John L. Egle

Dose-dependent sympathomimetic and cardioinhibitory effects of acrolein and formaldehyde in the anesthetized rat☆

Abstract Dose-effect relationships for iv formaldehyde and acrolein indicate that the cardiovascular actions of these aldehydes are qualitatively similar to acetaldehyde and propionaldehyde. Pressor responses appear to result from the release of catecholamines from sympathetic nerve endings and from the adrenal medulla. Concentrations of formaldehyde and acrolein required to produce significant pressor activity were found to be significantly lower than for acetaldehyde and propionaldehyde. The relative pressor potency for formaldehyde and acrolein was 10 and 100 times that of acetaldehyde, respectively. Higher doses of both formaldehyde and acrolein resulted in depressor responses which could be abolished by vagotomy. Thus, it appears that these aldehydes also exert a cardioinhibitory effect which is mediated by the vagus nerve. Inhalation studies with acrolein revealed that this aldehyde has significant cardiovascular activity at concentrations below those which might be encountered in cigarette smoke. The predominant effect of inhaled acrolein at these doses was a significant increase in blood pressure and heart rate. It would appear that the aldehydes, especially acrolein, may be more significantly involved in the cardiovascular response to cigarette smoke than was previously recognized.

Adrenergic receptors in the nucleus tractus solitarii of the rat

The nucleus tractus solitarii (NTS) is an area of the medulla in which baroreceptor afferent fibers mediating an inhibition of vasoconstriction terminate. The NTS also appears to be a site at which alpha-adrenergic receptors may be involved in blood pressure control. alpha- and beta-adrenergic agonists and antagonists were injected into the NTS via stainless steel cannulae and the effects on blood pressure determined. Norepinephrine (NE) and isoproterenol (ISO) caused dose-related decreases in mean arterial blood pressure (MABP). Phentolamine (PH) and propranolol (PR) caused dose-related increases in MABP. PH pretreatment in the NTS blocked the effects of ISO, but not NE. The effect of increased baroreceptor impulses to the NTS, produced by altering perfusion of the carotid sinus was blocked by propranolol. These results indicate the presence of beta- as well as alpha-receptors in the NTS, and also suggest the existence of presynaptic beta-receptors which facilitate neurotransmission.

Cardiovascular effects of intravenous acetaldehyde and propionaldehyde in the anesthetized rat

Abstract Acetaldehyde and propionaldehyde have both been previously shown to possess sympathomimetic activity and to affect the cardiovascular system. The objectives of the present investigation were to study the dose-effect relationships of the two aldehydes on the cardiovascular system of the anesthetized rat and to establish the mechanism of the pressor and depressor effects of the compounds. Low iv doses of acetaldehyde and propionaldehyde produced a consistent dose-related rise in blood pressure. These responses were slightly reduced by adrenalectomy and more strongly antagonized by pretreatment with reserpine or phentolamine. This indicates that the pressor effects of these compounds are primarily due to vasoconstriction mediated by norepinephrine released from sympathetic nerve endings in vascular smooth muscle. Higher doses of the two aldehydes produced a sharp fall in blood pressure and a severe bradycardia. Atropine reduced the hypotensive and cardioinhibitory effects of the aldehydes, suggesting that these actions are mediated by the vagus nerve. This was confirmed by experiments in vagotomized rats. After vagotomy, high doses of acetaldehyde and propionaldehyde produced an increase in blood pressure and a positive chronotropic response. The results of this study indicate that acetaldehyde and propionaldehyde exert two opposing actions on the cardiovascular system: (1) a sympathomimetic effect which predominates at doses below 20 mg/kg resulting in a rise in blood pressure; and (2) stimulation of higher centers resulting in bradycardia and hypotension with higher doses.

Acute toxicity of monochlorophenols, dichlorophenols and pentachlorophenol in the mouse

Acute oral LD50 values were determined for 2-, 3-, and 4-chlorophenol, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5 dichlorophenol and pentachlorophenol in male and female mice. LD50 values (mg/kg) ranged from 117 (females) and 177 (males) for pentachlorophenol to 2389 (females) and 2643 (males) for 3,5-dichlorophenol. It was found that 2-chlorophenol and 3-chlorophenol were considerably more toxic than the dichlorophenol series. Values for males and females were generally similar, the major differences being with pentachlorophenol and 2,5-dichlorophenol, where in both cases the female LD50 was lower.

Pharmacological effects of 1,2,3,5,6,10b-hexahydropyrido[2,3g]indolizine, a bridged-nicotine analog.

The racemate of a bridged-nicotine (BN) analog was synthesized and resolved into its enantiomers for pharmacological comparisons to (+)- and (-)-nicotine. The EC50 values for (-)- and (+)-nicotine and (-)- and (+)-BN were 4, 170, 53 and 400 microM, respectively, for producing contractions of guinea-pig ilea. (-)-Nicotine was an effective antinociceptive agent in the mouse tail-flick procedure at i.v. doses of 0.1-0.3 mg/kg, whereas the isomers of BN failed to alter tail-flick response in doses up to 5 mg/kg. (-)-Nicotine (0.01-0.3 mg/kg, i.v.) increased blood pressure and decreased heart rate in anesthetized rats. Neither (+)- nor (-)-BN altered blood pressure and heart rate in rats in this dosage range. At doses of 3-100 mg/kg, (+)-BN produced an increase in blood pressure without changing heart rate, while (-)-BN decreased both blood pressure and heart rate. Bridging the pyrrolidine and pyridine rings decreased biologic activity and did not result in stereoselectivity greater than that observed with (+)- and (-)-nicotine. It appears that there may be subpopulations of nicotine receptors to which the isomers of BN do not interact.

The effects of acetaldehyde and acrolein on blood pressure in guanethidine-pretreated hypertensive rats.

These experiments were undertaken to study the effect of the interaction of the antihypertensive agent guanethidine and two aldehydes possessing sympathomimetic activity on the blood pressure of spontaneously hypertensive rats (SHR). Acetaldehyde, when administered iv to acutely guanethidine-pretreated (15 mg/kg) SHRs under urethane anesthesia, caused a potentiated pressor response in the dose range of 3 to 40 mg/kg. When administered iv to chronically guanethidine-pretreated SHRs, a pressor response was noted at low doses and a depressor response at high doses. Acrolein (0.05 to 0.5 mg/kg) produced a pressor response at low doses and a depressor response at high doses in both acutely and chronically guanethidine-pretreated SHRs. Pressor responses, particularly to acetaldehyde, may be due to an enlarged tyramine-releasable pool, hyperreactivity of alpha adrenergic receptors of SHRs, or guanethidine inhibition of norepinephrine reuptake. Depressor responses to high doses of aldehydes may be attributed to vagal stimulation or direct vasodilation. It is concluded that there is a significant interaction between the aldehydes and guanethidine which may have implications for someone undergoing treatment with guanethidine for hypertension while being exposed to acetaldehyde and related compounds from ethanol and tobacco smoke.

Time course of the acute toxic effects of sublethal doses of chlordecone (Kepone).

Abstract Rats were monitored for toxic signs of chlordecone permitting the characterization of onset, peak, and duration of effects following administration of a single oral dose in corn oil. Tremors and abnormal gait were the major early features of toxicity. Both developed within 4 hr, reached a peak 2 days after treatment, had greatly diminished after 2 weeks, and were absent after 49 days. Exaggerated startle response followed a similar pattern but was less severe. Muscle weakness developed during Week 2 and was still increasing slightly in intensity at 49 days although recovery was occurring by the end of 6 months. Thus, while neurological effects are the most severe and rapidly developing effect of the pesticide, muscle weakness is the most persistent outward manifestation of chlordecone toxicity in the rat.

Acute and Subchronic Toxicity of 2,4-Dichlorophenol in CD-1 Mice

The acute oral LD50 of 2,4-dichlorophenol (2,4-DCP) employing corn oil as vehicle was determined to be 1352 mg/kg for female and 1276 mg/kg for male CD-1 mice. CD-1 mice of both sexes were exposed to 2,4-DCP in drinking water containing 10% Emulphor for 90 days at concentrations of 0.2, 0.6, and 2.0 mg/ml providing theoretical daily doses of 50, 150, and 500 mg/kg. These concentrations resulted in mean daily doses of 50, 143, and 491 mg/kg for females and 40, 114, and 383 mg/kg for males. In both sexes, fluid consumption was lower in the vehicle control group (10% Emulphor) and in the 2,4-DCP treated groups than in the naive controls (deionized water). There were no biologically significant differences in body weight gain between females or males in the vehicle control and experimental groups. No differences were found in terminal organ weights or organ weight ratios in either sex. Hematological differences were observed in males only and included an increase in leukocytes (high dose) and an increase in polymorphonuclears (low dose). Clinical chemistry parameters were altered in females only and included a decrease in creatinine (low dose), an increase in BUN/creatinine ratio (mid dose), and an increase in ALP (high dose). In an assessment of the hepatic microsomal mixed function oxidase system, no significant differences were found in the components of the system, component activity, the kinetics of ethylmorphine N-demethylase, or the metabolism of testosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

An evaluation of the cardiac sensitizing potential of a fabric protector in aerosol form, containing 1,1,1-trichloroethane☆☆☆

Abstract Experiments were designed to assess the cardiac sensitizing potential of Scotchgard Brand Fabric Protector FC-4101 [which contains 1,1,1-trichloroethane (TCE)] under simulated misuse conditions. Beagle dogs were prepared for telemetric monitoring of their electrocardiogram (ECG) and placed in a 290-liter chamber. They were observed for possible effects of inhalation exposure to FC-4101, alone or in combination with intravenous epinephrine (8 and 16 μg/kg) and/or stress induced by a 2-sec blast from an air horn. The effects of inhaled pure TCE with Freon 12 propellant were also investigated. Changes in heart rate consisted of a bradycardia (presumably of reflex origin) due to epinephrine and stress, and a mild tachycardia following exposure to FC-4101 producing a concentration of 5000 ppm TCE in air. Following exposure to FC-4101 producing a concentration of 10,000 ppm TCE in air and following exposure to concentrations of 5000 ppm TCE in air and 10,000 ppm TCE in air with Freon 12 propellant, no tachycardia occurred. Inhalation of FC-4101 did not act synergistically with exogenous epinephrine (8 μg/kg) or endogenous epinephrine released in response to stress to induce cardiac arrhythmias. The arrhythmias induced by 16 μg/kg of epinephrine and stress were not intensified by the concurrent inhalation of FC-4101, 5000 ppm TCE. It is concluded that the simulated misuse conditions utilized in this study, FC-4101 and pure TCE with Freon 12 propellant did not cause cardiac sensitization.

Dominant lethal assay of chlordecone and its distribution in the male reproductive tissues of the rat

Male rats received 3.6 or 11.4 mg/kg/day of chlordecone orally for 5 days. Some statistically significant events were seen in the reproductive data of females mated to males receiving chlordecone. However, these events did not follow a consistent pattern and do not suggest the conclusion that chlordecone causes dominant lethal effects. Male rats received a single oral dose (40 mg/kg) of chlordecone and were killed at 1, 2, 3, 5, 7, 14 or 21 days. Chlordecone was distributed throughout the reproductive tract. The descending order of concentration was seminal vesicular fluid greater than prostate greater than vas deferens greater than seminal vesicle greater than unwashed sperm greater than washed sperm. It is concluded that chlordecone is well distributed throughout the reproductive tract of the male rat, appears in the ejaculate, and does not appear to produce dominant lethal effects.