Increase In Vascular Reactivity Research Articles

Increasing Vascular Response to Injury Improves Tendon Early Healing Outcome in Aged Rats.

Tendon injuries positively correlate with patient age, as aging has significant effects on tendon homeostatic maintenance and healing potential after injury. Vascularity is also influenced by age, with both clinical and animal studies demonstrating reduced blood flow in aged tissues. However, it is unknown how aging effects vascularity following tendon injury, and if this vascular response can be modulated through the delivery of angiogenic factors. Therefore, the objective of this study is to evaluate the vascular response following Achilles tendon injury in adult and aged rats, and to define the alterations to tendon healing in an aged model following injection of angiogenic factors. It was determined that aged rat Achilles tendons have a reduced angiogenesis following injury. Further, the delivery of vascular endothelial growth factor, VEGF, caused an increase in vascular response to tendon injury and improved mechanical outcome in this aged population. This work suggests that reduced angiogenic potential with aging may be contributing to impaired tendon healing response and that the delivery of angiogenic factors can rescue this impaired response. This study was also the first to relate changes in vascular response in an aged model using in vivo measures of blood perfusion to alterations in healing properties.

Cardiovascular and Autonomic Responses after a Single Bout of Resistance Exercise in Men with Untreated Stage 2 Hypertension.

The aim of this paper is to assess the integrated responses of ambulatory blood pressure (BP), cardiac autonomic modulation, spontaneous baroreflex sensitivity (BRS), and vascular reactivity after a single bout of resistance exercise (RE) in men with stage 2 hypertension who have never been treated before. Ten hypertensive men were subjected to a RE session of three sets of 20 repetitions and an intensity of 40% of the 1-repetition maximum (RM) test in seven different exercises. For the control (CTR) session, the volunteers were positioned on the exercise machines but did not perform any exercise. Forearm blood flow was measured by venous occlusion plethysmography. We also analyzed the heart rate variability (HRV), ambulatory BP, blood pressure variability (BPV), and BRS. All measurements were performed at different timepoints: baseline, 20 min, 80 min, and 24 h after both RE and CTR sessions. There were no differences in ambulatory BP over the 24 h between the RE and CTR sessions. However, the area under the curve of diastolic BP decreased after the RE session. Heart rate (HR) and cardiac output increased for up to 80 and 20 min after RE, respectively. Similarly, forearm blood flow, conductance, and vascular reactivity increased 20 min after RE (p < 0.05). In contrast, HRV and BRS decreased immediately after exercise and remained lower for 20 min after RE. We conclude that a single bout of RE induced an increase in vascular reactivity and reduced the pressure load by attenuating AUC of DBP in hypertensive individuals who had never been treated with antihypertensive medications.

ERK and miRNA-1 target Cx43 expression and phosphorylation to modulate the vascular protective effect of angiotensin II

Aims and methodsWe previously reported that angiotensin II (AngII) restores the vascular reactivity diminished by hemorrhagic shock. In this study, we investigated whether the beneficial effects of AngII are related to regulation of gap junctions (GJs) and connexin43 (Cx43), and the implication of MAPK signaling and microRNA (miR-1) in this process. Key findingsOur results show that after hemorrhagic shock or hypoxia, the blockade of GJs or knockdown of Cx43 inhibits the AngII-induced increase in vascular reactivity of superior mesenteric arteries and the contractile response of vascular smooth muscle cells (VSMCs). AngII treatment increases Cx43 expression and phosphorylation at Ser262, and restores gap-junctional communication (GJIC) between VSMCs after hypoxia. The AngII-induced up-regulation of Cx43 expression and phosphorylation is blocked in cells transduced with ERK-siRNA, but is not blocked in cells transduced with p38-siRNA. miR-1 levels are elevated after hypoxia; AngII treatment reverses the up-regulation of miR-1, while ERK-siRNA abolishes that effect of AngII. In hypoxic cells, transfection of a miR-1 mimic into VSMCs decreases Cx43 expression and VSMC reactivity, whereas a miR-1 inhibitor increases both. Also in hypoxic cells, miR-1 eliminates the restoration effects of AngII on Cx43 expression and VSMC reactivity. SignificanceAngII provides protection of vascular function through the restoration of the expression and phosphorylation of Cx43 and its mediated GJIC in VSMCs. It is ERK that mediates the AngII-induced phosphorylation of Cx43 at Ser262. Additionally, miR-1 is involved in this process, and AngII may exert its protective effect partially by inhibiting miR-1 elevation via ERK signaling.

РОЛЬ ЭНДОТЕЛИАЛЬНОЙ ДИСФУНКЦИИ В ФОРМИРОВАНИИ ОСЛОЖНЕНИЙ САХАРНОГО ДИАБЕТА И ПЕРСПЕКТИВЫ ЕЕ КОРРЕКЦИИ РЕЦЕПТОРНЫМ АНТАГОНИСТОМ ИНТЕРЛЕЙКИНА-1

Цукровий діабет (ЦД) – неухильно прогресуюче захворювання, що вражає переважно осіб працездатного віку і швидко приводить до розвитку системних ускладнень. ЦД посідає третє місце в статистиці смертності після серцево-судинних і онкологічних захворювань. Основною причиною інвалідизації і летальності при ЦД є мікро- і макросудинних ускладнення, що призводять до розвитку серцево-судинних та цереброваскулярних захворювань. Діабет асоціюється з підвищеним ризиком розвитку інфаркту міокарда та ішемічного інсульту і з їх менш успішним результатом.Мета дослідження – провести загальний огляд і теоретичний аналіз репрезентативних фактів у галузі досліджень різних аспектів формування та прогресування ендотеліальної дисфункції при цукровому діабеті.Матеріали і методи. У статті використано дані з наукових праць, літературних джерел, офіційних документів, архівів, статистичних збірників, що опираються на фактичний матеріал. Застосовано поаспектний метод вирішення завдань оптимізації оцінки взаємозв'язків, взаємозалежності та значимості фактів, аргументованих доказів і теоретичних узагальнень, обґрунтування логічних висновків і практичних рекомендацій.Результати досліджень та їх обговорення. Основним фактором, що ушкоджує, є гіперглікемія, яка через активацію сорбітолового шляху, протеїнкінази С і глікування білків призводить до розвитку оксидативного стресу, зменшення утворення оксиду азоту, активації прозапального шляху NF-kB, що сприяє прискореному прогресуванню макроангіопатій, а також викликає ушкодження мікросудинного русла. Церебральна мікроангіопатія є частиною генералізованих судинних ускладнень, що спостерігаються при діабеті, і більш частий несприятливий результат у цих хворих може бути зумовлений системним характером судинного ураження і негативним впливом гіперглікемії на перебіг ішемічного процесу. Передбачається, що при ЦД раніше спостерігається пошкодження внутрішнього шару судинної стінки – ендотелію. Ендотелій у нормі забезпечує трофічну і захисну функції відносно інших верств судинної стінки. Саме ендотелію належить головна роль у підтримці тонусу судин і гемостазу, в розвитку ремоделювання і місцевого запалення (вироблення про- і протизапальних факторів). Порушення функції ендотелію і формування дисфункції ендотелію у хворих з інсулінорезистентністю призводить до підвищення судинної реактивності. Дисбаланс вазоконстрикторів і вазодилататорів є одним із ланок патогенезу діабетичних ангіопатій, оскільки тригерні фактори включають процеси запалення зі зміною функції гладком’язового шару і надмірним утворенням прозапальних цитокінів.Висновки. Застосування препаратів з ендотеліопротекторними властивостями можна розглядати як першочергову лінію ефективного попередження судинних і неврологічних ускладнень у хворих на ЦД. У статті обґрунтовуються перспективи корекції ендотеліальної дисфункції протизапальним цитокіновим препаратом – рецепторним антагоністом інтерлейкіну-1.

Effects of a novel ACE inhibitor, 3-(3-thienyl)-l-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in l-NAME-induced hypertensive rats.

Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by NG-nitro-l-arginine methyl ester (l-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-l-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin–angiotensin–aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in l-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in l-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the l-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the l-NAME model.

O053. Interictal cerebral posterior circulation in migraineurs with aura: a trancranial color-coded duplexsonography pilot study

Results An increase in vascular reactivity of mean flow diastolic velocity was observed during visual stimulation in headache-free subjects (Group 1, 10 patients) and in the patients affected by migraine with aura (Group 2, 7 patients), without any differences between right and left sides. Reactivity of mean flow diastolic velocity to visual stimulation was found significantly higher in Group 2 (mean ±SD, 42%±2.6%) vs Group 2 (mean SD, 33.6%±1.8%) (p < 0.001). In contrast, no differences in flow systolic velocity between the two groups were observed.

Contractile force is enhanced in Aortas from pendrin null mice due to stimulation of angiotensin II-dependent signaling.

Pendrin is a Cl−/HCO3 − exchanger expressed in the apical regions of renal intercalated cells. Following pendrin gene ablation, blood pressure falls, in part, from reduced renal NaCl absorption. We asked if pendrin is expressed in vascular tissue and if the lower blood pressure observed in pendrin null mice is accompanied by reduced vascular reactivity. Thus, the contractile responses to KCl and phenylephrine (PE) were examined in isometrically mounted thoracic aortas from wild-type and pendrin null mice. Although pendrin expression was not detected in the aorta, pendrin gene ablation changed contractile protein abundance and increased the maximal contractile response to PE when normalized to cross sectional area (CSA). However, the contractile sensitivity to this agent was unchanged. The increase in contractile force/cross sectional area observed in pendrin null mice was due to reduced cross sectional area of the aorta and not from increased contractile force per vessel. The pendrin-dependent increase in maximal contractile response was endothelium- and nitric oxide-independent and did not occur from changes in Ca2+ sensitivity or chronic changes in catecholamine production. However, application of 100 nM angiotensin II increased force/CSA more in aortas from pendrin null than from wild type mice. Moreover, angiotensin type 1 receptor inhibitor (candesartan) treatment in vivo eliminated the pendrin-dependent changes contractile protein abundance and changes in the contractile force/cross sectional area in response to PE. In conclusion, pendrin gene ablation increases aorta contractile force per cross sectional area in response to angiotensin II and PE due to stimulation of angiotensin type 1 receptor-dependent signaling. The angiotensin type 1 receptor-dependent increase in vascular reactivity may mitigate the fall in blood pressure observed with pendrin gene ablation.

Involvement of proteinase activated receptor-2in the vascular response to sphingosine 1-phosphate

S1P (sphingosine 1-phosphate) represents one of the key latest additions to the list of vasoactive substances that modulate vascular tone. PAR-2 (proteinase activated receptor-2) has been shown to be involved in cardiovascular function. In the present study, we investigated the involvement of PAR-2 in S1P-induced effect on vascular tone. The present study has been performed by using isolated mouse aortas. Both S1P and PAR-2 agonists induced endothelium-dependent vasorelaxation. L-NAME (N(G)-nitro-L-arginine methyl ester) and wortmannin abrogated the S1P-induced vasorelaxatioin, while significantly inhibiting the PAR-2-mediated effect. Either ENMD1068, a PAR-2 antagonist, or gabexate, a serine protease inhibitor, significantly inhibited S1P-induced vasorelaxation. Aortic tissues harvested from mice overexpressing PAR-2 displayed a significant increase in vascular response to S1P as opposed to PAR-2-null mice. Immunoprecipitation and immunofluorescence studies demonstrated that S1P(1) interacted with PAR-2 and co-localized with PAR-2 on the vascular endothelial surface. Furthermore, S1P administration to vascular tissues triggered PAR-2 mobilization from the plasma membrane to the perinuclear area; S1P-induced translocation of PAR-2 was abrogated when aortic rings were pre-treated with ENMD1068 or when caveolae dysfunction occurred. Similarly, experiments performed in cultured endothelial cells (human umbilical vein endothelial cells) showed a co-localization of S1P(1) and PAR2, as well as the ability of S1P to induce PAR-2 trafficking. Our results suggest that S1P induces endothelium-dependent vasorelaxation mainly through S1P(1) and involves PAR-2 transactivation.

Oxidative inhibition of the vascular Na+-K+ pump via NADPH oxidase-dependent β1-subunit glutathionylation: Implications for angiotensin II-induced vascular dysfunction

Glutathionylation of the Na+-K+ pump’s β1-subunit is a key molecular mechanism of physiological and pathophysiological pump inhibition in cardiac myocytes. Its contribution to Na+-K+ pump regulation in other tissues is unknown, and cannot be assumed given the dependence on specific β-subunit isoform expression and receptor-coupled pathways. As Na+-K+ pump activity is an important determinant of vascular tone through effects on [Ca2+]i, we have examined the role of oxidative regulation of the Na+-K+ pump in mediating angiotensin II (Ang II)-induced increases in vascular reactivity. β1-subunit glutathione adducts were present at baseline and increased by exposure to Ang II in rabbit aortic rings, primary rabbit aortic vascular smooth muscle cells (VSMCs), and human arterial segments. In VSMCs, Ang II-induced glutathionylation was associated with marked reduction in Na+-K+ATPase activity, an effect that was abolished by the NADPH oxidase inhibitory peptide, tat-gp91ds. In aortic segments, Ang II-induced glutathionylation was associated with decreased K+-induced vasorelaxation, a validated index of pump activity. Ang II-induced oxidative inhibition of Na+-K+ ATPase and decrease in K+-induced relaxation were reversed by preincubation of VSMCs and rings with recombinant FXYD3 protein that is known to facilitate deglutathionylation of β1-subunit. Knock-out of FXYD1 dramatically decreased K+-induced relaxation in a mouse model. Attenuation of Ang II signaling in vivo by captopril (8mg/kg/day for 7 days) decreased superoxide-sensitive DHE levels in the media of rabbit aorta, decreased β1-subunit glutathionylation, and enhanced K+-induced vasorelaxation. Ang II inhibits the Na+-K+ pump in VSMCs via NADPH oxidase-dependent glutathionylation of the pump’s β1-subunit, and this newly identified signaling pathway may contribute to altered vascular tone. FXYD proteins reduce oxidative inhibition of the Na+-K+ pump and may have an important protective role in the vasculature under conditions of oxidative stress.

Changes in the activity of the Renin Angiotensin System on resistance arteries in isolated perfused heart of hypertensive rats.

High blood pressure (HBP) is a disease with high morbidity and mortality worldwide and is considered one of the main etiological factors of multiple cardiac pathologies. One of the regulatory mechanisms of blood pressure is the Renin Angiotensin System (RAS). It is important consider adjuvant therapies to improve the outlook and quality of life of patients with HBP. One therapy that has been shown clinically to improve the condition of patients with HBP is hyperbaric oxygenation (HBO), that consists in subjecting a subject at a pressure greater than 2 atmospheres absolute with 100% oxygen. This therapy has been shown to improve vascular smooth muscle relaxation, increasing oxygenation of hypoxic tissues, decrease the degree of fibrosis, among other beneficial effects.MethodologyWe used rats Wystar of 340 ± 20 g. A corresponding groups were induced hypertension of renal origin by a surgical method (cellophane method) at the eighth day after surgery we began the therapy OHB. At the end of treatment, the rats were sacrificed getting heart, this was mounted on a system of isolated organ (Langendorff system). Curves to Angiotensin II (Ang II) were obtain in coronary resistance arteries.ResultsThe diastolic pressure measurement was obtained (150 ± 15 mmHg). The HBP group without treatment (control) showed an increase in vascular reactivity in comparison with the healthy group (control) after a dose of 1×10−7M of Ang II (p &lt;0.001). Whereas the study group no presented changes in vascular reactivity to any dose of Ang II, compared to healthy control group (p&gt;; 0.05).

Abstract 121: Cytochrome P450 1B1 Gene Disruption Prevents Cardiac Dysfunction Associated With DOCA-salt-induced Hypertension in Mice

Previously, we have shown that cytochrome P450 (CYP) 1B1 contributes to deoxycorticosterone acetate (DOCA) salt-induced hypertension and associated increase in vascular reactivity, endothelial dysfunction, and vascular oxidative stress in rats. This study was conducted to determine whether Cyp1b1 gene disruption protects against cardiac dysfunction, measured by echocardiography, in this model of hypertension in mice. Eight week old male mice were uninephrectomized, subcutaneously implanted with a DOCA pellet (50mg/kg) and given 1% saline in drinking water for 4 weeks, and blood pressure (BP) was measured weekly by tail cuff method. DOCA-salt treatment increased systolic BP in Cyp1b1 +/+ mice to a greater degree than in Cyp1b1 -/- mice (115 ± 3 to 188 ± 5 mmHg vs. 120 ± 5 to 152 ± 8 mmHg, respectively, P &lt; 0.05). DOCA-salt treatment produced cardiac dysfunction, as indicated by decreased fractional shortening (FS), ejection fraction (EF), and the ratio of peak early to late diastolic mitral annulus velocities (E′/A′), and an increase in both end-diastolic volume and end-systolic volume, in Cyp1b1 +/+ , but not Cyp1b1 -/- mice (Table 1). Cardiac production of reactive oxygen species, as indicated by 2-hydroxyethidium fluorescence intensity, was increased in DOCA-salt treated Cyp1b1 +/+ mice, which was attenuated in Cyp1b1 -/- mice. These data suggest that Cyp1b1 plays a pivotal role in cardiac dysfunction associated with DOCA-salt hypertension in mice by increasing oxidative stress, and that it could serve as a potential target for drugs to treat cardiovascular dysfunction associated with excess mineralocorticoid-salt hypertension.

Endothelial nitric oxide gene haplotype reduces the effect of a single bout of exercise on the vascular reactivity in healthy subjects

Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene reduce shear stress-induced nitric oxide production. Thus, we investigated the individual and combined impact of 3 variants in the eNOS gene (-786T>C, intron 4b4a, and 894G>T) on vascular reactivity before and after exercise. Sedentary, healthy subjects were studied (105 women/26 men, age 32 ± 1 years [mean ± standard error of the mean]). Genotypes were determined by polymerase chain reaction restriction fragment length polymorphism, and haplotypes were determined by a Bayesian-based algorithm. Vascular reactivity was evaluated by the percentage of change in forearm vascular conductance provoked by 5 minutes of circulatory occlusion before (baseline) and 10, 60, and 120 minutes after a maximal cardiopulmonary exercise test. Vascular reactivity increased 10 minutes after exercise in the entire sample (baseline: 218 ± 11% vs 10 minutes: 284 ± 15%, P < 0.001), remained increased at 60 minutes (239 ± 12%, P = 0.02 vs baseline), and returned to baseline at 120 minutes (210 ± 10%, P = 0.83 vs baseline). Genotype analysis showed that subjects with the 894G>T polymorphism had lower vascular reactivity than wild counterparts (group effect, P = 0.05). Furthermore, subjects with haplotype 2 (H2), containing the -786T>C and 894G>T polymorphisms, had lower vascular reactivity than wild counterparts (haplotype 1 [H1]) (group effect, P = 0.05), whereas subjects with haplotype 4 (H4), containing only the 894G>T polymorphism, had vascular reactivity similar to that of wild counterparts (H1) (group effect, P = 0.35). Altogether, these results indicate that the 894G>T polymorphism reduced exercise-mediated increase in vascular reactivity, particularly when it occurred concomitantly with the -786T>C polymorphism.

The beneficial vascular effects of cacao flavanols: having your cake and eating it too

a significant number of epidemiological studies report on the apparent beneficial effects of chocolate (i.e., cocoa) consumption on cardiovascular health, including reductions in morbidity and mortality ([1][1], [2][2], [4][3]). However, these reports are mostly of retrospective nature and do not

Contrast-Enhanced Sonographic Characterization of the Vascularity of the Repaired Rotator Cuff

To characterize the distribution of vascularity of the postoperative rotator cuff tendon using a maximum intensity projection technique after contrast-enhanced sonography. We retrospectively evaluated image data on 23 patients (11 male and 12 female) with intact rotator cuff repairs who had previously undergone contrast-enhanced sonography of their shoulders using lipid microspheres before and after a standardized exercise protocol. The patients were on average 3 months out from their surgery. Using offline image analysis software, a maximum intensity projection image was obtained for each patient, reflecting the regional vascular distribution within the repair and adjacent soft tissue. Subjective analysis was performed in 4 regions of interest: peribursal, articular medial, articular lateral, and suture anchor, independently by 2 musculoskeletal radiologists using a semiquantitative scale ranging from 0 to 4 for each region (0, no enhancement; 1, 1%-25% enhancement; 2, 26%-50%; 3, 51%-75%; and 4, 76%-100%). A combined vascularity score (0-8) was produced for each region and formed the basis for the subjective analysis. Using a Mann-Whitney nonparametric test, the data showed significantly higher regional enhancement in the peribursal and suture anchor regions compared to the tendon (P < .001). Exercise resulted in a statistically significant increase in the extent of enhancement in all regions (P < .002). Inter-rater reliability analysis using a weighted κ statistic showed strong agreement (0.63-0.64) for the suture anchor site and moderate agreement for the others (peribursal, 0.35-0.39; articular medial, 0.45-0.55; and articular lateral 0.32-0.33). The maximum intensity projection technique after contrast-enhanced sonography provides a topographic map of rotator cuff vascularity; the latter has been implicated as an important factor in promoting bone-tendon healing. Approximately 3 months after rotator cuff repair, the suture anchor and peribursal regions showed the most robust vascularity. Maximum intensity projection imaging further establishes that there is a global increase in vascular response at the repair site after exercise.

Effects of Ischemic Preconditioning on Vascular Reactivity and Calcium Sensitivity After Hemorrhagic Shock and Their Relationship to the Rho A-Rho-kinase Pathway in Rats

We investigated the effect of ischemic preconditioning (IPC) on vascular reactivity and calcium sensitivity after hemorrhagic shock and its relationship to the RhoA–Rho-kinase pathway. Using hemorrhagic-shock rats (40 mm Hg for 3 hours) and isolated rings of the superior mesenteric artery (SMA), the effects of IPC (abdominal aorta occlusion applied 2 hours before shock) on the pressor effect of norepinephrine (3 μg/kg), vascular reactivity and calcium sensitivity of SMA, and the activity and role of RhoA and Rho-kinase were investigated. IPC with 1-minute occlusion plus 5-minute loosening of aneurysm clips thrice significantly increased survival time and prevalence of survival at 24 hours of hemorrhagic-shock rats. This IPC condition also significantly increased the pressor response of norepinephrine and significantly improved the vascular reactivity and calcium sensitivity of the SMA. The activity of Rho-kinase and RhoA in the SMA decreased after hemorrhagic shock, but increased after IPC. Y-27632 (Rho-kinase antagonist) and C3 Transferase (RhoA antagonist) significantly decreased IPC-induced increase in vascular reactivity and calcium sensitivity. These results suggested that IPC can improve shock-induced vascular hyporeactivity and calcium desensitization. The RhoA–Rho-kinase pathway played an important part in this process. These findings suggested that the RhoA–Rho-kinase pathway may be a potential target to treat vascular hyporeactivity in severe trauma, shock, or multiple-organ dysfunction syndrome.

2,3′,4,5′-Tetramethoxystilbene prevents deoxycorticosterone-salt-induced hypertension: contribution of cytochrome P-450 1B1

Reactive oxygen species (ROS) contribute to various models of hypertension, including deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Recently, we have shown that ROS, generated by cytochrome P-450 1B1 (CYP1B1) from arachidonic acid, mediate vascular smooth muscle cell growth caused by angiotensin II. This study was conducted to determine the contribution of CYP1B1 to hypertension and associated pathophysiological changes produced by DOCA (30 mg/kg) given subcutaneously per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 wk. DOCA-salt treatment increased systolic blood pressure (SBP). Injections of the selective inhibitor of CYP1B1, 2,3',4,5'-tetramethoxystilbene (TMS; 300 μg/kg ip every 3rd day) initiated at the 4th week of DOCA-salt treatment normalized SBP and decreased CYP1B1 activity but not its expression in the aorta, heart, and kidney. TMS also inhibited cardiovascular and kidney hypertrophy, prevented the increase in vascular reactivity and endothelial dysfunction, and minimized the increase in urinary protein and K(+) output and the decrease in urine osmolality, Na(+) output, and creatinine clearance associated with DOCA-salt treatment. These pathophysiological changes caused by DOCA-salt treatment and associated increase in vascular superoxide production, NADPH oxidase activity, and expression of NOX-1, and ERK1/2 and p38 MAPK activities in the aorta, heart, and kidney were inhibited by TMS. These data suggest that CYP1B1 contributes to DOCA-salt-induced hypertension and associated pathophysiological changes, most likely as a result of increased ROS production and ERK1/2 and p38 MAPK activity, and could serve as a novel target for the development of agents like TMS to treat hypertension.

DOCA/Salt‐induced hypertension and associated increase in vascular reactivity and cardiac and vascular hypertrophy are mediated by cytochrome P450 1B1

Arachidonic acid (AA) metabolites derived via lipoxygenase and cytochrome P450 (CYP) 4A1, 12‐ and 20‐hydroxyeicosatetranoic acids (HETEs) respectively, have been implicated in the development of hypertension. CYP1B1 also metabolizes AA into HETEs in vitro. This study was conducted to determine the contribution of CYP1B1 in DOCA/Salt‐induced hypertension. DOCA, 30 mg/kg given sc. per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 weeks, increased mean arterial pressure (MAP) (154 ± 1 mmHg) compared to sham operated normotensive rats (95 ± 1 mmHg) (P&lt;0.05). Administration of CYP1B1 inhibitor, 2, 4, 3′, 5′‐tetramethoxystilbene (TMS, 300 μg/kg, i.p. every 3rd day) initiated at 4th week of DOCA/Salt treatment, decreased MAP to levels not different from normotensive levels (96 ± 1 mmHg) (P&gt;0.05). TMS also decreased CYP1B1 activity but not its expression in the aorta, heart and kidney and prevented the increase in mesenteric artery response to phenylephrine, cardiac and vascular hypertrophy, reactive oxygen species (ROS) production and ERK1/2 and p38 MAPK activity in the aorta produced by DOCA/Salt. These data suggest that DOCA/Salt‐induced hypertension is mediated by CYP1B1 as a result of increased ROS production, ERK1/2 and p38 MAPK activity, vascular reactivity and hypertrophy and could serve as a novel target for the development of agents like TMS for the treatment of hypertension.

It's not my nerves! Augmented pressor response to stress in multiparous rats is not associated with increased sympathetic outflow.

There is epidemiological evidence that multiparity (multiple pregnancies) increases the long‐term risk for cardiovascular disease. We have shown that multiparous rats have an augmented pressor response to stress. This is due, at least in part, to an oxidative stress induced increase in vascular reactivity. We proposed that the augmented pressor response in the multiparous rats was also the result of a greater increase in sympathetic outflow. Age‐matched multiparous and virgin rats were implanted with telemetric devices to monitor renal sympathetic nerve activity (Telemetry Research) and blood pressure (DSI). One week later, they were exposed to 10 sec air jet. The stress‐induced increase in integrated mean amplitude of nerve activity was significantly higher in the virgin animals (Virgin: 3.2±1.6 uV to 36.5±12.2 uV; Multiparous: 0.8±0.6 uV to 8.9±6.2 uV; P&lt;0.05). There was no difference between the groups with respect to the increase in spike frequency (Virgin: 28.2±7.8 to 36.6±10.0 spikes/sec; Multiparous: 16.6±2.8 to 28.6±1.4 spikes/sec; P&gt;0.05). We conclude that, contrary to our hypothesis, the augmented pressor response of multiparous rats is due solely to increased vascular reactivity, not to a greater increase in sympathetic outflow. (HSFC)

The Endothelin Receptor Antagonist CPU0213 is More Effective Than Aminoguanidine to Attenuate Isoproterenol-induced Vascular Abnormality by Suppressing Overexpression of NADPH Oxidas, ETA, ETB, and MMP9 in the Vasculature

An increase in reactive oxygen species (ROS) through NADPH oxidase activation frequently follows stress that activates beta-adrenoreceptors, leading to deterioration of cardiovascular disease. We hypothesized that upregulation of NADPH oxidase in the vasculature causes mild vascular spasm subsequent to chronic isoproterenol (ISO) administration, correlating significantly with activation of both ETA and ETB receptors. We tested whether the dual endothelin receptor antagonist CPU0213 is effective in reversing ISO-induced vascular abnormality by suppressing activated NADPH oxidase in the vasculature. Rats were injected with ISO (1 mg/kg, SC) for 10 days to induce vascular dysfunction and treated with CPU0213 (30 mg/kg, SC) or aminoguanidine (AMG, an inhibitor of iNOS, 100 mg/kg, PO) from day 7 to day 10. On day 11, we found an increase in vascular response to phenylephrine (Phe) and reductions in NO availability and acetylcholine (ACh)-induced relaxation in ISO-treated rats along with upregulated mRNA of ETA, ETB, iNOS, NADPH oxidase-Phox22 and Phox47, and matrix metalloproteinase 9 (MMP9). These abnormalities were attenuated by 3 days of intervention with CPU0213 but less with AMG. CPU0213 was more effective in relieving enhanced vascular constriction and reversal of ET receptor and MMP9 expression in the vasculature than was AMG. In conclusion, an upregulation of NADPH oxidase phox 22 and phox 47, ETA and ETB, and MMP9 correlates with vascular abnormality and the endothelin receptor antagonist CPU0213 was more effective than AMG in reversing ISO-induced enhanced vascular constriction by normalizing the above abnormal expression.

Microvascular soft tissue changes in alveolar distraction osteogenesis

The aim of the study was to quantify the effect of distraction osteogenesis on the changes in vascular density in the human oral mucosa. Alveolar distraction was performed in 10 patients with alveolar ridge deficiencies, while in the contralateral nondistracted site an implant was placed. The distraction device was activated after 7 days of latency starting with a distraction rate of 1 mm a day for a 1-week period. After completion of distraction the segments were held in fixation for 6 weeks. Microvascular images were obtained with the use of orthogonal polarization spectral imaging. From day 1 postoperatively until the end of consolidation, microvascular changes in capillary density were assessed. All patients had a good response to the osseous distraction. No dehiscence or infections were observed. In all patients microvascular changes consisted of a bilateral decrease in capillary density and capillary index immediately following surgery. No significant differences between the distraction site and nondistracted implant site were observed during the latency phase or consolidation phase. Capillary vessel count revealed a mean of 14.6 +/- 2.7 vessels per visual field (VF) at day 5 of distraction versus 16.6 +/- 2.9 vessels/VF in the nondistracted site, which increased to a mean of 33.4 +/- 4.0 vessels/VF at day 10 of distraction compared to 24.0 +/- 0.8 vessels/VF in nondistracted implant sites. During the consolidation period the mean number of vessels was comparable to preoperative levels (mean 26.0 vessels/VF). The increase in capillary density and capillary index was more pronounced during the activation phase of distraction compared to the implant site. The increase in vascular response during distraction osteogenesis mainly occurs in the activation phase of distraction.