Response Of Vascular Smooth Muscle Research Articles

Impairment of Coronary Arteriolar Endothelium-Dependent Dilation after Multi-Walled Carbon Nanotube Inhalation: A Time-Course Study

Engineered nanomaterials have been developed for widespread applications due to many highly unique and desirable characteristics. The purpose of this study was to assess pulmonary inflammation and subepicardial arteriolar reactivity in response to multi-walled carbon nanotube (MWCNT) inhalation and evaluate the time course of vascular alterations. Rats were exposed to MWCNT aerosols producing pulmonary deposition. Pulmonary inflammation via bronchoalveolar lavage and MWCNT translocation from the lungs to systemic organs was evident 24 h post-inhalation. Coronary arterioles were evaluated 24–168 h post-exposure to determine microvascular response to changes in transmural pressure, endothelium-dependent and -independent reactivity. Myogenic responsiveness, vascular smooth muscle reactivity to nitric oxide, and α-adrenergic responses all remained intact. However, a severe impact on endothelium-dependent dilation was observed within 24 h after MWCNT inhalation, a condition which improved, but did not fully return to control after 168 h. In conclusion, results indicate that MWCNT inhalation not only leads to pulmonary inflammation and cytotoxicity at low lung burdens, but also a low level of particle translocation to systemic organs. MWCNT inhalation also leads to impairments of endothelium-dependent dilation in the coronary microcirculation within 24 h, a condition which does not fully dissipate within 168 h. The innovations within the field of nanotechnology, while exciting and novel, can only reach their full potential if toxicity is first properly assessed.

Hypertension in Children and Adolescents: Epidemiology and Pathogenesis

High blood pressure is one among the leading contributors to burden of disease globally. Approximately 54 % of stroke and 47 % of ischemic heart disease events worldwide were attributable to high blood pressure in the year 2001. There is deficiency of data on the long-term outcome of hypertension in children. In spite of this, there is sufficient evidence to suspect that the health risks of hypertension in pediatric patients are substantial. Hypertension in childhood is known to result in hypertension in young adulthood. The epidemiology of hypertension in children is well represented from various studies conducted across continents. Factors like methodological issues in measurement, socio demographic differences, adiposity levels and ethnicity appear to influence the distribution of blood pressure as well as prevalence of hypertension in children. The etio-pathogenesis of essential (primary) hypertension is multi-factorial in origin. Obesity, insulin resistance, activation of sympathetic nervous system, alterations in sodium homeostasis, renin-angiotensin system changes, changes in vascular smooth muscle structure and reactivity, high serum uric acid levels, genetic factors and fetal programming have been reported to contribute to this disorder. The causes of secondary hypertension vary with age. Renal disorders and coarctation of the aorta are the most common causes of hypertension in children up to age 6 y. In older children, renal parenchymal disease remains the most frequent cause of increased blood pressure. Other causes of hypertension in children are relatively rare and include systemic arteritis and certain tumours, endocrine dysfunction, and neurologic disorders.

Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity

Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18-79 years; body mass index (BMI), 16.4-42.2 kg/m(2)], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI and percent body fat (percent BF via dual-energy X-ray absorptiometry)], and indexes of abdominal adiposity [waist circumference (WC) and waist-to-hip ratio (WHR)]. In a subgroup (n = 74), we also measured total abdominal fat (TAF), abdominal visceral fat (AVF), and subcutaneous fat (ASF) using computed tomography. Based on multiple linear regression, NID was negatively related to BMI [part correlation coefficient (r(part)) = -0.19, P = 0.004] and abdominal adiposity (WC, r(part) = -0.22; WHR, r(part) = -0.19; TAF, r(part) = -0.36; AVF, r(part) = -0.36; and ASF, r(part) = -0.30; all P ≤ 0.009) independent of sex, but only tended to be related to total percent BF (r(part) = -0.12, P = 0.07). In a subgroup of subjects with the highest compared with the lowest amount of AVF, NID was 35% lower (P = 0.003). Accounting for systolic blood pressure, HDL cholesterol, glucose, insulin resistance, adiponectin, and brachial artery diameter reduced or abolished some of the relations between NID and adiposity. In conclusion, NID is or tends to be negatively associated with measures of total adiposity (BMI and percent BF, respectively) but is consistently and more strongly negatively associated with abdominal adiposity. Adiposity may influence NID in part via other cardiovascular risk factors.

Effects of phosphate on vascular function under normal conditions and influence of the uraemic state

Increased serum phosphorus levels are associated with cardiovascular disease in patients with chronic kidney disease (CKD) and in the general population. High phosphate levels may play a direct role in vascular dysfunction. We investigated here the effects of phosphate loading and of the phosphate binder sevelamer-HCl on vascular function. CKD and non-CKD C57/BL6 mice were used to study the effects of CKD, phosphate, and sevelamer-HCl on vascular function and structure. In vitro, phosphate exhibited a direct vasoconstrictor effect on aortic rings. This effect was smaller in vessels from CKD than non-CKD mice and it was abolished by reactive oxygen species inhibitor dimethylthiourea. A high-phosphate diet (1.3%) increased phenylephrine-induced contraction and lowered acetylcholine-induced relaxation of aortic rings ex vivo, both in non-CKD and CKD mice. It also induced endothelial cell detachment. Sevelamer-HCl exposure in vitro normalized the endothelial dysfunction induced by 3.0 mM phosphate and restored endothelial integrity. Sevelamer-HCl treatment of CKD mice under normal diet (0.65% phosphate) improved the endothelial dysfunction, aortic systolic expansion rate, and pulse wave velocity, and it reduced the endothelial expression of adhesion molecules. Changes in extracellular phosphorus concentrations may directly modulate vascular function and thereby modulate the vascular smooth muscle response to physiological or pathological stimuli in normal and CKD mice. Whether serum phosphorus lowering and/or dietary phosphate restriction can improve arterial function in humans remains to be established.

Design, synthesis and vasodilative activity of tanshinone IIA derivatives

A new series of tanshinone IIA (DIIA) derivatives were synthesized through the reaction of brominated tanshinone IIA (1-Br DIIA) and aromatic acids in the presence of K2CO3. Twenty compounds were synthesized, and all of them were novel. Vasodilative activities for synthesized compounds were valuated in vitro on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats. The results showed that most compounds exhibited a concentration-dependent inhibition on the contractile response of norepinephrine. Four prepared compounds, 4, 5, 8 and 13 revealed relatively remarkable vasodilative activity.

Direct G protein signalling mediates components of the vascular smooth muscle response to insulin‐like growth factor

Like many organs, the vasculature possesses an intrinsic repair ability that is critical for homeostasis. This ability is intimately linked to smooth muscle cells (SMCs) through their unique phenotypic plasticity, which allows them to proliferate and migrate in response to specific stimuli. However, phenotypic modulation is also the major underlying phenomenon behind pathogenic vascular disease and post‐surgery repairPhysiological control of the SMC response involves the presence of circulating factors, such as Insulin‐like Growth Factor‐ 1 (IGF‐1). IGF‐1 acts via its receptor, a member of the tyrosine kinase receptor family, but it may also require a G protein. Thus, the objective of this study was to investigate the structural aspects of IGR‐1R coupling to a G protein in SMCs, as well as the contribution of this pathway to the cellular response.In primary SMCs, the IGF‐1R was found to interact with both Gαi and Gβ subunits and in the case of Gαi, this was a direct interaction. We found that IGF‐1‐induced activation of ERK1/2 was prevented with a Gβγ inhibitor, which also inhibited cell proliferation in response to IGF‐1. Specific cell‐penetrating Gαi inhibitor peptides were synthesized and these enabled identification of several unique downstream targets.These findings support the conclusion that the responses of vascular SMCs to IGF‐1 are elicited at least in part through interaction with a G protein.Source of research support: Canadian Institutes for Health Research

Reduced Vascular Smooth Muscle (VSM) Sensitivity to Contraction in ex vivo Hemorrhaged Rabbit Epigastric Artery (EA)

Compensation to hemorrhage includes vasoconstrictor‐induced VSM contraction. Severe hemorrhage can lead to reduced VSM reactivity to vasoconstrictors and decompensation. Vasoconstrictors not only cause VSM contraction, but also can activate a cellular negative feedback mechanism that causes prolonged VSM desensitization, termed VSM memory. To explore the hypothesis that VSM memory plays a role in decompensation, we studied EA reactivity ex vivo 45 min after severe hemorrhage. Compared to control rabbit EA removed before hemorrhage, EA after hemorrhage displayed depressed contractions to phenylephrine (PE) and histamine (HA). These data suggest that VSM memory participates in vascular decompensation during hemorrhagic shock. We more fully characterized VSM memory in rabbit and mouse arteries in vitro. Strong receptor stimulation (10–30 μM PE) for 30 min followed by PE washout to cause complete relaxation reduced the ability of G protein‐coupled receptor (GPCR) agonists (PE, HA, U‐46619 and vasopressin) and a non‐GPCR agonist (KCl) to subsequently contract renal, femoral, epigastric and mesenteric arteries for at least 1 hr after PE washout. These data indicate that high catecholamine concentrations can induce a generalized VSM desensitization in rabbit and mouse arteries (VSM memory) that may be responsible, in part, for vascular decompensation during hemorrhage. Funding: R01HL061320

Calcium blockers inhibit cyclosporine A-induced hyperreactivity of vascular smooth muscle cells

Cyclosporine belongs to the group of the most commonly used immunosuppressants. Hypertension occurs in approximately 30% of patients treated with this drug. However, the pathogenesis of this occurrence has not been explained to date. The purpose of our study was to clarify the mechanisms leading to the evolution of hypertension induced by cyclosporine A (CsA). We examined the changes in transmission within receptors and around the receptors. We also aimed to elucidate the mechanisms responsible for averting arterial hyperresponsiveness induced by the drug. Experiments were performed on isolated and perfused tail arteries of Wistar rats. Tissues surrounding the artery were removed and the proximal segment (length of 2-3 cm) was used for cannulation. Cannulated arteries were placed in a 20-ml glass chamber (vertical position). The contraction force in our model was measured by an increased degree of perfusion pressure with a constant flow rate (approximately 1 ml/min). The results showed that in the presence of CsA, the concentration-response curves/phenylephrine (PHE) curve shifted to the left. Cyclosporine increased the reactivity of the arteries to PHE. This effect was directly linked to the increase in the receptor reserve. The analysis of the reactivity of vascular smooth muscle showed that CsA increased the influx of calcium ions from the extracellular to the intracellular area. No difference was found between the contraction triggered by Bay-K8644 in the presence of CsA and the control probe. The increase in perfusion pressure induced by CsA was blocked by L-type calcium channel blockers (nifidipine and diltiazem). The results from our experiments show that CsA increases the reactivity of vessels to the effect of catecholamines. CsA also enhances signal transmission between G-protein coupled receptors (GPCRs) and calcium channels. The activation of protein kinase C also plays a significant role in this process. Our results suggest that the best choice for the pharmacotherapy of hypertension induced by CsA would be calcium channel antagonists.

Abstract 17226: Vascular Smooth Muscle Responsiveness to a Nitric Oxide Donor is Impaired in Healthy Adults with Increased Adiposity

Background- Vascular smooth muscle responsiveness to an exogenous nitric oxide donor (i.e., nitroglycerin-induced dilation; NID) is impaired in cardiovascular disease and in adults at risk for atherosclerosis. Although adiposity is associated with increased risk of atherosclerosis, its relation to NID is poorly defined. We sought to examine the relation of NID to total and abdominal adiposity in a healthy group of men and women varying widely in adiposity levels and age. Methods and Results- In 224 carefully screened adults (age:18-79 yrs, body mass index (BMI): 16.4-42.2 kg/m 2 ), we measured NID, total body adiposity (BMI and % body fat (%BF); dual-energy x-ray absorptiometry) and indices of abdominal adiposity (waist circumference (WC) and waist to hip ratio (WHR)). In a subgroup of 74 subjects, we also measured total abdominal (TAF), abdominal visceral (AVF) and subcutaneous fat (ASF) using CT scans. NID was determined as the vasodilator response (brachial ultrasonography) to 0.4 mg sublingual nitroglycerin. Based on multiple linear regression analyses, NID was negatively related to BMI (part correlation coefficient (r part )=-0.19, P=0.004) and not related with total %BF (r part =-0.12, P=0.07), whereas it was consistently negatively related with abdominal adiposity (WC, r part =-0.22; WHR, r part =-0.19; TAF, r part =-0.36; AVF, r part =-0.36; and ASF, r part =-0.30, all P≤0.009), independent of sex. Accounting for systolic blood pressure, high density lipoprotein (HDL) cholesterol and fasting blood glucose reduced all of the sex-independent relations between NID and adiposity by 3 to 42%, but overall the relations remained significant (P≤0.05). NID was 35% lower in a subgroup of subjects with the highest compared to the lowest quintile of abdominal visceral fat (P=0.003). This difference in NID was abolished after accounting for systolic blood pressure (P=0.2) and HDL cholesterol (P=0.1) but was not changed after accounting for fasting glucose (P=0.002). Conclusions- Total adiposity is modestly (BMI) or not related (% body fat) with NID, whereas abdominal adiposity is more consistently and strongly related with NID. Adiposity may influence NID in part via modulation of blood pressure, HDL cholesterol and/or fasting glucose.

Механізми впливу сірководню на скоротливу активність гладеньких м’язів судин щурів

The effect of endogenous and exogenous hydrogen sulfide (H2S) on contractile activity of vascular smooth muscle (VSM) was studied. The introduction of substrate synthesis H2S L-cysteine and its donor NaHS in vitro caused concentration-dependent relaxation of VSM of aorta and portal vein. Low concentrations of hydrogen sulfide donor (10(-5) mol/L) caused vasoconstriction of both types of the vessels. It was shown that the reaction of relaxation of VSM in response to NaHS is independent from endothelium. It was revealed that VSM of portal vein are more sensitive to the effects of H2S than VSM of aorta. Removing of aorta periadventitial adipose tissue showed no relaxation reply to the hydrogen sulfide donor NaHS in 70% of experiments. Some of the cellular mechanisms of hydrogen sulfide action were established, namely relaxation of aorta is depended on K(ATP) channel activation. This is manifested by a lack of relaxation of the aortic VSM due to K(ATP) channel inhibitor glibenclamide.

Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle.

Vascular smooth muscle tone is controlled by a balance between the cellular signaling pathways that mediate the generation of force (vasoconstriction) and release of force (vasodilation). The initiation of force is associated with increases in intracellular calcium concentrations, activation of myosin light-chain kinase, increases in the phosphorylation of the regulatory myosin light chains, and actin-myosin crossbridge cycling. There are, however, several signaling pathways modulating Ca(2+) mobilization and Ca(2+) sensitivity of the contractile machinery that secondarily regulate the contractile response of vascular smooth muscle to receptor agonists. Among these regulatory mechanisms involved in the physiological regulation of vascular tone are the cyclic nucleotides (cAMP and cGMP), which are considered the main messengers that mediate vasodilation under physiological conditions. At least four distinct mechanisms are currently thought to be involved in the vasodilator effect of cyclic nucleotides and their dependent protein kinases: (1) the decrease in cytosolic calcium concentration ([Ca(2+)]c), (2) the hyperpolarization of the smooth muscle cell membrane potential, (3) the reduction in the sensitivity of the contractile machinery by decreasing the [Ca(2+)]c sensitivity of myosin light-chain phosphorylation, and (4) the reduction in the sensitivity of the contractile machinery by uncoupling contraction from myosin light-chain phosphorylation. This review focuses on each of these mechanisms involved in cyclic nucleotide-dependent relaxation of vascular smooth muscle under physiological conditions.

Relationship of visit-to-visit and ambulatory blood pressure variability to vascular function in African Americans

Visit-to-visit clinic blood pressure variability (BPV) and 24-h BPV have both been identified as independent risk factors for cardiovascular (CV) morbidity and mortality; however, the mechanisms contributing to the increased CV risk as yet are unclear. The purpose of this study was to assess the relationship between BPV and endothelial function in a cohort of putatively healthy African Americans. A total of 36 African Americans who were sedentary, non-diabetic, non-smoking, free of CV and renal disease and not on antihypertensive medication followed an American Heart Association low fat, low salt diet for 6 weeks. Upon completion of the 6-week dietary stabilization period, participants underwent 24-h ambulatory BP monitoring and had their office blood pressure (BP) measured on 3 separate days. Right brachial artery diameter was assessed at rest, during reactive hyperemia (flow-mediated vasodilation: FMD), and after nitroglycerin administration (nitroglycerin-mediated vasodilation: NMD). Participants classified as having decreased endothelial function according to either %FMD or the FMD/NMD ratio had significantly higher 24-h BPV and a trend for higher visit-to-visit BPV when compared with participants with normal endothelial function. Continuous variable analyses revealed a significant positive association between NMD and 24-h diastolic BPV (DBPV). Visit-to-visit systolic BPV (SBPV), 24-h SBPV and 24-h DBPV were all negatively associated with the FMD/NMD ratio. All relationships remained significant after adjustment for age, body mass index and mean BP levels. These results may suggest that BPV is increased in African Americans with decreased endothelial function and is associated with the vascular smooth muscle response to nitric oxide.

Intermittent hypoxia augments pulmonary vascular smooth muscle reactivity to NO: regulation by reactive oxygen species

Intermittent hypoxia (IH) resulting from sleep apnea can lead to pulmonary hypertension. IH causes oxidative stress that may limit bioavailability of the endothelium-derived vasodilator nitric oxide (NO) and thus contribute to this hypertensive response. We therefore hypothesized that increased vascular superoxide anion (O(2)(-)) generation reduces NO-dependent pulmonary vasodilation following IH. To test this hypothesis, we examined effects of the O(2)(-) scavenger tiron on vasodilatory responses to the endothelium-dependent vasodilator ionomycin and the NO donor S-nitroso-N-acetylpenicillamine in isolated lungs from hypocapnic-IH (H-IH; 3 min cycles of 5% O(2)/air flush, 7 h/day, 4 wk), eucapnic-IH (E-IH; cycles of 5% O(2), 5% CO(2)/air flush), and sham-treated (air/air cycled) rats. Next, we assessed effects of endogenous O(2)(-) on NO- and cGMP-dependent vasoreactivity and measured O(2)(-) levels using the fluorescent indicator dihydroethidium (DHE) in isolated, endothelium-disrupted small pulmonary arteries from each group. Both E-IH and H-IH augmented NO-dependent vasodilation; however, enhanced vascular smooth muscle (VSM) reactivity to NO following H-IH was masked by an effect of endogenous O(2)(-). Furthermore, H-IH and E-IH similarly increased VSM sensitivity to cGMP, but this response was independent of either O(2)(-) generation or altered arterial protein kinase G expression. Finally, both H-IH and E-IH increased arterial O(2)(-) levels, although this response was more pronounced following H-IH, and H-IH exposure resulted in greater protein tyrosine nitration indicative of increased NO scavenging by O(2)(-). We conclude that IH increases pulmonary VSM sensitivity to NO and cGMP. Furthermore, endogenous O(2)(-) limits NO-dependent vasodilation following H-IH through an apparent reduction in bioavailable NO.

Pharmacological properties of isoidide dinitrate.

Abstract Isoidide dinitrate is a more active vasodepressor agent in anaesthetised animals than either of its geometric isomers, isosorbide dinitrate and isomannide dinitrate. Isoidide dinitrate also has the greatest vasodilator action of the three isomers on the vascular system of the dog hind leg and is a more potent hypotensive agent than isosorbide dinitrate in hypertensive rats. The greater activity of isoidide dinitrate may be attributable to its higher oil: water partition coefficient or enhanced drug-receptor interaction resulting from the spatial positions of the nitrate groups or both factors. No evidence was found for involvement of adrenergic receptors in responses of vascular or intestinal smooth muscle to isoidide dinitrate.

Parsing Aortic Aneurysms

See related article, pages 574–581 Aortic aneurysms are progressive enlargements of the aorta that can lead to life-threatening degenerative changes in the structure of the artery wall including medial dissections and wall rupture. The abdominal aorta is the most common site of aneurysm formation, yet the ascending thoracic aorta can also exhibit aneurysmal expansion with potentially dire outcomes. Ascending aortic aneurysms are frequently associated with connective tissue diseases such as Marfan's syndrome, a disorder of the extracellular matrix protein fibrillin-1.1 Mouse models carrying hypomorphic mutations in fibrillin-1 also develop aortic dilations associated with macrophage infiltration, elastin fragmentation, and enhanced transforming growth factor (TGF)β signaling in the artery wall.2 Aortic aneurysms in fibrillin-1 hypomorphic mice can be prevented by treatment with either anti-TGFβ neutralizing antibodies or with the angiotensin II (Ang II) type 1 (AT1) receptor antagonist losartan.3 Indeed, chronic infusion of Ang II into apoE −/− mice is an effective experimental model to induce aortic aneurysm formation and to study the molecular pathways underlying its pathogenesis.4 Ang II signals through 2 types of angiotensin receptors, AT1 and AT2.5 AT2 receptors have been shown to elicit antiproliferative responses in vascular smooth muscle cells (SMCs), possibly by antagonism of signaling through AT1 receptors.5 In mice, the AT1 receptor exists as 2 subtypes, AT1a and AT1b, and both receptor subtypes are expressed in the artery wall. The receptor that mediates angiotensin-induced contractile responses in vascular smooth muscle is predominantly the AT1b subtype.6 The AT1 receptor subtype that mediates aortic aneurysm formation has been unknown. In a study that appears in this issue of Circulation Research , Rateri et al used a series of mouse models to genetically dissect the process of Ang II–induced aneurysm …

Anti-Inflammatory Drugs in the Treatment of Meconium Aspiration Syndrome

Anti-Inflammatory Drugs in the Treatment of Meconium Aspiration Syndrome Meconium aspiration syndrome (MAS) is a major cause of respiratory distress in both the term and post-term neonates. Obstruction of the airways, dysfunction of pulmonary surfactant, inflammation, lung edema, pulmonary vasoconstriction and bronchoconstriction participate in the pathogenesis of this disorder. Since the inflammatory changes associated with meconium aspiration cause a severe impairment of the lung parenchyma including surfactant and influence the reactivity of both vascular and airway smooth muscle, administration of anti-inflammatory drugs may be of benefit also in the management of MAS. This article reviews effects of various anti-inflammatory drugs used in experimental models of MAS as well as in the treatment of newborns with meconium aspiration.

Role of Nitric Oxide in the Development of Vascular Contractile Dysfunction in Circulatory Shock

Various forms of circulatory shock (including septic shock) lead to an impairment o r vascular function, which importantly contributes to the development of multiple organ failure and mortality. The dysfunction of the blood vessels in shock consists or two principal components: vascular smooth muscle dysfunction, and endothelial dysfunction. The vascular smooth muscle dysfunction (a progressive, therapy-resistant loss or responsiveness of the vascular smooth muscle to vasoconstrictor catecholamines, such as noradrenaline) leads to a progressive deterioration of blood pressure in patients with circulatory shock. The endothelial dysfunction (loss of the ability of the vascular endothelium to produce nitric oxide and other local endothelium-derived factors) contributes to the impairment of microvascular blood flow, to the enhanced adhesion and activation of neutrophils and platelets, to coagulation problems, and perfusion/metabolism mismatch in the affected organs. Here we overview the role of nitric oxide (NO) in the pathogenesis of vascular contractile dysfunction in circulatory shock. We describe the results of published studies involving shock models induced by bacterial lipopolysaccharide (LPS), and by cecal ligation and puncture (CLP), a polymicrobial model of sepsis. Among the many contributing factors, we locus on the role of cyclic GMP (cGMP) dependent pathways as well as a number of cGMP independent pathways. We will also outline the role of oxidative/nitrosative stress, peroxynitrite and poly(ADP-ribose) polymerase (PARP) and vascular potassium channels in the sepsis-associated alterations in vascular smooth muscle contractility.

Essential hypertension in adolescents and children: Recent advances in causative mechanisms

Essential hypertension is the most common form of hypertension in adults, and it is recognized more often in adolescents than in younger children. It is well known that the probability of a diagnosis of essential hypertension increases with age from birth onward. The initiation of high blood pressure burden starts in childhood and continues through adolescence to persist in the remaining phases of life. The genesis of essential hypertension is likely to be multifactorial. Obesity, insulin resistance, activation of sympathetic nervous system, sodium homeostasis, renin-angiotensin system, vascular smooth muscle structure and reactivity, serum uric acid levels, genetic factors and fetal programming have been implicated in this disorder. In addition, erythrocyte sodium transport, the free calcium concentration in platelets and leukocytes, urine kallikrein excretion, and sympathetic nervous system receptors have also been investigated as other possible mechanisms. Obesity in children appears to be the lead contributor of essential hypertension prevalence in children and adolescents. Suggested mechanisms of obesity-related hypertension include insulin resistance, sodium retention, increased sympathetic nervous system activity, activation of renin-angiotensin-aldosterone, and altered vascular function. The etiopathogenesis of essential hypertension in children and adolescents appears to closely resemble that of adults. The minor variations seen could probably be due to the evolving nature of this condition. Many of the established mechanisms that are confirmed in adult population need to be replicated in the pediatric age group by means of definitive research for a better understanding of this condition in future.

Effect of pH Change on Vascular Smooth Muscle Contractility in Rat Superior Mesenteric Artery and Its Branches

Background: Extracellular and intracellular pH (pH o and pH i ), which can be changed in various pathological conditions such as hypoxia, affects vascular contractility. To elucidate the mechanism to alter vascular contractility by pH, the effects of pH on reactivity to vasocontracting agents, intracellular Ca²? influx, and Ca²? sensitivity in vascular smooth muscle were examined. Material and Method: Isometric contractions in rat superior mesenteric arteries (SMA) were observed. Intracellular Ca²? concentration ([Ca²?] i ) was recorded by microfluorometer using Fura-2/acetoxylmethyl ester in muscle cells. pH o was increased from 7.4 to 7.8 or decreased to 6.9 or 6.4. pH i was decreased by applying NH₄? or propionic acid or modulated by changing pH o after increasing membrane permeability using β-escin. Result: Decreases in pH o from 7.4 to 6.9 or 6.4 shifted concentration-response curve by norepinephrine (NE) or serotonin (SE) to the right and significantly increased half maximal effective concentration (EC50) to NE or SE. Increase in pH o from 7.4 to 7.8 shifted concentration-response curve by norepinephrine (NE) or serotonin (SE) to the left and significantly reduced EC50 to NE or SE. NE increased [Ca²?] i in cultured smooth muscle cells from SMA and the increased [Ca²?] i was reduced by decreases in pH o . NE-induced contraction was inhibited by NH₄?, whereas the resting tension was increased by NH₄? or propionic acid. When the cell membrane of SMA was permeabilized using β-escin, SMA was contracted by increasing extracellular Ca²? concentration from 0 to 10μM and the magnitude of contraction was decreased by a decrease in pH o and vice versa. Conclusion: From these results, it can be concluded that a decrease in pH o might inhibit vascular contraction by reducing the reactivity of vascular smooth muscle to vasoactive agents, Ca²? influx and the sensitivity of vascular smooth muscle to Ca²?.

Effects of chromium picolinate on vascular reactivity and cardiac ischemia-reperfusion injury in spontaneously hypertensive rats

Chromium picolinate [Cr(pic)3] is a nutritional supplement widely promoted to exert beneficial metabolic effects in patients with type 2 diabetes/impaired glucose tolerance. Frequent comorbidities in these individuals include systemic hypertension, abnormal vascular function and ischemic heart disease, but information on the effects of the supplement on these aspects is sparse. Utilizing male spontaneously hypertensive rats (SHR), we examined the potential impact of Cr(pic)3 on blood pressure, vascular reactivity and myocardial ischemia-reperfusion injury (IRI). Dietary Cr(pic)3 supplementation (as 10mg chromium/kg diet for six weeks) did not affect blood pressure of the SHR. Also, neither norepinephrine (NE) and potassium chloride (KCl)-induced contractility nor sodium nitroprusside (SNP)-induced relaxation of aortic smooth muscle from the SHR was altered by Cr(pic)3 treatment. However, Cr(pic)3 augmented endothelium-dependent relaxation of aortas, produced by acetylcholine (ACh), and this effect was abolished by N-nitro-L-arginine methyl ester (L-NAME), suggesting induction of nitric oxide (NO) production/release. Treatment with Cr(pic)3 did not affect baseline coronary flow rate and rate-pressure-product (RPP) or infarct size following regional IRI. Nonetheless, Cr(pic)3 treatment was associated with improved coronary flow and recovery of myocardial contractility and relaxation following ischemia-reperfusion insult. In conclusion, dietary Cr(pic)3 treatment of SHR alters neither blood pressure nor vascular smooth muscle reactivity but causes enhancement of endothelium-dependent vasorelaxation associated with NO production/release. Additionally, while the treatment does not affect infarct size, it improves functional recovery of the viable portion of the myocardium following IRI.