Various Forms Of Hypertension Research Articles

Research on Experimental Hypertension in Prague (1966-2009).

The study of ontogenetic aspects of water and electrolyte metabolism performed in the Institute of Physiology (Czechoslovak Academy of Sciences) led to the research on the increased susceptibility of immature rats to salt-dependent forms of hypertension since 1966. Hemodynamic studies in developing rats paved the way to the evaluation of hemodynamic mechanisms during the development of genetic hypertension in SHR. A particular attention was focused on altered renal function and kidney damage in both salt and genetic hypertension with a special respect to renin-angiotensin system. Renal damage associated with hypertension progression was in the center of interest of several research groups in Prague. The alterations in ion transport, cell calcium handling and membrane structure as well as their relationship to abnormal lipid metabolism were studied in a close cooperation with laboratories in Munich, Glasgow, Montreal and Paris. The role of NO and oxidative stress in various forms of hypertension was a subject of a joint research with our Slovak colleagues focused mainly on NO-deficient hypertension elicited by chronic L-NAME administration. Finally, we adopted a method enabling us to evaluate the balance of vasoconstrictor and vasodilator mechanisms in BP maintenance. Using this method we demonstrated sympathetic hyperactivity and relative NO deficiency in rats with either salt-dependent or genetic hypertension. At the end of the first decennium of this century we were ready to modify our traditional approach towards modern trends in the research of experimental hypertension. Keywords: Salt-dependent hypertension o Genetic hypertension o Body fluids o Hemodynamics o Ion transport o Cell membrane structure and function o Renal function o Renin-angiotensin systems.

Inflammatory Alterations to Renal Lymphatic Endothelial Cell Gene Expression in Mouse Models of Hypertension.

Hypertension (HTN) is a major cardiovascular disease that can cause and be worsened by renal damage and inflammation. We previously reported that renal lymphatic endothelial cells (LECs) increase in response to HTN and that augmenting lymphangiogenesis in the kidneys reduces blood pressure and renal pro-inflammatory immune cells in mice with various forms of HTN. Our aim was to evaluate the specific changes that renal LECs undergo in HTN. We performed single-cell RNA sequencing. Using the angiotensin II-induced and salt-sensitive mouse models of HTN, we isolated renal CD31+ and podoplanin+ cells. Sequencing of these cells revealed three distinct cell types with unique expression profiles, including LECs. The number and transcriptional diversity of LECs increased in samples from mice with HTN, as demonstrated by 597 differentially expressed genes (p < 0.01), 274 significantly enriched pathways (p < 0.01), and 331 regulons with specific enrichment in HTN LECs. These changes demonstrate a profound inflammatory response in renal LECs in HTN, leading to an increase in genes and pathways associated with inflammation-driven growth and immune checkpoint activity in LECs. These results reinforce and help to further explain the benefits of renal LECs and lymphangiogenesis in HTN.

Hipertenzija kod dece i adolescenata

Until recently, secondary hypertension used to be the most common form of hypertension in the paediatric population. Due to the increasing prevalence of obesity-related hypertension in children and adolescents, the share of secondary hypertension has decreased from 85% to 9%. Today, primary hypertension has become the dominant form of hypertension in the paediatric population. The purpose of this paper is to show the prevalence of various forms of hypertension and the prevalence of primary hypertension in children and adolescents relative to sex, age and body weight category in the General Hospital "Dr. Laza K. Lazarević" in Šabac. In children with secondary hypertension, the impact of body weight was not assessed since an organic cause of hypertension had been identified in these patients. All children from the age of a new-born to the age of 18 years with a diagnosis of hypertension (International Classification of Diseases, tenth revision (IDC-10), code I10-I15) in the period from 1 January 2013 to 31 December 2022 were selected from the medical digital database. This analysis included all children who showed blood pressure values above 95th percentile for age, sex and height in children under 13 and above 120/80 mmHg in children over 13, upon repeated measurements of blood pressure in the General Hospital, who were presumed to have hypertension. These children were referred to further evaluation at tertiary healthcare institutions, where a diagnosis of hypertension was made. Of the 134 children referred to the General Hospital due to elevated blood pressure levels measured in the primary care physician's office, hypertension was diagnosed in almost one in four subjects (24.6%). Primary hypertension was diagnosed in 18 (54.5%), secondary hypertension in 8 (24.2%) and white coat hypertension in 7 (21.2%) children. Primary hypertension was more common in boys (70.6%) than girls (37.5%). Among children with primary hypertension, overweight and obese children represented 66.7% of the group at the time of diagnosis. Statistical data analysis did not find a statistically significant difference in the prevalence of primary hypertension among the body weight or age categories. Since primary hypertension is the most significant and potentially reversible factor for the development of cardiovascular disease, early detection and treatment of primary hypertension in children is crucial in the prevention of cardiovascular disease in adults.

Renal denervation alters ambulatory blood pressure-derived salt sensitivity index in patients with uncontrolled hypertension.

Renal denervation (RDN) has been proven in multiple sham-controlled trials to lower blood pressure (BP) in various forms of hypertension. RDN-mediated interruption of sympathetic signaling through its effects on renal blood flow, salt retention, and renin release are likely contributors to the BP-lowering effects. However, the impact of RDN on salt sensitivity in humans has not yet been explored. We, therefore, investigated the effect of RDN on ambulatory BP monitoring-derived salt sensitivity in a cohort of patients with uncontrolled hypertension on habitual salt intake. RDN was performed in 153 hypertensive patients, who were categorized into low intermediate and high-salt sensitivity groups, based on the ambulatory BP monitoring-derived salt sensitivity index estimated prior to (baseline) and at 3, 6 and 12 months after the procedure as previously described. Crude and adjusted mixed effects ordinal regression models were fitted to test for changes in the proportions of salt sensitivity risk during follow-up. The proportions of individuals in the intermediate and high-salt sensitivity risk group increased after RDN and the odds for being in a higher estimated salt sensitivity risk group at 3, 6 and 12 months follow-up compared with baseline were highly significant during the 12 months follow-up period. Increased salt sensitivity after RDN may represent a compensatory mechanism to maintain renal capacity for adequate salt handling. This novel finding may have implications for patient management after RDN, such as prescription of salt moderation to further optimize RDN-induced BP-lowering efficacy.

Renal denervation as a management strategy for hypertension: current evidence and recommendations

Introduction The concept of targeting the renal sympathetic nerves therapeutically to lower blood pressure (BP) is based on their crucial role in regulating both renal and cardiovascular control. These effects are mainly mediated via three major mechanisms including alteration of renal blood flow, renin-release, and Na+ retention. Initial surgical approaches applying crude and unselected sympathectomy, while rendering significant BP lowering and cardiovascular event reducing properties, where plagued by side effects. More modern selective catheter-based denervation approaches selectively targeting the renal nerves have been shown to be safe and effective in reducing BP in various forms of hypertension and multiple comorbidities. Areas covered This article covers the background relevant for the concept of renal denervation (RDN), the evidence obtained from relevant randomized controlled trials to substantiate the safety and efficacy of RDN, and recently published clinical recommendations. Expert Opinion Catheter-based RDN is safe and has now been shown in sham-controlled randomized clinical trials to result in clinically meaningful BP lowering in both drug naïve hypertensive patients and those on concomitant antihypertensive therapy. Real world data from a large global registry further supports the clinical utility of RDN. It now seems time to embed renal denervation into routine clinical care.

Abstract P205: Finger Ring Provides Nocturnal Blood Pressure Dipping Status Based On Analysis Of Oscillatory Photoplethysmography

Ambulatory blood pressure monitoring is more useful for the diagnosis of various forms of hypertension including white coat and morning surge as well as other conditions that are associated with increased morbidity and mortality such as sleep apnea. Nocturnal changes in blood pressure (BP) can also aid in the diagnosis of various manifestations of blood pressure independent of hypertension known as salt sensitivity (SS) and inverse salt sensitivity (ISS) of blood pressure. SS individuals experience an increase in BP on a high salt diet while ISS individuals experience a paradoxical increase in BP on a low salt diet. SS and ISS phenotypes affect approximately 18% and 15% of normotensives, respectively, which may result in significant morbidity and mortality similar to untreated hypertension. Consuming a personally appropriate salt diet can result in a circadian drop in BP during sleep, and failure to “dip” can lead to significant cardiovascular diseases. Nocturnal dipping is usually recorded using an ambulatory blood pressure monitoring (ABPM) device. Arterial pulse wave measurements using oscillatory photoplethysmography (OP) are minimally invasive when compared to an inflatable cuff, which can disturb sleep and raise blood pressure. We measured nocturnal blood pressure using a ring based photoplethysmograph (SensoGram Technologies, Plano Texas). A UVA Salt Study participant wore their device upon going to bed and then uploaded nocturnal data to the internet each morning. Systolic and diastolic BP is capable of being measured 30 times a minute for approximately 9 hours and providing over 5000 data points each night. Three representative dipping profiles for an individual yielded a dipping reduction of 24% ± 3% for systolic and 40% ± 10% for diastolic (1 - mid-sleeping lowest value/start of evening highest value). This additional data afforded by nocturnal BP measurement is anticipated to improve diagnostic opportunities in the measurement of SS and ISS phenotypes and provide the user with reassurance that nocturnal BP dipping is occurring.

Recent Advances in Immunity and Hypertension.

Persistent immune system activation plays an important role in the development of various forms of hypertension. Activation of the innate immune system, inflammation, and subsequent adaptive immune system response causing end-organ injury and dysfunction ultimately leads to hypertension and its associated sequelae including coronary artery disease, heart failure, stroke, and chronic kidney disease. In this review, we will provide updates on the innate and adaptive immune cells involved in hypertension, the current understanding of how the immune system gets activated, and examine the recently discovered mechanisms involved in several forms of experimental hypertension.

Abstract P273: Increased Inhibition of Potassium Channel Currents by Angiotensin II in Sympathetic Neurons may Contribute to a Sustained Blood Pressure Elevation in (mRen2)27 Rats.

It is well established that the increased sympathetic tone may contribute to initiation and progression of various forms of hypertension. Several lines of evidence suggest a link between the renin-angiotensin system and sympathetic nerve activity in hypertension, and the previous studies in animal models demonstrated increased sympathetic output in the presence of Angiotensin II (AngII). To elucidate potential underlying molecular mechanisms of such phenomenon, we compared the effect of AngII on the whole-cell potassium channel currents in superior cervical ganglia (SCG) neurons isolated from hypertensive (mRen2)27 rats with overexpression of renin gene, and control Sprague Dawley® (SD) rats. In both groups, the whole-cell potassium channel currents were identified as rapidly-activating, 4-Aminopyridine-sensitive transient A-type currents, as well as slowly-activating tetraethylammonium-sensitive delayed rectifier currents. When the cell membrane was depolarized to -40, -30 and -20 mV from a holding potential of -80 mV, AngII (100 nM) profoundly inhibited A-type current, but the magnitude of such inhibition was not significantly different between neurons isolated from (mRen2)27 (38.1±6.2%, 47.8±5.7% and 52.1±5.7%; n=11) and SD rats (37.2±4.6%, 44.±4.5% and 46.1±4.8%; n = 13). Delayed rectifier potassium channel currents were isolated by holding cells at -40 mV, which resulted in complete elimination of the transient A-type current. In contrast to transient current, inhibition of the delayed rectifier current by AngII in the range of membrane potentials between +20 and +80 mV was significantly greater (p<0.05) in neurons obtained from (mRen2)27 rats (11.0±3.2% to 25.0±2.9%, n=12) when compared to SD rats (4.7±1.5% to 16.3±2.7%, n = 12). In both groups, inhibition of both channel types was completely abolished by 10 uM Losartan, indicating involvement of AT1 receptors. Our results suggest that in (mRen2)27 hypertensive rats, the increased inhibitory effect of AngII on delayed rectifier potassium channel currents could possibly lead to lowering spike threshold, which, in turn, could elevate sympathetic outflow and lead to sustained blood pressure elevation.

75 Central blood pressure and arterial stiffness in various forms of hypertension in pregnancy

Introduction Arterial stiffness and central pressure measurements should be considered as recommended tests for the evaluation of cardiovascular risk in general population, whereas in pregnancy, their meaningfulness is not established. The estimation of these parameters for early detection of preeclampsia may be helpful. Objectives To evaluate the central (aortic) blood pressure (BP) and arterial stiffness in women with various forms of hypertension and their prognostic role in development of preeclampsia (PE). Methods In a prospective cohort study there were included 300 pregnant women: 106 – with chronic hypertension (CH) – group 1; 63 – with gestational hypertension (GH) – group 2; 10 – with PE – group 3; 21 – with preeclampsia superimposed on chronic hypertension (CH+PE) – group 4 and 100 – without hypertension (comparison group) – group 5. Ambulatory BP monitoring oscillometric measurement method with the definition of the central (aortic) BP and arterial stiffness parameters (augmentation index, reflected wave transit time, arterial stiffness index) in 16–22 weeks of pregnancy was performed in all patients using a 24–h BP monitoring system, ie, BPLab® and Vasotens® technology (Petr Telegin, Nizhny Novgorod, Russian Federation). Statistical analysis was performed using the statistical software package MedCalc®, version 11.5.0 (Mann–Whitney test, Kruskal–Wallis test, Pearson’s chi-squared test, logistic regression analysis, ROC-analysis). Statistical significance was considered to be a p Results The average peripheral (brachial) systolic blood pressure (SBP) 24 h was higher in all pregnant women with hypertension: with CH (130 ± 8.8 mmHg), with GAG (136 ± 6.9 mm Hg), with PE (136 ± 6.9 mmHg), with PE superimposed on CH (138 ± 7.9 mmHg) vs comparison group (118 ± 5.1 mmHg p1,2,3,4-5 Conclusions 24-h blood pressure monitoring in pregnant women with hypertension in 16–22 weeks of gestation may be useful to obtain additional information about central SBP and arterial stiffness as a prognostic parameters for prediction of preeclampsia.

Different blood pressure responses to opioids in 3 rat hypertension models: role of the baseline status of sympathetic and renin-angiotensin systems.

Opioids interact with sympathetic and renin-angiotensin systems in control of mean arterial pressure (MAP). Our earlier finding that biphalin, a synthetic enkephalin analogue, decreased MAP in anaesthetized spontaneously hypertensive rats (SHR) prompted us to further explore this action, to get new insights into pathogenesis of various forms of hypertension. Biphalin effects were studied in SHR, uninephrectomized rats on a high-salt diet (HS/UNX), and rats with angiotensin-induced hypertension (Ang-iH). Besides MAP, renal and iliac blood flows (RBF, IBF) and vascular resistances were measured. In anaesthetized and conscious SHR, biphalin (300 μg·h-1·kg-1 i.v.) decreased MAP by ∼10 and ∼20 mm Hg, respectively (P < 0.001). In anaesthetized HS/UNX and normotensive rats, MAP increased by ∼6-7 mm Hg (P < 0.02); without anaesthesia, only transient decreases occurred. MAP never changed in Ang-iH rats. Morphine (1.5 mg·h-1·kg-1 i.v.) decreased MAP in HS/UNX but only transiently so without anaesthesia; such anaesthesia dependence of response was also seen in normotensive rats. Ang-iH rats never responded to morphine. Hypotensive effect in SHR only depends primarily on the reduction by biphalin of vascular responsiveness to increased sympathetic stimulation; such increase is well documented for SHR. No MAP response to biphalin or morphine in Ang-iH could depend on angiotensin-induced alterations of the vascular wall morphology and function.

Determination of Ghrelin?s Role in the Pathogenesis of Pregnancy Induced Hypertension

Background: Ghrelin is a stomach-produced polypeptide hormone that stimulates hunger and secretion of growth hormone. Abnormalities in ghrelin secretion are well documented in obese patients, but explored little in patients with various forms of hypertension. Notably, ghrelin is indirectly involved in blood pressure regulation in pregnancy induced hypertension. Material and methods: The present study aimed to assess ghrelin concentration in venous blood of 19 nonpregnant (NP), 20 healthy pregnant (HP) and 20 hypertensive pregnant (PIH). It also included assessing blood ghrelin concentration of 21 obese hypertensive pregnant (OPIH) women before and one hour after eating. Ghrelin secretion was estimated 1-3 days before delivery. Results: All experimental groups of pregnant women (HP, PIH, and OPIH) showed significantly reduced ghrelin plasma level as compared with NP (812 ± 83, 716 ± 66, and 717 ± 52 vs 1057 ± 74, respectively). We found no significant ghrelin reduction after eating in obese hypertensive pregnant women. The blood ghrelin concentration in pregnant women negatively correlated with mean arterial pressure. In spite of the differences in ghrelin concentration in women, whom a decrease in ghrelin concentration after a standard meal was observed compared to women, who didn’t reduce of ghrelin secretion no differences were found in mean arterial pressure. Conclusion: The relationship between arterial hypertension and ghrelin secretion disorders during hypertensive pregnancy is uncertain and requires further examination.

Mitochondria: a pathogenic paradigm in hypertensive renal disease.

Mitochondria were first described in 1840 as bioblasts, elementary organisms responsible for vital cellular functions, but were subsequently named mitochondria, from the Greek names mitos (thread) and chondros (granule), which describes their appearance during spermatogenesis.1 Their discovery generated substantial interest given their structure resembling bacteria, which led in subsequent years to important scientific discoveries positioning mitochondria as the energy powerhouse of the cell. The unique architecture of mitochondria, consisting of 2 membranes (outer and inner) and compartments (intermembrane space and matrix), is crucial for their vital functions. Mitochondria serve not only as primary sources of cellular energy, but also modulate several cellular processes, including oxidative phosphorylation, calcium homeostasis, thermogenesis, oxygen sensing, proliferation, and apoptosis.2 Therefore, mitochondrial injury and dysfunction might be implicated in the pathogenesis of several diseases. Hypertension accounts for nearly 30% of patients reaching end-stage renal disease.3 Renal injury secondary to hypertension or to ischemia associated with renovascular hypertension (distal to renal artery stenosis) may have significant and detrimental effect on health outcomes. Studies have highlighted several deleterious pathways, including inflammation, oxidative stress, and fibrosis that are activated in the hypertensive kidney, eliciting functional decline.4,5 However, the precise molecular mechanisms responsible for renal injury have not been fully elucidated. Over the past few years, increasing evidence has established the experimental foundations linking mitochondrial alterations to hypertensive renal injury (Table). Mitochondriopathies, abnormalities of energy metabolism secondary to sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA) genes, may contribute to the development and progression of hypertension and its complications. In addition, several studies have reported mitochondrial damage and dysfunction consequent to hypertensive renal disease. View this table: Table. Evidence of Renal Mitochondrial Damage in Models of Hypertension and Antihypertensive Treatment Importantly, hypertensive-induced renal injury is characterized by activation of several deleterious pathways, including oxidative stress, renin–angiotensin–aldosterone …

Angiotensin converting enzyme and Alzheimer's disease

Alzheimer's disease (AD) is an incurable degenerative disease of the central nervous system, leading to dementia. The basis of AD is neurodegenerative process that leads to death of neurons in the cerebral cortex. This neurodegenerative process is associated with the formation of neurofibrillary tangles in the brain and the deposition of senile plaques, the main component of which is a beta-amyloid peptide (Ab). Risk factors for AD are age, as well as hypertension, atherosclerosis, diabetes and hypercholesterolemia in the pathogenesis of which involved angiotensin converting enzyme (ACE) – key enzyme of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems. Recently it was discovered that ACE, along with other metallopeptidases, participates in the metabolism of Ab, cleaving the bonds at the N-terminal and C-terminal region of the molecule Ab. The role of the ACE in the degradation processes of Ab takes an interest. It is associated with the fact that the using of ACE inhibitors is the main therapeutic approach used in the treatment of various forms of hypertension and other cardiovascular diseases. However, until now not been resolved, can be used antihypertensive drugs that inhibit RAS for the treatment or prevention of AD. Currently, there are numerous studies on finding the relationship between RAS and AD.

Estimation of the efficacy of the measurement of plasma renin activity and direct renin in diagnostics of primary aldosteronism

The objective of the present study was to estimate the informative value of the measurements of aldosterone level, direct renin, and plasma renin activity as well as the relationships between these characteristics for differential diagnostics of various forms of hypertension and, first and foremost, of primary aldosteronism. We have examined a total of 162 patients. The results of differential tests were used to allocate them to a few groups including 41 patients presenting with primary aldosteronism, 52 ones with incidentalomas, 26 with essential hypertension, and 43 with various endocrine diseases and normal arterial pressure (control groups). The aldosterone levels, direct renin, and plasma renin activity were measured in blood samples taken in morning hours from the patients in the supine position. The aldosterone to plasma renin activity (A/PRA) and aldosterone to direct renin (A/DR) ratios were calculated. The elevated blood aldosterone level is currently believed to be the principal criterion for primary aldosteronism in the patients suffering arterial hypertension. The RIA technology is the method of choice for the measurement of aldosterone levels. The determination of the A/PR ratio significantly improves the detectability of the disease. The use of direct renin level instead of kinetic renin ensures the high efficacy of screening for primary aldosteronism and its early diagnostics. The cut-off point for the calculation of the A/PRA ratio to differentiate between primary aldosteronism and incidentalomas is 2160 pmol/mcg/hr (sensitivity 100%, specificity 97.8%) in comparison with the analogous cut-off point for the discrimination between primary aldosteronism and endocrine pathology without hypertension is 49 pmol/mU (sensitivity 100%, specificity 95%). The cut-off point for the calculation of the A/PR ratio to differentiate between primary aldosteronism and incidentalomas is 2160 pmol/mcg/hr (sensitivity 89.5%, specificity 99%) in comparison with the analogous cut-off point for the discrimination between primary aldosteronism and endocrine pathology without hypertension is 1432 pmol/mcg/hr (sensitivity 89.5%, specificity 100%). It is concluded that the results of determination of direct renin level in the blood plasma are independent of the endogenous angiotensinogen level, less variable and more reproducible than than the results of the measurement of plasma renin activity. The aldosterone to direct renin ratio may be used for the screening of primary aldosteronism.

Angiotensin converting enzyme and Alzheimer’s disease

Alzheimer's disease (AD) is an incurable degenerative disease of the central nervous system, leading to dementia. The basis of AD is neurodegenerative process that leads to death of neurons in the cerebral cortex. This neurodegenerative process is associated with the formation of neurofibrillary tangles in the brain and the deposition of senile plaques, the main component of which is a beta-amyloid peptide (Abeta). Risk factors for AD are age, as well as hypertension, atherosclerosis, diabetes and hypercholesterolemia in the pathogenesis of which involved angiotensin converting enzyme (ACE)--key enzyme of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems. Recently it was discovered that ACE, along with other metallopeptidases, participates in the metabolism of Abeta, cleaving the bonds at the N-terminal and C-terminal region of the molecule Abeta. The role of the ACE in the degradation processes of Abeta takes an interest. It is associated with the fact that the using of ACE inhibitors is the main therapeutic approach used in the treatment of various forms of hypertension and other cardiovascular diseases. However, until now not been resolved, can be used antihypertensive drugs that inhibit RAS for the treatment or prevention of AD. Currently, there are numerous studies on finding the relationship between RAS and AD.

Counterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic Hypertension

Our discussion regarding the dominant mechanism responsible for hypertension calls to mind the famous poem, “The Blind Men and the Elephant,” by John Godfrey Saxe based on an ancient fable from India. In essence, the blind men described the elephant based on their specific encounter, thus

ABNORMAL CALCIUM HOMEOSTASIS IN ARTERIAL MYOCYTES FROM MILAN HYPERTENSIVE STRAIN RATS: PP.29.177

Polymorphisms in the genes encoding adducin, a membrane-skeletal protein, are associated with hypertension in humans and rats (Milan hypertensive strain, MHS). MHS rats, with their control normotensive strain (MNS), are a model for a subgroup of patients with essential hypertension. The relationship between adducin gene polymorphisms and renal dysfunction has been well-studied, but the mechanisms that underlie vascular functional abnormalities are unclear. Ca2+ homeostasis plays a crucial role in the genesis of vascular myogenic tone, and increases in cytosolic Ca2+ concentration ([Ca2+]cyt) appear to underlie at least part of the increased peripheral vascular resistance in hypertension. We hypothesize that Ca2+ signaling mediated by Na/Ca exchanger (NCX) and TRPC-encoded receptor-operated Ca2+ channels is up-regulated in MHS mesenteric artery myocytes compared with that in MNS. The [Ca2+]cyt was determined with digital imaging of Fura-2-loaded freshly dissociated mesenteric artery smooth muscle cells (ASMCs). On average, the MNS rats had a mean systolic BP (SBP) of 113 ± 1 mmHg; the SBP of the MHS rats was significantly higher (144 ± 2 mmHg, P < 0.05). Freshly dissociated MHS ASMCs had significantly higher resting [Ca2+]cyt than did MNS ASMCs (97 ± 2 nM vs. 78 ± 3 nM, P < 0.05). Receptor-operated entry was activated by the diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG). In the presence of extracellular Ba2+, OAG (100 μM)-induced elevations of cytosolic Ba2+ (Fura-2 340/380 nm ratio) were significantly larger in MHS ASMCs. The ATP (5 μM)-induced Ca2+ responses were also augmented in MHS ASMCs (729 ± 70 nM vs. 533 ± 44 nM, P < 0.05). These changes in MHS ASMCs correlate with ∼3-fold up-regulation of TRPC6, while expression of other TRPCs was not changed. Recently we showed that expression of TRPC6 and NCX1 in ASMCs is inter-related and TRPC6 and NCX1 are both up-regulated in ouabain hypertensive rats (Pulina et al., Amer. J. Physiol. 298(1):H263-H274, 2010). Here, we show that NCX1 is also robustly (∼13-fold) up-regulated in MHS ASMCs. The findings suggest that up-regulation of NCX1 and TRPC6 can represent a general downstream phenomenon intrinsic to various forms of hypertension.

Endothelium-dependent and -independent relaxations in aortic rings obtained from hypertensive hooded (Aguti) rats.

Experimental hypertension studies are few in the hooded (Aguti) rat. The present study was designed to investigate the usefulness of this rat strain for experimental hypertension studies and to test the hypothesis that the hypertension may be associated with a diminution of endothelium dependent and independent relaxations. Hypertension was induced in inbred hooded rats (n=8 each) by administering 8% salt in the diet and /or 100 mg/kg/day Nomega-nitro-L-arginine-methyl-ester (L-NAME) in the drinking water for six and/or four weeks respectively. The rats were anaesthetized using a 25% urethane and 1% chloralose mixture given intraperitoneally at a dose of 5 mg/kg. Their blood pressure was measured invasively. Thereafter, relaxations of rat aortic preparations to acetylcholine, histamine and sodium nitroprusside (SNP) were assessed using standard organ bath conditions. Probability level of 0.05 was taken as statistically significant. The mean arterial pressure (MAP;mm Hg) rose significantly in all test groups (Salt: 148.3 +/- 4.6; L-NAME: 181.7 +/-8.3; Salt+L-NAME:154.9 +/-8.7) compared with control (94.2 +/-6.8; [P < 0.05]. The MAP was significantly [P < 0.05] higher in the L-NAME group than in all the other groups. The heart rate fell significantly in the salt + L-NAME group compared to control [P <0.05].The IC50 of acetylcholine in aortic rings from L-NAME rats (7.9 x 10(-1) +/- 6.0 x 10(-3)) was significantly higher than in rings from control (9.4 x 10(-8) +/- 2.8 x 10(-8)), salt (7.8 x 10(-7) +/- 4.7 x 10(-7)) and salt + L-NAME (3.3 x 10 (-7) +/- 2.1 x 10(-7)) rats [P < 0.05]. The IC50 of histamine and SNP in the rings from the test groups of rats showed no significant difference from control. Also, endothelium dependent and independent relaxations were preserved in the various forms of hypertension studied except in chronic NOS inhibition where the former was attenuated in response to acetylcholine.

A cannabinoid receptor, sensitive to O‐1918, is involved in the delayed hypotension induced by anandamide in anaesthetized rats

Intravenous injection of the endocannabinoid anandamide induces complex cardiovascular changes via cannabinoid CB(1), CB(2) and vanilloid TRPV1 receptors. Recently, evidence has been accumulating that in vitro, but not in vivo, anandamide relaxes blood vessels, via an as yet unidentified, non-CB(1) vascular cannabinoid receptor, sensitive to O-1918 (1,3-dimethoxy-5-2-[(1R,6R)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-benzene). We here examined whether the anandamide-induced hypotension in urethane-anaesthetized rats was also mediated via a non-CB(1) vascular cannabinoid receptor. Effects of two antagonists (O-1918 and cannabidiol) of the non-CB(1) vascular cannabinoid receptor on anandamide-induced changes in mean, systolic and diastolic blood pressure (MBP, SBP, DBP), mesenteric (MBF) and renal (RBF) blood flow and heart rate (HR) in urethane-anaesthetized rats was examined. In anaesthetized rats, anandamide (1.5-3 micromol.kg(-1)) and its stable analogue methanandamide (0.5 micromol.kg(-1)) caused a delayed and prolonged decrease in MBP, SBP, DBP, MBF and RBF by about 10-30% of the respective basal values without changing HR. In pithed rats, anandamide (3 micromol.kg(-1)) decreased blood pressure by about 15-20% of the basal value without affecting HR, MBF and RBF. All vascular changes were reduced by about 30-70% by cannabidiol and O-1918 (3 micromol.kg(-1), each). Non-CB(1) cannabinoid vascular receptors, sensitive to O-1918, contribute to the hypotensive effect of anandamide in anaesthetized rats. Activation of these receptors may be therapeutically important as the endocannabinoid system could be activated as a compensatory mechanism in various forms of hypertension.

Structural properties of lipid reconstructs and lipid composition of normotensive and hypertensive rat vascular smooth muscle cell membranes

Multiple cell membrane alterations have been reported to be the cause of various forms of hypertension. The present study focuses on the lipid portion of the membranes, characterizing the microviscosity of membranes reconstituted with lipids extracted from the aorta and mesenteric arteries of spontaneously hypertensive (SHR) and normotensive control rat strains (WKY and NWR). Membrane-incorporated phospholipid spin labels were used to monitor the bilayer structure at different depths. The packing of lipids extracted from both aorta and mesenteric arteries of normotensive and hypertensive rats was similar. Lipid extract analysis showed similar phospholipid composition for all membranes. However, cholesterol content was lower in SHR arteries than in normotensive animal arteries. These findings contrast with the fact that the SHR aorta is hyporeactive while the SHR mesenteric artery is hyperreactive to vasopressor agents when compared to the vessels of normotensive animal strains. Hence, factors other than microviscosity of bulk lipids contribute to the vascular smooth muscle reactivity and hypertension of SHR. The excess cholesterol in the arteries of normotensive animal strains apparently is not dissolved in bulk lipids and is not directly related to vascular reactivity since it is present in both the aorta and mesenteric arteries. The lower cholesterol concentrations in SHR arteries may in fact result from metabolic differences due to the hypertensive state or to genes that co-segregate with those that determine hypertension during the process of strain selection.