Female mammals have long been neglected in biomedical research. The NIH mandated enrollment of women in human clinical trials in 1993, but no similar initiatives exist to foster research on female animals. We reviewed sex bias in research on mammals in 10 biological fields for 2009 and their historical precedents. Male bias was evident in 8 disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyze results by sex. Underrepresentation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies. The majority of articles in several journals are conducted on rats and mice to the exclusion of other useful animal models. The belief that non-human female mammals are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation. We recommend that when only one sex is studied, this should be indicated in article titles, and that funding agencies favor proposals that investigate both sexes and analyze data by sex.

Bilateral electrolytic lesions in the suprachiasmatic nuclei permanently eliminated nocturnal and circadian rhythms in drinking behavior and locomotor activity of albino rats. The generation of 24-hr behavioral rhythms and the entrainment of these rhythms to the light-dark cycle of environmental illumination may be coordinated by neurons in the suprachiasmatic region of the rat brain. Destruction of the medial preoptic area had no effect on 24-hr drinking rhythms.The widespread occurrence and biological significance of 24-hr rhythms has been extensively documented (1, 2). Although rhythmic variations in animal behavior and physiology are ordinarily synchronized with fluctuations in light and temperature (1), many rhythms persist in free-running form with periods of about 24 hr (circadian rhythms) in the absence of all obvious entraining stimuli. Such demonstrations are generally interpreted as reflecting the operation of a biological clock within the animal (1).The identification of the neural substrate responsible for the 24-hr behavioral rhythms of mammals has yet to be accomplished (3,4). Circadian rhythms have been remarkably resistant to many forms of interference with the nervous system, including such radical treatments as anoxia, convulsions, poisoning, anesthesia, and acute stress (4). Some loss of rhythmicity in eating, but not in drinking, behavior of rats occurs after lesions are placed in the region of the ventromedial hypothalamus (5). However, these lesions also interfere with the homeostatic control of eating and body weight, and it is difficult to assess their effects on the biological clock per se.Several circadian neuroendocrine rhythms have been eliminated by lesions or surgical isolation of the anterior hypothalamus from the medial basal hypothalamus (6). In addition, recent anatomical studies have once again raised the possibility of direct visual input to the anterior hypothalamus via retino-hypothalamic pathways terminating in the suprachiasmatic nuclei and arcuate region (7,8). These considerations, and our previous failure to disrupt nocturnal drinking rhythms with lesions that interrupted the primary and accessory visual pathways (9), suggested to us that the suprachiasmatic region might be involved in the generation and entrainment of behavioral rhythms.In the present experiment we attempted to interfere with circadian drinking and activity rhythms of rats by selectively damaging several regions of the hypothalamus.Abbreviations: LD, light-dark cycle; SCN, suprachiasmatic nucleus; MPO, medial preoptic nucleus. METHODSAdult ovariectomized Sprague-Dawley rats were housed individually in cages with free access to food and water. The experimental room was illuminated by fluorescent lights providing cool white light; the average intensity of illumination at the face of the cage was 6 ft-c. The light-dark cycle (L-D) consisted of alternating 12-hr periods of light and darkness; the dark period began at 9 p.m. At various times animals were maintained on a reversed I-D cycle (the dail...

No abstract

No abstract

No abstract

Abstract-Chronic heart failure (CHF) is often associated with excitation of the sympathetic nervous system. This event is thought to be a negative predictor of survival in CHF. Sympathoexcitation and central angiotensin II (Ang II) have been causally linked. Recent studies have shown that NAD(P)H oxidase-derived reactive oxidant species (ROS) are important mediators of Ang II signaling. In the present study, we tested the hypothesis that central Ang II activates sympathetic outflow by stimulation of NAD(P)H oxidase and ROS in the CHF state. CHF was induced in male New Zealand White rabbits by chronic ventricular tachycardia. Using radio telemetry of arterial pressure and intracerebroventricular infusions, experiments were performed in the conscious state. Renal sympathetic nerve activity (RSNA) was recorded as a direct measure of sympathetic outflow. Intracerebroventricular Ang II significantly increased RSNA in sham (131.5Ϯ13.3% of control) and CHF (193.6Ϯ11.9% of control) rabbits. The increase in CHF rabbits was significantly greater than in sham rabbits (PϽ0.01). These responses were abolished by intracerebroventricular losartan, tempol, or apocynin. Resting RSNA was significantly reduced by intracerebroventricular losartan, tempol, or apocynin in CHF rabbits but not in sham rabbits. Intracerebroventricular administration of the superoxide dismutase inhibitor diethyldithio-carbamic acid increased RSNA significantly more in sham compared with CHF rabbits. NADPHdependent superoxide anion production in the rostral ventrolateral medulla (RVLM) was increased by 2.9-fold in CHF rabbits compared with sham rabbits. Finally, increases in the RVLM mRNA and protein expression of Ang II type 1 (AT 1 ) receptor and subunits of NAD(P)H oxidase (p40 phox , p47 phox , and gp91 phox ) were demonstrated in CHF rabbits. These data demonstrate intense radical stress in autonomic areas of the brain in experimental CHF and provide evidence for a tight relationship between Ang II and ROS as contributors to sympathoexcitation in CHF. Key Words: free radicals Ⅲ angiotensin receptors Ⅲ RVLM Ⅲ ventricular pacing I t is now well accepted that neural and humoral excitation are two of the primary and most reproducible sequelae of the chronic heart failure (CHF) syndrome. 1 Excessive sympathetic activation not only exacerbates the heart failure state but also is prognostic of death and complications. 2 A variety of humoral substances have been shown to be elevated in the CHF state, 1,3 of which angiotensin II (Ang II) has been considered a prime candidate for a substance that modulates sympathetic outflow because it has been known for some time that Ang II can alter sympathetic function at several sites from the central nervous system to the periphery. 4 Indeed, many of the current therapeutic targets in the treatment of CHF relate to reducing Ang II generation or blocking the effects of Ang II at its receptor sites. Despite its importance in central regulation of sympathetic outflow and cardiovascular homeostasis in the CHF state, the pre...

Background: Women experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs. Methods: Searches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased. Results: For most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88% of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29% of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugs Conclusions: Sex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.

The present study aimed to determine whether peripheral and/or central chemoreflex function is altered in chronic heart failure (CHF) and whether altered chemoreflex function contributes to sympathetic activation in CHF. A rabbit model of pacing-induced CHF was employed. The development of CHF (3-4 wk of pacing) was characterized by an enlarged heart, an attenuated contractility, and an elevated central venous pressure. Renal sympathetic nerve activity (RSNA) and minute volume (MV) of ventilation in response to stimulation of peripheral chemoreceptors by isocapnic/hypoxic gases were measured in the conscious state. It was found that the baseline RSNA at normoxia was higher in CHF rabbits than in sham rabbits (35. 00 +/- 4.03 vs. 20.75 +/- 2.87% of maximum, P < 0.05). Moreover, the magnitudes of changes in RSNA and MV in response to stimulation of the peripheral chemoreceptors and the slopes of RSNA-arterial PO2 and MV-arterial PO2 curves were greater in CHF than in sham rabbits. Inhibition of the peripheral chemoreceptors by inhalation of 100% O2 decreased RSNA in CHF but not in sham rabbits. The central chemoreflex function, as evaluated by the responses of RSNA and MV to hyperoxic/hypercapnic gases, was not different between sham and CHF rabbits. These data suggest that an enhancement of the peripheral chemoreflex occurs in the rabbit model of pacing-induced CHF and that the enhanced peripheral chemoreflex function contributes to the sympathetic activation in the CHF state.