Associations between urinary organophosphate ester metabolites and measures of adiposity among U.S. children and adults: NHANES 2013-2014.

BACKGROUND: Organophosphate esters (OPEs) are synthetic chemicals found in many consumer products, including furniture, electronics, processed foods, and building materials. Emerging in vitro and in vivo studies suggest that OPEs are metabolism disrupting compounds; however, epidemiologic studies investigating their associations with adiposity markers are sparse. OBJECTIVE: We examined cross-sectional associations between OPE biomarkers and adiposity measures among U.S. children and adults participating in the National Health and Nutrition Examination Survey (NHANES: 2013-2014). METHODS: Concentrations of five OPE metabolites were quantified in urine: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), bis(2-chloroethyl) phosphate (BCEP), dibutyl phosphate (DBUP), and bis(1-chloro-2-propyl) phosphate (BCPP). We conducted covariate-adjusted logistic and linear regressions to examine associations between log2-transformed and dichotomized OPE metabolite concentrations and obesity, body mass index (BMI), and waist circumference (WC), separately among 784 children (6-19 years) and 1672 adults (≥20 years). We also assessed heterogeneity of associations by sex. RESULTS: DBUP concentrations were inversely associated with the prevalence odds of being obese vs. normal weight in children (adjusted Prevalence Odds Ratio, aPOR: 0.82, 95% Confidence Interval, 95% CI: 0.70, 0.95) and adults (aPOR: 0.83, 95% CI: 0.72, 0.96). DBUP was also significantly associated with lower BMI z-scores (ß:-0.08, 95% CI:-0.17, 0.01) and WC (ß:-0.71, 95% CI: -1.49, 0.07) in children. BCEP concentrations were associated with increased prevalence odds of being overweight vs. normal weight (aPOR: 1.15, 95% CI: 1.01, 1.32) among children; similar, albeit not statistically significant, relationships were observed with other child adiposity outcomes. Among adults, detectable BCPP concentrations were associated with increased prevalence odds of being obese vs. normal weight (aPOR: 1.70, 95% CI: 1.21, 2.38) and having a high vs. normal WC (aPOR: 1.51, 95% CI: 1.11, 2.07) as well as higher BMI (ß: 1.31, 95% CI: 0.30, 2.33). Other OPE metabolites were not consistently associated with adiposity measures among adults. Although associations of BCPP exposure with adiposity outcomes were generally inverse among boys, but not girls, we did not observe consistent evidence of sexually-dimorphic associations for other OPE metabolites. CONCLUSIONS: Exposure to select OPEs may be differentially associated with body size among children and adults. Given the cross-sectional design of the present study, future prospective studies are needed to confirm these findings.

Effect of gender in centrally induced angiotensin II hypertension in dogs.

This study was designed to investigate the relation between gender, an endogenous inhibitor of the Na+-K+ pump, and volume-dependent hypertension induced by stimulation of the brain renin-angiotensin system and increased salt intake. Angiotensin II (20 ng/min i.c.v.) was infused for 4 weeks in five dogs of each sex with saline as the drinking fluid. In male dogs, angiotensin II induced parallel pressor (30%) and dipsogenic responses (70%), whereas no hypertension and no increase in fluid intake were observed in females. In contrast, the activity of the Na+-K+ pump as assessed by 86Rb uptake was independent of gender. Our data provide novel evidence that gender plays a determining role in the physiological properties of centrally administered angiotensin II.

Syntheses and pharmacological activity of substituted imidazolidinethiones and thiomidazolines.

A series of imidazolidinethiones and thioimidazolines was synthesized and tested for their effects on both forced and spontaneous motor activity as well as for their ability to raise the convulsion threshold. The proton NMR spectra for the thioimidazolines synthesized were unusual in that they showed a sharp singlet for the ring ethylene unit rather than the expected A2B2 pattern. The thioimidazolines, 5 and 7, were the most active CNS depressants and had the highest safety index. Significantly, the isomeric imidazolidinethiones, 8 and 9, were comparatively much less effective while being considerably more toxic.

Central alpha-adrenergic control of blood pressure. Effects of clonidine withdrawal.

Studies were undertaken to investigate the role of the CNS in withdrawal hypertension caused by abrupt cessation of long-term clonidine treatment. The studies were conducted on male wistar rats receiving clonidine, 100 micrograms/kg subcutaneously twice daily for seven days. Withdrawal hypertension occurred 16 to 18 hours following the last injection of clonidine. Pressor responses to posterior hypothalamic stimulation were significantly potentiated in the rats undergoing clonidine withdrawal, and the depressor response to a single injection of 10 micrograms of clonidine into the lateral cerebral ventricle was significantly attenuated in these animals. Studies on pithed rats demonstrated that destruction of the CNS eliminated the withdrawal hypertension. These data suggest that alpha-adrenoreceptors in the nucleus tractus solitarius play an important role in the normal maintenance of blood pressure, and a decrease in sensitivity of these receptors could result in the development of a hypertensive state.

Effect of presynaptic alpha-adrenoceptor blockade on responses to cardiac nerve stimulation in anesthetized dogs.

Phentolamine caused significant potentiation of chronotropic responses to cardioaccelerator nerve stimulation (CANS) in pentobarbital-anesthetized dogs without impairing neuronal reuptake of norepinephrine. In a separate group of dogs, desipramine produced slight augmentation of CANS responses which were potentiated further by phentolamine administration. These results provide support for the hypothesis that presynaptic alpha-adrenergic receptors play an inhibitory role in sympathetic neurotransmission and demonstrate that this mechanism is also functioning during stimulation of the cardioaccelerator nerve in pentobarbital-anesthetized dogs.

Presynaptic dopamine receptors as mediators of dopamine-induced inhibition of neurogenic vasoconstriction.

I.v. infusion of dopamine (10 microgram/kg/min) caused significant attenuation of renal vasoconstrictor responses to sympathetic nerve stimulation in pentobarbital-anesthetized dogs, whereas renal vasoconstrictor responses to exogenously administered norepinephrine were unaffected. Desipramine treatment significantly potentiated the inhibitory effect of dopamine on neurogenic vasoconstriction. Pretreatment with pimozide, a dopamine receptor blocking agent, prevented the inhibitory influence of dopamine on renal sympathetic nerve function. These results demonstrate that dopamine can inhibit neurogenic vasoconstriction by activating presynaptic dopamine receptors present on renal sympathetic nerves.

Influence of several anesthetic agents on the effect of delta9-tetrahydrocannabinol on the heart rate and blood pressure of the mongrel dog.

delta9-Tetrahydrocannabinol (delta9-THC) 1 mg/kg, i.v. produced a slight but significant reduction in the heart rate of conscious mongrel dogs, and these effects were greatly potentiated by pentobarbital and/or urethane anesthesia. However, significant increase in the heart rate was noted following delta9-THC administration in the dogs anesthetized with a combination of morphine plus chloralose; further, neither morphine nor chloralose alone could reverse the bradycardic effects of delt9-THC. Tachycardia induced by delta9-THC in these dogs could be reversed by bilateral vagotomy or by pretreatment of the animals with methylatropine, or propranolol and/or practolol. The data indicated a complex interaction between delta9-THC and morphine-chloralose combination and the tachycardia induced by delta9-THC under this anesthesia may be due to release of epinephrine by a reflexogenic mechanism involving afferent vagi. Further, while the bradycardic effects of delta9-THC were essentially identical under pentobarbital or urethane anesthesia, the hypotensive effects were similar in urethane or chloralose anesthetized dogs. The study emphasizes that anesthetic interaction should be taken into consideration while investigating mechanisms of actions of pharmacological agents.

Central cardiovascular effects of phentolamine in chloralose-anesthetized cats.

Phentolamine (50, 100 and 200 microng/min for 30 min) perfused through the cerebroven system of chloralose-anesthetized cats produced dose-related reductions in tricular blood pressure. Evidence is presented which suggests that this hypotensive activity was due to an interaction at central nervous system sites and was not attributable to escape of the compound from the brain. Centrally administered phentolamine was more effective in lowering blood pressure than the i.v. infusion of phentolamine at a dose (25 microng/kg/min for 30 min) which markedly antagonized peripheral alpha-adrenoceptors. In addition, central phentolamine induced bradycardia in contrast to the tachycardia which accompanied i.v. administration. By limiting the perfusion of phentolamine to selected portions of the cerebrospinal fluid spaces a major site of action responsible for the hypotensive activity was located outside the ventricles in an area accessible from the subarachnoid spaces. A second, less important site, anterior to the midbrain adjacent to the ventricular system apparently contributed to the hypotension. Phentolamine, introduced centrally, also impaired reflexogenic bradycardia elicited by pressor doses of norepinephrine. Both the sympathetic withdrawal and the vagal activation which account for this reflex seemed to be antagonized by phentolamine.

Facilitation of cardiac sympathetic function by angiotensin II: role of presynaptic angiotensin receptors.

Intravenous infusion of two separate doses of angiotensin II in pentobarbital-anesthetized, desipramine-treated animals produced dose-related increases in arterial blood pressure and caused significant potentiation of the cardioacceleration observed during the stimulation of the right postganglionic cardiac sympathetic nerve fibers. Positive chronotropic effects of intravenous norepinephrine were not altered during angiotensin II infusion. Prior administration of Saralasin, an angiotensin receptor antagonist, caused significant attenuation of the pressor action of angiotensin II, and also significantly antagonized the facilitatory effect of angiotensin II on sympathetic transmission to the myocardium. These results suggest that angiotensin II can cause facilitation of sympathetic nerve function to the myocardium via an action on angiotensin receptors which may be located on sympathetic nerve terminals.

Time-course effects of oral guanethidine administration on cardiovascular and autonomic effects on dogs.

The time-course effects of guanethidine (2.5 mb/kg/day, p.o.) administered for 2 days, 7 days and 7-8 months were investigated in dogs. Guanethidine treatment for 2 days failed to produce any significant alterations in sympathetic neuronal activity to the myocardium, resting neurogenic tone in the perfused hind limb vasculature and lumbar sympathetic neuronal transmission. Following guanethidine administration for a peroid of 7 days both cardiac and lumbar sympathetic neuronal activity was markedly and significantly depressed with concomitant reduction in heart rate and resting neurogenic tone to the hind limb. However, continued treatment with guanethidine for a period of 7-8 months resulted in complete restoration of cardiac as well as lumbar sympathetic neuronal activity. Both heart rate and resting neurogenic tone were also returned to placebo levels. The development of tolerance of these sympathetic nerves to guanethidine treatment was not associated with any alterations in the activity of adrenergic receptors. Further, there was a significant and time-dependent increase in cholinergic vasocilator activity in the lumbar sympathetic chain which could account for the exertional hypotension noted in the patients receiving guanethidine treatment.

Effect of propranolol of vascular responses to sympathetic nerve stimulation and plasma renin activity in mongrel dogs.

I.v administration of propranolol (0.2 mg/kg and 1.0 mg/kg) to pentobarbital-anesthetized dogs produced blockade of cardiac beta-receptors and a significant decrease in heart rate. However, only the higher dose of propranolol demonstrated a significant hypotensive effect. Furthermore, this hypotensive action of propranolol was not associated with either adrenergic neruron blockade or changes in plasma renin activity. These results indicate that the initial hypotensive action of propranolol in mongrel dogs is not due to the blockade of beta-receptors, alterations in peripheral sympathetic nervous transmission or plasma renin activity. On the other hand, the action that propranolol is reported to have within the central system may play an important role in accounting for the acute blood pressure lowering action of the compound in mongrel dogs.

Studies on the mechanism of the cardiovascualr effects of methyldopa.

Oral administration of methyldopa (100 mg/kg, twice daily for 3 days) to mongrel dogs produced a significant decrease in blood pressure and heart rate. The drug treatment affected neither the resting venous tone nor the cardiac output. Thus, the hypotensive effect of the drug was predominantly due to a reduction in total peripheral resistance. Vasoconstrictor responses of the renal vasculature to sympathetic nerve stimulation were significantly impaired after methyldopa at all the frequencies, while mesenteric vasoconstrictor responses to sympathetic nerve stimulation were impaired only at the lower stimulation frequencies. In addition, methylnorepinephrine was a significantly less potent vasoconstrictor than norepinephrine in the renal vasculature, but was equipotent to norepinephrine in the mesentery. The finding of a reduction in the renal vascular resistance of methyldopa-treated dogs, with no such alteration in the mesenteric vascular resistance, is consistent with the nerve stimulation studies. Therefore, the results of the present investigation indicate that in addition to the existing evidence favoring a central site of action for methyldopa, the impairment of peripheral sympathetic neuronal function is also of importance in accounting for the hemodynamic alterations observed following treatment with methyldopa.

Effects of acute administration of delta9-tetrahydrocannabinol on pulmonary hemodynamics of anesthetized dogs.

I.v. administration of delta9-THC (2.5 mg/kg) To anesthetized dogs resulted in a decrease in heart rate, pulmonary blood flow (PBF), and a significant increase in pulmonary artery pressure (PAP) and total pulmonary vascular resistance (PVR). The increase in PVR to delta9-THC was significantly reduced by cardiac pacing, and was virtually abolished either by bilateral vagotomy or by pretreatment with hexamethonium. The data indicated the delta9-THC induced elevation of PVR was mediated via reflexogenic mechanisms involving afferent vagi and efferent autonomic pathways.

Effect of methyldopa treatment on peripheral sympathetic nerve function in the dog.

Administration of methyldopa (100 mg/kg, p.o. twice daily for 3 days) to mongrel dogs produced a significant decrease in the mean blood pressure (MBP) and heart rate (HR). Chronotropic responses to cardioaccelerator nerve stimulation and vasoconstrictor responses to lumbar sympathetic nerve stimulation were significantly attenuated in the treated dogs. Pressor and chronotropic responses to bilateral carotid occlusion (BCO) and tyramine were also markedly reduced following treatment with methyldopa, which is consistent with the clinical findings that chronic methyldopa treatment in hypertensive patients impairs cardiovascular reflexes. Methylnorepinephrine (MNE) was significantly less potent than norepinephrine (NE) in producing an increase in MBP or hindleg perfusion pressure, while the chronotropic and inotropic potency of MNE was about equal to NE. These results indicate that treatment with methyldopa in the dog does indeed produce an impairment of peripheral sympathetic neuronal function to certain organs and this peripheral effect of the drug may be of importance in accounting for its antihypertensive action in the dog.

Effects of several catecholamines on sympathetic transmission to the myocardium: role of presynaptic alpha-adrenoceptors.

Effects of several alpha-adrenoceptor agonists on presynaptic alpha-adrenoceptors were evaluated by studying chronotropic responses to cardioaccelerator nerve stimulation in anesthetized dogs. I.v. infusions of norepinephrine (NE), methylnorepinephrine (MNE), epinephrine (E) or phenylephrine (PHE) in desipramine-treated dogs caused significant attenuation of nerve stimulation responses. The inhibitory influence of all these agents could be prevented by prior treatment with phentolamine, but not with haloperidol. Comparisons of relative pressor and presynaptic inhibitory actions of these compounds revealed that in equipressor doses, MNE caused a significantly greater attenuation of nerve stimmulation responses than NE, while PHE had similar pressor and presynaptic inhibitory activity to that of NE. The inhibition of chronotropic responses to nerve stimulation observed following E was significantly greater compared to its relative pressor effect. These results demonstrate the existence of a presynaptic alpha-adrenoceptor mechanism modulating cardiac rate in intact dogs and indicate that the false transmitter MNE may be more potent than NE in imparing neuronal transmission by an action on presynaptic alpha-adrenoceptors.

Enhancement of reflex vagal bradycardia following intracerebroventricular administration of methysergide in cats.

Metehysergide in total doses of 100, 200 and 400 micrograms injected into the fourth cerebral ventricle of cats potentiated the reflex bradycardic responses which were evoked by i.v. pressor doses of norepinephrine. Methysergide (400 micrograms) injected i.v., or intracerebroventricularly in vagotomized cats did not affect the reflex bradycardia. These results suggest that the enhancement of reflex vagal activation is due to an action of methysergide in the central nervous system. Intracerebroventricular methysergide significantly reduced the resting arterial pressure and heart rate, while i.v. administration caused only significant bradycardia. Carotid occlusion responses were depressed following both i.v. and intracerebroventricular methysergide. The magnitude of reductions in arterial pressure and heart rate following the injection of methysergide into the fourth cerebral ventricle were the same in vagotomized cats and in intact vagus preparations. It is suggested that depression of cardiovascular function is due to a central action of methysergide and is mediated by reduction in sympathetic outflow.

Involvement of central alpha-adrenoceptors in the hypotensive and bradycardic effects of (--)-delta 9-trans-tetrahydrocannabinol.

I.v. administration of (--)-delta9-trans-tetrahydrocannabinol (delta 9-THC) to chloralose-anesthetized cats produced a decrease in blood pressure and heart rate. Studies conducted to investigate the mechanism of these changes revealed that the hypotensive and bradycardic effects of delta 9-THC (0.1 mg/kg, i.v.) could be significantly antagonized following intraventricular (i.v.t.) perfusion with alpha-adrenergic receptor blocking agent phentolamine, while a larger dose of delta 9-THC (0.25 mg/kg, i.v.) still produced significant hypotension and bradycardia. I.v.t. perfusion of phentolamine (100 mug/min for 30 min) caused a fall in blood pressure and heart rate which were reversible and produced blockade of central alpha-adrenergic receptors. These results provide evidence for the involvement of central alpha-adrenergic receptors in the hypotensive and bradycardic actions of delta 9-THC and indicate that other receptor mechanisms may also be involved in mediating these responses observed following administration of delta 9-THC.

Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of the anesthetized dogs.

Cardiovascular effects of several imipramine analogs were investigated in the anesthetized mongrel dogs. Significant reduction in the cardiac output produced by lower doses (2.5 mg/kg, i.v.) of imipramine and 2-OH-DMI was not due to a depression of myocardial contractility. In contrast, 2-OH-imipramine (1.25 mg/kg) and DMI (2.5 mg/kg) significantly reduced contractility within 10 min after i.v. administration; however, significant decrease in the cardiac output did not occur until after 60 min. Higher doses (5 mg/kg) of imipramine, DMI and 2-OH-DMI significantly attenuated cardiac rate, contractility and output within 5 min after i.v. administration. 2-OH-imipramine, 2.5 mg/kg, i.v., depressed contractility and cardiac output to a degree equivalent to that produced by 5 mg/kg of imipramine, DMI and 2-OH-DMI. 3-Chloro-imipramine (5 mg/kg, i.v.) induced decrease in the cardiac output was essentially due to a significant reduction in the heart rate since the effects of this compound on the contractility were transient in nature. 3-Cl-8-OH-metabolite of this compound had no significant effects on the cardiovascular system. The results of this investigation demonstrated that the complex cardiovascular effects of tricyclic antidepressants observed in these studies were perhaps due to a direct and/or autonomically mediated effects on the heart and vasculature. Further, the data support the conclusions that the activity of the parent compounds together with that of the metabolites contributes to overall changes observed. While all the agents are capable of reducing cardiac output, 2-OH-metabolite of imipramine appears to be most toxic on the myocardium and 3-Cl-imipramine possessed only transient effects on the contractile properties.

Cardio-respiratory responses to rowing ergometry and treadmill exercise soon after myocardial infarction.

PURPOSE: The aim of this study was to compare the cardio-respiratory differences between rowing ergometry and treadmill exercise in beta-blocked men participating in exercise rehabilitation soon after myocardial infarction (postMI). METHODS: Eleven males all receiving beta-blockade medication were measured for oxygen consumption (VO2), respiratory exchange ratio (RER), and rating of perceived exertion (RPE) at individualized submaximal exercise target heart rates (THR) during 6 min of exercise on each of a motorized treadmill and a rowing ergometer 2-6 wk (4.9 +/- 1.4) postMI. RESULTS: The mean THR of the group, predetermined from an exercise ECG stress test, was 107 +/- 16 beats x min(-1). No significant difference was found between rowing versus treadmill VO2 (19.4 +/- 3.2 vs 19.7 +/- 4.2 mL x kg(-1) x min(-1); P = 0.53) or RPE (12.6 +/- 1 vs 12.7 +/- 1; P = 0.72). RER was significantly greater (P = 0.02) during rowing (0.99 +/- 0.07) compared with treadmill exercise (0.94 +/- 0.07). CONCLUSION: Exercising at a specified submaximal THR during rowing versus treadmill exercise in beta-blocked men participating in very early cardiac rehabilitation represents the same VO2 and RPE. A significantly greater RER was, however, apparent during rowing compared with treadmill exercise; thus, agreement was shown with previous studies on healthy individuals where rowing ergometry was less metabolically efficient than treadmill exercise. The results suggest that establishing a THR from a standard treadmill stress test soon after MI is not only suitable for walking/treadmill exercise but also in setting exercise intensity for rowing ergometry.