PM-induced cardiac oxidative stress and dysfunction are mediated by autonomic stimulation.

Epidemiological studies show that increases in particulate air pollution (PM) are associated with increases in cardiopulmonary morbidity and mortality. However, the mechanism(s) underlying the cardiac effects of PM remain unknown. We used pharmacological strategies to determine whether oxidants are implicated in PM-dependent cardiac dysfunction and whether PM-induced increase in autonomic stimulation on the heart mediates cardiac oxidative stress and toxicity. Adult Sprague-Dawley rats were exposed to either intratracheal instillation of urban air particles (UAP 750 microg) or to inhalation of concentrated ambient particles (CAPs mass concentration 700+/-180 microg/m3) for 5 h. Oxidative stress and cardiac function were evaluated 30 min after UAP instillation or immediately after exposure to CAPs. Instillation of UAP led to significant increases in heart oxidants measured as organ chemiluminescence (UAP: 38+/-5 cps/cm2, sham: 10+/-1 cps/cm2) or thiobarbituric acid reactive substances (TBARS, UAP: 76+/-10, Sham 30+/-6 pmol/mg protein). Heart rate increased immediately after exposure (UAP: 390+/-20 bpm, sham: 350+/-10 bpm) and returned to basal levels over the next 30 min. Heart rate variability (SDNN) was unchanged immediately after exposure, but significantly increased during the recovery phase (UAP: 3.4+/-0.2, Sham: 2.4+/-0.3). To determine the role of ROS in the development of cardiac malfunction, rats were treated with 50 mg/kg N-acetylcysteine (NAC) 1 h prior to UAP instillation or CAPs inhalation. NAC prevented changes in heart rate and SDNN in UAP-exposed rats (340+/-8 and 2.9+/-0.3, respectively). To investigate the role of the autonomic nervous system in PM-induced oxidative stress, rats were given 5 mg/kg atenolol (beta-1 receptor antagonist), 0.30 mg/kg glycopyrrolate (muscarinic receptor antagonist) or saline immediately before exposure to CAPs aerosols. Both atenolol and glycopyrrolate effectively prevented CAPs-induced cardiac oxidative stress (CL(ATEN): 11+/-1 cps/cm2, CL(GLYCO): 10+/-1 cps/cm2, TBARS(ATEN): 40+/-6 pmol/mg protein, TBARS(GLYCO): 38+/-6 pmol/mg protein). These data indicate that PM exposure increases cardiac oxidants via autonomic signals and the resulting oxidative stress is associated with significant functional alterations in the heart.

Mechanical responses of the rat uterus, cervix, and bladder to stimulation of hypogastric and pelvic nerves in vivo.

Mechanical activities of the uterus, cervix, and bladder were recorded in vivo in anesthetized rats during electrical stimulation of either the hypogastric or pelvic nerve. Ovariectomized controls and hormone-treated groups were used as well as pregnant and postpartum rats. Stimulation of either hypogastric or pelvic nerve produced voltage- and frequency-dependent contractions of the three organs with no evidence of apparent inhibition. All evoked responses were completely abolished by tetrodotoxin, suggesting that these nerves are common pathways of innervation to the three organs. Atropine abolished uterine and cervical responses to both hypogastric and pelvic nerve stimulation, whereas bladder responses were only partly reduced. Hexamethonium almost totally blocked the evoked responses of the uterus and cervix. Phentolamine partly blocked uterine and cervical responses, and propranolol or physostigmine enhanced uterine and cervical responses to both hypogastric and pelvic nerve stimulation. These results suggest that motor innervation to the rat uterus and cervix is predominantly postganglionic cholinergic, with some alpha- and beta-adrenergic components, and that the bladder is innervated by mainly cholinergic and also noncholinergic nerves. Estrogen and estrogen-plus-progesterone pretreatment significantly increased the responses of uterus and cervix but not bladder. Uterine and cervical responses to either hypogastric or pelvic nerve stimulation were markedly reduced late in pregnancy and reappeared within 7 days after delivery.

A comparative study of behavioural and autonomic effects of atropine and Atropa belladonna.

Atropa belladonna L. (Solanaceae) tincture was compared with atropine for its anticholinergic activity, both in vivo and in vitro. In all tests, the biological activity of A. belladonna resulted greater than that suggested by its alkaloid content. The results suggest the presence in A. belladonna leaves of unknown compounds with a significant biological activity.

The effects of upper incisor separation on the submandibular and sublingual glands of rats.

The effects of upper incisor separation on the submandibular and sublingual glands of rats were examined biochemically, immunohistologically, and radio-immunologically during 28 days of treatment. Lateral separation of the upper incisors by application of force from an orthodontic appliance caused significant enlargement of the sublingual and submandibular glands of rats by three and seven days, respectively, after the beginning of the orthodontic treatment. This enlargement was followed by a significant increase of both RNA and DNA content, with some evidence of hyperplasia and hypertrophy. The enlargement was also associated with a significant increase of substance P at early stages after treatment, suggesting the involvement of the sensory nerves. These changes were largely inhibited by phenoxybenzamine, an alpha-adrenergic blocker, but not by atropine or morphine. Wet weights and RNA contents of the sublingual glands were markedly reduced by atropine. In comparison with control animals, the enlarged submandibular glands of rats subjected to orthodontic treatment secreted additional proteins identical with those secreted by glands enlarged by chronic administration of isoproterenol. In addition, chemical sympathectomy with 6-hydroxydopamine and phenoxybenzamine stimulated the synthesis of these abnormal proteins, but atropine and morphine did not. In contrast, protease activities in the convoluted granular tubule cells in the submandibular glands were increasingly reduced after treatment, as seen in rats subjected to chronic treatment with isoproterenol. However, the submandibular and sublingual glands completely recovered after removal of the orthodontic appliance.

Influence of autonomic drugs on the motility of the sphincter of Oddi in the opossum.

We have evaluated the effect of various autonomic drugs on the electromyographic activity of the sphincter of Oddi and the small intestine of seven opossums. Hexamethonium bromide and atropine sulfate abolished and bethanechol increased the frequency of spike bursts in the sphincter of Oddi and duodenum. Phenylephrine and epinephrine increased the number of spike bursts in the sphincter of Oddi after a short period of stimulation. No spike potentials were seen in the duodenum after infusion of norepinephrine. Clonidine and dobutamine decreased spike burst activity in the sphincter of Oddi and duodenum. Terbutaline also decreased the frequency of spike bursts in the sphincter of Oddi but did not change the number in the duodenum. Prior infusion of antagonists blocked partially or totally the effect of all respective agonists except for yohimbine, which did not inhibit the effect of clonidine. These findings suggest that the sphincter of Oddi may have cholinergic, alpha 1, alpha 1, beta 1 and beta 2-adrenergic receptors. Cholinergic agonists stimulate and alpha 2, beta 1 and beta 2-adrenergic agonists inhibit the motility of the sphincter of Oddi and the small intestine. Alpha-adrenergic agonists stimulate the motility of the sphincter of Oddi and inhibit the motility of the small intestine.

[Effects of guanabenz on the cardiovascular system, in comparison with clonidine and guanethidine].

Cardiovascular actions of guanabenz, a new antihypertensive agent, were studied in comparison with those of clonidine and guanethidine. Guanabenz, administered intravenously, produced a rise of blood pressure which was followed by a prolonged fall in anesthetized dogs. Guanabenz also decreased the heart rate, inhibited the respiration, and produced an alteration in T wave and a prolongation of PQ or TP interval in the ECG of the dog. Such effects of guanabenz on blood pressure and heart rate were observed in the cat, rabbit and rat, but there was a slight species-difference in the effects. Clonidine, but not guanethidine, produced responses similar to those of guanabenz. The potency of guanabenz to produce hypotension and bradycardia was approximately 1/10 that of clonidine and 10 times higher than that of guanethidine. The depressor effect of guanabenz was not observed in the spinal cats; thus, the blood pressure rose after the administration. When guanabenz was administered intracerebroventricularly or into the nucleus tractus solitarius of rats, the initial pressor response was not produced, and the depressor and bradycardiac responses were observed. Guanabenz, administered intravenously or intra-arterially, produced an inhibition of cardiac functions, decreased the blood flow of common carotid and femoral arteries, and elevated the perfusion-pressure of the hindlimb in the dog. In the isolated rabbit and guinea-pig atria, guanabenz produced negative inotropic and chronotropic effects and attenuated the rate of rise of the action potential. The contractile responses to serotonin and histamine in the isolated rabbit thoracic aorta were noncompetitively inhibited by guanabenz. From these results, it is suggested that the hypotensive and bradycardiac actions of guanabenz are mediated via central actions, as well as those of clonidine. Furthermore, in addition to the central actions, it was found that guanabenz acts directly on cardiovascular tissues and attenuates the responsiveness.