Exaggerated Hypertensive Response Research Articles

Usability of myocardial work parameters to demonstrate subclinical myocardial involvement in normotensive individuals with exaggerated hypertensive response in treadmill exercise testing.

Early determination of changes in myocardial functions is essential for the protection of cardiovascular diseases. This study aimed to evaluate myocardial work parameters in healthy individuals who developed an exaggerated hypertensive response during the treadmill exercise test procedure. The study included a total of 64 patients for whom an exercise electrocardiography test was planned for functional capacity evaluation. The study population was divided according to the presence of exaggerated hypertensive response to exercise (EBPRE) (SBP/DBP ≥210/105mmHg in males ≥190/105mmHg in females) and normal blood pressure response to exercise (NBPRE). Patients' echocardiographic evaluations were made at rest, and myocardial work parameters were calculated. There was no statistical difference between the groups (NBPRE vs. EBPRE, respectively) in terms of left ventricular 2,3 and 4 chamber strains and global longitudinal strain (GLS) values (-20.6±-2.3, -19.7±-1.9, p:.13; -21.3±-2.7, -21±-2.4, p:.68; -21.2±-2.2, -21.2±-2.3, p:.93; and -20.8±-1.5, -20.4±-1.5, p:.23, respectively). Global constrictive work (GCW), global waste work (GWW), and global work efficiency (GWE) were not statistically different between the two groups (2374±210, 2465±204, p:.10; 142±64, 127±42, p:.31; 94.3±2.5, 95.1±1.5, p:.18, respectively). In contrast, global work index (GWI) parameters were different between the two groups (2036±149, 2147±150, p<.001). The GWI was independently associated with EBPRE (odds ratio with 95% 3.32 (1.02-11.24), p=.03). The partial effect plots were used for GWI to predict EBPRE, according to the results, an increase in GWI predicts probability of exaggerated hypertensive response. In conclusion, Myocardial work analyses might be used to identify early signs of myocardial involvement in normotensive patients with EBPRE.

Exaggerated Systolic Blood Pressure Increase with Exercise and Myocardial Ischemia on Exercise Stress Echocardiography.

Central Illustration : Exaggerated Systolic Blood Pressure Increase with Exercise and Myocardial Ischemia on Exercise Stress Echocardiography ESBPRE: exaggerated systolic blood pressure response to exercise; HR: heart rate; SBP: systolic blood pressure. The association between exaggerated systolic blood pressure response to exercise (ESBPRE) and myocardial ischemia is controversial and little studied in patients with established or suspected chronic coronary syndrome. To verify the relationship between myocardial ischemia and ESBPRE in patients undergoing exercise stress echocardiography (ESE). This is a cross-sectional study with 14,367 patients undergoing ESE, from January 2000 to January 2022, divided into the following 2 groups: G1, composed of patients whose peak systolic pressure increased ≥ 90 mmHg (value corresponding to the 95th percentile of the study population), and G2, patients who did not demonstrate an exaggerated hypertensive response. The groups were compared using Student's t and chi-square tests. P values < 0.05 were considered significant. Logistic regression was also performed to identify independent risk factors for myocardial ischemia, ESBPRE, complaints of typical chest pain prior to the exam, and angina during the test. Of the 14,367 patients, 1,500 (10.4%) developed ESBPRE, and 7,471 (52.0%) were female. The percentages of previous complaints of typical chest pain, angina during the test, and myocardial ischemia in patients with ESBPRE were 5.8%, 2.4% and 18.1%, compared to 7.4%, 3.9%, and 24.2%, in patients without ESBPRE, respectively (p = 0.021,p = 0.004, p < 0.001). In multivariate analysis, ESBPRE was independently associated with a lower probability of myocardial ischemia (odds ratio: 0.73; 95% confidence interval: 0.58 to 0.93; p = 0.009). Exaggerated increase in systolic blood pressure during ESE may be a marker for excluding myocardial ischemia.

Editing of the myosin phosphatase regulatory subunit suppresses angiotensin II induced hypertension via sensitization to nitric oxide mediated vasodilation.

Alternative splicing of exon 24 (E24) of the myosin phosphatase regulatory subunit (Mypt1) tunes smooth muscle sensitivity to NO/cGMP-mediated vasorelaxation and thereby controls blood pressure (BP) in otherwise normal mice. This occurs via the toggling in or out of a C-terminal leucine zipper (LZ) motif required for hetero-dimerization with and activation by cGMP-dependent protein kinase cGK1α. Here we tested the hypothesis that editing (deletion) of E24, by shifting to the LZ positive isoform of Mypt1, would suppress the hypertensive response to angiotensin II (AngII). To test this, mice underwent tamoxifen-inducible and smooth muscle-specific deletion of E24 (E24 cKO) at age 6 weeks followed by a chronic slow-pressor dose of AngII (400 ng/kg/min) plus additional stressors. E24 cKO suppressed the hypertensive response to AngII alone or with the addition of a high salt diet. This effect was not a function of altered salt balance as there were no differences in intake or renal excretion of sodium. This effect was NO dependent as L-NAME in the drinking water caused an exaggerated hypertensive response in the E24cKO mice. E24cKO mouse mesenteric arteries were more sensitive to DEA/NO-induced vasorelaxation and less responsive to AngII- and α-adrenergic-induced vasoconstriction at baseline. Only the latter two effects were still present after 2 weeks of chronic AngII treatment. We conclude that editing of Mypt1 E24, by shifting the expression of naturally occurring isoforms and sensitizing to NO-mediated vasodilation, could be a novel approach to the treatment of human hypertension.

A20 in Myeloid Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T-Cell Activation.

The ubiquitin-editing protein A20 in dendritic cells (DCs) suppresses NF-κB (nuclear factor-κB) signaling and constrains DC-mediated T-cell stimulation, but the role of A20 in modulating the hypertensive response requires elucidation. Here, we tested the hypothesis that A20 in CD11c-expressing myeloid cells mitigates Ang II (angiotensin II)-induced hypertension by limiting renal T-cell activation. Mice with heterozygous deletion of A20 in CD11c-expressing myeloid cells (DC ACT[Cd11c-Cre+A20flox/wt]) have spontaneous DC activation but have normal baseline blood pressures. In response to low-dose chronic Ang II infusion, DC ACT mice compared with WT (wild type) controls had an exaggerated hypertensive response and augmented proportions of CD62LloCD44hi effector memory T lymphocytes in the kidney lymph node. After 10 days of Ang II, DC ACT kidneys had increased numbers of memory effector CD8+, but not CD4+ T cells, compared with WTs. Moreover, the expressions of TNF-α (tumor necrosis factor-α) and IFN-γ (interferon-γ) were upregulated in the DC ACT renal CD8+ T cells but not CD4+ T cells. Saline challenge testing revealed enhanced renal fluid retention in the DC ACT mice. DC ACT kidneys showed augmented protein expression of γ-epithelial sodium channel and NHE3 (sodium-hydrogen antiporter 3). DC ACT mice also had greater reductions in renal blood flow following acute injections with Ang II and enhanced oxidant stress in the vasculature as evidenced by higher circulating levels of malondialdehyde compared with WT controls. To directly test whether enhanced T-cell activation in the DC ACT cohort was responsible for their exaggerated hypertensive response, we chronically infused Ang II into lymphocyte-deficient DC ACT Rag1 (recombination activating protein 1)-deficient (Rag1-/-) mice and WT (Cd11c-Cre-A20flox/wt) Rag1-/- controls. The difference in blood pressure elevation accruing from DC activation was abrogated on the Rag1-/- strain. Following stimulation of the renin-angiotensin system, A20 suppresses DC activation and thereby mitigates T-cell-dependent blood pressure elevation.

A novel role for myeloid endothelin-B receptors in hypertension.

AimsHypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype.Methods and results In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB−/−), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB−/− mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies.ConclusionMφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.

Abstract 019: A20 in Dendritic Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T Cell Activation

The ubiquitin-editor protein A20 in dendritic cells (DCs) suppresses NF-κB signaling and inhibits their capacity to activate T cells by limiting DC expression of co-stimulatory molecules. We previously reported that mice with spontaneous DC activation due to heterozygous deletion of A20 in DCs (CD11c-cre+ A20 flox/wt = DC ACT) have an exaggerated hypertensive response to low dose (300 ng/kg/min) chronic angiotensin (Ang) II infusion (143±2 vs. 131±4 mmHg; p=0.04) and augmented proportions of effector T cells in the kidney lymph node. Here, we explored the mechanism through which A20 in DCs limits blood pressure elevation. After 7 days of chronic Ang II infusion, flow cytometric analysis of kidney homogenates from wild-type (WT = CD11c-cre - A20 flox/wt ) and DC ACT mice revealed similar numbers of renal DCs in the 2 groups (2832±342 vs. 2531±435; p=NS). By contrast, numbers of CD11b + Ly6C hi inflammatory monocytes (9849±1108 vs. 6019±597; p=0.01) and CD8 + T cells (1757±101 vs. 908±155; p&lt;0.03) were increased in the DC ACT kidneys compared to WT controls. Accordingly, the DC ACT kidneys showed upregulated mRNA expression for the pro-hypertensive cytokines TNF-α (1.6±0.2 vs. 1±0.2; p&lt;0.02) and IL-17A (2.3±0.6 vs. 1±0.3; p=0.09) and the mononuclear cell chemokine CCL5 (1.9±0.27 vs. 1±0.11; p=0.01). Both monocytes and T cells have been implicated in the pathogenesis of hypertension. Therefore, to directly test whether enhanced T cell activation in the DC ACT cohort was responsible for their augmented hypertensive response, we chronically infused Ang II into lymphocyte-deficient DC ACT Rag1 -/- mice and WT (CD11c-cre- A20 flox/wt ) Rag1 -/- controls for 4 wks. In WT Rag1 -/- and DC ACT Rag1 -/- mice, radiotelemetry blood pressures (128±1 vs. 128±2 mmHg; p=NS) and heart to body weight ratios (6.0±0.1 vs. 6.4±0.2 mg/g body wt) were similar during Ang II, suggesting that T cells are required to mediate the augmented hypertensive response accruing from DC activation due to A20 deficiency. Thus, following stimulation of the renin angiotensin system, A20 suppresses DC activation and thereby mitigates T cell-dependent blood pressure elevation. These studies identify a novel target through which to limit the engagement of adaptive immunity during chronic hypertension.

Acid‐Sensing Ion Channels (ASICs) 2 and 3 Buffer Pulmonary Vasoreactivity and ASIC2 Protects Against the Development of Chronic Hypoxia ‐Induced Pulmonary Hypertension

Acid‐sensing ion channels (ASICs) are widely expressed cation channels of the ENaC/Degenerin superfamily which conduct hyperpolarizing inward cation currents through the plasma membrane in response to a variety of stimuli. Our laboratory previously defined the role of ASIC1 as a mediator of chronic hypoxia (CH) –induced pulmonary hypertension. ASIC2 and ASIC3 are also expressed in pulmonary arteries, but their roles in the regulation of pulmonary vascular resistance and the development of CH‐induced pulmonary hypertension have not been investigated. ASIC2 and ASIC3 primarily conduct Na+ and therefore may play a role in the regulation of membrane potential in pulmonary artery smooth muscle cells (PASMC). We hypothesized that these channels contribute to pulmonary vasoreactivity and the development of CH‐induced pulmonary hypertension. Interestingly, we found that acute hypoxia‐, U46619‐, and high KCl‐induced increases in pulmonary vascular resistance were augmented in isolated‐perfused lungs from ASIC2 knockout (ASIC2−/−) and ASIC3 knockout (ASIC3−/−) mice compared to wild‐type (WT) mice, indicating that both ASIC2 and ASIC3 play inhibitory roles in these responses. Since increased acute pulmonary vasoreactivity could be associated with an exaggerated hypertensive response to CH‐exposure we also tested the role of ASIC2 and ASIC3 in the development of CH‐induced pulmonary hypertension. Right ventricular systolic pressure (RVSP), measured under isoflurane anesthesia, was not different between normoxia‐exposed ASIC2−/− or ASIC3−/− and WT mice. Following 4 weeks of CH exposure (PB = 0.5 atm), RVSP was higher in CH− exposed ASIC2−/− compared to CH‐exposed WT and ASIC3−/− mice. These data indicate that although ASIC2 and ASIC3 both play inhibitory roles in acute pulmonary vasoreactivity, only ASIC2 plays an inhibitory role in the development of CH‐induced pulmonary hypertension. ASICs have been implicated in central chemoreception and ventilatory responses to hypercapnia and hypoxia raising the possibility that ASIC2−/− mice develop more severe hypoxemia than WT mice during exposure to hypoxia, so we measured arterial blood gases in both normoxia‐ and CH‐exposed WT and ASIC2−/− mice in room air and during exposure to hypoxia or hypercapnia. Arterial O2, CO2, and pH levels were not different between WT and ASIC2−/− mice under any of these conditions, indicating that the exaggerated hypertensive response of ASIC2−/− mice to CH is not a result of more severe hypoxemia. In conclusion, ASIC2 and ASIC3 both play inhibitory roles in hypoxia‐, U46619‐, and KCl‐induced pulmonary vasoconstriction, and ASIC2 protects against CH‐induced pulmonary hypertension. Future studies will address the mechanisms of these roles, investigating the possibilities that ASIC2 and ASIC3 inhibit the activity of ASIC1 in PASMC, or that ASIC2 and ASIC3 reside in endothelial cells, contributing to endothelial inhibition of pulmonary vasoconstriction.Support or Funding InformationSupported by National Heart, Lung, and Blood Institute Grants R01 HL‐111084 (to N.L. Jernigan), T32 HL007736 (to T.C. Resta), National Institute of General Medical Science R25 GM060201 (to M.C. Werner‐Washburne), and K12 (to A. Wandinger‐Ness)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Exaggerated hypertensive response to exercise and myocardial ischemia in patients with known or suspected coronary artery disease

ObjectivesThe association between an exaggerated hypertensive response to exercise (EHRE) and the probability of ischemia in stress tests is controversial. Our purpose was to determine the possible association between an EHRE and the development of chest pain and electrocardiographic or echocardiographic ischemia with exercise. Patients and methodsA retrospective observational study was conducted of 10,047 patients with known or suspected coronary artery disease referred for exercise echocardiography. A logistic regression analysis assessed the effect of developing an EHRE (defined as a maximum systolic blood pressure with exercise ≥220mmHg) and the onset of chest pain and electrocardiographic and echocardiographic changes suggestive of ischemia. ResultsA total of 402 patients developed an EHRE. The rates of angina, electrocardiographic ischemia and echocardiographic ischemia among the patients with an EHRE were 8.2, 16.2 and 22.6% versus 13.8, 14.7 and 27.5%, respectively, for patients without an EHRE (p=.001, p=.4, p=.032). After a multivariate fit, EHRE was associated with a lower probability of exercise-induced angina (OR, 0.44; 95% CI 0.30–0.65; p<.001) and echocardiographic ischemia (OR, 0.63; 95% CI 0.48–0.83; p=.001) but not with the onset of electrocardiographic ischemia. ConclusionsEHRE is associated with a lower prevalence of angina and echocardiographic ischemia in patients with known or suspected coronary artery disease.

Respuesta hipertensiva exagerada al ejercicio e isquemia miocárdica en pacientes con enfermedad coronaria conocida o sospechada

ObjectivesThe association between an exaggerated hypertensive response to exercise (EHRE) and the probability of ischaemia in stress tests is controversial. Our purpose was to determine the possible association between an EHRE and the development of chest pain and electrocardiographic or echocardiographic ischaemia with exercise. Patients and methodsA retrospective observational study was conducted of 10,047 patients with known or suspected coronary artery disease referred for exercise echocardiography. A logistic regression analysis assessed the effect of developing an EHRE (defined as a maximum systolic blood pressure with exercise ≥220mmHg) and the onset of chest pain and electrocardiographic and echocardiographic changes suggestive of ischaemia. ResultsA total of 402 patients developed an EHRE. The rates of angina, electrocardiographic ischaemia and echocardiographic ischaemia among the patients with an EHRE were 8.2, 16.2 and 22.6% versus 13.8, 14.7 and 27.5%, respectively, for patients without an EHRE (p=.001, p=.4, p=.032). After a multivariate fit, EHRE was associated with a lower probability of exercise-induced angina (OR, 0.44; 95% CI 0.30-0.65; p<.001) and echocardiographic ischaemia (OR, 0.63; 95% CI 0.48-0.83; p=.001) but not with the onset of electrocardiographic ischaemia. ConclusionsEHRE is associated with a lower prevalence of angina and echocardiographic ischaemia in patients with known or suspected coronary artery disease.

Preoperative β-blockade and hypertension in the first hour of functional endoscopic sinus surgery.

Local anesthetic with epinephrine is commonly injected into the nasal mucosa during functional endoscopic sinus surgery (FESS). Systemic absorption of epinephrine following local injection may occur, resulting in a mild sympathetic response. This study seeks to determine whether an exaggerated sympathetic response to epinephrine is demonstrated in patients undergoing FESS treated preoperatively with established pharmacologic beta (β) adrenoceptor blockade. A retrospective analysis of adult patients undergoing FESS at a tertiary care university hospital. The primary outcome was the occurrence of an exaggerated hypertensive response within the first hour of surgical time defined by a relative increase (>20%) in the first measured intraoperative systolic blood pressure (SBP) prior to induction of anesthesia, or a single SBP value above 200 mm Hg. A mixed effects logistic regression model was developed to identify independent predictors of an exaggerated hypertensive response and describe the variance in the outcome attributable to the surgeon and anesthesiologist. There were 2,051 patients identified. Independent predictors of an exaggerated intraoperative hypertensive event included: preoperative β-blocker use (adjusted odds ratio [AOR]: 3.33), female gender (AOR: 1.92), body mass index (AOR: 1.03), lower baseline SBP (AOR: 0.93), and advanced age (AOR: 1.03). The C statistic for the model was 0.8881. Preoperative β-blocker use is an independent predictor of an exaggerated hypertensive response within the first hour of operative time. An exaggerated hypertensive effect should be anticipated in patients presenting for FESS with established pharmacologic β-blockade, and caution should be applied to use of epinephrine-containing solutions. 4. Laryngoscope, 127:1496-1505, 2017.

Exaggerated hypertensive response to combretastatin A-4 phosphate in hypertensive rats: Effective pharmacological inhibition by diltiazem

Combretastatin A-4 phosphate (CA4P), a tubulin depolymerizing agent, shows promise in anti-cancer therapy and is associated with dose-dependent transient hypertension. The cardiac consequence of this hypertensive effect is unknown. This study was conducted to examine the cardiotoxic effect of CA4P on a rat model of hypertension. Hypertensive rats were created by feeding a 6% high salt (HS) diet to Dahl salt sensitive (DSS) rats for 2.5weeks. Cardiac toxicity was measured using serum troponin I levels 24h after CA4P administration. In rats fed HS diet, there was a significant increase in mean arterial blood pressure (MAP) from baseline, which was further increased by 80% following CA4P administration with peak systolic blood pressure (BP) of 247mmHg. Treatment with the calcium channel blockers, diltiazem and nicardipine, completely inhibited the hypertensive effects of CA4P. Nitroglycerin or enalapril, however, failed to completely block the hypertensive effects of CA4P. CA4P injection also significantly increased the cardiac troponin I level in hypertensive rats though pretreatment with diltiazem effectively blocked troponin I increase after CA4P administration. Based on these findings, an exaggerated hypertensive response to CA4P is associated with myocardial damage in hypertensive rats. Calcium channel blockers effectively blocked both CA4P induced hypertension and cardiac damage.

Exercise-induced hypertension among healthy firefighters—a comparison between two different definitions

Different studies have yielded conflicting results regarding the association of hypertensive response to exercise and cardiovascular morbidity. We compared two different definitions of exaggerated hypertensive response to exercise and their association with cardio-respiratory fitness in a population of healthy firefighters. We examined blood pressure response to exercise in 720 normotensive male career firefighters. Fitness was measured as peak metabolic equivalent tasks (METs) achieved during maximal exercise treadmill tests. Abnormal hypertensive response was defined either as systolic blood pressure ≥ 200 mm Hg; or alternatively, as responses falling in the upper tertile of blood pressure change from rest to exertion, divided by the maximal workload achieved. Using the simple definition of a 200 mm Hg cutoff at peak exercise less fit individuals (METs ≤12) were protected from an exaggerated hypertensive response (OR 0.45, 95%CI 0.30–0.67). However, using the definition of exercise-induced hypertension that corrects for maximal workload, less fit firefighters had almost twice the risk (OR 1.8, 95%CI 1.3–2.47). Blood pressure change corrected for maximal workload is better correlated with cardiorespiratory fitness. Systolic blood pressure elevation during peak exercise likely represents an adaptive response, whereas elevation out of proportion to the maximal workload may indicate insufficient vasodilation and a maladaptive response. Prospective studies are needed to best define exaggerated blood pressure response to exercise.

Abstract 225: Loss of Either Renal or Systemic ACE2 contributes to the Hypertensive Response to Chronic Angiotensin II

Angiotensin Converting Enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin II (AngII). ACE2 is broadly expressed in cardiovascular tissues, with highest expression in the kidney. We have previously shown that mice with targeted deletion of the Ace2 gene have an exaggerated response to AngII-induced hypertension (HTN) associated with elevated renal AngII levels. Based on these findings, we now hypothesize that ACE2 in the kidney decreases AngII levels and is therefore responsible for its anti-hypertensive effects. To test this, we utilized renal cross-transplantation to eliminate ACE2 specifically from the kidney or all other tissues. We studied male ACE2 knockout (KO) mice and wild-type (WT) littermates on (C57BL/6 x 129/SvEv)F 1 background. Kidney transplants were performed to generate four experimental groups: 1) wild-type, 2) renal ACE2 KO, 3) systemic ACE2 KO, and 4) global ACE2 KO. All kidney function was provided entirely by the single transplanted kidney. After baseline measurements, mice were infused with AngII (1000ng/kg/min) chronically for two weeks while mean arterial blood pressures (MAP) were measured with radiotelemetry. There were no significant differences in baseline MAPs among groups. Similar to our prior study, the response to AngII infusion was exaggerated in mice with global ACE2 deficiency compared to WT control mice (152±6 vs.144±7 mmHg; p =0.03, n=10). However, the presence of ACE2 in either the kidney or systemic tissues restored MAPs to levels similar to that of the WT group (renal ACE2 KO 140±7mmHg, p&lt;0.01 vs. global ACE2 KO; systemic ACE2 KO 140±5 mmHg, p&lt;0.01 vs. global KO). This effect was equivalent between the renal KO and systemic KO groups. Global ACE2 deficiency leads to an exaggerated hypertensive response to chronic AngII administration. Thus, restoration of ACE2 in either the kidney or in systemic tissues is sufficient to abrogate this enhanced hypertensive response. Our data suggest equivalent effects of both renal and extra-renal ACE2 in hypertension.

Early Life Stress Sensitizes Rats to Angiotensin II–Induced Hypertension and Vascular Inflammation in Adult Life

Maternal separation during early life is an established chronic behavioral model of early life stress in rats. It is known that perinatal adverse environments increase activity of the renin-angiotensin (Ang) system, specifically Ang II, in adulthood. The aim of this study was to investigate whether the effects of early life stress augment the sensitivity of the Ang II pathway. Using Wistar Kyoto rats, the maternal separation (MS) protocol was performed by separating approximately half of the male pups from their mother 3 h/d from days 2 to 14 of life. Pups remaining with the mother at all times were used as controls. Maternal separation did not influence the plasma basal parameters, such as blood glucose, insulin, Ang II, Ang 1-7 and plasma renin activity. Furthermore, body weight, blood pressure, and heart rate were similar in MS and control rats. The acute pressor response to Ang II was not different in anesthetized MS and control rats. However, the chronic infusion of Ang II (65 ng/min SC) elicited an exaggerated hypertensive response in MS compared with control rats (P<0.05). Surprisingly, HR was dramatically increased during the second week of Ang II infusion in MS compared with control rats (P<0.05). This enhanced Ang II sensitivity was accompanied by a greater vascular inflammatory response in MS versus control rats. Chronic Ang II infusion increased vascular wall structure in both groups similarly. These data indicate that early life stress sensitizes rats to an increased hemodynamic and inflammatory response during Ang II-induced hypertension.

Microsomal prostaglandin E synthase-1 and blood pressure regulation

Prostaglandin E (PGE)(2) is a major arachidonic acid metabolite in a wide variety of tissues and is implicated in the control of inflammatory as well as physiological responses. At least three major forms of PGE synthase (PGES) have recently been cloned and characterized: membrane-associated PGES (mPGES)-1, mPGES-2, and cytosolic PGES (cPGES). Among them, mPGES-1 is highly inducible by cytokine and is critically involved in pain and inflammatory responses. Emerging evidence suggests that mPGES-1 may also participate in blood pressure (BP) regulation through an impact on renal and vascular functions. Within the kidney, mPGES-1 predominates in the distal nephron where its expression is highly inducible by salt loading. Mice lacking mPGES-1 exhibit blunted natriuretic response paralleled with remarkably suppressed nitric oxide production, leading to salt-sensitive hypertension. These mice also exhibit an exaggerated hypertensive response to angiotensin II infusion. Together, these results suggest that mPGES-1 may be an important physiological regulator of BP.

Pharmacological Analysis of the Enhanced Pressor Response to Central Cholinergic Stimulation in Spontaneously Hypertensive Rats

Central cholinergic pressor neurons exist at several levels of the neuraxis. Activation of these neurons in spontaneously hypertensive rats (SHR) can lead to an exaggerated hypertensive response when compared with normotensive control animals (WKY). Our earlier studies demonstrated that intravenous injection of the indirect acting agonist physostigmine, but not the direct agonist arecoline, resulted in an exaggerated pressor response in SHR. The purpose of this study was to determine whether discrete injection of cholinergic agonists directly into the CNS would also result in an exaggerated pressor response in SHR. Cholinergic pressor neurons in the posterior hypothalamus may be activated following injection of cholinergic agonists into the lateral cerebral ventricles (l.c.v. injection). Cholinergic pressor neurons in the medulla may be activated following injection of agonists into the cisterna magna (i.c. injection). L.c.v. injection of arecoline in freely-moving animals evoked a pressor response in both SHR and WKY rats that was not significantly different between the two strains. Prior depletion of brain acetylcholine with hemicholinium-3 did not affect the pressor response to l.c.v. arecoline, confirming the postsynaptic site of action of the agonist. Surprisingly, l.c.v. injection of physostigmine also did not result in an exaggerated pressor response in SHR. In contrast, injection of physostigmine into the cisterna magna did produce an enhanced hypertensive response in SHR compared to WKY rats. These results are consistent with the presence of two cholinergic pressor systems; however, only the medullary cholinergic system appears to play a prominent role in spontaneous hypertension. Also the hypothalamic (rostral) cholinergic system does not appear to directly interact with the caudal system.

Exercise in children before and after coarctectomy: Hemodynamic, echocardiographic, and biochemical assessment

After repair of coarctation of the aorta, some patients with normal blood pressure at rest have an exaggerated hypertensive response to activity. Blood pressure response to exercise was studied in 15 children, aged 5 to 15 years, prior to and at periods up to 6 months following coarctectomy. Preoperatively, 11 to 15 children had systolic hypertension at rest and 12 of 15 after exercise. After surgery, only one child had mild systolic hypertension at rest, whereas exercise-induced hypertension persisted in 33% of patients (all older than 10 years). Exercise plasma renin activity was elevated preoperatively but normalized following surgery. No significant difference was seen in resting and exercise plasma catecholamine levels measured before and after surgery. Over the follow-up period of 6 months, echocardiographic evidence of left ventricular hypertrophy regressed in the younger patients but not in the older patients with exercise-induced hypertension. Exercise testing defines a subgroup of patients with exercise-induced hypertension evident soon after surgery. Structural upper segment arterial vessel wall changes in the older patient may explain these observations.

Renin Activity in Patients with End-Stage Kidney Disease.

Excerpt Patients with end-stage renal disease maintained on chronic dialysis have an exaggerated hypertensive response to overhydration which has been found to be partially corrected by bilateral n...