Impact of angiotensin II receptor antagonism on the sex-selective dysregulation of cardiovascular function induced by in utero dexamethasone exposure.

In utero exposure to glucocorticoids in late gestation programs changes in cardiovascular function. The objective of this study was to determine the degree to which angiotensin II mediates sex-biased changes in autonomic function as well as basal and stress-responsive cardiovascular function following in utero glucocorticoid exposure. Pregnant rats were administered the synthetic glucocorticoid dexamethasone (Dex; 0.4 mg/kg/day sc) or vehicle on gestation days 18-21. Mean arterial pressure, heart rate, and heart rate variability (HRV) were measured via radiotelemetry in freely moving, conscious adult rats. To evaluate the impact of stress, rats were placed in a restraint tube for 20 min. In a separate cohort of rats, restraint stress was performed before and after chronic treatment with the angiotensin type 1 receptor antagonist, losartan (30 mg/kg/day ip). Frequency domain analysis of HRV was evaluated, and data were integrated into low-frequency (LF, 0.20-0.75 Hz) and high-frequency (HF, 0.75-2.00 Hz) bands. Prenatal Dex resulted in an exaggerated pressor and heart rate response to restraint in female offspring that was attenuated by prior losartan treatment. HF power was higher in vehicle-exposed female rats compared with Dex females. Following losartan, HF power was equivalent between female vehicle and Dex-exposed rats. In utero exposure to Dex produced female-biased alterations in stress-responsive cardiovascular function, which may be indicative of a reduction in parasympathetic activity. Moreover, these findings suggest this autonomic dysregulation may be mediated, in part, by long-term changes in renin-angiotensin signaling.NEW & NOTEWORTHY Our findings reveal the involvement of angiotensin II on sex-selective cardiovascular function and autonomic changes in adult offspring exposed to dexamethasone during the last 4 days of gestation. We show that angiotensin II receptor blockade reverses the exaggerated pressor and heart rate response to acute restraint stress and the autonomic dysregulation observed in female, but not male, offspring exposed to dexamethasone in utero.

Persistent change in cardiac fibroblast physiology after transient ACE inhibition.

Transient angiotensin-converting enzyme (ACE) inhibition induces persistent changes that protect against future nitric oxide synthase (NOS) inhibitor-induced cardiac fibrosis and inflammation. Given the role of fibroblasts in mediating these effects, the present study investigates whether prior ACE inhibition produced persistent changes in cardiac fibroblast physiology. Adult male spontaneously hypertensive rats (SHRs) were treated with vehicle (C+L) or the ACE inhibitor, enalapril (E+L) for 2 wk followed by a 2-wk washout period and a subsequent 7-day challenge with the NOS inhibitor N(ω)-nitro-l-arginine methyl ester. A third set of untreated SHRs served as controls. At the end of the study period, cardiac fibroblasts were isolated from control, C+L, and E+L left ventricles to assess proliferation rate, collagen expression, and chemokine release in vitro. After 7 days of NOS inhibition, there were areas of myocardial injury but no significant change in collagen deposition in E+L and C+L hearts in vivo. In vitro, cardiac fibroblasts isolated from C+L but not E+L hearts were hyperproliferative, demonstrated increased collagen type I gene expression, and an elevated secretion of the macrophage-recruiting chemokines monocyte chemoattractant protein-1 and granulocyte macrophage-colony stimulating factor. These findings demonstrate that in vivo N(ω)-nitro-l-arginine methyl ester treatment produces phenotypic changes in fibroblasts that persist in vitro. Moreover, this is the first demonstration that transient ACE inhibition can produce a persistent modification of the cardiac fibroblast phenotype to one that is less inflammatory and fibrogenic. It may be that the cardioprotective effects of ACE inhibition are related in part to beneficial changes in cardiac fibroblast physiology.

Protection against L-NAME-induced reduction in cardiac output persists even after cessation of angiotensin-converting enzyme inhibitor treatment.

AIM: We have demonstrated that short-term angiotensin-converting enzyme (ACE) inhibition in adult spontaneously hypertensive rats produces cardiac changes that persist following cessation of treatment that result in a reduced inflammatory, proliferative and fibrotic response to the nitric oxide synthase inhibitor N(ω) -Nitro-l-arginine methyl ester (L-NAME). The present study examines whether prior ACE inhibition with enalapril also protects against L-NAME-induced cardiac dysfunction. METHODS: Rats were treated with enalapril (Enal + L) or tap water (Con, Con + L) for 2 weeks followed by a 2-week washout period. At this point, Con + L and Enal + L rats were treated with L-NAME for 10 days. Hearts were perfused in the working mode, mean arterial pressure (MAP) was assessed via radiotelemetry, and myocardial injury was evaluated in hematoxylin and eosin-stained sections. RESULTS: L-NAME increased MAP by a similar magnitude in Con + L and Enal + L. L-NAME-induced statistically significant decreases in flow-mediated functional parameters in Con + L rats including cardiac output, stroke volume and coronary flow. This was prevented by prior enalapril treatment. Prior enalapril did not prevent L-NAME-induced myocardial injury, but may have lessened the degree of it. Regardless of treatment, changes in cardiac function did not correlate with myocardial injury. CONCLUSION: Despite equivalent impact on MAP and incidence of myocardial infarction, prior enalapril treatment resulted in the preservation of cardiac function following L-NAME. Understanding the mechanisms by which transient ACE inhibition protects against reductions in cardiac function in the absence of ongoing treatment may reveal novel targets for heart failure treatment.

Evaluating a theory-based health education intervention to improve awareness of prostate cancer among men in Western Jamaica.

OBJECTIVE: To evaluate the impact of a theory-based health education intervention on awareness of prostate cancer and intention to screen among men in Western Jamaica. METHODS: One hundred and eighty-eight men attending outpatient clinics in a hospital in Western Jamaica completed an interviewer-administered pretest survey. Following the pretest, participants received a health education intervention related to prostate cancer and an immediate post-test survey RESULTS: There were statistically significant increases in the percentage of correct responses between the pretest and post-test (p < 0.05). The greatest improvement was among items measuring knowledge of prostate cancer screening tests. Participants moved across the Stages of Change theoretical constructs indicating intention to screen. CONCLUSION: The sample was receptive to information about prostate cancer and the use of a theory-based educational intervention positively influenced knowledge of prostate cancer risk factors, symptoms, and types of screenings. PRACTICE IMPLICATIONS: This theory-based patient education programme can be replicated to promote awareness of prostate cancer and informed screening methods including potential risk associated with screening behaviours.

Common therapeutic strategies in the management of sexual dysfunction and cardiovascular disease.

Sexual dysfunction is a frequent complication of treated and untreated cardiovascular disease. In fact, approximately 30% of hypertensives have been found to suffer from erectile dysfunction (ED) resulting from arterial dysfunction. Recent evidence has suggested that ED may be an early indicator of subclinical cardiovascular disease. In women, the evidence is similar, but more limited, showing that in hypertensive patients there is an increased prevalence of sexual dysfunction involving decreased vaginal lubrication, decreased orgasm, and increased pain. Clouding the issue, however, is that some antihypertensive agents may induce sexual dysfunction in hypertensives with normal sexual function. In contrast to the chronic treatments used in hypertension, therapies for ED involve acute treatments (none currently approved for women) targeting vasodilation of penile arteries, resulting in erection. Common to the treatment of hypertension and ED is that the current therapies were not designed to target underlying disorders of local, neural, vascular, or endocrine origin. In fact, while blood pressure is lowered, and erectile responses are improved with the respective therapies, the causal abnormalities may progress thereby limiting the long-term effectiveness of the medication. Some antihypertensive agents have been shown to have additional effects beyond blood pressure reduction and their impact on sexual function is a key focus of this review. This review examines the current and future strategies for treatments of male and female sexual dysfunction and the potential for therapeutic modalities that go beyond the recovery of the responses by targeting the fundamental mechanisms common to both sexual dysfunction and cardiovascular disease.

A framework for the present and future development of experimental models of female sexual dysfunction.

Female sexual dysfunction (FSD) is currently categorized according to disorders of (i). desire, (ii). arousal, (iii). orgasm and (iv). sexual pain. The advancement of research defining the physiological, pathophysiological and psychological mechanisms of these disorders, and to develop treatments for FSD, has been hampered by the paucity of experimental paradigms and animal models. It may be that animal models of FSD are best suited to address arousal disorders that include persistent or routine inability to attain or maintain genital lubrication or engorgement. Although still limited in scope, experimental models of FSD have involved a range of in vitro to in vivo methodologies. Specifically, the in vitro and in situ models include vaginal or clitoral smooth muscle preparations, histological evaluation and vaginal blood flow assessments. Previously, in vivo studies of sexual responses focussed on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method. Recently, a new model of female sexual arousal was developed using pharmacological CNS stimulation; responses that were found to be sensitive to cardiovascular status, aging and hormonal conditions. It is important that a wide variety of animal models continue to be developed to reflect the multifactorial basis of the condition.

Evidence for centrally initiated genital vasocongestive engorgement in the female rat: findings from a new model of female sexual arousal response.

PURPOSE: In spite of rapidly growing interest, few research tools have been developed to study female sexual dysfunction. Using the D(1)/D(2) agonist, apomorphine (APO), our objective was to develop a new model of the sexual arousal response in female rats based on one previously established for the male condition. METHODS: APO (80 micro g/kg, s.c.) was given during proestrus (P), estrus (E), metestrus (M), early diestrus (DI) and late diestrus (DII), and in ovariectomized (OVX) female Wistar rats. APO-induced behavioral and genital responses were characterized (30 min) using video monitoring. RESULTS: APO-induced reproducible, periodic morphological changes in the external genitalia. The onset, timing and duration of these female APO responses were consistent with genital vasocongestive arousal (GVA) responses in males (ie erections). APO-induced GVAs occurred throughout the estrous cycle, peaking in E (1.4+/-1.21 overall; 0.9+/-0.64 in DII; 1.8+/-1.66 in E) and were markedly diminished by ovariectomy (OVX, 0.4+/-0.51). CONCLUSION: APO induced a reproducible sexual arousal response in female rats involving obvious genital vasocongestive engorgement. Further, the findings demonstrate that the APO-induced genital arousal responses are hormonally regulated.

Bioenergetic remodeling of heart during treatment of spontaneously hypertensive rats with enalapril.

We used spontaneously hypertensive rats to study remodeling of cardiac bioenergetics associated with changes in blood pressure. Blood pressure was manipulated with aggressive antihypertensive treatment combining low dietary salt and the angiotensin-converting enzyme inhibitor enalapril. Successive cycles of 2 wk on, 2 wk off treatment led to rapid, reversible changes in left ventricular (LV) mass (30% change in <10 days). Despite changes in LV mass, specific activities of bioenergetic (cytochrome-c oxidase, citrate synthase, lactate dehydrogenase) and reactive oxygen species (ROS) (total cellular superoxide dismutase) enzymes were actively maintained within relatively narrow ranges regardless of treatment duration, organismal age, or transmural region. Although enalapril led to parallel declines in mitochondrial enzyme content and ventricular mass, total ventricular mtDNA content was unaffected. Altered enzymatic content occurred without significant changes in relevant mRNA and protein levels. Transcript levels of gene products involved in mtDNA maintenance (Tfam), mitochondrial protein degradation (LON protease), fusion (fuzzy onion homolog), and fission (dynamin-like protein, synaptojanin-2alpha) were also unchanged. In contrast, enalapril-mediated ventricular and mitochondrial remodeling was accompanied by a twofold increase in specific activity of catalase, an indicator of oxidative stress, suggesting that rapid cardiac adaptation is accompanied by tight regulation of mitochondrial enzyme activities and increased ROS production.

Recovery of erectile function after brief aggressive antihypertensive therapy.

PURPOSE: We have previously demonstrated that antihypertensive therapy could structurally modulate blood vessels in the penis, although the impact on erectile function was not established. Given the importance of inadequate penile arterial inflow as a cause of erectile dysfunction we determined in spontaneously hypertensive rats the impact of brief aggressive antihypertensive therapy on structurally based penile vascular resistance, erectile function and mean arterial pressure during and after treatment. MATERIALS AND METHODS: Young (15-week-old) and aged (40-week-old) spontaneously hypertensive rats were treated for 2 weeks (enalapril 30 mg./kg. daily plus a low salt diet). Mean arterial pressure was continuously monitored via radio telemetry. Erectile responses were assessed by administering apomorphine (80 microg./kg. subcutaneously) before, during and after treatment. Structurally based vascular resistance was determined in the isolated, perfused penile vasculature 2 weeks after stopping treatment in aged spontaneously hypertensive rats. Certain responses were determined, including resistance at maximum dilatation (lumen size) and at maximum constriction (medial bulk), and EC50 of the alpha-adrenoceptor agonist methoxamine. RESULTS: In the period after the cessation of drug treatment there was a persistent reduction in the level of arterial pressure (16%) and a doubling of erectile responses compared with pre- treatment. Cardiac and vascular structure regressed, as determined by the mean decrease plus or minus standard deviation in vascular resistance at maximum dilatation (21% +/- 4.5%) and mean reduction in left ventricle mass (10.4% +/- 3.7%). Furthermore, treatment induced a significant right shift in alpha1-adrenoceptor concentration response curve in treated versus control rats (mean EC50 1.09 +/- 0.111 versus 0.76 +/- 0.111). CONCLUSIONS: The improvement in erectile function after brief aggressive treatment may be related to improvement in structurally based vascular resistance within the penis and the decrease in responsiveness of alpha1-adrenoceptor mediated erectolytic signaling. These findings are suggestive of a new therapeutic strategy for hypertension and erectile dysfunction.

Antihypertensive drugs induce structural remodeling of the penile vasculature.

PURPOSE: There is a strong association between hypertension and erectile dysfunction. Studies of the treatment of hypertension have shown that some pharmacological agents are capable of inducing regression of the vascular structure during treatment. We determined whether penile vascular structure is as susceptible as other vascular beds to regression during antihypertensive drug treatment. MATERIALS AND METHODS: Adult spontaneously hypertensive rats were treated for 1 or 2 weeks with 30 mg./kg. enalapril daily, or for 2 weeks with 45 mg./kg. hydralazine daily. Structurally based vascular resistance was determined in isolated penile and skeletal muscle vascular beds perfused with Tyrode-dextran. A cumulative alpha1-adrenoceptor concentration constrictor response curve to 1 to 100 microg./ml. methoxamine was constructed and the maximum constrictor response (vasopressin, methoxamine and angiotensin II) indicating the tissue yield point (that is the average medial bulk of vascular smooth muscle) was determined. The hearts were excised and the ventricles were separated and weighed. RESULTS: Enalapril treatment progressively regressed cardiac and vascular structure during the 1 and 2-week treatment periods with a mean tissue yield point plus or minus standard deviation of -5.91% +/- 5.1% (p <0.05) and -12.1% +/- 6.0% (p <0.05), and a mean left ventricle mass of -11.8% +/- 2.2% (p <0.05) and -13.6% +/- 3.2% (p <0.05), respectively. Hydralazine treatment for 2 weeks was less effective on vascular regression with a mean yield of -7.3% +/- 2.9% (p <0.05) and it did not alter left ventricle hypertrophy compared with controls (3.7% +/- 5.0%). CONCLUSIONS: The data suggest that renin-angiotensin system inhibition may at least partially normalize penile vascular structure. The impact of these changes on erectile function must be determined.

The penis is not protected--in hypertension there are vascular changes in the penis which are similar to those in other vascular beds.

In hypertension, small arteries in a variety of vascular beds undergo structural changes that increase resistance. To assess whether there are differential structural changes in the penis that accompany hypertension, we began with determining structurally-based vascular resistance properties in penile and hindlimb vascular beds of adult spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. In anesthetized SHR, the penile and hindlimb vasculature were isolated and perfused, maximum dilation was induced, and a flow-pressure assessment and alpha 1-adrenoceptor agonist concentration-response curves were generated. Both the baseline and maximum constrictor responses were similar in the two beds of each strain, and overall the maximum structurally-based vascular resistance in SHR was higher than in SD rats. Our data suggests that the penile vasculature is not protected from the structural changes that take place in the other vascular beds in hypertension. There does not appear to be an underlying functional control mechanism that protects the penile vasculature from structural changes that may have a negative impact on penile blood flow.

Paget's disease of the vulva: prevalence of associated vulvar adenocarcinoma, invasive Paget's disease, and recurrence after surgical excision.

OBJECTIVE: Our aim was to determine the prevalence of associated vulvar adenocarcinoma, invasive Paget's disease, and recurrence of Paget's disease of the vulva. STUDY DESIGN: A retrospective review of tumor and pathology registries at 8 institutions is presented. Patients with recurrent disease were excluded. Histologic slide review was performed. RESULTS: The median age of the 100 patients was 70 years. The median duration of pruritus before surgery was 2 years. Thirty-four percent of patients experienced a recurrence at a median of 3 years. There was a 12% prevalence of invasive vulvar Paget's disease and a 4% prevalence of associated vulvar adenocarcinoma. One patient died of Paget's disease with associated vulvar adenocarcinoma. CONCLUSIONS: Paget's disease of the vulva is rarely associated with an underlying vulvar adenocarcinoma or invasive Paget's disease, but there is a high recurrence rate.

A new method and apparatus that prevents the rebreathing of expired carbon dioxide of sleeping neonates and infants.

This study was done to measure the effect on inspiratory carbon dioxide (CO2) levels of infants exposed to the infant Crib Air (ICA) apparatus, a novel device which circulates room air within the infant's crib. Twenty-one healthy, sleeping infants and neonates (mean age = 14.7 weeks) were studied in a prospective crossover trial. All infants were studied lying face down or with the face placed passively to the side in their cribs. Inspiratory CO2 levels were recorded over a 30 minute period by measuring the concentration of CO2 immediately adjacent to the infants' nose and mouth. During the first 15 minute period, the baseline concentration of inspiratory CO2 was recorded. The infants were then exposed to the ICA apparatus in their cribs for 15 minutes and the concentrations of inspiratory CO2 were measured. Mean inspiratory CO2 levels in infants lying face down decreased from 8.5 to 1.4 mm Hg after ICA exposure (P < 0.001). Infants studied with their face placed passively to the side experienced a similar decrease in inspired CO2 concentrations. We conclude that the level of inspired CO2 by sleeping infants can be significantly reduced by the ICA regardless of the position of the infant's head.

Vertical extrusion: literature review and report of a case.

To date, the scientific literature has documented, primarily, successful methods and techniques of treatment involving vertical extrusion. The purpose of this article is to review the literature and report on a case that demonstrates the multidisciplinary approach required to successfully manage a reversible complication involving the restoration of an adult maxillary central incisor that had sustained an oblique crown-root fracture.

Evaluation of titanium dental implant osseointegration in posterior edentulous areas of micro swine.

This study investigated the micro swine (Sus scrofa) as an animal model for research in osseointegrated implant systems. As the first in a series of investigations based on this model, the study focused on the histological evaluation of the bone-implant interface of Brånemark implants. Ten titanium implants were placed in posterior edentulous areas of the swine for longitudinal evaluation of healing and osseointegration. Six-week and 18-week post-operative specimens were removed en bloc at the time of death. The samples were fixed in glutaraldehyde, embedded in acrylic, and sectioned with a diamond wafering saw. The specimens were viewed under SEM and photographed. The percentage of bone that was in direct contact with the coronal, middle, and apical segments of the implant, referred to as the contact length fraction (CLF), was determined by use of a digitizing analyzer. All implant fixtures became exposed through the soft tissue within one week of placement. Of the ten titanium fixtures placed, three failed--one by post-surgical day 14 due to food impaction into the surgical site, and the other two because of failure to osseo-integrate. Bone contact with the successfully integrated implant surfaces ranged from 19.2 to 58.5%, with a mean of approximately 34%. Osseointegration did not appear to increase over the experimental time period, since there was no difference in the percentage of bone contact between the 18-week and the six-week specimens. The lack of soft-tissue coverage over the implants caused bone loss, but did not significantly affect osseointegration in the coronal third. The micro swine appears to be a suitable animal model for use in implant research in posterior edentulous regions.