different age groups. At a stable alveolar concentration of 0.84 volumes per cent halothane, ventricular arrhythmias could not be elicited in one- to three-day-old pigs by a 100 micrograms X kg-1 infusion of epinephrine. PVCs were produced in 50- to 55-day-old pigs at a mean epinephrine dose of 9.55 micrograms X kg-1. Heart rate, systolic blood pressure, and rate-pressure product were significantly higher before and during the epinephrine infusion in the 50- to 55-day-old pigs. It is concluded that there is an age dependent effect upon epinephrine induced arrhythmias during halothane anaesthesia in pigs.

Comparison of cardiovascular effects of thiopental and pentobarbital at equivalent levels of CNS depression.

Thiopental and pentobarbital have been used in high doses to protect the brain from injury following hypoxia or to reduce intracranial pressure. This study was performed to determine whether these barbiturates differ in cardiovascular effects when present in plasma concentrations that produce equivalent CNS effects. The effects of thiopental and pentobarbital on heart rate, stroke volume/kg, cardiac output/kg, systemic vascular resistance, mean arterial pressure, and central venous pressure were statistically indistinguishable at plasma concentrations of each barbiturate ranging from 50% to 100% of their concentration producing EEG silence. Three of the seven dogs given thiopental developed ventricular bigeminy at plasma concentrations ranging from 45% to 65% of their concentration producing EEG silence. Lidocaine (1.4-2.0 mg/kg intravenously) reversed the bigeminy to sinus rhythm. When given more than the amount needed to produce a flat EEG, five of the seven dogs given thiopental died, but all dogs given pentobarbital survived. Pentobarbital may be a better choice than thiopental when large doses are indicated.

Effects of halothane on glucose-stimulated insulin secretion and glucose oxidation in isolated rat pancreatic islets.

Previous studies have shown that halothane inhibits glucose-stimulated insulin secretion. This study was designed to determine whether the mechanism of inhibition involves a reduction in glucose metabolism. The effects of halothane on glucose (16.7 mM)-stimulated insulin secretion and glucose oxidation were studied in isolated rat pancreatic islets. Halothane, 0.11 mM (0.5 MAC), 0.22 mM (1.0 MAC), and 0.33 mM (1.5 MAC), inhibited glucose-stimulated insulin release in a dose-related manner by 5.2 per cent (NS), 21.0 per cent (P < 0.05), and 32.6 per cent (P < 0.01), respectively. At the 0.33 mM (1.5 MAC) concentration, halothane did not significantly inhibit the oxidation of 6-14C-glucose to 14CO2, although higher concentrations of halothane did result in significant inhibition. The data suggest that halothane's inhibitory effect on glucose-stimulated insulin secretion is not due to interference with glucose oxidation.

Reduction of enflurane-induced spike activity by scopolamine.

The possibility of enflurane-induced spike activity being related to a cholinergic mechanism was investigated. Thirty mongrel dogs were anesthetized with an inspired enflurane concentration of 3.5 +/- 0.09% (mean +/- SD) to obtain a sustained EEG spike activity. Scopolamine, in 0.04 mg/kg to 0.4 mg/kg IV doses, significantly decreased the spike activity (p less than 0.05). We speculate that a central cholinergic muscarinic mechanism is at least partly responsible for the EEG spike activity produced by enflurane.

Inhibition by ether of glucose-stimulated insulin secretion in isolated pieces of rat pancreas.

Addition of glucose (16.7 mM) to isolated pieces of rat pancreas increased insulin secretion 5.4-fold over basal secretion rates. Ether at 1, 1.5 and 2 MAC inhibited this insulinogenic effect of glucose in a dose-related manner by 5, 18 (P less than 0.01) and 29 (P less than 0.01) per cent, respectively.

Mechanisms of chronotropic effects of volatile inhalation anesthetics.

The chronotropic effects of all currently available volatile anesthetics were investigated in isolated rat atrial preparations. Anesthetic ethers, diethyl ether, methoxyflurane, and enflurane elicited a dose-dependent positive chronotropic effect. Fluroxene produced a slight depression at low concentrations. The halogenated hydrocarbon anesthetics, halothane, chloroform, and trichloroethylene, did not show a uniform pattern. Halothane's effect was small and biphasic. Chloroform caused a dose-dependent decrease in heart rate, and trichloroethylene caused a marked positive chronotropic effect. The dose-response curves in all anesthetics remained unaltered in the presence of either 3 x 10(-7) M dl-propranolol or 1 x 10(-6) M atropine. It is concluded that volatile anesthetics elicit significant direct chronotropic actions on rat atrial preparations. The mechanism of their actions does not involve stimulation of beta-adrenergic or cholinergic receptors.

The mechanism of the positive chronotropic action of diethyl ether on rat atria.

Diethyl ether elicited a dose-dependent increase in the intrinsic frequency of contraction of isolated rat atrial preparations. The maximum effect (plus 34 per cent) occurred with 230 mg ether/100 ml medium. This ether concentration corresponds to a partial pressure of 29.2 mm Hg or 3 MAC. The positive chronotropic action of ether was not reduced in atria obtained from rats pretreated with reserpine (4 mg/kg, ip) although this treatment markedly reduced the effect of tyramine on frequency of contraction. The positive chronotropic response to 0.01 muM isoproterenol was inhibited by the beta-adrenergic antagonist 0.3 mgM dl-propranolol but remained unimpaired in the presence of 0.3 mgM d-propranolol (a much weaker antagonist). In contrast, the atrial response to ether was similar in the presence of either d- or dl-propranolol. Atropine, in concentrations that completely blocked the negative chronotropic action of acetylcholine, did not increase the frequency of contraction, suggesting that the positive chronotropic effect of ether is not due to an atropine-like activity of ether. Our results indicate that the positive chronotropic effect of ether on isolated rat atrial preparations is not mediated via catecholamine release, nor does it represent direct stimulation of beta-adrenergic receptors or block of cholinergic receptors. (Key words: Anesthetics, volatile, diethyl ether; Heart, atria, diethyl ether.).