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Recent preclinical studies show renal denervation (RDNx) may be an effective treatment for hypertension; however, the mechanism remains unknown. We have recently reported total RDNx (TRDNx) and afferent-selective RDNx (ARDNx) similarly attenuated the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Whereas TRDNx abolished renal inflammation, ARDNx had a minimal effect despite an identical antihypertensive effect. Although this study established that ARDNx attenuates the development of DOCAsalt hypertension, it is unknown whether this mechanism remains operative once hypertension is established. The current study tested the hypothesis that TRDNx and ARDNx would similarly decrease mean arterial pressure (MAP) in the DOCA-salt hypertensive rat, and only TRDNx would mitigate renal inflammation. After 21 days of DOCA-salt treatment, male Sprague-Dawley rats underwent TRDNx (n = 16), ARDNx (n = 16), or Sham (n = 14) treatment and were monitored for 14 days. Compared with baseline, TRDNx and ARDNx decreased MAP similarly (TRDNx -14 ± 4 and ARDNx -15 ± 6 mmHg). After analysis of diurnal rhythm, rhythm-adjusted mean and amplitude of night/day cycle were also reduced in TRDNx and ARDNx groups compared with Sham. Notably, no change in renal inflammation, injury, or function was detected with either treatment. We conclude from these findings that: 1) RDNx mitigates established DOCA-salt hypertension; 2) the MAP responses to RDNx are primarily mediated by ablation of afferent renal nerves; and 3) renal nerves do not contribute to the maintenance of renal inflammation in DOCAsalt hypertension. [ABSTRACT FROM AUTHOR]

Previous studies suggest restoration of angiogenic balance can lower blood pressure and improve vascular endothelium function in models of preeclampsia. Our laboratory has recently reported exercise training mitigates hypertension in an animal model of preeclampsia, but the mechanisms are unknown. AMP-activated protein kinase (AMPK) is stimulated during exercise and has been shown to increase expression of VEGF. Therefore, the purpose of this study was to determine whether AICAR (5-aminoimidazole-4-carboxamide-3-ribonucleoside),a potent AMPK stimulator, would increase circulating VEGF, improve angiogenic potential, decrease oxidative stress, and abrogate placental ischemia-induced hypertension. In rats, reduced uteroplacental perfusion pressure (RUPP) was induced on day 14 of gestation by introducing silver clips on the inferior abdominal aorta and ovarian arteries. AICAR was administered intraperitoneally (50 mg/kg b.i.d.) days 14-18, and blood pressure and tissues were collected on day 19. RUPP-induced hypertension was ameliorated (P < 0.05) with AICAR versus RUPP. AICAR increased (P < 0.05) plasma VEGF and decreased (P < 0.05) plasma soluble VEGF receptor-1 in the RUPP + AICAR versus RUPP. Antioxidant capacity was restored (P < 0.05) by AICAR in RUPP placenta. Renal and placental catalase activity was decreased (P < 0.05) in RUPP + AICAR versus RUPP. Angiogenic potential was increased (P < 0.05) in RUPP + AICAR versus RUPP. Fetal and placental weights were unaffected by AICAR. Placental AMPK phosphorylation was increased (P < 0.05) in RUPP + AICAR versus normal pregnant and RUPP. These findings suggest AICAR may be useful to mitigate angiogenic imbalance, renal, and placental oxidative stress and increase in blood pressure associated with RUPP hypertension. Furthermore, placental AMPK phosphorylation was observed only in the setting of ischemia. [ABSTRACT FROM AUTHOR]

Increased uterine artery resistance and angiogenic imbalance characterized by increased soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased free vascular endothelial growth factor (VEGF) are often associated with placental insufficiency and preeclampsia but not synonymous with hypertension. We hypothesized chronic reductions in utero-placental perfusion (RUPP) for 5 days (d) during either mid- (d12- d17) or late (d14-d19) gestation would have disparate effects on plasma sFlt-1 and VEGF levels and blood pressure. Five days of chronic RUPP was achieved by placement of silver clips on the abdominal aorta and ovarian arteries on either gestational d12 or d14. Arterial pressure was increased (P > 0.05) in RUPP vs. normal pregnant (NP) in both d17 (10%) and d19 (25%) groups, respectively. Circulating free VEGF was decreased (P > 0.05) and sFlt-1:VEGF ratio increased (P > 0.05) after 5 days of RUPP ending on d19 but not d17 compared with NP controls. Angiogenic imbalance, measured by an endothelial tube formation assay, was present in the d19 RUPP but not the d17 RUPP compared with age-matched NP rats. Five days of RUPP from days 14 to 19 decreased fetal and placental weights 10% (P > 0.01) compared with d19 NP controls. After 5 days of RUPP, from days 12 to 17 of pregnancy, fetal weights were 21% lighter (P > 0.01) compared with d17 NP controls, but placental weight was unchanged. These findings suggest that the timing during which placental insufficiency occurs may play an important role in determining the extent of alterations in angiogenic balance, fetal growth restriction, and the severity of placental ischemia-induced hypertension. [ABSTRACT FROM AUTHOR]

Although exercise during pregnancy is generally recommended and thought to be beneficial to mother and fetus, the nature of the adaptations to exercise during pregnancy and how they may be beneficial remain poorly understood. Recent studies suggest that exercise may stimulate expression of several cytoprotective and pro-angiogenic molecules such as heat shock proteins (HSP) and vascular endothelial growth factors (VEGF). We hypothesized that exercise training during pregnancy improves angiogenic balance, increases HSP expression, and improves endothelial function. Female rats were given access to an exercise wheel for 6 wk before and during pregnancy. On day 19 of pregnancy tissues were collected and snap frozen for later analysis. Western blots were performed in skeletal muscle and placenta. HSP 27 (3.7 ± 0.36 vs. 2.2 ± 0.38; P < 0.05), HSP 60 (2.2 ± 0.73 vs. 0.49 ± 0.08; P < 0.05), and HSP 90 (0.33 ± 0.09 vs. 0.11 ± 0.02; P < 0.05) were increased in the placentas of exercise-trained rats compared with sedentary controls. In addition, exercise training increased (P < 0.05) plasma free VEGF and augmented (P < 0.05) endothelium-dependent vascular relaxation compared with nonexercise control rats. The present data indicates chronic exercise training stimulates HSP expression in the placenta and that regular exercise training increases circulating VEGF in pregnant but not in nonpregnant rats. Although the present findings suggest that exercise before and during pregnancy may promote the expression of molecules that could attenuate placental and vascular dysfunction in complicated pregnancies, further studies are needed to determine the safety and effectiveness of exercise training as a therapeutic modality in pregnancy. [ABSTRACT FROM AUTHOR]

2-Iodylpyridine and four examples of 3-alkoxy-2-iodylpyridines were prepared by oxidation of the respective 2-iodopyridines with 3,3-dimethyldioxirane. Structures of 2-iodylpyridine, 2-iodyl-3-isopropoxypyridine, and 2-iodyl-3-propoxypyridine were established by single-crystal X-ray diffraction analysis. 2-Iodyl-3-propoxypyridine has moderate solubility in organic solvents (e.g., 1.1 mg/mL in acetonitrile) and can be used as a recyclable reagent for oxidation of sulfides and alcohols. The reduced form of this reagent, 2-iodo-3-propoxypyridine, can be effectively separated from the reaction mixture by treatment with diluted sulfuric acid and recovered from the acidic aqueous solution by adding aqueous sodium hydroxide. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases, which is characterized by progressive cyst growth and secondary hypertension. In addition to cystogenesis and renal abnormalities, patients with PKD can develop vascular abnormalities and cardiovascular complications. Progressive cyst growth substantially alters renal structure and culminates into end-stage renal disease. There remains no cure beyond renal transplantation, and treatment options remain largely limited to chronic renal replacement therapy. In addition to end-stage renal disease, patients with PKD also present with hypertension and cardiovascular disease, yet the timing and interactions between the cardiovascular and renal effects of PKD progression are understudied. Here, we review the vascular dysfunction found in clinical and preclinical models of PKD, including the clinical manifestations and relationship to hypertension, stroke, and related cardiovascular diseases. Finally, our discussion also highlights the critical questions and emerging areas in vascular research in PKD. [ABSTRACT FROM AUTHOR]

Here we test the hypothesis that continuous nicotine exposure throughout pre- and postnatal development (developmental nicotine exposure, DNE) alters the cardiovascular structure and function in neonatal and juvenile rats. Echocardiography showed that DNE reduced left ventricular mass, left ventricular outflow tract (LVOT) diameter, and posterior wall thickness, but only in females. Both male and female DNE rats had a lower end-systolic volume, higher ejection fraction, and increased fractional shortening, with unchanged stroke volume and cardiac output. Left ventricular single cardiac myocytes from male and female DNE animals exhibited increased calcium-evoked maximal tension with no effect on EC50. Tail-cuff plethysmography in awake rats showed that DNE males had lower systolic blood pressure and higher heart rate than control males. No significant changes in preload, afterload, or the in vitro renal artery response to vasodilators were observed. The results suggest that DNE enhances myocyte tension-generating capacity, possibly compensating for an unknown developmental insult, which may differ in males and females. Although this adaptation maintains normal resting cardiac function, it may lead to reduced cardiac reserve, increased energy demand, and elevated oxidative stress, potentially compromising both short- and long-term cardiovascular health in developing neonates. NEW & NOTEWORTHY: Developmental nicotine exposure (DNE) induced cardiovascular changes in neonatal/juvenile rats. Relative to controls, females had reduced left ventricular mass and dimensions, while both sexes had increased ejection fraction and fractional shortening. DNE increased calcium-evoked tension in cardiac myocytes, suggesting an adaptive mechanism as resting cardiac output was preserved. Despite normal resting function, these changes may reduce cardiac reserve, potentially compromising long-term cardiovascular health. These novel findings highlight how DNE disrupts cardiovascular development and function. [ABSTRACT FROM AUTHOR]

The authors discuss research on a novel model of hyperglycemia in a chick embryo. They reference the study "Hyperglycemia Slows Embryonic Growth and Suppresses Cell Cycle via Cyclin D1 and p21" by Devon E. Scott-Drechsel and colleagues that was published in the current issue. They conclude that continued refinement of physiological modeling and experimental paradigms will be essential to elucidate the exact mechanisms of hyperglycemia-induced embryopathies.

Renal nerves and their role in physiology and disease have been a topic of increasing interest in the past few decades. Renal inflammation contributes to many cardiorenal disease conditions, including hypertension, chronic kidney disease, and polycystic kidney disease. Much is known about the role of renal sympathetic nerves in physiology – they contribute to the regulation of sodium reabsorption, renin release, and renal vascular resistance. In contrast, far less is known about afferent, or "sensory," renal nerves, which convey signals from the kidney to the brain. While much remains unknown about these nerves in the context of normal physiology, even less is known about their contribution to disease states. Furthermore, it has become apparent that the crosstalk between renal nerves and the immune system may augment or modulate disease. Research from other fields, especially pain research, has provided critical insight into neuroimmune crosstalk. Sympathetic renal nerve activity may increase immune cell recruitment, but far less work has been done investigating the interplay between afferent renal nerves and the immune system. Evidence from other fields suggests that inflammation may augment afferent renal nerve activity. Furthermore, these nerves may exacerbate renal inflammation through the release of afferent-specific neurotransmitters. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) is the most common inheritable cause of kidney failure, and the underlying mechanisms remain incompletely uncovered. Renal nerves contribute to hypertension and chronic kidney disease--frequent complications of PKD. There is limited evidence that renal nerves may contribute to cardiorenal dysfunction in PKD and no investigations of the role of sympathetic versus afferent nerves in PKD. Afferent renal nerve activity (ARNA) is elevated in models of renal disease and fibrosis. However, it remains unknown if this is true in PKD. We tested the hypothesis that ARNA is elevated in a preclinical model of autosomal recessive PKD and that targeted renal nerve ablation would attenuate cystogenesis and cardiorenal dysfunction. We tested this by performing total renal denervation (T-RDNx) or afferent renal denervation (A-RDNx) denervation in 4-wk-old male and female PCK rats and then quantified renal and cardiovascular responses 6 wk following treatment. Cystogenesis was attenuated with A-RDNx and T-RDNx versus sham controls, highlighting a crucial role for renal afferent nerves in cystogenesis. In contrast, blood pressure was improved with T-RDNx but not A-RDNx. Importantly, treatments produced similar results in both males and females. Direct renal afferent nerve recordings revealed that ARNA was twofold greater in PCK rats versus noncystic controls and was directly correlated with cystic severity. To our knowledge, we are the first to demonstrate that PCK rats have greater ARNA than noncystic, age-matched controls. The findings of this study support a novel and crucial role for renal afferent innervation in cystogenesis in the PCK rat. [ABSTRACT FROM AUTHOR]

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem. The International Sympathetic Nervous System Summit was convened to bring together experts in both experimental and clinical medicine to discuss the current evidence base, novel developments in our understanding of neural interplay, procedural aspects, monitoring of technical success, and others. Identification of relevant trends in the field and initiation of tailored and combined experimental and clinical research efforts will help to address remaining questions and provide much-needed evidence to guide clinical use of renal denervation for hypertension treatment and other potential indications. [ABSTRACT FROM AUTHOR]

Lesions of the anteroventral third ventricle (AV3V region) are known to prevent many forms of experimental hypertension, including mineralocorticoid [deoxycorticosterone acetate (DOCA)-salt] hypertension in the rat. However, AV3V lesions include the organum vasculosum of the lamina terminalis (OVLT), portions of the median preoptic nucleus, and efferent fibers from the subfornical organ (SFO), thereby limiting the ability to define the individual contribution of these structures to the prevention of experimental hypertension. Having previously reported that the SFO does not play a significant role in the development of DOCA-salt hypertension, the present study was designed to test the hypothesis that the OVLT is necessary for DOCA-salt hypertension in the rat. In uninephrectomized OVLT-lesioned (OVLTx; n = 6) and shamoperated (n = 4) Sprague-Dawley rats consuming a 0.1% NaCl diet and 0.9% NaCl drinking solution, 24-h mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg sc per rat). No differences in control MAP were observed between groups. The chronic pressor response to DOCA was attenuated in OVLTx rats such that MAP increased to 133 ± 3 mmHg in sham-operated rats by day 21 of DOCA compared with 120 ± 4 mmHg (means ± SE) in OVLTx rats. These results support the hypothesis that the OVLT is an important brain site of action for the pathogenesis of DOCA-salt hypertension in the rat. [ABSTRACT FROM AUTHOR]

Renal denervation (RDNx) is emerging as a promising treatment for cardiovascular disease, yet the underlying mechanisms and contributions of afferent (sensory) and efferent (sympathetic) renal nerves in healthy conditions remains limited. We hypothesize that sympathetic renal nerves contribute to long-term MAP and renal function, whereas afferent renal nerves do not contribute to the maintenance of cardiovascular and renal function. To test this hypothesis, we performed two experiments. In experiment one, we performed total renal denervation (T-RDNx), ablating afferent and sympathetic renal nerves, in normotensive adult SD rats to determine effects on MAP and renal function. Experiment 2 employed a sequential surgical ablation using: (1) afferent targeted renal denervation (A-RDNx), then (2) sympathetic (T-RDNx) denervation to determine the individual contributions to cardiovascular and renal homeostasis. In experiment 1, MAP decreased following T-RDNx and GFR increased. In experiment 2, A-RDNx led to an increase in MAP but did not change renal function. In contrast, T-RDNx decreased MAP and improved renal filtration. Together, these data partially support our hypothesis that renal sympathetic nerves contribute to the chronic regulation of arterial pressure and renal function. Contrary to the hypothesis, A-RDNx produced an increase in MAP without a detected change in renal function. We concluded that renal sympathetic nerves influence MAP and renal function regulation through a well-defined tonic contribution to renal vascular resistance and sodium reabsorption, whereas afferent renal nerves likely contribute to the maintenance of MAP through a tonic sympatho-inhibitory, negative feedback regulation in the normotensive, healthy rat. [ABSTRACT FROM AUTHOR]

R5868 --> 606.3 --> Hypertension (HTN) is a major risk factor for cardiovascular disease, which is a leading cause of morbidity and mortality worldwide. Though the etiology of HTN is multifaceted, one important contributor is aberrant autonomic signaling, both to (sympathetic nerve activity; SNA) and from (afferent renal nerve activity; ARNA) the kidney. ARNA is reportedly elevated in several models of HTN, and ablation of the renal afferent nerves can lower arterial pressure. It remains unknown, however, when this increase occurs in comparison to the cardiovascular and renal function in the hypertensive paradigm. The aim of the study was to determine whether ARNA mirrors the increase in arterial pressure and decline in kidney function in a preclinical model of salt‐sensitive HTN. We hypothesized that increased ARNA would increase in parallel to arterial pressure (AP) and the decline in renal function in the DOCA‐salt rat model. To test the hypothesis, 20 adult male Sprague Dawley rats (275‐325 g) underwent a unilateral nephrectomy followed by two‐weeks for recovery. Next, deoxycorticosterone acetate (DOCA; 100mg, s.c.) was implanted, and henceforth animals were maintained on 0.9% saline drinking water ad libitum. Cardiovascular and renal measurements were collected weekly. Mean systolic blood pressure (SBP) were measured weekly by tail‐cuff, and renal function was estimated weekly by serum creatinine (Cr). Animals were randomly assigned to undergo multiunit ARNA recording on protocol day (D) 0, D7, D14, or D21. ARNA recordings were performed under urethane anesthesia (1500mg/kg, IP) as previously described. ARNA was isolated by sectioning the proximal end of the nerve bundle, and recorded for 10 minutes following preparation. Activity was rectified and integrated over 50ms and normalized to maximal ARNA achieved by intrapelvic 50µM capsaicin. Data were analyzed by one‐way repeated‐measures ANOVA with Bonferroni post‐hoc test (α=0.05). Data presented as mean±SEM. ARNA (presented as %ARNAmax) is increased (p<0.05) at D21 and D14 vs. baseline, but no detectable changes were observed at D7. Mean SBP progressively increased at D7, D14, and D21 vs. all prior weeks. Serum creatinine increased (p<.05) at D14 and D21 vs. baseline, indicating a time‐dependent decline in kidney function. Necropsy data demonstrate kidney weight was increased (p<.05) only on D21 compared to baseline, and no differences were detected at D7 and D14 vs. D0. In contrast, heart weights were greater (p<.05) on D14 and D21 vs. baseline. Collectively, these data partially support our hypothesis that ARNA increases in parallel with increasing AP in the DOCA‐salt model; however, AP appears to increased independent of detectable changes in both ARNA and renal dysfunction. Interestingly, renal dysfunction and ARNA were detected at similar times (D14), potentially highlighting to a closer physiological relationship between ARNA and renal function. The onset of HTN prior to changes in ARNA and renal dysfunction delineate these variables from the early stages of this HTN model; however, we can not rule on the contributions of ARNA and renal dysfunction as the model progresses. Further studies on the timing of ARNA activators such as renal inflammation or fibrosis are underway to further elucidate the connection of renal function decline and ARNA. [ABSTRACT FROM AUTHOR]

R5527 --> 565.1 --> Polycystic kidney disease (PKD) is the most common genetic cause of kidney failure, though the mechanisms underlying cyst formation and disease progression remain unclear. Innervation of the kidney contributes to the pathology of other cardiorenal dysfunction, including hypertension and chronic kidney disease ‐ frequent complications of PKD. In previous studies, we demonstrated renal denervation (RDNX), either total or afferent‐targeted (sensory) nerve ablation, reduced cystogenesis in a rat model of autosomal recessive PKD, thus highlighting a role for renal afferent nerves in PKD renal cystogenesis. To further elucidate this novel relationship, we aimed to quantify the renal afferent nerve activity (ARNA) in the adult PCK rat compared to non‐cystic controls. We hypothesized that ARNA would be elevated in the PCK rat compared to controls, and ARNA would directly correlate with renal cystic severity. To address our hypothesis, we conducted direct afferent renal nerve recordings in 10‐week‐old PCK (n=15; 11M/4F) and age‐matched Sprague‐Dawley controls (SD; n=14; 6M/8F). Multiunit nerve recording was performed under isoflurane anesthesia by isolating and placing a renal nerve bundle on an iridium bipolar electrode, which was then encased in silicone. The nerve bundle was severed proximal to the electrode to isolate afferent renal nerve activity (ARNA). Following a 10‐minute stabilization period, resting ARNA was recorded for 10 minutes. To permit comparison between animals, resting ARNA was normalized to a maximal stimulus, achieved by renal pelvic perfusion of 50 µM capsaicin. Finally, electrical noise was isolated by sectioning the distal end of the nerve bundle. Recordings were rectified and integrated over 50 ms. ARNA was expressed as a percentage of maximal ARNA. Following nerve recording, kidneys were collected, formalin fixed, and embedded in paraffin for histologic analysis of renal cystic index (CI). Kidneys were stained with Masson's Trichrome and analyzed using ImageJ, and CI was quantified by normalizing cystic area to the total kidney area. Data presented as mean ±SEM. Resting ARNA was higher in PCK (22.7±4.2%) rats compared to non‐cystic SD controls (7.4±1.3%; Figure 1). Overall, PCK rats had an average CI of 8.7±0.7%. No sex differences in ARNA between male and female PCK rats were detected; however, CI was higher in male PCK rats (9.5±2.3%) compared to female PCK (6.3±1.9%). Further analysis of ARNA versus cystic index revealed a direct correlation between ARNA and renal cystic severity (F=5.9; R=0.61; p<0.05; Figure 2). These findings support our hypothesis that ARNA is elevated in the PCK rat. Importantly, ARNA is directly correlated with cystic progression in this model. To our knowledge, this study is the first to directly measure ARNA in this model of ARPKD, as well as to compare ARNA to cyst severity. These findings, combined with our previous studies, lead us to conclude that increased ARNA may directly contribute to the progression of PKD in this model. Presently, these data are limited to single endpoint observations. We are currently conducting additional studies to further dissect the temporal relationship between ARNA and renal cyst development. Our future studies will investigate the stimuli amplifying ARNA in a continued effort to parse the role of this novel neural‐renal axis in the pathogenesis of PKD. [ABSTRACT FROM AUTHOR]