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This document is a special issue of the International Journal of Molecular Sciences titled "Sympathetic Nerves and Cardiovascular Diseases." It explores the role of altered sympathetic nerve activity (SNA) in the pathogenesis of various cardiovascular diseases (CVDs), including hypertension, atherosclerosis, heart failure, peripheral artery disease, diabetic wound healing, and chronic pain-associated CVDs. The special issue includes five review articles and six original research articles that provide insights into the molecular mechanisms and potential therapeutic strategies related to SNA and CVDs. The findings contribute to our understanding of the importance of the sympathetic nervous system in CVD pathogenesis and may lead to the development of new therapies for CVDs. [Extracted from the article]

During underwater submersion, the body responds by conserving O[subscript 2] and prioritizing blood flow to the brain and heart. These physiological adjustments, which involve the nervous, cardiovascular, and respiratory systems, are known as the diving response and provide an ideal example of integrative physiology. The diving reflex can be stimulated in the practical laboratory setting using breath holding and facial immersion in water. Our undergraduate physiology students complete a laboratory class in which they investigate the effects of stimulating the diving reflex on cardiovascular variables, which are recorded and calculated with a Finapres finger cuff. These variables include heart rate, cardiac output, stroke volume, total peripheral resistance, and arterial pressures (mean, diastolic, and systolic). Components of the diving reflex are stimulated by 1) facial immersion in cold water (15°C), 2) breathing with a snorkel in cold water (15°C), 3) facial immersion in warm water (30°C), and 4) breath holding in air. Statistical analysis of the data generated for each of these four maneuvers allows the students to consider the factors that contribute to the diving response, such as the temperature of the water and the location of the sensory receptors that initiate the response. In addition to providing specific details about the equipment, protocols, and learning outcomes, this report describes how we assess this practical exercise and summarizes some common student misunderstandings of the essential physiological concepts underlying the diving response.

Atherosclerosis is characterized by the narrowing of the arterial lumen due to subendothelial lipid accumulation, with hypercholesterolemia being a major risk factor. Despite the recent advances in effective lipid-lowering therapies, atherosclerosis remains the leading cause of mortality globally, highlighting the need for additional therapeutic strategies. Accumulating evidence suggests that the sympathetic nervous system plays an important role in atherosclerosis. In this article, we reviewed the sympathetic innervation in the vasculature, norepinephrine synthesis and metabolism, sympathetic activity measurement, and common signaling pathways of sympathetic activation. The focus of this paper was to review the effectiveness of pharmacological antagonists or agonists of adrenoceptors (α1, α2, β1, β2, and β3) and renal denervation on atherosclerosis. All five types of adrenoceptors are present in arterial blood vessels. α1 blockers inhibit atherosclerosis but increase the risk of heart failure while α2 agonism may protect against atherosclerosis and newer generations of β blockers and β3 agonists are promising therapies against atherosclerosis; however, new randomized controlled trials are warranted to investigate the effectiveness of these therapies in atherosclerosis inhibition and cardiovascular risk reduction in the future. The role of renal denervation in atherosclerosis inhibition in humans is yet to be established. [ABSTRACT FROM AUTHOR]

A solitary functioning kidney (SFK) from birth predisposes to hypertension and kidney dysfunction, and this may be associated with impaired fluid and sodium homeostasis. Brief and early angiotensin-converting enzyme inhibition (ACEi) in a sheep model of SFK delays onset of kidney dysfunction. We hypothesized that modulation of the renin–angiotensin system via brief postnatal ACEi in SFK would reprogram renal sodium and water handling. Here, blood pressure (BP), kidney haemodynamics and kidney excretory function were examined in response to an isotonic saline load (0.13 ml/kg/min, 180 min) at 20 months of age in SFK (fetal unilateral nephrectomy at 100 days gestation; term 150 days), sham and SFK+ACEi sheep (ACEi in SFK 4–8 weeks of age). Basal BP was higher in SFK than sham (∼13 mmHg), and similar between SFK and SFK+ACEi groups. Saline loading caused a small increase in BP (∼3–4 mmHg) the first 2 h in SFK and sham sheep but not SFK+ACEi sheep. Glomerular filtration rate did not change in response to saline loading. Total sodium excretion was similar between groups. Total urine excretion was similar between SFK and sham animals but was ∼40% less in SFK+ACEi animals compared with SFK animals. In conclusion, the present study indicates that water homeostasis in response to a physiological challenge is attenuated at 20 months of age by brief early life ACEi in SFK. Further studies are required to determine if ACEi in early life in children with SFK could compromise fluid homeostasis later in life. [ABSTRACT FROM AUTHOR]

Gut dysfunction has emerged as a contributor to hypertension, the leading risk factor for disease globally, including stroke, heart failure, and kidney disease. This is underpinned by breakdown of the homeostatic relationship connecting intestinal epithelial function, the microbiota and immune responses. Antihypertensive medications have been shown to reverse intestinal dysfunction and gut dysbiosis. However, the mechanisms underlying this restoration of gut structure and function remain largely unknown. In this review, we examine current knowledge supporting a role for impaired intestinal epithelial permeability in hypertension, focusing on electrolyte movement, the renin-angiotensin-aldosterone system, and the restorative effects of orally administered antihypertensive medications and antibiotics. Further work is required to determine if the association between intestinal dysfunction and hypertension is causal. This is a rapidly evolving field, with intestinal dysfunction and dysbiosis representing an area that may be exploited to improve treatment of hypertension and cardiovascular disease. [ABSTRACT FROM AUTHOR]

A child with a congenital solitary functioning kidney (SFK) may develop kidney disease from early in life due to hyperfiltration injury. Previously, we showed in a sheep model of SFK that brief angiotensin-converting enzyme inhibition (ACEi) early in life is reno-protective and increases renal functional reserve (RFR) at 8 months of age. Here we investigated the long-term effects of brief early ACEi in SFK sheep out to 20 months of age. At 100 days gestation (term = 150 days) SFK was induced by fetal unilateral nephrectomy, or sham surgery was performed (controls). SFK lambs received enalapril (SFK+ACEi; 0.5 mg/kg, once daily, orally) or vehicle (SFK) from 4 to 8 weeks of age. At 8, 14 and 20 months of age urinary albumin excretion was measured. At 20 months of age, we examined basal kidney function and RFR via infusion of combined amino acid and dopamine (AA+D). SFK+ACEi resulted in lower albuminuria (~40%) at 8 months, but not at 14 or 20 months of age compared with vehicle-SFK. At 20 months, basal GFR (~13%) was lower in SFK+ACEi compared with SFK, but renal blood flow (RBF), renal vascular resistance (RVR) and filtration fraction were similar to SFK. During AA+D, the increase in GFR was similar in SFK+ACEi and SFK animals, but the increase in RBF was greater (~46%) in SFK+ACEi than SFK animals. Brief ACEi in SFK delayed kidney disease in the short-term but these effects were not sustained long-term. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effect of the sympatholytic drug moxonidine on atherosclerosis. The effects of moxonidine on oxidised low-density lipoprotein (LDL) uptake, inflammatory gene expression and cellular migration were investigated in vitro in cultured vascular smooth muscle cells (VSMCs). The effect of moxonidine on atherosclerosis was measured by examining aortic arch Sudan IV staining and quantifying the intima-to-media ratio of the left common carotid artery in apolipoprotein E-deficient (ApoE−/−) mice infused with angiotensin II. The levels of circulating lipid hydroperoxides in mouse plasma were measured by ferrous oxidation-xylenol orange assay. Moxonidine administration increased oxidised LDL uptake by VSMCs via activation of α2 adrenoceptors. Moxonidine increased the expression of LDL receptors and the lipid efflux transporter ABCG1. Moxonidine inhibited mRNA expression of inflammatory genes and increased VSMC migration. Moxonidine administration to ApoE−/− mice (18 mg/kg/day) decreased atherosclerosis formation in the aortic arch and left common carotid artery, associated with increased plasma lipid hydroperoxide levels. In conclusion, moxonidine inhibited atherosclerosis in ApoE−/− mice, which was accompanied by an increase in oxidised LDL uptake by VSMCs, VSMC migration, ABCG1 expression in VSMCs and lipid hydroperoxide levels in the plasma. [ABSTRACT FROM AUTHOR]

Mesenchymal (human amniotic mesenchymal stem cell [HAMSC]) and epithelial cells (human amnion epithelial cell [HAEC]) derived from human amniotic membranes possess characteristics of pluripotency. However, the pluripotency of HAMSC and HAEC are sustained only for a finite period. This in vitro cell growth can be extended by cell immortalisation. Many well‐defined immortalisation systems have been used for artificially overexpressing genes such as human telomerase reverse transcriptase in HAMSC and HAEC leading to controlled and prolonged cell proliferation. In recent years, much progress has been made in our understanding of the cellular machinery that regulates the cell cycle when immortalised. This review summarises the current understanding of molecular mechanisms that contribute to cell immortalisation, the strategies that have been employed to immortalise amnion‐derived cell types, and their likely applications in regenerative medicine. [ABSTRACT FROM AUTHOR]

A high salt (HS) diet is associated with an increased risk for cardiovascular diseases (CVDs) and fibrosis is a key contributor to the organ dysfunction involved in CVDs. The activation of the renin angiotensin type 2 receptor (AT2R) has been considered as organ protective in many CVDs. However, there are limited AT2R-selective agonists available. Our first reported β-substituted angiotensin III peptide, β-Pro7-AngIII, showed high selectivity for the AT2R. In the current study, we examine the potential anti-fibrotic and anti-inflammatory effects of this novel AT2R-selective peptide on HS-induced organ damage. FVB/N mice fed with a 5% HS diet for 8 weeks developed cardiac and renal fibrosis and inflammation, which were associated with increased TGF-β1 levels in heart, kidney and plasma. Four weeks' treatment (from weeks 5–8) with β-Pro7-AngIII inhibited the HS-induced cardiac and renal fibrosis and inflammation. These protective effects were accompanied by reduced local and systemic TGF-β1 as well as reduced cardiac myofibroblast differentiation. Importantly, the anti-fibrotic and anti-inflammatory effects caused by β-Pro7-AngIII were attenuated by the AT2R antagonist PD123319. These results demonstrate, for the first time, the cardio- and reno-protective roles of the AT2R-selective β-Pro7-AngIII, highlighting it as an important therapeutic that can target the AT2R to treat end-organ damage. [ABSTRACT FROM AUTHOR]

The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the 'first hit' and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 [+ or -] 1, 103 [+ or -] 1, and 102 [+ or -] 2 mmHg). On a high-salt diet, MAP increased 9.1 [+ or -] 1.9 mmHg in HET1K mice (P < 0.05) and 5.4 [+ or -] 0.9 mmHg in HET2K mice (P < 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype. nephron number; congenital nephron deficit; hypertension; unilateral renal agenesis; salt sensitivity doi: 10.1152/aj prenal.00049.2010.

McArdle AM, Roberts CT, Maduwegedera D, Flower RL, Denton KM. Chronic maternal hypertension characterized by renal dysfunction is associated with reduced placental blood flow during late gestation in rabbits. Am J Physiol Regul lntegr Comp Physiol 298: R1043-R1049, 2010. First published January 20, 2010; doi: 10.1152/ajpregu.00202.2009.--Maternal hypertension associated with renal disease is a common pregnancy complication. Previously, we have shown in a rabbit model of mild hypertension that offspring from hypertensive mothers have increased blood pressure as adults, In human pregnancy, hypertension has been associated with decreased utero-placental blood flow. The aim of this study was to determine placental blood flow (PBF) in mild (2-kidney-l-wrapped; 2K-IW) and moderate (2-kidney-2-wrapped; 2K-2W) rabbit models of maternal hypertension. We hypothesized that PBF would be inversely related to the severity of the hypertension. PBF and renal blood flow (RBF) were measured using microspheres on day 28 of a 32-day gestation, in normotensive (sham), 2K-1W, and 2K-2W hypertensive groups. Mean arterial pressure (MAP, ~7 mmHg, P < 0.05) was increased, and RBF (~35%, P < 0.05) was reduced in the 2K-1W and 2K-2W (MAP ~20 mmHg, P < 0.01; RBF ~53%, P < 0.05) groups compared with the sham group. In the 2K-1W group, PBF fell by ~12% (P = 0.08) and fetal-toplacental weight ratio increased by ~12% (P < 0.01) compared with the sham group, reflecting an increase in the functional capacity of the placenta to deliver nutrients to the fetus. In the 2K-2W group, PBF decreased ~51% (P < 0.05) compared with the sham group, without changes in placental efficiency. Thus, in late gestation, placental blood flow was significantly reduced in the moderate hypertension group, without accompanying changes in fetal or placental weight or placental efficiency. In contrast, mild hypertension resulted in an increase in placental efficiency, without significant changes in placental blood flow. These findings suggest that mild and moderate hypertension may alter placental delivery of nutrients via differing mechanisms dependent upon the severity of the hypertension. placental blood flow; rabbit; hypertension; renal blood flow doi: 10.1152/ajpregu.00202.2009.

We examined whether deficits in glomerular capillary surface area associated with a congenital nephron deficit could be corrected by glomerular hypertrophy. Using unbiased stereological techniques, we examined the time course and mode of glomerular hypertrophy in mice lacking one allele for glial cell line-derived neurotrophic factor (GDNF). These GDNF heterozygous (Het) mice are born with ~30% less nephrons than wild-type (WT) littermates. An additional group of GDNF Het mice received the angiotensin type 1 ([AT.sub.1])-receptor antagonist candesartan (Cand; 10 mg x [kg.sup.-1] x [day.sup.-1]) from 5 wk of age to determine the role of [AT.sub.1] receptors in the compensatory hypertrophy. At 10 wk of age, the total volume of renal corpuscles, glomerular capillary surface area, and length of glomerular capillaries in the kidneys of GDNF Het mice were all markedly (~45%) less than that of WT mice (P < 0.001). However, by 30 wk, and persisting at 60 wk of age, GDNF Het and WT mice did not significantly differ in any of these parameters. Furthermore, conscious 24-h mean arterial pressure (MAP) did not differ between GDNF Het and WT mice at any time point. MAP of GDNF Het-Cand mice was 20-30 mmHg less than that of GDNF Het-vehicle mice at all three ages, but Cand treatment did not significantly alter glomerular capillary dimensions. In conclusion, we have demonstrated that the deficit in glomerular capillary surface area associated with a congenital nephron deficit can be corrected for in adulthood by an increase in the total length of glomerular capillaries. This process does not require [AT.sub.1] receptor activation. 24-hour blood pressure; nephron endowment; kidney; glomerular capillary surface area; stereology; glomerular hypertrophy

The risk of developing many adult-onset diseases, including hypertension, type 2 diabetes, and renal disease, is increased in low-birth-weight individuals. A potential underlying mechanism contributing to the onset of these diseases is the formation of a low nephron endowment during development. Evidence from the human, as well as many experimental animal models, has shown a strong association between low birth weight and a reduced nephron endowment. However, other animal models, particularly those in which the mother is exposed to elevated glucocorticoids for a short period, have shown a 20-40% reduction in nephron endowment without discernible changes in the birth weight of offspring. Such findings emphasize that a low birth weight is one, but certainly not the only, predictor of nephron endowment and suggests reduced nephron endowment and risk of developing adult-onset disease, even among normal-birth-weight individuals. Recognition of the dissociation between birth weight and nephron endowment is important for future studies aimed at elucidating the role of a reduced nephron endowment in the developmental programming of adult disease. glucocorticoid exposure; kidney development; hypertension

Keywords: Editorials; hypertension; morbidity; mortality; pregnancy EN Editorials hypertension morbidity mortality pregnancy 302 304 3 01/19/23 20230201 NES 230201 B See related article, pp 291-301 b Hypertensive disorders of pregnancy are a complex spectrum of diseases encompassing gestational hypertension, chronic hypertension, preeclampsia, and superimposed preeclampsia. Known for decades, a common feature of hypertensive pregnancy disorders is aberrant cardiovascular adaptations in response to pregnancy. Pregnant women were recruited into three cohorts: low-risk normotensive pregnancies, high-risk normotensive pregnancies, and gestational hypertension developed in late pregnancy. [Extracted from the article]

The aim of this study was to determine the contribution of neuropeptide Y (NPY) [Y.sub.1] receptors in neurally mediated reductions in renal medullary perfusion. In pentobarbital sodium-anesthetized rabbits, electrical stimulation of the renal nerves (RNS, 0.5-16 Hz) decreased renal perfusion in a frequency-dependent manner. Under control conditions, 4 Hz reduced cortical and medullary perfusion by -85 [+ or -] 3% and -43 [+ or -] 7%, whereas 8 Hz reduced them by -93 [+ or -] 2% and -73 [+ or -] 4%, respectively. After [Y.sub.1] receptor antagonism with BIBO3304TF (0.1 mg/kg plus 0.2 mg*[kg*.sup.-1][h.sup.-1]), RNS reduced perfusion less (by -65 [+ or -] 9% and -12 [+ or -] 8% at 4 Hz). [[alpha].sub.1]-Adrenoceptor antagonism with prazosin (0.2 mg/kg plus 0.2 mg [kg.sup.-1][h.sup.-1]) also inhibited RNS-induced reductions in renal perfusion (-80 [+ or -] 4% and -37 [+ or -] 10% reductions in the cortex and medulla, respectively, at 8 Hz). When given after BIBO3304TF treatment, prazosin inhibited RNS-induced reductions in cortical and medullary perfusion more profoundly (-57 [+ or -] 12% and -25 [+ or -] 9% reductions, respectively, at 8 Hz). [Y.sub.1] receptor- and [[alpha].sub.1]-adrenoceptor-blockade were confirmed by testing vascular responses to renal arterial NPY and phenylephrine boluses. NPY-positive immunolabeling was observed around interlobular arteries, afferent and efferent arterioles, and in the outer medulla. In conclusion, [Y.sub.1] receptors and [[alpha].sub.1]-adrenoceptors contribute to RNS-induced vasoconstriction in the vessels that control both cortical and medullary perfusion. Consistent with this, NPY immunostaining was associated with blood vessels that control perfusion in both regions. There also seems to be an interaction between [Y.sub.1] receptors and [[alpha].sub.1]-adrenoceptor-mediated neurotransmission in the control of renal perfusion. renal medullary blood flow; sympathetic nervous system; BIBO3304TF

Predominant postglomerular vascular resistance response to reflex renal sympathetic nerve activation during ANG II clamp in rabbits. Am J Phvsiol Regul Integr Comp Physiol 287: R780-R786, 2004. First published June 10, 2004; 10.1152/ ajpregu.00202.2004.--We have shown previously that a moderate reflex increase in renal sympathetic nerve activity (RSNA) elevated glomerular capillary pressure, whereas a more severe increase in RSNA decreased glomerular capillary pressure. This suggested that the nerves innervating the glomerular afferent and efferent arterioles could be selectively activated, allowing differential control of glomerular capillary pressure. A caveat to this conclusion was that intrarenal actions of neurally stimulated ANG II might have contributed to the increase in postglomerular resistance. This has now been investigated. Anesthetized rabbits were prepared for renal micropuncture and RSNA recording. One group (ANG II clamp) received an infusion of an angiotensin-converting enzyme inhibitor (enalaprilat, 2 mg/kg bolus plus 2 mg*[kg.sup.-1]*[h.sup.-1]) plus ANG II (~20 ng*[kg.sup.-1]*[min.sup.-1]), the other vehicle. Measurements were made before (room air) and during 14% [O.sub.2]. Renal blood flow decreased less during ANG II clamp compared with vehicle [9 [+ or -] I% vs. 20 [+ or -] 4%, interaction term ([P.sub.GT]) < 0.051, despite a similar increase in RSNA in response to 14% [O.sub.2] in the two groups. Arterial pressure and glomerular filtration rate were unaffected by 14% [O.sub.2] in both groups. Glomerular capillary pressure increased from 33 [+ or -] 1 to 37 [+ or -] 1 mmHg during ANG II clamp and from 33 [+ or -] 2 to 35 [+ or -] 1 mmHg in the vehicle group before and during 14% [O.sub.2], respectively ([P.sub.GT] < 0.05). During ANG II clamp, postglomerular vascular resistance was still increased in response to RSNA during 14% [O.sub.2], demonstrating that the action of the renal nerves on the postglomerular vasculature was independent of the renin-angiotensin system. This further supports our hypothesis that increases in RSNA can selectively control pre- and postglomerular vascular resistance and therefore glomerular ultrafiltration. kidney: renal innervation; glomerular capillary pressure: renal micropuncture: hypoxia