Increased Blood Pressure Response Research Articles

The regulatory effects of mesedin and beditin alpha2-adrenoblockers on the functional activity of the nervous, cardiovascular, and endocrine systems in rats under the hypoxic conditions.

One of the reasons of the development of pathologies causing death is hypoxia. The purposes of this study were (1) to study some physiological and biochemical mechanisms of α2-adrenoblockers, which ensure the tissue resistance increase to hypoxia; (2) to offer new drugs contributing to the increase of tissues' stability towards the hypoxic affection; and (3) to submit new medications to surpass by their anti-hypoxic activity of those already used in modern medicine and have some advantages. The reactivity of postsynaptic vascular α2-adrenoceptors was determined on the damaged spinal cord expressed by the blood pressure increase in response to intravenous administration of azepexole that selectively binds to α2-adrenoceptors. Determination of the systemic hemodynamic values and the vascular resistance to the blood flow was performed by the method with plastic microspheres of marked isotopes. pO2 in the blood and the oxygen-transporting function were determined in a sample of 0.1ml of blood in 30, 90, and 180min after the α2-adrenoblockers' injections. It has been found that one of the major hemodynamic effects of mesedin and beditin was an improvement in cardiac output, as well as a prolonged increase in coronary blood flow and vasodilation of the heart vessels. Some anti-hypoxic mechanisms of the studied α2-adrenoblockers are an improvement of blood oxygen-transporting function followed by tissue oxygenation and the increased level of corticosterone and resistance to hypoxia. Revealing the mechanisms of action of the postsynaptic α2-adrenoceptors suggests that mesedin and beditin are potentially effective therapeutic means for many hypoxic conditions.

Abstract 023: Prior Sflt1 Induced Preeclampsia Exacerbates Post-partum Hypertension-mediated Aortic Stiffness And Hypercholesterolemia-induced Atherosclerotic Inflammation

Preeclampsia (PE) is new high blood pressure (BP) and organ damage occurring late in pregnancy in association with increased soluble VEGF receptor (sFlt1). PE survivors have increased risk of future hypertension and myocardial infarction/stroke. We hypothesized that exposure to high sFlt1 during pregnancy exacerbates hypertension and atherosclerosis post-partum. PE was induced by transient adenoviral expression of sFlt1 compared to control virus in pregnant mice. PE mice had elevated sFlt1, BP and kidney damage during pregnancy which resolve post partum. Two months post-partum, prior PE mice had significantly increased BP response to high salt diet. After high BP stimuli, we studied large and small artery function. Prior PE mice had diminished nitric oxide-mediated vasodilation and stiffer aortas with more fibrosis as measured by pulse wave velocity (Con:3.7 vs sFlt:5.9 mm/ms, p<0.0001) and trichrome staining (Con:13.7% vs sFlt:33.9%, p=0.0009). Atherosclerosis studies exposed LDLR knockout mice to PE followed by high fat diet feeding for 8 weeks. Body weight, fasting glucose and cholesterol were not altered by prior PE. Aortic roots were histologically analyzed for plaque size and composition. Aortic root plaque size (Con:73.3 vs sFlt:78.0 AU, p=0.60) and necrotic core were not different between groups. Aortic arch plaque inflammation was quantified via flow cytometry showing significantly increased plaque CD45+ leukocytes (sFlt:1.6 fold, p=0.036) and T cells (sFlt:1.8 fold, p=0.031) from mice with prior PE. Atheroprone mice with prior PE had significantly increased aortic expression of CCL22 (sFlt:1.5 fold, p=0.047), providing a potential mechanism for increased T cell infiltration into atherosclerotic plaques. Experimental PE produces a state of enhanced sensitivity to hypertensive stimuli and increased vascular inflammation in atherosclerotic plaques supporting the concept that PE directly exacerbates hypertension, vascular stiffness, and atherosclerotic inflammation independent of pre-existing risk factors.

CORRELATION BETWEEN BLOOD PRESSURE RESPONSE TO SUB MAXIMAL EXERCISE AND LEFT VENTRICULAR HYPERTROPHY

Objective: Currently, there is no common consent on what constitutes a normal increase in blood pressure (BP) during physical activity and, consequently, what constitutes an exaggerated increase in BP response to exercise. At this stage, the processes, and clinical consequences of hypertensive response to exercise (HRE) remain unknown. Even in those who do not have hypertension or other cardiovascular disorders, a hypertensive response to exercise (HRE) is common. An increased blood pressure response to exercise is a legitimate risk marker for future hypertension, as previous research has demonstrated. HRE has among its contributors the endothelial dysfunction and an increase in afterload. in terms of neurohormonal aspects Excess sympathetic nervous system activation and an increase in angiotensin II appear to be crucial mechanisms in HRE, according to studies. Design and method: Of the 84 eligible participants, men (n 46) women (n 38) with I and II degree hypertension (n 32) and pre hypertension (n 22). The study analysis included the subjects with an age range of 18-64 years (mean age 42.1±12.7 years) With or without left ventricular hypertrophy (LVH) described as normal, Concentric hypertrophy, Eccentric hypertrophy, concentric remodeling. Results: For most of the subjects on the initial evaluation, we discovered echocardiographic evidence of concentric hypertrophy. Among the resting and exercise BP indices, submaximal SBP was the strongest correlate of LV mass (r = 0.40, P<0.04). In multivariate analysis, maximal SBP was independently associated with LV mass and concentric LV hypertrophy, after adjustment for lean body mass and gender. Submaximal exercise SBP is a modest but still independent predictor of LV remodeling (grade and type of LV geometry) in population with prehypertension, I and II grade hypertension. Conclusions: More frequent clinical control of resting BP, an echocardiogram, a 24-hour BP ambulatory monitoring as a more dynamic test, and at least annual repetition of the exercise test, to follow up the same abnormal response, as more studies are needed and a consensus regarding the abnormal response of the BP during exercise. Our study can be of clinical importance to prevent future adverse events linked to hypertension induced organ damage.

Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia.

Preeclampsia is a syndrome of high blood pressure (BP) with end organ damage in late pregnancy that is associated with high circulating soluble VEGF receptor (sFlt1 [soluble Fms-like tyrosine kinase 1]). Women exposed to preeclampsia have a substantially increased risk of hypertension after pregnancy, but the mechanism remains unknown, leaving a missed interventional opportunity. After preeclampsia, women have enhanced sensitivity to hypertensive stress. Since smooth muscle cell mineralocorticoid receptors (SMC-MR) are activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure in pregnancy induces a postpartum state of enhanced SMC-MR responsiveness. Postpartum BP response to high salt intake was studied in women with prior preeclampsia. MR transcriptional activity was assessed in vitro in sFlt1-treated SMC by reporter assays and PCR. Preeclampsia was modeled by transient sFlt1 expression in pregnant mice. Two months post-partum, mice were exposed to high salt and then to AngII (angiotensin II) and BP and vasoconstriction were measured. Women exposed to preeclampsia had significantly enhanced salt sensitivity of BP verses those with a normotensive pregnancy. sFlt1 overexpression during pregnancy in mice induced elevated BP and glomerular endotheliosis, which resolved post-partum. The sFlt1 exposed post-partum mice had significantly increased BP response to 4% salt diet and to AngII infusion. In vitro, SMC-MR transcriptional activity in response to aldosterone or AngII was significantly increased after transient exposure to sFlt1 as was aldosterone-induced expression of AngII type 1 receptor. Post-partum, SMC-MR-KO mice were protected from the enhanced response to hypertensive stimuli after preeclampsia. Mechanistically, preeclampsia mice exposed to postpartum hypertensive stimuli develop enhanced aortic stiffness, microvascular myogenic tone, AngII constriction, and AngII type 1 receptor expression, all of which were prevented in SMC-MR-KO littermates. These data support that sFlt1-induced vascular injury during preeclampsia produces a persistent state of enhanced sensitivity of SMC-MR to activation. This contributes to postpartum hypertension in response to common stresses and supports testing of MR antagonism to mitigate the increased cardiovascular risk in women after PE.

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer's Disease.

α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (β and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer's disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson's disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

Contribution of afferent renal nerve signals to acute and chronic blood pressure regulation in stroke-prone spontaneously hypertensive rats.

The activation of sympathetic nervous system plays a critical role in the development of hypertension. The input from afferent renal nerves may affect central sympathetic outflow; however, its contribution to the development of hypertension remains unclear. We investigated the role of afferent renal nerves in acute and chronic blood pressure regulation using normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Acute chemical stimulation of afferent renal nerves elicited larger increases in blood pressure and renal sympathetic nerve activity in young 9-week-old SHRSP compared to WKY. Selective afferent renal denervation (ARDN) and conventional total renal denervation (TRDN) ablating both afferent and efferent nerves in young SHRSP revealed that only TRDN, but not ARDN, chronically attenuated blood pressure elevation. ARDN did not affect plasma renin activity or plasma angiotensin II levels, whereas TRDN decreased both. Neither TRDN nor ARDN affected central sympathetic outflow and systemic sympathetic activity determined by neuronal activity in the parvocellular region of hypothalamic paraventricular nucleus and rostral ventrolateral medulla and by plasma and urinary norepinephrine levels, respectively. Renal injury was not apparent in young SHRSP compared with WKY, suggesting that renal afferent input might not be activated in young SHRSP. In conclusion, the chronic input from afferent renal nerves does not contribute to the development of hypertension in SHRSP despite the increased blood pressure response to the acute stimulation of afferent renal nerves. Efferent renal nerves may be involved in the development of hypertension via activation of the renin-angiotensin system in SHRSP.

High-Dose Nitrate Supplementation Attenuates the Increased Blood Pressure Responses to Isometric Blood Flow Restriction Exercise in Healthy Males.

The effect of nitrate (NO3−) supplementation on blood pressure (BP) responses during large muscle mass isometric and ischaemic exercise in healthy young adults is unclear. The aim of the present study was to assess the effect of 5-day supplementation of NO3− on BP responses during a short isometric contraction and a sustained ischaemic contraction. In a randomised, double-blinded, crossover design, 14 healthy active young adults underwent BP measurements after 5 days of either NO3− (NIT) or placebo (PLA) supplementation. Beat-by-beat BP was measured at pre- and post-exercise rest, and during a short (20 s) isometric contraction at 25% maximal strength and throughout a sustained ischaemic contraction. Plasma nitrite (NO2−) concentration increased significantly after NO3− supplementation compared to placebo (475 ± 93 nmol·L−1 vs. 198 ± 46 nmol·L−1, p < 0.001, d = 3.37). Systolic BP was significantly lower at pre- (p = 0.051) and post-exercise rest (p = 0.006), during a short isometric contraction (p = 0.030), and throughout a sustained ischaemic contraction (p = 0.040) after NO3− supplementation. Mean arterial pressure was significantly lower at pre- (p = 0.004) and post-exercise rest (p = 0.043), during a short isometric contraction (p = 0.041), and throughout a sustained ischaemic contraction (p = 0.021) after NO3− supplementation. Diastolic BP was lower at pre-exercise rest (p = 0.032), but not at post-exercise rest, during a short isometric contraction, and during a sustained ischaemic contraction (all p > 0.05). Five days of NO3− supplementation elevated plasma NO2− concentration and reduced BP during a short isometric contraction and a sustained ischaemic contraction in healthy adults. These observations indicate that multiple-day nitrate supplementation can decrease BP at rest and attenuate the increased BP response during isometric exercise. These findings support that NO3− supplementation is an effective nutritional intervention in reducing SBP and MAP in healthy young males during submaximal exercise.

Assessment of cardiorespiratory fitness and physiological responses with different ergometers in people with bipolar disorder: data from the FINEXT-BD study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III Background Bipolar disorder (BD) is a mental illness in which manic and depressive episodes are combined. People with BD are associated with an unhealthy lifestyle. Assessment of cardiorespiratory fitness (CRF) indicates the overall health of the person and is essential for the design of the exercise intensity ranges in an individualized way. The assessment of CRF can be performed with different ergometers (treadmill, T vs. cycloergometer, C) and the results may differ. Purpose To analyze and compare the CRF and physiological responses of two peak, progressive and ramped protocols on different ergometers (T and C) in people with BD. Methods Physiological variables (peak blood pressure, test duration, ventilatory threshold, peak heart rate, peak oxygen uptake [VO2peak], peak metabolic equivalent) assessed by cardiopulmonary exercise tests (T and C) were measured in participants (n=28, 67.8% women, 45.9±12.5 yr old) with BD. Results Differences were found in peak systolic blood pressure (T=148±29.5 vs. C=184±32.7 mmHg, P&amp;lt;0.001, Cohen's d=1.14), peak diastolic blood pressure (T=79±10.7 vs. v=88±17.1 mmHg, P&amp;lt;0.01, Cohen's d=0.72) and test duration (C=9.4±3.6 vs. T=11.3±4.9 min, P&amp;lt;0.01, Cohen's d=0.43) with higher values in C (24.5%, 12.4% and 19.6%, respectively). No other statistically significant (P&amp;gt;0.05) between ergometers-differences were found in the rest of studied variables, including VO2peak as the gold standard of CRF assessment (T=23.8±7.6 vs. C=24.6±7.7 mL·kg-1·min-1). Conclusions The no differences between ergometers (T vs. C) when assessing CRF and physiological responses in people with BD indicate that both modes of assessment could be used interchangeably. The increased blood pressure response in C compared to T could be due to unfamiliarity with the ergometer and the physiological factors that determine blood pressure.

Parental obesity alters offspring blood pressure regulation and cardiovascular responses to stress: role of P2X7R and sex differences.

We examined the impact of parental obesity on offspring blood pressure (BP) regulation and cardiovascular responses to stress. Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diet (HH). Body weight, calorie intake, and fat mass were measured at 22 wk of age when cardiovascular phenotyping was performed. Male and female HH offspring were 15% heavier than NH and 70% heavier than NN offspring. Male HH and HN offspring had elevated BP (121 ± 2 and 115 ± 1 mmHg, by telemetry) compared with male NH and NN offspring (108 ± 6 and 107 ± 3 mmHg, respectively) and augmented BP responses to angiotensin II, losartan, and hexamethonium. Male HH and HN offspring also showed increased BP responses to air-jet stress (37 ± 2 and 38 ± 2 mmHg) compared with only 24 ± 3 and 25 ± 3 mmHg in NH and NN offspring. Baseline heart rate (HR) and HR responses to air-jet stress were similar among groups. In females, BP and cardiovascular responses to stress were similar among all offspring. Male H diet-fed offspring from obese H diet-fed purinoreceptor 7-deficient (HH-P2X7R-KO) parents had normal BP that was similar to control NN-P2X7R-KO offspring from lean parents. These results indicate that parental obesity leads to increased BP and augmented BP responses to stress in their offspring in a sex-dependent manner, and the impact of parental obesity on male offspring BP regulation is markedly attenuated in P2X7R-KO mice.

Parental Obesity Alters Offspring Blood Pressure Regulation and Cardiovascular Responses to Stress: Role of P2X7R and Sex Differences

The prevalence of obesity has increased dramatically in the United States during the past three decades. This increase has occurred in children, adolescents and adults of both sexes and all ethnic groups. In addition, the proportion of women and men of reproductive age who are overweight and obese has been increasing considerably, and maternal obesity and excessive gestational weight gain may predispose their offspring to health‐related consequences during childhood and adulthood, and increase cardiovascular responses to stress. Therefore, we examined the impact of parental (maternal + paternal) obesity on offspring blood pressure (BP) regulation and cardiovascular responses to stress. Offspring from normal (N) diet‐fed C57BL/6J parents were fed either N (NN, n=5 per sex) or a high fat (H) diet (NH, n=5‐7 per sex) from weaning until adulthood. Offspring from obese H diet‐fed parents were also fed N (HN, n=5‐6 per sex) or H diet (HH, n=5‐8 per sex). Body weight, calorie intake and fat mass were measured at 22 weeks of age when cardiovascular phenotyping was performed. Male and female HH offspring were 15% heavier than NH and 70% heavier than NN offspring. Male HH and HN offspring had elevated BP (121±2 and 115±1 mmHg, by telemetry) compared to male NH and NN offspring (108±6 and 107±3 mmHg, respectively) and augmented BP response to angiotensin II, losartan and hexamethonium. Male HH and HN offspring also showed increased BP response to acute air‐jet stress (37±2 and 38±2 mmHg) compared to only 24±3 and 25±3 mmHg in NH and NN offspring. Baseline heart rate (HR) and HR responses to air‐jet stress were similar among groups. In females, BP and cardiovascular responses to stress were similar among all offspring. Male H diet‐fed offspring from obese H diet‐fed purinoreceptor 7 deficient (HH‐P2X7R‐KO) parents had normal BP that was similar to control NN‐P2X7R‐KO offspring from lean parents. These results indicate that parental obesity leads to increased BP and augmented BP response to stress in their offspring in a sex‐dependent manner and that the impact of parental obesity on male offspring BP regulation is markedly attenuated in P2X7R‐KO mice.

SFlt1‐Induced Preeclampsia Enhances Cardiovascular Response to Post Partum Hypertensive Stimuli via Smooth Muscle Mineralocorticoid Receptor

BackgroundPreeclampsia (PE), a syndrome of high blood pressure (BP) and renal damage in late pregnancy, is associated with increased soluble VEGF receptor (sFlt1) and survivors have increased risk of future hypertension and cardiovascular disease.HypothesisSince smooth muscle cell mineralocorticoid receptor (SMC‐MR) can be activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure during pregnancy may induce a post‐partum state of enhanced vascular sensitivity via SMC‐MR activation.Methods/ResultsA PE model was induced by transient viral expression of sFlt1 in pregnant C57Bl6 mice. Elevated serum sFlt1, BP and glomerular endotheliosis was confirmed which all resolve post‐partum. In a small cohort of women with prior PE, we confirm salt sensitivity of BP. Thus, postpartum mice were implanted with telemetric BP monitors and exposed to repeated hypertensive stimuli (high salt and subsequent AngII). Mice with prior PE had a significantly increased BP response to hypertensive stimuli. Microvascular arteries from mice after PE and hypertensive stimuli had enhanced ex vivomyogenic tone and AngII vasoconstriction. To test the direct impact of sFlt1 on SMC‐MR function, cultured SMC (Pac1) were transiently exposed to sFlt1 (24 hours on then off) to mimic the post‐PE state. SMC‐MR transcriptional activity in response to aldosterone and AngII were significantly increased after sFlt1 exposure as measured by luciferase reporter assay. Target gene expression was also enhanced after sFlt1 exposure. Finally, the role of SMC‐MR in the post‐PE phenotype was tested in vivo by PE induction in SMC‐MR‐KO vs MR‐intact littermates. Post partum, SMC‐MR‐KO mice were protected from the PE‐induced increase in aortic stiffness, microvascular myogenic tone and AngII vasoconstriction.ConclusionsFlt1‐induced PE produces a state of enhanced sensitivity to stimuli that may be mediated by increased activation of SMC‐MR. These data support the use of MR antagonists to mitigate the increased risk of cardiovascular disease in women exposed to PE.

Does exercise stress testing carry an incremental prognostic value beyond resting office blood pressure?

Does exercise stress testing carry an incremental prognostic value beyond resting office blood pressure?

The roles of sodium and volume overload on hypertension in chronic kidney disease.

Chronic kidney disease (CKD) is associated with increased risk of cardiovascular (CV) events, and the disease burden is rising rapidly. An important contributor to CV events and CKD progression is high blood pressure (BP). The main mechanisms of hypertension in early and advanced CKD are renin-angiotensin system activation and volume overload, respectively. Sodium retention is well known as a factor for high BP in CKD. However, a BP increase in response to total body sodium or volume overload can be limited by neurohormonal modulation. Recent clinical trial data favoring intensive BP lowering in CKD imply that the balance between volume and neurohormonal control could be revisited with respect to the safety and efficacy of strict volume control when using antihypertensive medications. In hemodialysis patients, the role of more liberal use of antihypertensive medications with the concept of functional dry weight for intensive BP control must be studied.

Abstract 14155: Exposure to sFlt1-Induced Preeclampsia Enhances the Future Vascular Response to Hypertensive Stimuli in Mice in a Smooth Muscle Mineralocorticoid Receptor Dependent Manner

Preeclampsia (PE), a syndrome of high blood pressure (BP) and renal damage in late pregnancy, is associated with increased soluble VEGF receptor (sFlt1) and survivors have increased risk of future hypertension with increased angiotensin II (AngII) and salt sensitivity. Since smooth muscle cell mineralocorticoid receptor (SMC-MR) can be activated by hypertensive stimuli, we hypothesized that high sFlt1 exposure during pregnancy may induce a post-partum state of enhanced vascular sensitivity via SMC-MR activation. A PE model was induced by transient viral expression of sFlt1 in pregnant C57Bl6 mice. Elevated serum sFlt1, BP and glomerular endotheliosis was confirmed which all resolve post-partum. Two months later, resistance arteries from post-PE mice show no change in vasoconstriction to AngII but with increased mRNA ratio of the pro-constrictive AngII receptor-1(ATR1) to the vasodilatory ATR2. In a small cohort of women with prior PE, we confirm salt sensitivity of BP thus, postpartum mice were implanted with telemetric BP monitors and exposed to high salt or AngII (600mg/kg/day) infusion. Mice with prior PE had a significantly increased BP response to hypertensive stimuli. Microvessels from mice after PE and hypertensive stimuli had enhanced ex vivo myogenic tone and AngII vasoconstriction. To test the direct impact of sFlt1 on SMC-MR function, cultured SMC (Pac1) were transiently exposed to sFlt1 (24 hours on then off) to mimic the post-PE state. SMC-MR transcriptional activity in response to aldosterone and AngII were significantly increased after sFlt1 exposure as measured by luciferase reporter assay. SMC-MR activation and target gene expression was also enhanced after sFlt1 exposure (including AT1R/AT2R ratio). Finally, the role of SMC-MR in the post-PE phenotype was tested in vivo by PE induction in SMC-MR-KO vs MR-intact littermates. Post partum, SMC-MR-KO mice were protected from the PE-induced increase in aortic stiffness, microvascular myogenic tone and AngII vasoconstriction. sFlt1-induced PE produces a state of enhanced sensitivity to AngII that may be mediated by increased activation of SMC-MR. These data support the use of MR antagonists to mitigate the increased risk of cardiovascular disease in women exposed to PE.

Kinetensin Increases Blood Pressure by Activation of Angiotensin‐II Type 1 Receptors, in Isoflurane Anesthetized Male Mice

Kinetensin, a peptide consisting of nine amino acids, originally isolated from pepsin-treated human plasma, shows sequence homology with serum albumin, angiotensin (Ang)-II and neurotensin (Mogard et al., 1986). Due to its interesting homology with the C-terminal end of neurotensin and Ang-II, it was earlier suggested that this peptide might have neurotensin- or Ang-II-like biological activity. Earlier, in-vitro studies revealed the functional role of kinetensin in releasing histamine from mast cells (Sydbom et al., 1989); however, the cardiovascular role of kinetensin, in-vivo, has never been established. In the present study, we investigated first the functional role of kinetensin on blood pressure (BP) and heart rate (HR) variables in mice. Under isoflurane anaesthesia, 12 male C57Bl6/J mice (30-33 g) were implanted with a Millar catheter into their left common carotid artery for continuous recording of BP and HR. The right jugular vein was implanted with flexible cannula for intravenous administration of drugs or saline. Raw traces were obtained using PowerLab (ADInstruments) and analogue signals were digitized using LabChart8 software. Under stable baselines, kinetensin was administered intravenously (1, 10, 100 μg in 0.1 mL of saline). In comparison to vehicle, kinetensin dose-dependently increased BP (2 ±0, 8 ±1, 29 ±4 mmHg, respectively) with a variable response in HR (-6 ±6, -7 ±16, 2 ±11 bpm, respectively), log-dose regression R2 = 0.77, p<0.001 for BP and R2 = 0.001, p<0.91 for HR, n=6. BP responses were precisely reproducible at approximately 10 min intervals and there was no desensitization effect observed for the highest kinetensin dose of 100 μg, 29±4 and 33±4, p=0.268, n=6. Interestingly, pre-treatment with an AT1-receptor antagonist (losartan, 15 mg/kg, i.v.), completely eliminated the kinetensin-mediated (100 μg dose) BP increase (pre-losartan 29±4 versus post-losartan -3±1 mmHg, respectively, p<0.001). In another cohort (n=6), pre-treatment with a ganglionic-blocker (chlorisondamine, 5 mg/kg) substantially reduced baseline BP, however subsequent administration of kinetensin i.v. produced delayed (~ 1 min) with much bigger and prolonged increases in BP responses (55±5 mmHg; p<0.001) compared to untreated mice (~ 5 sec, 29 ±4 mmHg, p<0.001). Our preliminary results show for the first time that kinetensin increases BP in a dose-dependent manner via activation of AT1 receptors, similar to Ang-II. Blockade of autonomic nervous control innervating vasculature produces similar increases in BP with much longer latencies strongly suggests a potential neuropeptide secretion role, such as arginine vasopressin. Further studies are needed to explore the kinetensin role in the central nervous system-mediated autonomic and neuroendocrine functions.

α-Adrenergic receptor blockade attenuates pressor response during mental stress in young black adults.

Black individuals exhibit increased blood pressure (BP) responses to sympathetic stimulation that are associated with an increased risk of hypertension (HTN). We tested the hypothesis that α1‐adrenergic blockade inhibits the increased BP response during and after 45‐min stress in young normotensive Black adults, which may be mediated, in part, by dampened vasoconstriction and decreased renal sodium retention. Utilizing a double‐masked randomized, crossover study design, 51 normotensive Black adults (31 ± 8 yr) were treated with either a placebo or 1 mg/day of prazosin for 1 week. On the final day of each treatment, hemodynamic measures and urinary sodium excretion (UNaV) were collected before (Rest), during (Stress) and after (Recovery) 45 min of mental stress induced via a competitive video game task. During the Stress period, diastolic BP and total peripheral resistance (TPR) were significantly lower with prazosin compared to placebo (p < .05 for both). Similarly, we observed lower systolic BP, diastolic BP, and TPR during the Recovery period with prazosin versus placebo (p < .05 for both). There was no effect of prazosin on stress‐associated UNaV. The change in systolic BP from Rest to Recovery was positively associated with the change in TPR with both treatments (p < .05 for both). In summary, prazosin treatment dampened BP reactivity to 45‐min mental stress and lowered post‐stress BP over the recovery period, which was linked to reduce TPR in young normotensive Black adults. These results suggest that α1‐adrenergic receptor activity may contribute to BP responses and delayed BP recovery to prolonged mental stress through increased vasoconstriction in Black adults.

Diabetic Cardiovascular Autonomic Neuropathy, the Handgrip Test and Ambulatory Blood Pressure Monitoring Parameters: Are There Any Diagnostic Implications?

Cardiovascular autonomic neuropathy (CAN) is a common complication of diabetes mellitus. Cardiovascular reflex tests (CARTs) are the gold standard in the diagnosis of CAN, but the handgrip test is no longer recommended to be performed. Previously, the inverse association between the presence of hypertension and handgrip test abnormality was demonstrated and hypertension as major cause for excessive diastolic blood pressure rise during handgrip testing in diabetic individuals proposed. The aim of the present study is to describe more precisely the association between handgrip test and hypertension by performing ambulatory blood pressure monitoring (ABPM) among diabetic patients. A more comprehensive evaluation of the relationship between cardiovascular autonomic function, hypertension and the handgrip test was targeted using heart rate variability (HRV) analysis. Our study involved 163 patients with diabetes. Cardiovascular autonomic neuropathy was assessed by the CARTs and sustained handgrip test was performed. All patients underwent ABPM and HRV analysis well. CAN was diagnosed in 69 patients. Significant associations were found between the diastolic blood pressure increase in response to handgrip exercise and the 24-h (rho = 0.245, p = 0.003), daytime (rho = 0.230, p = 0.005) and night-time (rho = 0.230, p = 0.006) mean systolic and 24-h diastolic (rho = 0.176, p = 0.034) blood pressure values, systolic blood pressure load (rho = 0.252, p = 0.003) and systolic (rho = 0.236, p = 0.005) and diastolic (rho = 0.165, p = 0.047) hyperbaric impacts. Higher values of ambulatory blood pressure monitoring parameters are associated with greater increases in diastolic blood pressure during isometric handgrip exercise. Diastolic blood pressure elevations during the handgrip test are also correlated, in order to diminished heart rate variability parameters attributable to parasympathetic dysfunction highlighting the pivotal role of sympathetic overactivity in evolving handgrip test results. Our study provides further evidence on the inverse association between handgrip test abnormality and hypertension in diabetic patients.

Experimental preeclampsia results in post‐partum sensitivity to hypertensive stimuli

Preeclampsia (PE) is a syndrome of new onset high blood pressure (BP) with renal damage during late pregnancy that is associated with increased circulating anti‐angiogenic proteins, including soluble VEGF receptor (sFlt1). Women exposed to PE have increased risk of future cardiovascular disease, including hypertension, with evidence of a “hyper‐responsive” renin‐angiotensin‐aldosterone system (RAAS) persisting post‐partum. Aldosterone (Aldo) and angiotensin II (AngII) can activate vascular smooth muscle cell mineralocorticoid receptor (SMC‐MR), causing changes in gene transcription that contribute to increased BP. Thus, we hypothesized that exposure to increased sFlt1 during pregnancy may induce a state of persistent sensitivity to hypertensive stress by enhanced SMC‐MR activity post‐partum .We established a model that reproduces the hallmarks of PE by viral overexpression of sFlt1 compared to control virus in pregnant C57Bl6 mice. Using telemetry to measure blood pressure, we demonstrate that sFlt1 injection results in increased serum sFlt1, elevated BP and glomerular endotheliosis, the hallmark of PE‐induced renal damage, in late pregnancy that all resolve post‐partum. Two months post‐partum, wire myography studies performed on 3rd order mesenteric resistance vessels ex vivo reveal that sFlt1‐injected females (“prior‐PE”) have a vasoconstrictor sensitivity to AngII (1e‐9 dose: 0.16mN vs. 1.42mN, p=0.059) . To test whether prior PE results in increased sensitivity to hypertensive stimuli, post‐partum mice were exposed to various high salt diet conditions or to a moderate pressor dose of AngII (600mg/kg/day infusion) while BP was monitored via telemetry. Mice with prior PE had a trend toward an increased peak BP in response to 2% sodium (11.71mmHg vs. 3.62mmHg, p=0.09) and a significantly increased BP response to 4% sodium (8.88mmHg vs 5.34mmHg, p&lt;0.05). Prior PE mice also had a significantly enhanced BP response to AngII versus those with normotensive pregnancies (22.83 mmHg vs 4.46 mmHg, p=0.0005). Plasma Aldo measured via radioimmunoassay tended to be higher in mice with prior PE (4.65nM vs 2.09nM, P=0.08). Since SMC‐MR can be activated by AngII, we investigated the extent of AngII‐induced SMC‐MR activation after PE using qPCR to measure known SMC‐MR target genes. In microvessels from mice with prior PE, mRNA expression showed increased AT1R (relative expression 3.69 vs 1.30, p&lt;0.05), Cav1.2 (2.29 vs 1.11, p=0.06) and PlGF (1.92 vs 1.20, p=0.11). Studies are underway to determine whether SMC‐specific deletion of MR or post‐partum pharmacologic MR inhibition can protect against enhanced BP sensitivity to AngII and high salt diet after sFlt1‐induced PE.sFlt1‐induced PE produces a state of enhanced sensitivity to hypertensive stimuli that may be mediated by increased activation of SMC‐MR. If confirmed, these data support the use of spironolactone as a therapy to mitigate the increased risk of cardiovascular disease in women exposed to PE.Support or Funding InformationNIH T32HL007609 (LAB), NIH R25GM066567 (BVC)

Redefining Blood Pressure Assessment - The Role of the Ambulatory Blood Pressure Monitoring Study for Drug Safety.

According to models developed from large epidemiological studies, mean increases in systolic blood pressure of 2-3mmHg can increase the risk of cardiovascular (CV) adverse events, especially in patients with a high risk for CV disease. There are new regulatory recommendations for the use of a safety ambulatory blood pressure monitoring (ABPM) study to assess the blood pressure (BP) effects of drugs used chronically. The ABPM study collects BP measurements over 24hours at baseline and during treatment in patients with underlying CV risk. Our evaluation of ABPM studies submitted to the US Food and Drug Administration (FDA) shows these studies can provide precise estimates of BP changes and lack a pronounced placebo response. With the assessment of BP effects in development programs, opportunities exist for developing quantitative safety models to predict CV risk, support dose selection, identify patients with increased BP response, and provide insight into underlying mechanisms.

The Effect of Age on Exercise Blood Pressure Responses Following Short‐term Water Deprivation

Aging impairs regulation of body fluid homeostasis (attenuated thirst sensations, blunted anti‐diuretic hormone release, and reduced renal function) leading to a greater incidence of hypernatremia (elevated serum sodium concentrations ([sNa+])). Previous studies suggest significantly greater increases in [sNa+] following water deprivation (WD) in older adults (OA) compared to young adults (YA). This is problematic as data from animal models suggest a relation between plasma hypernatremia and exaggerated blood pressure (BP) responses during sympathoexcitatory stimuli. This is clinically relevant in humans because exaggerated BP responses to sympathoexcitatory stimuli is associated with greater future incidence of hypertension. However, it is unknown whether WD causes greater increases in [sNa+] and consequently larger increases in BP responses during sympathoexcitatory stimuli in OA compared to YA.PURPOSETo test the hypothesis that WD causes greater increases in [sNa+] and consequently larger increases in BP responses during exercise pressor reflex activation in OA compared to YA.METHODSTwenty‐five healthy YA (11F/14M; age: 25±1 yrs; BMI: 23±1 kg/m2; screening BP: 108±2/59±2 mmHg) and eight healthy OA (7F/1M; age: 67±2 yrs; BMI: 23±1 kg/m2; screening BP: 119±5/77±3 mmHg) completed two hydration conditions in random crossover fashion. A normal hydration control visit (CON; 23mL water/kg bodyweight/day for three days) and WD visit (stepwise reduction in water intake over three days followed by a 16h WD prior to testing) were separated by at least one week. Beat‐to‐beat BP was measured via finger photoplethysmography throughout a ten‐minute baseline, isometric handgrip exercise (HG; 30% MVC, two minutes), and post‐exercise ischemia (PEI; upper arm occlusion, three minutes). Changes in [sNa+] and resting BP were analyzed using two‐way independent group ANOVAs (condition x age). Responses during the final minute of HG and all three minutes of PEI were each compared to the baseline period using a two‐way ANCOVA (condition x age, with resting brachial systolic BP as a covariate). Significance was set a priori at p&lt;0.05.RESULTSBoth age groups had higher [sNa+] during WD compared to CON (YA: 141.3±0.5 vs. 142.6±0.5, OA: 142.2±1.0 vs. 143.1±0.8 mmol/L, condition: p=0.024, age: p=0.421, interaction: p=0.601). OA had higher resting BP than YA during both conditions (YA: 112±2 vs. 112±2, OA: 144±8 vs. 139±7 mmHg, condition: p=0.220, age: p&lt;0.001, interaction: p=0.076). Systolic BP responses were not different between age groups or conditions during HG (YA: Δ15±2 vs. 17±2, OA: Δ18±7 vs. 16±2 mmHg, F(1,61)=0.539, p=0.708, partial η2=0.04), or PEI (YA: Δ14±2 vs. 17±3, OA: Δ23±6 vs. 20±2 mmHg, F(1,61)=0.331, p=0.567, partial η2=0.005; CON vs. WD mean±SEM for all results).CONCLUSIONThese preliminary data suggest that short‐term WD does not elicit larger increases in [sNa+] or larger increases in BP responses during exercise pressor reflex activation in OA compared to YA.Support or Funding InformationNIH Grant 1R01HL128388 (WBF &amp; SDS), NIGMS P20GM113125, and University Doctoral Fellowship (JCW).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.