Several Models Of Hypertension Research Articles

T-cells regulate albuminuria but not blood pressure or tissue damage in the Dahl SSCD247+/+ rat model of hypertension

Previous studies have demonstrated a key role for renal inflammation in the progression of salt-sensitive hypertension (SS-HTN). Pharmacological and genetic inhibition of inflammation blunts the progression of hypertension in several models, including Dahl salt-sensitive (SS) rats. Traditionally, it has been difficult to separate the pathological effects of renal T-cells from those of exposure of the kidney to elevated pressure since the inhibition of renal inflammation results in a reduction in blood pressure, and vice versa. Therefore, improved renal function and reduced injury after the suppression of inflammation may be the result of reduced renal T-cells, reduced blood pressure, or both. In these studies, we took advantage of a loss of protection from SS-HTN in SS rats lacking T-cells, SS CD247-/- rats, to isolate the pathological effects of renal T-cells from those of hypertension on the kidney.Studies were performed on male SS CD247+/+ and SS CD247-/- rats obtained from heterozygous breeders. From birth rats were maintained on a purified control salt diet (CS, 0.4% NaCl) and switched to a high-salt diet (HS, 4.0% NaCl) during experiments.In contrast to previous studies, we found that MAP following 21-days of HS was not significantly different between SS CD247+/+ and SS CD247-/- rats (SS CD247+/+ : 156 ± 2.2 mmHg, n=16 vs SS CD247-/- : 151 ± 2.2mmHg, n=14, p=0.05). Using flow-cytometry we confirmed that the loss of protection from SS-HTN was not due to the reconstitution of T-cells in the SS CD247-/- rats. T-cells were absent in the kidneys of SS CD247-/- rats after 21-days of HS, comprising 0.06 ± 0.015% of live renal cells, compared to 26.08 ± 2.13% in SS CD247+/+ rats (p= 0.006, n=4+7).Despite the equivalent levels of SS-HTN, we found that the SS CD247-/- rats demonstrated significantly lower levels of albuminuria than their wild-type littermates (528 ± 73 mg/g, n=5 vs 963 ± 156 mg/g, n=7, p=0.008). In contrast to the albuminuria, we found that kidney injury, specifically tubular protein casts and glomerular injury, were not significantly different between SS CD247+/+ and SS CD247-/- rats, while there was a significant correlation between these factors and MAP at tissue collection. RNA-sequencing data confirmed this correlation between injury and MAP – only 99 genes differed significantly in the outer medulla of SS CD247-/- and SS CD247+/+ rats, while >4000 genes differed significantly across the range of pressures evaluated.These findings demonstrate that the pathological effects of renal T-cells are primarily manifested in albuminuria and that the effects of pressure substantially outweigh the effects of T-cell infiltration on histologic injury and transcriptomics of the kidney in SS-HTN. R01HL152166. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 053: Increased Arterial Pressure Precedes Renal Dysfunction And Elevated Renal Sympathetic And Afferent Nerve Activity In Deoxycorticosterone-Salt Rat

Hypertension (HTN) is a primary risk factor for cardiovascular disease - the leading cause of death worldwide. HTN is multifaceted but a key factor is aberrant autonomic signaling, including renal sympathetic (RSNA) and afferent nerve activity (ARNA). ARNA is elevated in several models of HTN and renal afferent nerve ablation can mitigate the HTN. It is unknown if ARNA rises before changes in blood pressure (BP) or renal function in HTN. This study aimed to determine when renal nerve activity changes vis a vis BP and renal function in a model of salt sensitive HTN. We hypothesized increased ARNA and RSNA would coincide with a rise in BP and decline in renal function. To test this hypothesis, 24 uninephrectomized male Sprague Dawley rats (300g) received a deoxycorticosterone acetate (DOCA; 100mg, SC) implant and 0.9% NaCl drinking water. Renal function (serum creatinine; Cr) and systolic BP (SBP; tail cuff) were measured weekly. Animals were randomly allocated to acute renal nerve recording on protocol day (D) 0, 7, 14, or 21. Multiunit RSNA and ARNA were recorded serially, as ARNA was isolated after sectioning proximal side. RSNA is expressed as bursts/heartbeat, ARNA and expressed as %ARNA max (response to intrapelvic capsaicin). Data were analyzed by one-way ANOVA with Bonferroni post hoc. Data presented as mean±SEM; *p<.05 vs D0. SBP (mmHg) progressively increased on D7 (*152 ± 3), D14 (*171 ± 3), and D21 (*197 ± 7) vs D0 (138 ± 3). ARNA (%) increased at D14 (*23.0 ± 4.7) and D21 (*34.2 ± 4.4) vs D0 (10.1 ± 0.8), but no changes were detected at D7 (13.4 ± 2.1). No changes in RSNA from D0 were detected. Cr (mg/dL) increased at D14 (*1.2 ± 0.1) and D21 (*1.2 ± 0.1) vs D0 (0.9 ± 0.0), indicating a decline in kidney function. These data do not support the hypothesis that ARNA and RSNA increase in parallel to increasing BP. Rather, BP appears to initially increase independent of detectable changes in RSNA, ARNA or renal dysfunction. Interestingly, renal dysfunction and elevated ARNA were detected on D14, which coincides with our previous report that renal inflammation is first detected at D14. These data do not support a causal role of ARNA in this model. Rather, ARNA may subsequently drive disease progression. Further studies on the cause of increased ARNA and inflammation interaction are underway.

ROS Suppression by Egg White Hydrolysate in DOCA-Salt Rats—An Alternative Tool against Vascular Dysfunction in Severe Hypertension

This study aimed to evaluate the potential for lowering blood pressure and beneficial effects on mesenteric resistance arteries (MRA) and conductance vessels (aorta) produced by dietary supplementation of an egg white hydrolysate (EWH) in rats with severe hypertension induced by deoxycorticosterone plus salt treatment (DOCA-salt), as well as the underlying mechanisms involved. The DOCA-salt model presented higher blood pressure, which was significantly reduced by EWH. The impaired acetylcholine-induced relaxation and eNOS expression observed in MRA and aorta from DOCA-salt rats was ameliorated by EWH. This effect on vessels (MRA and aorta) was related to the antioxidant effect of EWH, since hydrolysate intake prevented the NF-κB/TNFα inflammatory pathway and NADPH oxidase-induced reactive oxygen species (ROS) generation, as well as the mitochondrial source of ROS in MRA. At the plasma level, EWH blocked the higher ROS and MDA generation by DOCA-salt treatment, without altering the antioxidant marker. In conclusion, EWH demonstrated an antihypertensive effect in a model of severe hypertension. This effect could be related to its endothelium-dependent vasodilator properties mediated by an ameliorated vessel’s redox imbalance and inflammatory state.

Hypertension Precedes Changes in Afferent Renal Nerve Activity and Renal Dysfunction in DOCA‐Salt Rat Model

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

The virtually mature B-type natriuretic peptide (BNP1-32) is a precursor for the more effective BNP1-30.

Background and PurposeThe B‐type natriuretic peptide (BNP1‐32) exerts vasorelaxing and cardioprotective activity. BNP is used as a biomarker for the diagnosis of cardiopathological conditions and recombinant BNP1‐32 as a drug for the treatment of such. BNP1‐32 has a short half‐life and thus, similar to other vasoactive peptides like angiotensin II and bradykinin, can be enzymatically truncated forming bioactive metabolites. We aimed to investigate the metabolism of BNP1‐32 in the mouse lung, to identify potential new BNP metabolites and to disclose their biological activity compared to the BNP1‐32, in vitro and in vivo. Experimental ApproachUsing HPLC and MS, we identified a new BNP metabolite, BNP1‐30, in the lung being generated by endothelin‐converting enzyme‐1.Key ResultsBNP1‐30 is more efficient in stimulating the guanylyl cyclase (GC) receptor A and, in contrast to BNP1‐32, is also able to profoundly stimulate the GC‐B. In vivo, BNP1‐30 reduced the mean arterial BP of normotensive mice after acute infusion significantly more than BNP1‐32. In a model of severe hypertension, a 3‐day infusion of BNP1‐30 was able to reduce systolic BP by 30 mmHg and to improve markers of heart failure, while BNP1‐32 was without significant effect.Conclusions and ImplicationsOur results suggest that BNP1‐32 is the precursor for the biologically more active BNP1‐30 leading to a fundamental extension of the natriuretic peptide system. Due to expanded activity, BNP1‐30 might be a promising treatment option for cardiovascular diseases. Furthermore, its potency as a new diagnostic marker of specific cardiac diseases should be evaluated.

A switch from GABA inhibition to excitation of vasopressin neurons exacerbates the development angiotensin II-dependent hypertension.

Hypothalamic magnocellular neurons secrete vasopressin into the systemic circulation to maintain blood pressure by increasing renal water reabsorption and by vasoconstriction. When blood pressure rises, baroreflex activation normally inhibits vasopressin neurons via activation of GABAergic inputs. However, plasma vasopressin levels are paradoxically elevated in several models of hypertension and in some patients with essential hypertension, despite increased blood pressure. We have previously shown that vasopressin neuron activity is increased early in the development of moderate angiotensin II-dependent hypertension via blunted baroreflex inhibition of vasopressin neurons. Here, we show that antagonism of vasopressin-induced vasoconstriction slows the development of hypertension and that local administration of a GABAA receptor antagonist inhibits vasopressin neurons during, but not before, the onset of hypertension. Taken together, our data suggest that vasopressin exacerbates the increase in blood pressure evident early in the development hypertension and that blunted baroreflex inhibition of vasopressin neurons is underpinned by an excitatory shift in their response to endogenous GABA signalling. This article is protected by copyright. All rights reserved.

Gut microbiota in hypertension.

Hypertension, which is present in about one quarter of the world's population, is responsible for about 41% of the number one cause of death - cardiovascular disease. Not included in these statistics is the effect of sodium intake on blood pressure, even though an increase or a marked decrease in sodium intake can increase blood pressure. This review deals with the interaction of gut microbiota and the kidney with genetics and epigenetics in the regulation of blood pressure and salt sensitivity. The abundance of the gut microbes, Firmicutes and Bacteroidetes, is associated with increased blood pressure in several models of hypertension, including the spontaneously hypertensive and Dahl salt-sensitive rats. Decreasing gut microbiota by antibiotics can increase or decrease blood pressure that is influenced by genotype. The biological function of probiotics may also be a consequence of epigenetic modification, related, in part, to microRNA. Products of the fermentation of nutrients by gut microbiota can influence blood pressure by regulating expenditure of energy, intestinal metabolism of catecholamines, and gastrointestinal and renal ion transport, and thus, salt sensitivity. The beneficial or deleterious effect of gut microbiota on blood pressure is a consequence of several variables, including genetics, epigenetics, lifestyle, and intake of antibiotics. These variables may influence the ultimate level of blood pressure and control of hypertension.

Abstract 19094: Antihypertensive Properties of Subcutaneous M-ANP, a Novel Designer Atrial Natriuretic Peptide, in a Canine Model of Chronic Angiotensin-II Induced Hypertension

Introduction: Blood pressure (BP) control remains low despite combination therapy in resistant hypertension (RH). Thus, there is an unmet need for novel strategies targeting RH. Recently we have reported that M-ANP, a novel Mayo engineered ANP-based peptide, possesses greater and more sustained biological actions compared to ANP and is more resistant to neprilysin degradation. The current study was designed to investigate for the first time the efficacy of a single daily subcutaneous (SQ) injection of M-ANP using a chronic canine model of hypertension induced by angiotensin II (Ang-II). Hypothesis: We hypothesize that a daily SQ M-ANP injection would have potent BP lowering and renal enhancing properties in our chronic hypertensive canine model. Methods: We induced hypertension in canines (n=5) by continuous Ang II (80 ng/kg/min) osmotic mini-pump administration for 24 days. Continuous 24 hour mean BP (MBP) was measured by telemetry and a 24 hour urine collection was used to assess urinary volume, sodium (Na) and cGMP, the second messenger for the ANP system. M-ANP was administered SQ for 5 days (10μg/kg/day). Data are mean±SE. ΨP<0.05 Ang II Day 16 vs. baseline; *P<0.05 Ang II Day 16 vs. M-ANP (Table 1). Results: Chronic Ang II administration resulted in model of severe hypertension, with an increase in MBP from 112±2 to 157±2 mmHg (day 16). As seen in Table 1, M-ANP significantly reduced MBP, significantly increased plasma cGMP as well as urinary cGMP excretion, urinary volume rate (UV) and urinary Na excretion (UNa), without significant changes in heart rate (HR). Furthermore, there was a trend for plasma ANP to increase and plasma aldosterone to decrease with SQ M-ANP injection. Conclusions: This study demonstrates for the first time that chronic SQ administration of M-ANP reduces BP, activates plasma cGMP, and increases UV and UNa, without significant changes in HR in an experimental model of chronic hypertension.

Angiotensin-II-derived reactive oxygen species on baroreflex sensitivity during hypertension: new perspectives

Hypertension is a multifactorial disorder, which has been associated with the reduction in baroreflex sensitivity (BRS) and autonomic dysfunction. Several studies have revealed that increased reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase, following activation of type 1 receptor (AT1R) by Angiotensin-(Ang) II, the main peptide of the Renin–Angiotensin–Aldosterone System (RAAS), is the central mechanism involved in Ang-II-derived hypertension. In the present review, we will discuss the role of Ang II and oxidative stress in hypertension, the relationship between the BRS and the genesis of hypertension and how the oxidative stress triggers baroreflex dysfunction in several models of hypertension. Finally, we will describe some novel therapeutic drugs for improving the BRS during hypertension.

Abstract 250: Endothelial Cell Endothelin (ET-1) Production is Enhanced with Increasing NaCl Concentration.

It has recently been demonstrated that increasing salt intake results in an accumulation of sodium within the interstitium of the skin of normal rats, which leads to an immune response that is necessary to maintain normal blood pressure. ET-1 mediates increased inflammation in several models of hypertension and is increased in response to high salt intake. However, it is unknown if ET-1 production is increased by endothelial cells in response to increasing NaCl concentration. Therefore, we hypothesized that increasing the media NaCl concentration will lead to an increase in ET-1 production by human umbilical venous endothelial cells (HUVECs). Exposure of HUVECs for 2 hours to a 40 mosm increase in NaCl results in a significant increase in ET-1 mRNA (1.65±0.14 fold increase vs. control; n=3, p<0.05). This increase in Na+ concentration is similar to that observed in the interstitium of the skin of rats placed on a high NaCl diet. Furthermore, exposure to +40 mosm of mannitol, an effective osmolyte, or urea, an ineffective osmolyte, had no effect on ET-1 mRNA (1.1 ± 0.04 fold change and 1.07 ± .08 fold change vs. control, respectively; n=3, p<0.05) suggesting that a direct effect of NaCl, not osmolality, is responsible for the increase in ET-1 mRNA. Moreover, +40 mosm of sodium acetate (NaAc) or choline chloride (ChCl) resulted in an increase in ET-1 mRNA very similar to that seen by increasing NaCl (1.74±0.14 (NaCl), 1.54±0.05 (NaAc), and 1.59±0.03 (ChCl) fold change vs. control, n=3, p<0.05), suggesting that either the Na or Cl ion increases ET-1 expression. These data demonstrate that vascular endothelial cells express ET-1 in response to increases in NaCl concentration, and may be important in mediating the extrarenal inflammatory response to a high salt diet.

Abstract 320: Cardiovascular Phenotype of PCSK9 Knockout Mice

Proprotein convertase subtisilin kexin type 9 (PCSK9) promotes LDL receptor (LDLR) degradation and its absence confers life-long low LDL-cholesterol, protection against coronary artery disease. Afro-americans patients with nonsense PCSK9 mutations are less prone to hypertension and plasma PCSK9 is weakly associated to blood pressure (BP) in large cohorts. Recent evidences suggest that PCSK9 degrades the VLDLR in the adipose tissue. This receptor has been involved in hypoxia-induced lipotoxicity following myocardial infarction. Objectives: We aimed at verifying whether PCSK9 affects heart VLDLR content, myocardial function and BP. Methods: We used PCSK9 -/- and PCSK9+/+ mouse littermates (n = 4-6 per group, 3 to 4 month-old males). Two-dimensional LV long-axis and M-mode images were obtained by echocardiography. Mice were also chronically treated with L-NAME (2 mg/kg/d), angiotensin II (minipump, 1 mg/kg/d ) or DOCA-Salt following unilateral nephrectomy.". BP was measured under a 12:12-hour light/dark schedule using a radiotelemetry system or by computerized tail cuff plethysmography. Results: Hearts from random-fed PCSK9 -/- mice didn’t have more VLDLR content (protein and mRNA) than those of PCSK9+/+ mice and had equal TG contents. Fasting (12h) increased myocardial TG contents to the same extent in both genotypes (+ 100%, fed PCSK9++, PCSK9 -/- vs fasted PCSK9++, PCSK9-/-: 18±5,4 microg/mg, 18,5± 11 microg/mg vs 36±3,5 microg/mg, 38± 5,1 microg/mg, n=3). Despite a ∼6-fold increase in plasma PCSK9 concentrations compared to C57Bl6J mice, hearts from LDLR knockout mice had equal quantities of VLDLR protein. Injecting (i.v.) 125 μg of hPCSK9 in PCSK9+/+ mice (>300 times the physiological concentration) led to an 83% (p<0.05) decrease in mature VLDLR, in the heart and to a >90% decrease of hepatic LDLR, as measured by western blot 1h after the injection. Thus, supra-physiological concentrations of PCSK9 can acutely degrade the VLDLR in mouse heart. The dimensions of the ventricular cavity and the thickness of the septal and the posterior walls as well as LV systolic and diastolic functions were unchanged in PCSK9 -/- mice. In addition, PCSK9-deficiency did not alter either basal BP or the elevated BP in several models of hypertension. Collectively these results show that PCSK9 deficiency is neutral on blood pressure or myocardium function at a young age in mice. Plasma PCSK9 at physiological or pathophysiological concentrations do not decrease VLDLR content in the heart.

Alpha2-adrenergic receptor distribution and density within the nucleus tractus solitarii of normotensive and hypertensive rats during development

The nucleus tractus solitarii (NTS), located in the brainstem, is one of the main nuclei responsible for integrating different signals in order to originate a specific and orchestrated autonomic response. Antihypertensive drugs are well known to stimulate alpha2-adrenoceptor (alpha2R) in brainstem cardiovascular regions to induce reduction in blood pressure. Because alpha2R impairment is present in several models of hypertension, the aim of the present study was to investigate the distribution and density of alpha2R binding within the NTS of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during development (1,15,30 and 90day-old) by an in vitro autoradiographical study. The NTS shows heterogeneous distribution of alpha2R in dorsomedial/dorsolateral, subpostremal and medial/intermediate subnuclei. Alpha2R increased from rostral to caudal dorsomedial/dorsolateral subnuclei in 30 and 90day-old SHR but not in WKY. Alpha2R decreased from rostral to caudal subpostremal subnucleus in 15, 30 and 90day-old SHR but not in WKY. Medial/intermediate subnuclei did not show any changes in alpha2R according to NTS levels. Furthermore, alpha2R are decreased in SHR as compared with WKY in all NTS subnuclei and in different ages. Surprisingly, alpha2R impairment was also found in pre-hypertensive stages, specifically in subpostremal subnucleus of 15day-old rats. Finally, alpha2R decrease from 1 to 90day-old rats in all subnuclei analyzed. This decrease is different between strains in rostral dorsomedial/dorsolateral and caudal subpostremal subnuclei within the NTS. In summary, our results highlight the importance of alpha2R distribution within the NTS regarding the neural control of blood pressure and the development of hypertension.

Angiotensin-(1-7) Blockade Attenuates Captopril- or Hydralazine-induced Cardiovascular Protection in Spontaneously Hypertensive Rats Treated With NG-nitro-l-Arginine Methyl Ester

We assessed the contribution of angiotensin-(1-7) [Ang-(1-7)] to captopril-induced cardiovascular protection in spontaneously hypertensive rats (SHRs) chronically treated with the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (SHR-l). NG-nitro-L-arginine methyl ester (80 mg/L) administration for 3 weeks increased mean arterial pressure (MAP) from 196 ± 6 to 229 ± 3 mm Hg (P < 0.05). Treatment of SHR-l with Ang-(1-7) antagonist [d-Ala7]-Ang-(1-7) (A779; 744 μg·kg(-1)·d(-1) ip) further elevated MAP to 253 ± 6 mm Hg (P < 0.05 vs SHR-l or SHR). Moreover, A779 treatment attenuated the reduction in MAP and proteinuria by either captopril (300 mg/L in drinking water) or hydralazine (1.5 mg·kg(-1)·d(-1) ip). In isolated perfused hearts, the recovery of left ventricular function from global ischemia was enhanced by captopril or hydralazine treatment and was exacerbated with A779. The Ang-(1-7) antagonist attenuated the beneficial effects of captopril and hydralazine on cardiac function. Recovery from global ischemia was also improved in isolated SHR-l hearts acutely perfused with captopril during both the perfusion and reperfusion periods. The acute administration of A779 reduced the beneficial actions of captopril to improve recovery after ischemia. We conclude that during periods of reduced nitric oxide availability, endogenous Ang-(1-7) plays a protective role in effectively buffering the increase in blood pressure and renal injury and the recovery from cardiac ischemia. Moreover, Ang-(1-7) contributes to the blood pressure lowering and tissue protective actions of captopril and hydralazine in a model of severe hypertension and end-organ damage.

Intermittent Hypoxia in Rats Increases Myogenic Tone Through Loss of Hydrogen Sulfide Activation of Large-Conductance Ca 2+ -Activated Potassium Channels

Myogenic tone, an important regulator of vascular resistance, is dependent on vascular smooth muscle (VSM) depolarization, can be modulated by endothelial factors, and is increased in several models of hypertension. Intermittent hypoxia (IH) elevates blood pressure and causes endothelial dysfunction. Hydrogen sulfide (H(2)S), a recently described endothelium-derived vasodilator, is produced by the enzyme cystathionine γ-lyase (CSE) and acts by hyperpolarizing VSM. Determine whether IH decreases endothelial H(2)S production to increase myogenic tone in small mesenteric arteries. Myogenic tone was greater in mesenteric arteries from IH than sham control rat arteries, and VSM membrane potential was depolarized in IH in comparison with sham arteries. Endothelium inactivation or scavenging of H(2)S enhanced myogenic tone in sham arteries to the level of IH. Inhibiting CSE also enhanced myogenic tone and depolarized VSM in sham but not IH arteries. Similar results were seen in cerebral arteries. Exogenous H(2)S dilated and hyperpolarized sham and IH arteries, and this dilation was blocked by iberiotoxin, paxilline, and KCl preconstriction but not glibenclamide or 3-isobutyl-1-methylxanthine. Iberiotoxin enhanced myogenic tone in both groups but more in sham than IH. CSE immunofluorescence was less in the endothelium of IH than in sham mesenteric arteries. Endogenouse H(2)S dilation was reduced in IH arteries. IH appears to decrease endothelial CSE expression to reduce H(2)S production, depolarize VSM, and enhance myogenic tone. H(2)S dilatation and hyperpolarization of VSM in small mesenteric arteries requires BK(Ca) channels.

Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis

Thromboxane A(2) and other eicosanoids such as isoprostanes contribute to vascular proliferation and atherosclerosis by binding to the thromboxane/prostaglandin endoperoxide receptors. The effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on aorta remodeling were evaluated in spontaneously hypertensive stroke-prone rats (SHRSPs), a model of severe hypertension, endothelial dysfunction, vascular inflammation, and cerebrovascular diseases. Male SHRSPs were allocated to three groups receiving a standard diet (n = 5) or a high-sodium permissive diet plus vehicle (n = 6) or plus terutroban (30 mg · kg(-1) · day(-1); n = 6). After 6 wk of dietary treatment, all of the animals were injected with bromodeoxyuridine and simultaneously euthanized for aorta collection. The aortic media thickness-to-lumen ratio significantly (P < 0.0001) increased in the salt-loaded rats compared with the rats fed a standard diet, whereas terutroban treatment completely prevented media thickening (P < 0.001). When compared with vehicle, terutroban was also effective in preventing cell proliferation in the media, as indicated by the reduced number of bromodeoxyuridine-positive (P < 0.0001) and proliferating cell nuclear antigen-positive cells (P < 0.0001). Severe fibrosis characterized by a significant accumulation of collagen and fibronectin in the vascular wall was observed in the vehicle-treated rats (P < 0.01) but was completely prevented by terutroban (P < 0.001). The latter also inhibited heat shock protein-47 (P < 0.01) and TGF-1β expression (P < 0.001), which were significantly increased by the high-salt diet. In conclusion, terutroban prevents the development of aorta hyperplasia and has beneficial effects on fibrotic processes by affecting TGF-β and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.

A high fat diet reduces blood pressure, but not cardiac hypertrophy in spontaneously hypertensive rats

High fat diets can attenuate cardiac hypertrophy in Dahl Salt Sensitive rats (DSS), a model of severe hypertension, cardiac hypertrophy &amp; dysfunction, independent of changes in blood pressure. We hypothesized that a high fat diet can prevent hypertrophy in spontaneously hypertensive rats (SHR), a model of gradually increasing hypertension. Five‐week old SHR and Wistar Kyoto (WKY; normotensive control) rats were fed either a low fat (LF) or high fat (HF) diet with 10% and 60% of Calories from lard, respectively, for 10 weeks. In contrast to our hypothesis, cardiac hypertrophy was unchanged in SHR HF vs. SHR LF but, surprisingly, blood pressure was lower in SHR HF. Pooled statistical analysis also indicated lower plasma glucose (2 h fast) in HF vs. LF rats. These data indicate a markedly different response to high fat diets in the SHR vs. those previously reported in the DSS rats.(Different letters denote significant differences at p&lt;0.05)

Heme Oxygenase in Regulation of Renal Function and Blood Pressure

The regulation of blood pressure is dependent on multiple interacting mechanisms that influence body fluid volume, sodium balance, and vascular function. Impairments in kidney function can lead to activation of the renin- angiotensin system and inappropriate sodium and fluid retention leading to hypertension. The heme-heme oxygenase sys- tem is a recently identified antihypertensive regulatory mechanism. Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, free iron and carbon monoxide (CO). Biliverdin is converted to bilirubin by biliverdin reductase and is an endogenous antioxidant. In this review, we discuss the role of HO in regulating kidney function and blood pressure in normal conditions and during hypertension. CO modulates renal vascular tone and salt transport. CO exerts renal vasodila- tory effects causing an increase in renal blood flow. Induction of HO also alters expression and activity of renal heme en- zymes that regulate renal hemodynamics and renal function. While HO inhibition causes an increase in blood pressure, renal HO induction attenuates the development of hypertension in several models of hypertension suggesting an important role for HO in regulation of renal function and blood pressure.

Intermittent hypoxia in rats augments myogenic contraction in mesenteric arteries.

Myogenic tone is an important regulator of vascular resistance and is increased in several models of hypertension. Ca2+ sparks can decrease vascular smooth muscle contraction and have been proposed to regulate myogenic tone. We previously reported that exposing rats to eucapnic intermittent hypoxia (E‐IH) to simulate sleep apnea causes hypertension and augments agonist‐induced vascular reactivity. We hypothesized that E‐IH increases myogenic reactivity and decreases Ca2+ spark frequency in rat mesenteric arteries. Small mesenteric arteries were dissected from rats exposed to E‐IH or air cycling (Sham) for 14 days. Intracellular Ca2+ concentration ([Ca2+]i) and inner diameter (i.d.) were recorded in pressurized arteries loaded with fura‐2 AM. Rapid intracellular Ca2+ events were recorded in arteries loaded with fluo‐4 AM. Elevating intraluminal pressure from 60 to 100 mmHg increased myogenic tone and global [Ca2+]i in arteries from E‐IH rats (13.20 ± 5.49 to 30.63 ± 5.56 % Ca2+‐free i.d. and 1.33 ± 0.11 to 1.56 ± 0.11 F340/F380) but not those from Sham rats (11.56 ± 2.95 to 13.97 ± 3.37 % Ca2+‐free i.d. and 1.30 ± 0.07 to 1.44 ± 0.08 F340/F380). The same pressure step tended to increase spark frequency in Sham but not E‐IH arteries. These results support our hypothesis that E‐IH augments the development of myogenic tone through increased global [Ca2+]i associated with decreased Ca2+ spark frequency.

ACUTE PRESSURE–NATRIURESIS RELATIONSHIP FOLLOWING WITHDRAWAL OF CHRONIC NORADRENALINE INFUSION

1. Pathological changes to the kidney, such as vascular remodelling, have been found in several models of hypertension and may contribute to the maintenance of hypertension or confer susceptibility to redeveloping hypertension after the original prohypertensive stimulus is withdrawn. 2. To investigate whether noradrenaline-induced hypertension induces persistent, functionally important changes to the kidney, the acute pressure-natriuresis relationship was characterized in anaesthetized rats under controlled neural and hormonal conditions following chronic (14 days) intravenous infusion of noradrenaline (48 microg/kg per h) or vehicle (0.04 mg/mL ascorbic acid and 0.156 mg/mL NaH2PO4 2 H2O in 10 IU/mL heparinized saline). 3. Conscious mean arterial pressure was significantly elevated by infusion of noradrenaline at 48 microg/kg per h (+10 +/- 2 mmHg at Day 14; P < 0.01 vs vehicle group). The acute relationships between arterial pressure and renal blood flow, glomerular filtration rate, Na+ excretion and urine flow were not significantly different between the noradrenaline- and vehicle-infused rats immediately after termination of noradrenaline infusion. 4. In summary, chronic intravenous noradrenaline infusion did not cause persistent changes in renal function, indicating that, in contrast with many models of hypertension, this model does not induce underlying prohypertensive changes to the kidney.

Prevention and Reversal by Enalapril of Target Organ Damage in Angiotensin II Hypertension

Angiotensin-converting enzyme inhibitors (ACE-Is) prevent target organ damage in several models of hypertension. The aim of this study was to assess the influence of the ACE-I enalapril (10 mg/kg(-1) per day, gavage) on the cardiovascular alterations and production of free radicals induced by chronic infusion of angiotensin II (Ang II, 200 ng/kg(-1) per minute, s.c.) in Sprague-Dawley rats. Enalapril was given concomitantly for the 10 days of Ang II infusion (prevention) or from day 10 to 17 of Ang II infusion (intervention). The influence of the NADPH oxidase inhibitor apocynin (600 mg/L(-1) in drinking water) was evaluated. Enalapril and apocynin had no effect on hypertension in the prevention and intervention studies. Enalapril prevented the increase in heart weight index (HWI), carotid cross-sectional area (CSA) and albuminuria induced by Ang II. Enalapril reduced HWI and albuminuria whereas CSA was not affected in the intervention study. Apocynin had effects comparable to enalapril. Both enalapril and apocynin reduced the overproduction of superoxide anion by the left ventricle and rise in advanced oxidation protein products induced by Ang II. Therefore, the antioxidant but not the antihypertensive effect of enalapril may participate in the prevention and treatment of the Ang II-induced cardiovascular and renal alterations.