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An increased level of sodium-lithium countertransport (SLC) activity has been associated with salt-sensitive hypertension. Previous findings have suggested that dysregulation of the renin-angiotensin-aldosterone system (RAAS) may be involved in the mechanism linking elevated SLC activity and hypertension. Therefore, baboons with different levels of SLC activity were given two diets differing in sodium content, with and without an angiotensin II (ANG II) infusion, to investigate the relationship between SLC activity, the RAAS, and physiological regulation by sodium. Although we anticipated that high SLC (HSLC) activity would be associated with inappropriate function of the RAAS and greater arterial pressure sensitivity to dietary sodium and ANG II and that low SLC (LSLC) activity would be associated with the least BP sensitivity, we found that the LSLC phenotype correlated with BP sensitivity similar to the HSLC phenotype, and the normal SLC (NSLC) phenotype showed the least BP sensitivity to dietary sodium and ANG II.

The path from Gila monster venom to the diabetes medication Exenatide runs through an American Diabetes Association meeting in 1996. There, Department of Veterans Affairs researcher, endocrinologist, and Golden Goose Award winner Dr. John Eng presented results on how a compound in Gila monster venom affects insulin production, catching the attention of a small biotechnology company, Amylin Pharmaceuticals. After receiving U.S. Food and Drug Administration approval in 2005, the resulting drug Exenatide is now used by millions of people to manage Type 2 diabetes. The story of Dr. Eng and Amylin is just one of many—spanning all science and technology disciplines—that exemplify the important role of conferences in advancing science, developing the next generation of scientific talent, and bringing new technologies and potential cures to the benefit of society. In 2012, the White House Office of Management and Budget instituted new government-wide regulations ([ 1 ][1]) that substantially cut spending on conference participation and travel and require the senior leadership to review agency-wide conference costs that exceed $100,000, with more stringent requirements for costs in excess of $500,000. At current prices for travel and lodging, this would cover the cost of only a few hundred attendees, whereas the Departments of Defense and Energy each employ over 100,000 scientists and engineers either directly or as contractors. The U.S. Congress has further limited travel to international conferences to 50 employees per agency for most agencies. In response, federal agencies have developed costly tracking and approval systems, and approvals now often require more than a dozen signatures. Under these new restrictive regulations, members of the scientific community employed by federal agencies have been subject to approval processes that have ballooned from weeks to as much as 9 months, and some scientists and engineers are now choosing not to request travel at all. The Government Accountability Office ([ 2 ][2]) and White House Office of Science and Technology Policy ([ 3 ][3]) have shown that this has led to reductions in conference participation among these colleagues, to the detriment of science as a whole. This is why we and our colleagues in the science and technology community recently wrote a letter to the U.S. Congress expressing our deep concerns about the stifling impacts of these policies on science and engineering, and encouraging them to act ([ 4 ][4]). The letter was signed by more than 100 organizations and institutions that collectively represent and support millions of scientists, engineers, and mathematicians. ![Figure][5] PHOTO: © LEONARDO PATRIZI/[ISTOCKPHOTO.COM][6] We hear from policy-makers in Congress and regulators at federal agencies that current problems stem, in part, from a lack of understanding of why scientific and technical conferences are important parts of the work of each and every member of our community, not fancy junkets. So today, we and our colleagues are reaching out to ask for your help. Tell us about a collaboration that started at a conference and led to an exciting new discovery, or how an interaction at a conference was critical to your career as a young scientist or engineer. Because current regulations affect federal employees and contractors most, we especially encourage stories that involve collaborations with colleagues at national labs or research institutes. Submit your experiences at [www.aaas.org/yourstory][7] ([ 5 ][8]). 1. [↵][9]Executive Office of the President, Office of Management and Budget M-12-12, “Promoting Efficient Spending to Support Agency Operations” ([www.whitehouse.gov/sites/default/files/omb/memoranda/2012/m-12-12.pdf][10]). 2. [↵][11]U.S. Government Accountability Office, “Defense science and technology: Further DOD and DOE actions needed to provide timely conference decisions and analyze risks from changes in participation,” GAO Highlights (2015); [www.gao.gov/assets/670/668845.pdf][12]. 3. [↵][13]L. Rein, “How the federal travel crackdown hits scientists especially hard,” Washington Post, 25 March 2015; [www.washingtonpost.com/blogs/federal-eye/wp/2015/03/25/the-white-house-asked-federal-scientists-how-bad-its-crackdown-on-travel-is-the-answer-bad/][14]. 4. [↵][15]Letter to Senate Appropriations Committee ([www.aaas.org/sites/default/files/SApprops%20S%26T%20Conference%20Travel%20Letter.pdf][16]). 5. [↵][17]AAAS, publisher of Science , led the above-referenced letter to the U.S. Congress and is also hosting the story collection. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: pending:yes [6]: http://ISTOCKPHOTO.COM [7]: http://www.aaas.org/yourstory [8]: #ref-5 [9]: #xref-ref-1-1 "View reference 1 in text" [10]: http://www.whitehouse.gov/sites/default/files/omb/memoranda/2012/m-12-12.pdf [11]: #xref-ref-2-1 "View reference 2 in text" [12]: http://www.gao.gov/assets/670/668845.pdf [13]: #xref-ref-3-1 "View reference 3 in text" [14]: http://www.washingtonpost.com/blogs/federal-eye/wp/2015/03/25/the-white-house-asked-federal-scientists-how-bad-its-crackdown-on-travel-is-the-answer-bad/ [15]: #xref-ref-4-1 "View reference 4 in text" [16]: http://www.aaas.org/sites/default/files/SApprops%20S%26T%20Conference%20Travel%20Letter.pdf [17]: #xref-ref-5-1 "View reference 5 in text"

The IACUC is one of the most important committees at a research institution and plays a critical role in the success of an animal care and use program. It is the responsibility of the institution to provide IACUC members with adequate and appropriate training. The authors explore various IACUC training options.

SUMMARY 1. Increased dietary salt increases blood pressure in many hypertensive individuals, producing salt-sensitive hypertension (SSH). The cause is unknown, but a major component appears to be activation of the sympathetic nervous system. The purpose of this short review is to present one hypothesis to explain how increased dietary salt increases sympathetic activity in SSH. 2. It is proposed that increased salt intake causes salt retention and raises plasma sodium chloride (NaCl) concentrations, which activate sodium/osmoreceptors to trigger sympathoexcitation. Moreover, we suggest that small and often undetectable increases in osmolality can drive significant sympathoexcitation, because the gain of the relationship between osmolality and increased sympathetic activity is enhanced. Multiple factors may contribute to this facilitation, including inappropriately elevated levels of angiotensin II or aldosterone, changes in gene expression or synaptic plasticity and increased sodium concentrations in cerebrospinal fluid. 3. Future studies are required to delineate the brain sites and mechanisms of action and interaction of osmolality and these amplification factors to elicit sustained sympathoexcitation in SSH.

Despite its usefulness as a nongenetic model of hypertension, little information is available regarding baroreflex function in the Grollman, renal wrap model of hypertension in the rat. Baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) were studied in male, Sprague-Dawley rats hypertensive (HT) for 1 or 4–6 wk after unilateral nephrectomy and figure-8 ligature around the remaining kidney or normotensive (NT) after sham surgery. Rats were anesthetized with Inactin and RSNA, and HR was recorded during intravenous infusions of sodium nitroprusside or phenylephrine to lower or raise mean arterial pressure (MAP). Response curves were analyzed using a logistic sigmoid function. In 1- and 4-wk HT rats the midpoints of RSNA and HR reflex curves were shifted to the right ( P < 0.05). Comparing NT to 1- or 4-wk HT rats, the gain of RSNA-MAP curves was no different; however, gain was reduced in the HR-MAP curves at both 1 and 4 wk in HT rats ( P < 0.05). In anesthetized rats the HR range was small; therefore, MAP and HR were measured in conscious rats during intravenous injections of three doses of phenylephrine and three doses of sodium nitroprusside. Linear regressions revealed a reduced slope in both 1- and 4-wk HT rats compared with NT rats ( P < 0.05). The results indicate that baroreflex curves are shifted to the right, to higher pressures, in hypertension. After 1–4 wk of hypertension the gain of baroreflex regulation of RSNA is not altered; however, the gain of HR regulation is reduced.

The ovariectomized (OVX) Dahl salt-sensitive (DS) rat fed a low-salt diet is a model of postmenopausal hypertension. In addition to estrogen loss, aging can also contribute to postmenopausal hypertension. We hypothesized that: (1) female DS rats on a low-salt diet become hypertensive with age; (2) ovariectomy accelerates age-dependent hypertension in the DS rat caused by estrogen depletion; and (3) this hypertension correlates with increased type 1 angiotensin receptor (AT 1 R) number (Bmax). Blood pressure was monitored by telemetry from 3 to 12 months and AT 1 R Bmax was determined by Scatchard analysis in glomeruli and adrenal cortex. Three groups of DS rats were studied: intact, OVX, and 17β-estradiol–replaced OVX (OVX+E). In intact rats, aging to 12 months resulted in hypertension (159±6 mm Hg) and an 82% decrease in estrogen. Blood pressure in OVX was significantly higher than OVX+E through 12 months of age (173±4 versus 150±8 mm Hg). At 4 months, OVX increased AT 1 R Bmax compared with intact and OVX+E in both glomeruli and adrenal cortex. Aging also increased AT 1 R Bmax in these tissues in intact rats. In summary, female DS rats fed a low-salt diet have hypertension develop with age, that is accelerated by OVX and attenuated by estrogen replacement. Concurrently, AT 1 Rs are upregulated by age and OVX, which is prevented by estrogen replacement. This study suggests that an increased activity of the renin angiotensin system contributes to the development of hypertension, and estrogen protects against this process.

Aim: The sympathetic nervous system plays an important role in the regulation of physiological homeostasis under basal conditions and in response to acute and chronic stressors. It is known that multiple levels of the neuroaxis, including the paraventricular nucleus (PVN) of the hypothalamus, are involved in regulation of efferent sympathetic nerve discharge (SND). This review focuses on the role of the PVN in regulation of functional characteristics of efferent SND. Results: The available experimental evidence indicates that the level of efferent sympathetic nerve activity is altered after microinjection of numerous substances into the PVN, including excitatory amino acids, -aminobutyric acid (GABA A ) receptor agonists and antagonists, and PVN nitric oxide synthase inhibitors. In addition, antagonism of PVN GABA A receptors changes the pattern of synchronized discharge bursts in efferent sympathetic nerves and enhances the frequency-domain coupling between low-frequency bursts in sympathetic nerve pairs. Finally, PVN microinjections of excitatory amino acids (L-glutamate, D,L-homocysteic acid) have been shown to produce non-uniform changes in the level of efferent sympathetic nerve activity. Conclusion: These findings support the concept that the PVN is an important component of the central neurocircuitry regulating functional characteristics (basal level of activity, bursting pattern, and relationships between discharges in nerves innervating different targets) of efferent sympathetic nerve outflow.

Abstract —Endothelin (ET) and the sympathoadrenal system contribute to the development and maintenance of deoxycorticosterone acetate (DOCA)-salt hypertension. ET can act directly on the adrenal medulla to enhance the release of catecholamines. In addition, the level of ET peptide is increased in the adrenal glands of DOCA-salt hypertensive rats. Therefore, we tested the hypothesis that ET enhances adrenal medullary catecholamine release during DOCA-salt hypertension. The infusion of exogenous ET-1 into an isolated, perfused adrenal gland preparation resulted in an increase in the basal release of norepinephrine (NE) and epinephrine (EPI) in control and DOCA-salt hypertensive rats. Nerve-stimulated (0.3 Hz) release of NE was significantly inhibited during ET-1 infusion in the DOCA-salt hypertensive rats but not in the control rats. The role of endogenous ET on basal and nerve-stimulated NE and EPI release was also examined. An infusion of either BQ-123 (10 −7 mol/L), an ET A receptor antagonist, or BQ-788 (10 −7 mol/L), an ET B receptor antagonist, did not alter basal NE or EPI release in either control or DOCA-salt hypertensive rats. BQ-788 did not alter nerve-stimulated release of NE and EPI. In contrast, the nerve-stimulated release of EPI, but not NE, was enhanced during BQ-123 infusion in DOCA-salt hypertensive rats. Nerve-stimulated NE and EPI release was unaffected by BQ-123 in the control rats. These data suggest that ET can stimulate adrenal medullary catecholamine release in normotensive and DOCA-salt hypertensive rats. However, ET also inhibits adrenal medullary catecholamine release in DOCA-salt hypertensive rats.

Abstract —The purpose of this study was to determine whether sinoaortic deafferentation (SAD) alters the severity of hypertension or sympathoadrenal contribution to mean blood pressure (MAP) during renal wrap hypertension. Male Sprague-Dawley rats were implanted with radiotelemetry transmitters for 24-hour recording of MAP and heart rate. All rats underwent either SAD or sham SAD (Intact) surgery and were allowed to recover for 10 to 14 days. The rats were then assigned to a normotensive (Sham) group or a hypertensive (Wrap) group in which 1-kidney figure-8 renal wrap was performed. SAD increased the acute MAP response to renal wrap (Intact-Sham=5±1 mm Hg, Intact-Wrap=45±3 mm Hg, SAD-Sham=3±3 mm Hg, SAD-Wrap=58±4 mm Hg) and increased the lability of MAP (SD of MAP; Intact-Sham=3.8±0.2, Intact-Wrap=4.2±0.3, SAD-Sham=9.6±1.4, SAD-Wrap=9.7±1.4). MAP was not different between SAD and Intact rats during 4 weeks after renal wrap or sham surgery; however, induction of hypertension produced additional MAP variability that was independent of SAD (Intact-Sham=4.6±0.4, Intact-Wrap=6.2±0.6, SAD-Sham=6.3±0.5, SAD-Wrap=10.8±1.5). In a separate group of rats, the sympathoadrenal contribution to MAP was assessed by the depressor response to ganglionic blockade and plasma norepinephrine at rest and after neuronal uptake inhibition with desipramine. The depressor response to ganglionic blockade was significantly increased by renal wrap and by SAD (Intact-Sham=−49±2 mm Hg, Intact-Wrap=−73±4 mm Hg, SAD-Sham=−77±5 mm Hg, SAD-Wrap=−96±6 mm Hg). In the 3 groups with enhanced ganglionic blockade responses, desipramine caused a significant increase in plasma norepinephrine. These results indicate that SAD does not alter the development of renal wrap hypertension but does increase the sympathoadrenal contribution to MAP in both normotensive and hypertensive animals.

We hypothesized that lack of a functional serotonin transporter (SERT) would increase basal blood pressure and enhance the development of deoxycorticosterone acetate (DOCA)-salt hypertension compared to wild type (WT) controls. Mean arterial blood pressure was measured in WT and SERT knockout (KO) mice and rat models through radiotelemetry. Basal blood pressures were not different between respective WT and KO. Moreover, blood pressure elevated similarly (∼ 50 mm Hg) in all strains given DOCA and salt. Thus, the lack of functional SERT did not prevent development of DOCA-salt induced hypertension or modify basal blood pressure significantly.

Epidemiological studies have suggested an association among chronic hyperinsulinemia, insulin resistance, and hypertension. However, the causality of this relationship remains uncertain. In this study, chronically catheterized conscious rats were made hyperinsulinemic for 7 days (approximately 90 mU/l, i.e., threefold over basal), while strict euglycemia was maintained (approximately 130 mg/dl, coefficient of variation10%) by using a modification of the insulin/glucose clamp technique. Control rats received vehicle infusion. Baseline mean arterial pressure and heart rate were 125 +/- 5 mmHg and 427 +/- 12 beats/min and remained unchanged during the 7-day infusion of insulin (127 +/- 7 mmHg; 401 +/- 12 beats/min) or vehicle (133 +/- 4 mmHg; 411 +/- 10 beats/min). Baseline plasma epinephrine (88 +/- 15 pg/ml), norepinephrine (205 +/- 31 pg/ml), and sodium balance (0.34 +/- 0.09 mmol) remained constant during the 7-day insulin or vehicle infusion. After 7 days of insulin or vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-3H]glucose infusion to quantitate whole-body glucose uptake, glycolysis, glucose storage (total glucose uptake minus glycolysis), and hepatic glucose production. Compared with vehicle-treated rats, 7 days of sustained hyperinsulinemia resulted in a reduction (P0.01) in insulin-mediated glucose uptake, glucose storage, and glycolysis by 39, 62, and 26%, respectively. Hepatic glucose production was normally suppressed after 7 days of hyperinsulinemia. Neither insulin-stimulated glucose uptake nor glucose storage correlated with blood pressure or heart rate. In conclusion, 7 days of euglycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but does not increase blood pressure, catecholamine levels, or sodium retention. This indicates that hyperinsulinemia-induced insulin resistance is not associated with the development of hypertension in rats who do not have a genetic predisposition for hypertension. Because hyperinsulinemia was initiated in normal rats under euglycemic conditions, additional (inherited or acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.

Within the paraventricular nucleus (PVN), there is a balance between the excitatory and inhibitory neurotransmitters that regulate blood pressure; in hypertension, the balance shifts to enhanced excitation. Nitric oxide (NO) is an atypical neurotransmitter that elicits inhibitory effects on cardiovascular function. We hypothesized that reduced PVN NO led to elevations in blood pressure during both the onset and sustained phases of hypertension due to decreased NO synthase (NOS) and increased asymmetrical dimethylarginine (ADMA; an endogenous NOS inhibitor) and symmetric dimethylarginine (SDMA). Elevated blood pressure, in response to PVN bilateral microinjections of a NO inhibitor, nitro-l-arginine methyl ester, was blunted in renal wrapped rats during the onset of hypertension ( day 7) and sustained renal wrap hypertension ( day 28) compared with sham-operated rats. Adenoviruses (Ad) encoding endothelial NOS (eNOS) or LacZ microinjected into the PVN [1 × 109plaque-forming units, bilateral (200 nl/site)] reduced mean arterial pressure compared with control ( Day 7, Ad LacZ wrap: 144 ± 7 mmHg and Ad eNOS wrap: 117 ± 5 mmHg, P ≤ 0.05) throughout the study ( Day 28, Ad LacZ wrap: 123 ± 1 mmHg and Ad eNOS wrap: 108 ± 4 mmHg, P ≤ 0.05). Western blot analyses of PVN NOS revealed significantly lower PVN neuronal NOS during the onset of hypertension but not in sustained hypertension. Reduced SDMA was found in the PVN during the onset of hypertension; however, no change in ADMA was observed. In conclusion, functional indexes of NO activity indicated an overall downregulation of NO in renal wrap hypertension, but the mechanism by which this occurs likely differs throughout the development of hypertension.

Aldosterone has been linked to the deleterious cardiovascular effects of obesity in humans. The association of aldosterone with obesity in rodents is less well defined, particularly in models of diet-induced obesity. We hypothesized that adrenal aldosterone production and aldosterone synthase expression would be increased in rats with obesity-induced hypertension. Male Sprague Dawley rats were fed a high-fat (HF: 36% fat) or control diet from 3 wk of age, and mean arterial pressure (MAP) was measured by telemetry. MAP was increased after 4 wk of HF diet; this was 6 wk before changes in body weight. Mineralocorticoid receptor antagonism did not prevent the HF-induced increase in MAP. After 17 wk on the diets, HF rats had increased body and fat weights (abdominal and epididymal) and were insulin resistant (Homeostasis Model Assessment index: 3.53 ± 0.43 vs. 8.52 ± 1.77; control vs. HF, P < 0.05). Plasma aldosterone levels were increased in the HF rats (64.14 ± 14.96 vs. 206.25 ± 47.55 pg/ml; control vs. HF, P < 0.05). This occurred independently of plasma renin activity (4.8 ± 0.92 vs. 4.73 ± 0.66 ng/ml/h, control vs. HF). The increase in aldosterone was accompanied by a 2-fold increase in adrenal aldosterone synthase mRNA expression and zona glomerulosa hypertrophy. Rats were also studied after 8 wk of HF diet, a time when MAP, but not body weight, was increased. At this time plasma aldosterone was unchanged but plasma renin activity was increased (4.4 ± 0.5 vs. 8.1 ± 1.3 ng/ml/h; control vs. HF, P < 0.05). These studies suggest that rats fed a HF diet from weaning may be a useful model for studying obesity-associated hyperaldosteronism.

Neuroanatomic studies describing forebrain projections to the lateral parabrachial nucleus suggest a central integrative role in cardiovascular regulation. We performed this study to examine the role of this pontine nucleus in the maintenance of one-kidney, figure-8 renal-wrap hypertension. Bilateral ibotenic acid ablation of the lateral parabrachial nucleus was performed 4 weeks after induction of hypertension or sham operation. In hypertensive rats, ablation produced a significant reduction in mean arterial pressure from 160 +/- 4 to 118 +/- 2 mm Hg and a transient but significant increase in heart rate from 381 +/- 5 to 408 +/- 8 beats per minute on the first day after ablation; arterial pressure returned to preablation values by day 5 after ablation. In sham-operated, normotensive animals, arterial pressure was not altered by ablation, and a transient but significant increase in heart rate from 384 +/- 8 to 419 +/- 7 beats per minute was again observed. Before ablation, trimethaphan administration produced a significantly greater drop in arterial pressure in hypertensive (delta-72.8 +/- 4.6 mm Hg) versus normotensive (delta-55.7 +/- 4.1 mm Hg) animals. This effect was eliminated on day 1 after ablation yet returned on day 4 after ablation. In blood samples obtained before ablation and on days 1 and 4 after ablation, circulating plasma catecholamine concentrations in both groups remained unchanged. These observations suggest that, because of possible alternate neural compensatory mechanisms, lateral parabrachial nucleus ablation produces a significant yet transient reversal of renal-wrap hypertension. Thus, the lateral parabrachial nucleus may contribute to the increased sympathetic nervous system function associated with this model.

Women are exposed to estrogen in several forms, such as oral contraceptive pills and hormone replacement therapy. Although estrogen was believed to be cardioprotective, lately, its beneficial effects are being questioned. Recent studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM) may play a role in the development of hypertension. Therefore, we hypothesized that chronic exposure to low levels of estradiol-17β (E2) leads to hypertension in adult-cycling female Sprague Dawley (SD) rats potentially through generation of superoxide in the RVLM. To test this hypothesis, young adult (3 or 4 mo old) female SD rats were either sham-implanted or implanted (subcutaneously) with slow-release E2 pellets (20 ng/day) for 90 days. A group of control and E2-treated animals were fed lab chow or chow containing resveratrol (0.84 g/kg of chow), an antioxidant. Rats were implanted with telemeters to continuously monitor blood pressure (BP) and heart rate (HR). At the end of treatment, the RVLM was isolated for measurements of superoxide. E2 treatment significantly increased mean arterial pressure (mmHg) and HR (beats/min) compared with sham rats (119.6 ± 0.8 vs. 105.1 ± 0.7 mmHg and 371.7 ± 1.5 vs. 354.4 ± 1.3 beats/min, respectively; P < 0.0001). Diastolic and systolic BP were significantly increased in E2-treated rats compared with control animals. Superoxide levels in the RVLM increased significantly in the E2-treated group (0.833 ± 0.11 nmol/min·mg) compared with control (0.532 ± 0.04 nmol/min·mg; P < 0.05). Treatment with resveratrol reversed the E2-induced increases in BP and superoxide levels in the RVLM. In conclusion, these findings support the hypothesis that chronic exposure to low levels of E2 induces hypertension and increases superoxide levels in the RVLM and that this effect can be reversed by resveratrol treatment.

The present study was undertaken to determine the hemodynamic responses associated with stimulation of the hypothalamic paraventricular nucleus (PVN). Male Sprague-Dawley rats (n = 21) were instrumented with guide cannulas directed bilaterally at the PVN, with an electromagnetic flow probe placed on the ascending aorta and with femoral venous and arterial catheters. Bicuculline methiodide (BMI, 2 mM) was infused bilaterally (100 nl/20 min) into the PVN region before and after treatment with the beta 1-adrenergic antagonist, metoprolol bitartrate (2 mg/kg iv) or the alpha 1-adrenergic receptor antagonist, prazosin hydrochloride (2 mg/kg iv). Infusion of BMI into the PVN increased mean arterial pressure by 17 +/- 2 mmHg, and heart rate rose by 91 +/- 8 beats/min. Cardiac index increased 17 +/- 3%, whereas total peripheral resistance index was not altered significantly. After metoprolol treatment, the mean arterial pressure response to BMI was similar to control (16 +/- 2 mmHg), but the tachycardia was reduced significantly (10 +/- 4 beats/min). In addition, the blood flow response was changed qualitatively. Total peripheral resistance increased 13 +/- 3%, whereas the cardiac index response was abolished (1 +/- 2%). After prazosin treatment, BMI administration into the PVN failed to increase arterial pressure (-1 +/- 4 mmHg). Nevertheless, the BMI infusion was associated with significant hemodynamic effects. Total peripheral resistance index decreased (-24 +/- 6%), whereas cardiac index and stroke volume index increased 34 +/- 8 and 17 +/- 5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Venous capacitance plays an important role in cardiovascular homeostasis. The anatomical loci within the central nervous system involved in modulating venous function remain to be elucidated. Stimulation of the hypothalamic paraventricular nucleus is known to increase sympathoadrenal outflow and arterial blood pressure. The present study was undertaken to determine whether electrical stimulation of the paraventricular nucleus can also affect the venous circulation. Mean circulatory filling pressure (MCFP) was used as an index of venous tone. Male Long Evans rats were initially anesthetized with pentobarbital (i.p.; 60 mg/kg) and subsequently maintained with urethane (i.v.; 600 mg/kg). Blood pressure and systemic venous pressure were monitored via catheters in the femoral artery and vein and heart rate eas derived from the pulsatile blood pressure signal. A latex tipped balloon was placed in the right atrium via the right jugular vien. Mean circulatory filling pressure was calculated from the arterial and venous plateau pressures recorded during five second balloon inflations. Arterial pressure, systemic venous pressure, heart rate and mean circulatory filling pressure were monitored before and during unilateral monopolar electrical stimulation (0.5 ms pulses at 50 Hz for a train duration of 10 s with constant current intensities of 100, 150, 200, and 300 μA) of the paraventricular nucleus. Increased graded stimulation of the paraventricular nucleus increased blood pressure by 6 ± 2, 8 ± 1, 13 ± 2 and 26 ± 5 mm Hg while heart rate changed by −22 ± 6, −18 ± 6 and −15 ± 9 bpm and+10 ± 10 bpm, respectively. Moreover, graded increases in MCFP of 0.64 ± 0.09, 1.04 ± 0.21, 1.19 ± 0.11 and 1.50 ± 0.25 mm Hg were observed concurrently. The results demonstrate, for the first time, that in addition to the documented effects on the arterial circulation, stimulation of the paraventricular nucleus induces systemic venoconstriction.

Brain and peripheral renin-angiotensin systems are important in blood pressure maintenance. Circulating ANG II stimulates brain RAS to contribute to the increase mean arterial pressure (MAP). This mechanism has not been fully clarified, so it was hypothesized that reducing angiotensin type 1a (AT1a) receptors (AT1aRs) in the paraventricular nucleus (PVN) would diminish intravenous ANG II-induced increases in MAP. Adenoviruses (Ad) encoding AT1a small hairpin RNA (shRNA) or Ad-LacZ (marker gene) were injected into the PVN [1 × 109 plaque-forming units/ml, bilateral (200 nl/site)] of male Sprague-Dawley rats instrumented with radiotelemetry transmitters for MAP and heart rate measurements and with venous catheters for drug administration. No differences in weight gain or basal MAP were observed. ANG II (30 ng·kg−1·min−1 iv, 15 μl/min for 60 min) was administered 3, 7, 10, and 14 days after PVN Ad injection to increase blood pressure. ANG II-induced elevations in MAP were significantly reduced in PVN Ad-AT1a shRNA rats compared with Ad-LacZ rats (32 ± 6 vs. 8 ± 9 mmHg at 7 days, 35 ± 6 vs. 10 ± 6 mmHg at 10 days, and 32 ± 2 vs. 1 ± 5 mmHg at 14 days; P < 0.05). These observations were confirmed by acute administration of losartan (20 nmol/l, 100 nl/site) in the PVN prior to short-term infusion of ANG II; the ANG II-pressor response was attenuated by 69%. In contrast, PVN Ad-AT1a shRNA treatment did not influence phenylephrine-induced increases in blood pressure (30 μg·kg−1·min−1 iv, 15 μl/min for 30 min). Importantly, PVN Ad-AT1a shRNA did not alter superior mesenteric arterial contractility to ANG II or norepinephrine; ACh-induced arterial relaxation was also unaltered. β-Galactosidase staining revealed PVN Ad transduction, and Western blot analyses revealed significant reductions of PVN AT1 protein. In conclusion, PVN-localized AT1Rs are critical for short-term circulating ANG II-mediated elevations of blood pressure. A sustained suppression of AT1aR expression by single administration of shRNA can interfere with short-term actions of ANG II.

Consumption of a high-fat (HF) diet is a contributing factor for the development of obesity. HF diet per se acts as a stressor, stimulating hypothalamo-pituitary-adrenal (HPA) axis activity resulting in elevated glucocorticoid levels; however, the mechanism behind this activation is unclear. We hypothesized that consumption of an HF diet activates HPA axis by increasing norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, leading to elevation in corticotrophin-releasing hormone (CRH) concentration in the median eminence (ME) resulting in elevated serum corticosterone (CORT).To test this hypothesis, diet-induced obese (DIO) and diet-resistant (DR) rats were exposed to either chow or HF diet for 6 weeks.At the end of 6 weeks, NE in the PVN was measured using HPLC, CRH in the ME, and CORT and leptin levels in the serum were measured using RIA and ELISA, respectively. The gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in NE synthesis, and leptin receptor in brainstem noradrenergic nuclei were also measured.HF diet increased PVN NE in both DIO and DR rats (P0.05). However, this was accompanied by increases in CRH and CORT secretion only in DR animals, but not in DIO rats. Leptin receptor mRNA levels in the brainstem noradrenergic areas were not affected in both DIO and DR rats. However, HF diet increased TH mRNA levels only in DIO rats.Significant differences occur in all the arms of HPA axis function between DIO and DR rats. Further studies are needed to determine whether this could be a causative factor or a consequence to obesity.

This study examines the relation between sympathetic activity and in vivo insulin-mediated glucose metabolism in a rat model of acquired hypertension. Two groups of conscious, unrestrained rats were studied in the postabsorptive state: sham-operated normotensive rats (n = 10) and renal-wrapped hypertensive rats (n = 10). Mean arterial pressure was increased in the hypertensive compared with the normotensive group in the fed (184 +/- 9 versus 144 +/- 6 mm Hg; p less than 0.01) and in the fasting (147 +/- 8 versus 112 +/- 7 mm Hg; p less than 0.01) state. After a 24-hour fast, hepatic glucose production, plasma glucose, insulin, and norepinephrine concentrations were similar in the two groups. Blood pressure did not change in either group during the 3-milliunits/kg.min euglycemic insulin clamp study; however, plasma norepinephrine concentration rose significantly in hypertensive (207 +/- 24 versus 329 +/- 11 pg/ml; p less than 0.05) but not in normotensive rats (229 +/- 23 versus 267 +/- 27 pg/ml; p = NS). During the insulin clamp study, the hepatic glucose production was similar in the hypertensive (3.8 +/- 0.8 mg/kg.min) compared with the normotensive (4.0 +/- 0.3 mg/kg.min) rats. Insulin-mediated glucose uptake was significantly higher in hypertensive than in normotensive rats (33.0 +/- 0.7 versus 25.8 +/- 0.8; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The contribution of the sympathetic nervous system and vasopressin to the maintenance of arterial pressure was investigated in high sodium-fed rats 4 weeks after the induction of one-kidney, figure-8 renal wrap hypertension. Arterial pressure was significantly greater in renal-wrapped rats than in sham-operated animals. The contribution of the sympathetic nervous system was assessed functionally by measuring the arterial pressure response to ganglionic blockade and estimating the apparent rate of release of norepinephrine. The contribution of vasopressin was assessed by administration of the vascular antagonist d(CH2)5Tyr(Me)-AVP. Whole-animal vascular responsiveness and cardiac baroreceptor reflex sensitivity were determined by graded intravenous bolus injections of angiotensin II, vasopressin, and phenylephrine. Hypertensive rats demonstrated an exaggerated reduction in arterial pressure to autonomic blockade before and after blockade of vascular vasopressin receptors. There was a significant 27% increase in the apparent rate of release of norepinephrine into the plasma. Administration of d(CH2)5Tyr(Me)-AVP did not affect arterial pressure when given alone. However, after ganglionic blockade, inhibition of the vasopressin system elicited similar falls in blood pressure in both normotensive and hypertensive rats. Arterial pressure dose-response effects of phenylephrine, angiotensin II, and vasopressin were similar between renal-wrapped and sham-operated animals; however, cardiac baroreceptor reflex sensitivity was suppressed in the hypertensive rats. These studies indicate that the maintenance of arterial pressure in chronic, high sodium renal-wrap hypertension is associated with an augmented sympathetic nervous system function.

The contribution of the paraventricular nucleus region of the hypothalamus (PVN) to the maintenance of one-kidney, figure-8 renal wrap hypertension was determined in this study. Electrolytic ablation of the PVN was performed 4 wk after the production of hypertension or sham operation. Ablation of the PVN region significantly reduced mean arterial pressure (MAP) from 150 +/- 9 to 110 +/- 3 mmHg in the hypertensive rats. In the sham-hypertensive group, the lesion decreased MAP from 118 +/- 2 to 99 +/- 4 mmHg. In both groups of animals MAP from 118 +/- 2 to 99 +/- 4 mmHg. In both groups of animals MAP returned to prelesion values by day 7 postlesion. When ganglionic blockade was performed on day 7 postlesion, the fall in MAP was greater in hypertensive rats (-44 +/- 5 mmHg) than in normotensive rats (-26 +/- 3 mmHg). In a separate group of rats studied 3 days after PVN ablation, ganglionic blockade produced similar decreases in MAP in the wrapped and sham-operated animals. These studies suggest that the PVN contributes to the increased functional sympathetic nervous system associated with one-kidney, figure-8 renal hypertension. Although ablation of the PVN region decreases MAP, neural mechanisms compensate to return MAP to hypertensive levels.

The present study was undertaken to determine whether gamma-aminobutyric acid in the paraventricular nucleus contributes to the regulation of cardiovascular function. Blood pressure and heart rate were recorded and plasma catecholamines were measured in conscious rats receiving microinfusions of either artificial cerebrospinal fluid or a gamma-aminobutyric acid antagonist, bicuculline methiodide, bilaterally into the paraventricular nucleus. Artificial cerebrospinal fluid had no effect on any of the recorded variables. In contrast, infusion of bicuculline into the region of the paraventricular nucleus produced increases in blood pressure (20 +/- 2 mm Hg), heart rate (110 +/- 11 beats/min), and plasma concentrations of norepinephrine (640 +/- 107 pg/ml) and epinephrine (1,266 +/- 267 pg/ml). Pretreatment with a ganglionic blocking agent abolished both the blood pressure (-1 +/- 2 mm Hg) and heart rate (5 +/- 18 beats/min) effects. Bilateral adrenal medullectomy reduced the changes in plasma norepinephrine concentrations (81 +/- 14 pg/ml) significantly and abolished the changes in plasma epinephrine concentrations (5 +/- 4 pg/ml). Conversely, adrenal medullectomy reduced the pressor effects (18 +/- 2 mm Hg) only slightly while the heart rate responses were attenuated (42 +/- 9 beats/min) by approximately 50%. These results suggest that an endogenous gamma-aminobutyric acid system exerts a tonic inhibitory effect on the sympathetic nervous system at the level of the paraventricular nucleus of the hypothalamus.

The objective of this study was to determine if ablation of the lateral parabrachial nucleus (LPBN) would prevent angiotensin II-induced hypertension in rats. Thirteen male Sprague-Dawley rats were studied. Bilateral electrolytic lesions in the LPBN were produced in six rats; the remaining seven rats were subjected to sham lesion surgery only. All rats were instrumented with vascular catheters and housed in metabolism cages. Daily measurements during the 16-day protocol included arterial pressure, heart rate, water intake, urine output, and urinary sodium excretion. Periodically throughout the protocol depressor responses to ganglion blockade and to blockade of V1-type vasopressin receptors also were measured. The protocol was divided into three control-period days, 10 days of continuous (24 hr/day) angiotensin II infusion (10 ng/min i.v.), and three recovery-period days. There were no significant differences between the two groups of rats for any variable during the control period. During angiotensin II infusion, sham-lesion rats exhibited a progressive increase in arterial pressure and the depressor response to ganglion blockade and a decrease in urinary sodium excretion. No other variable was significantly changed. In rats with LPBN lesions, arterial pressure was significantly increased only on days 1 and 3 of angiotensin II infusion. No other variable was affected. It was concluded that ablation of the LPBN in rats prevented sustained hypertension during intravenous infusion of angiotensin II by interfering with neurogenic pressor mechanisms normally activated by the peptide.

The authors discuss the impact of regulatory burden on the research enterprise, with emphasis on animal care and use programs. They identify three sources of regulatory burden: specific requirements in law and regulation, interpretive requirements or "guidance" by regulatory agencies, and self-imposed regulatory burden resulting from institutional interpretations. Attempting to minimize the risks of noncompliance through the overzealous application of "requirements" does not necessarily benefit the animals. Balancing risks associated with animal research and burden in a successful program requires clear and consistent communication among all stakeholders--the institutional leadership, institutional animal care and use committee (IACUC), attending veterinarian and staff, and scientists. An evaluation tool is provided for institutions to assess their approach to required and voluntary activities in their animal care program. Drawing on the knowledge and experience gained in a combined 40 years of serving on, managing, training, and evaluating animal care programs, the authors conclude that institutions must thoughtfully balance their research and compliance needs to successfully maintain their institutional goals. They stress that a culture of compliance based on knowledge of the regulations, dedication to quality animal care, reasoned use of science-based performance standards, and the judicious application of professional judgment is the foundation for facilitation of research in the context of animal welfare and regulatory compliance.

The present studies examine the contribution of the ventrolateral lateral parabrachial nucleus (VLLPBN) to the regulation of plasma arginine vasopressin (PAVP) release in response to either a baroreceptor or osmotic stimulus. These studies were carried out in rats with bilateral electrolytic lesions of the VLLPBN. Baroreceptor-induced stimulation of PAVP was achieved by decreasing blood pressure with combined blockade of the renin-angiotensin system with captopril (3 mg/kg iv) and the sympathetic nervous system with chlorisondamine, (11 mg/kg sc). Osmotic release of vasopressin was elicited by a 2-h intravenous infusion of hypertonic saline, (3.0 meq/ml, 0.01 ml/min). Blood pressure and heart rate were monitored throughout the experiments. Blood samples for determination of PAVP, plasma osmolality (posm), plasma sodium (PNa), and plasma potassium (PK) were taken before (base line) and after treatment in each study. The VLLPBN-lesioned rats secreted significantly more vasopressin in response to hypotension produced by combined renin-angiotensin and sympathetic nervous system blockade than did control rats. There was no significant difference between groups in Posm, PNa, or PK, or cardiovascular changes. In contrast, hypertonic saline infusion did not produce any differential changes between groups.

To investigate the faster rate of renal disease progression in men compared with women, we addressed the following questions in the renal wrap (RW) model of hypertension: 1) Do sex differences exist in RW-induced renal injury, which are independent of sex differences in blood pressure? 2) Do sex differences in nitric oxide (NO) production exist in RW hypertension? Male (M) and female (F) rats underwent sham-operated (M-Sham, n = 7; F-Sham, n = 10) or RW (M-RW, n = 13; F-RW, n = 14) surgery for 9 wk. Markers of renal injury, including the glomerulosclerosis index (F-RW, 0.70 ± 0.1 vs. M-RW, 2.2 ± 0.6; P < 0.05), mean glomerular volume (F-RW, 1.05 ± 0.050 × 106 vs. M-RW, 1.78 ± 0.15 × 106 μm3; P < 0.001), and proteinuria (F-RW, 68.7 ± 15 vs. M-RW, 124 ± 7.7 mg/day; P < 0.001) were greater in RW males compared with RW females. Endothelial NO synthase protein expression was elevated in the renal cortex (3.2-fold) and medulla (2.2-fold) 9 wk after RW in males, whereas no differences were observed in females. Neuronal NO synthase protein expression was unchanged in the renal cortex in males and in both the renal cortex and medulla in females, whereas in the male medulla, neuronal NOS was decreased by 57%. These data suggest the degree of renal injury is greater in male compared with female rats in RW hypertension despite similar degrees of hypertension and renal function and may involve sex differences in renal NO metabolism.

Acute blockade of γ-aminobutyric acid (GABA)-A receptors in the hypothalamic paraventricular nucleus (PVN) increases mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). However, the underlying neural mechanisms have not been fully determined. We tested the hypothesis that responses to GABA-A receptor blockade in the PVN require activation of local ionotropic excitatory amino acid (EAA) receptors. MAP, HR, and renal SNA responses to unilateral PVN microinjection of bicuculline methobromide (BIC, 0.1 nmol) were recorded before and after ipsilateral PVN injection of either vehicle (saline), the nonselective ionotropic EAA receptor antagonist kynurenate (KYN), the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5), or the non-NMDA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium (NBQX). Responses to PVN-injected BIC were unaltered by vehicle injection. In contrast, injection of KYN (7.2 nmol; n=4) nearly abolished ABP and renal SNA responses to BIC ( P P P P

The goal of this study was to determine whether γ-aminobutyric acid (GABA)ergic transmission and GABA binding are altered in chronic renal-wrap hypertension. Three groups of hypertensive and sham-operated rats were prepared for separate protocols. Four weeks later, the animals were prepared with femoral artery catheters for the measurement of mean arterial pressure. In all groups, blood pressure was significantly higher in the renal-wrapped animals. In the first study, bilateral microinjection of the GABA-A antagonist, bicuculline (50 pmol/site), into the paraventricular nucleus of the hypothalamus (PVN) caused a greater increase in arterial pressure (21.9±1.4 versus 16.7±1.8 mm Hg, P P =0.064) in hypertensive rats. [ 3 H]Flunitrazepam was used to measure binding to the GABA-A receptor. Magnocellular neurons and the adjacent medial parvicellular neurons had more intense binding compared with the remainder of the PVN. B max was greater for the higher density binding area; the K d value was less in the high-density region. There were no differences in these parameters between normotensive and hypertensive animals. Competitive reverse transcription–polymerase chain reaction was used to measure the expression of mRNA for the α 1 subunit of the GABA-A receptor. No difference was observed in the mRNA between renal-wrapped and sham-operated rats. In summary, inhibition of GABA-A receptors in the PVN is augmented in the chronic phase of hypertension and is unrelated to a change in the expression of the number or affinity to the receptor. These findings suggest that the greater GABAergic activity is the result of an increase in GABA release in the PVN in chronic renal-wrap hypertension.

Abstract —Female sex hormones protect against the development of Dahl hypertension mediated by increases in dietary sodium. The role of female sex hormones in the reversal of Dahl hypertension mediated by decreases in dietary sodium is unknown. The goal of this study was to identify sex differences in the reversal of Dahl hypertension and the associated changes in water and electrolyte homeostasis. Male (M, n=8), female (F, n=8), and ovariectomized female (OVX, n=9) Dahl salt-sensitive rats were instrumented with an abdominal radiotelemetry device for 24-hour monitoring of blood pressure (BP) and heart rate. Daily measurements of food intake, water intake, and urine output were recorded as diet was changed from a low-sodium diet (0.15% NaCl) to a diet containing 8% NaCl. The diet was then changed back to 0.15% NaCl. The responses to changes in the salt diet were compared with responses observed in rats (M, n=4; F, n=4; OVX, n=4) that were maintained on 0.15% NaCl during the experiment. Sex differences in BP were observed when M, F, and OVX rats were fed 8% NaCl diet for 2 weeks (152±4, 141±3, and 154±5 mm Hg, respectively). BP was significantly greater ( P

1. Females are protected against the development of hypertension. The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho-adrenal nervous system and to determine if these differences support the hypothesis that, in females, the regulation of the sympathetic nervous system (SNS) is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented. 2. The central control of sympatho-adrenal function is different in females and responses vary during the oestral and menstrual cycles. Pathways regulating the SNS appear to be less sensitive to excitatory stimuli and more sensitive to inhibitory stimuli in females compared with males. 3. Gender differences in arterial baroreflex sensitivity suggest that females may have a greater baroreflex sensitivity, such that alterations in blood pressure are more efficiently controlled than in males. Cardiopulmonary reflex inhibition of sympathetic nerve activity is greater in females, possibly resulting in a greater renal excretory function. 4. An attenuated sensitivity to adrenergic nerve stimulation, but not to noradrenaline (NA), suggests that gender differences in noradrenergic neurotransmission may protect females against sympathetic hyperactivity. Gender differences in the regulation of NA release via presynaptic alpha 2-adrenoceptors, the vasoconstrictor response to the cotransmitter neuropeptide Y and the clearance of catecholamines are consistent with this hypothesis. 5. Similarly, attenuated stress-induced increases in plasma catecholamines in women suggest that females are less sensitive and/or less responsive to adrenal medullary activation. This is supported by findings of gender differences in adrenal medullary catecholamine content, release and degradation. 6. We conclude that there is strong evidence that supports the hypothesis that, in females, the regulation of the SNS is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented.