Long-term Regulation Of Blood Pressure Research Articles

Environmental Cadmium Exposure Induces an Increase in Systolic Blood Pressure by Its Effect on GFR

Chronic exposure to the nephrotoxic metal pollutant, cadmium (Cd), has been associated with hypertension, but the mechanism by which it raises blood pressure is not understood. We hypothesize that exposure to Cd reduces the glomerular filtration rate (GFR), which in turn causes a rise in blood pressure. Data were collected from 447 Thai subjects with a mean age of 51.1 years, of which 48.8% had hypertension, 15.4% had diabetes, and 6.9% had an estimated GFR (eGFR) below 60 mL/min/1.73 m2 (low eGFR). More than half (58.8%) and 23.9% had moderate and severe tubular proteinuria, respectively. The mean blood and urinary Cd concentrations were 2.75 and 4.23 µg/L, respectively. Doubling of body burden of Cd increased the prevalence odds ratios (POR) for low eGFR and severe tubular proteinuria 41% and 48%, respectively. The POR for hypertension rose twofold in those with blood Cd levels of 0.61–1.69 µg/L or urinary Cd excretion levels ≥ 0.98 µg/g creatinine. In the hypertensive group, the eGFR was inversely associated with age (β = −0.517), the Cd excretion rate (β = −0.177), and diabetes (β = −0.175). By mediation analysis, an increase in SBP was attributable totally to the effect of Cd on GFR. Thus, blood pressure appeared to rise as GFR fell. This finding is consistent with the well-known role of the kidney in long-term blood pressure regulation, and explains a universally high prevalence of hypertension among patients with low eGFR.

The Role of Dopamine D2 receptors and Oxidative Stress in the Pathogenesis of Hypertension

Globally, hypertension is the number one risk factor for death, affecting more than 1 billion people. Hypertension is the result of the interactions among genetics, epigenetics, environment, and lifestyle. The long-term regulation of blood pressure rests on renal and non-renal mechanisms. The impaired renal sodium handling in hypertension is caused by aberrant counter-regulatory natriuretic/anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin systems are anti-natriuretic pathways. A counter-regulatory natriuretic pathway is the renal dopaminergic system. Aberrant dopaminergic regulation of renal sodium transport in hypertension is caused by a decrease in renal dopamine synthesis and/or dysfunction of any of the 5 dopamine receptors (D1R, D2R, D3R, D4R, & D5R). Normally, an increase in sodium intake increases while a decrease in sodium intake decreases blood pressure, albeit transiently until sodium balance is achieved. However, ~50 % of hypertensive and ~26% of normotensive subjects have increased blood pressure on high sodium intake, a case of salt sensitivity, while ~20 % have increased blood pressure on a low sodium intake, a case of inverse salt sensitivity. Low and high sodium intakes are associated with increased incidence of cardiovascular events/mortality. In humans with inverse salt sensitivity, there is a linear relationship between the number of single nucleotide polymorphisms in DRD2 (rs6276 and 6277) and decreased renal D2R expression. The increase in blood pressure on a low sodium diet may be due to increased activities of the renin-angiotensin and sympathetic nervous systems that cannot be counteracted by D2R. Hypertension may be a cause or consequence of inflammation or oxidative stress. Deficient D2R function causes renal inflammation independently of the increase in blood pressure. Subjects carrying DRD2 single nucleotide polymorphisms have increased inflammation, mediated by decreased regulation of the miR-217-Wnt5a-Ror2 pathway. The D2R, via paraoxonase2 and sestrin2, maintains normal redox balance and blood pressure. In summary, the D2R is important in the maintenance of normal blood pressure by regulating renal sodium transport, vascular reactivity, inflammation, and redox balance.

Altered baroreflex sensitivity at rest and during Valsalva maneuver in healthy male offspring of hypertensive patients

A family history of hypertension puts young adults at a higher risk of developing hypertension, that too, at an earlier age than their parents. Recent studies suggest that the baroreflex mechanism, which takes care of the short-term regulation of blood pressure (BP), also plays a role in the long-term regulation of BP. Studies have reported decreased baroreflex sensitivity (BRS) in hypertensives. Reduced BRS is shown to herald the future occurrence of cardiovascular diseases (CVD) and helps in risk stratification AIM: Toassess BRS at rest and during the Valsalva maneuver among apparently healthy male offspring (age 18-35 years) of hypertensive patients. We recruited 37 participants whose parents (either/both) were hypertensive in the study group and whose parents (both) were not hypertensive in the control group. We measured basic anthropometric parameters (height, weight, waist circumference), cardiovascular parameters (heart rate and BP), short-term heart rate variability, and BRS (at rest and during Valsalva). We found that BRS at rest and BRS during the Valsalva maneuver were reduced among healthy male offspring of hypertensive parents than in healthy male offspring of non-hypertensive parents. Further, HRV indices and Valsalva ratio showed a sympathovagal imbalance in the form of decreased vagal and increased sympathetic activity. The reduced BRS and sympathovagal imbalance in male offspring of hypertensive parents reveal the early risk of developing hypertension in the future.

S-51-1: SYMPATHETIC REGULATION OF SALT SENSITIVITY

This presentation will cover recent advances relating the role of the sympathetic nervous system in the regulation of the salt sensitivity of blood pressure. Recent studies from our laboratory have elucidated the previously unknown role of PVN specific Galphai2 signal transduction in the prevention of the development of the salt sensitivity of blood pressure. We will discuss these findings and their potential translational relevance. Highlighting the role(s) of the renal sympathetic nerves in the modulation of sodium reabsorption and long-term blood pressure regulation we will highlight recent advances in the role(s) of the afferent renal nerves in the salt sensitivity of blood pressure and how increased renal sympathetic outflow influences the expression and activity of the renal sodium chloride cotransporter.

Vasomotor symptoms of menopause, autonomic dysfunction, and cardiovascular disease.

Cardiovascular disease (CVD), the leading cause of death among US adults, is more prevalent in menopausal females compared with age-matched males. Vasomotor symptoms of menopause (VMS; hot flashes/flushes and night sweats) are common among females undergoing menopausal transition and have been associated with elevated blood pressure (BP) and increased CVD risk. Autonomic dysregulation of BP has been posited as a contributing factor to the elevated CVD risk in menopausal females with VMS. This review includes 1) a brief overview of the relationship between VMS and CVD, 2) mechanisms of hot flushes and their potential impact on short- and long-term BP regulation, and 3) how the disruption of autonomic function associated with VMS might provide a mechanistic pathway to CVD development. Finally, this review will highlight knowledge gaps and future directions toward better understanding of hot flush physiology and VMS contributions to CVD.

Abstract 12625: Genome-Wide Analysis Revealed Genetic Control of the Renin-Angiotensin-Aldosterone System in the General Population

Introduction: The Renin-Angiotensin Aldosterone system (RAAS) is the major player in the long-term blood pressure (BP) regulation. The RAAS is targeted by commonly used anti-hypertensive drugs, but despite its importance, little is still known about its genetics, partially due to the technical difficulties in the quantification of the involved biomarkers. Methods: Using mass-spectrometry, we simultaneously quantified in serum equilibrium angiotensin I, angiotensin II and aldosterone on 2105 participants to the Cooperative Health Research In South Tyrol study (CHRIS), who were either normotensive or under documented anti-hypertensive drug (AHD) treatment. We derived proxies of renin activity (PRA-S= angiotensin I + angiotensin II), angiotensin-converting enzyme activity (ACE-S= angiotensin I / angiotensin II) and adrenal gland function (AA2-ratio =aldosterone/ angiotensin II). We tested association of these biomarkers with 1,085,897 SNPs imputed against a population specific whole-exome-sequencing-based panel, adjusting for age, sex, AHD, and assuming an additive genetic model using Regenie v3.1.1. Results: Study participants were 21 to 95 years old, and 52% were females. Most participants (86%) received specific AHD treatments. ACE-S was associated with variants spanning the ACE gene. The top association was seen at rs4363 (p=2.8E-18), already associated with serum ACE level, and replicating previous findings in an Asian population sample. We found strong evidence of association of angiotensin II and AA2-ratio with the stop gained rs27044 (p=8.2E-10) in the ERAP1, involved in angiotensin II degradation. We observed a borderline association between aldosterone and the synonymous rs7275 at SMARCA4/LDLR (p=5.85E-8), previously related to lipid metabolism. We also report a novel suggestive association between angiotensin I and rs2274978 in the Xaa-Pro aminopeptidase I (XPNPEP1; p=9.49E-6). Conclusions: While some results await replication in an independent cohort, findings are consistent with known physiology, and shed light on genetic background of BP regulation.

Evidence for a Prehypertensive Water Dysregulation Affecting the Development of Hypertension: Results of Very Early Treatment of Vasopressin V1 and V2 Antagonism in Spontaneously Hypertensive Rats.

In addition to long-term regulation of blood pressure (BP), in the kidney resides the initial trigger for hypertension development due to an altered capacity to excrete sodium and water. Betaine is one of the major organic osmolytes, and its betaine/gamma-aminobutyric acid transporter (BGT-1) expression in the renal medulla relates to interstitial tonicity and urinary osmolality and volume. This study investigated altered water and sodium balance as well as changes in antidiuretic hormone (ADH) activity in female spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats from their 3–5 weeks of age (prehypertensive phase) to SHR’s 28–30 weeks of age (established hypertension-organ damage). Young prehypertensive SHRs showed a reduced daily urine output, an elevated urine osmolarity, and higher immunostaining of tubule BGT-1, alpha-1-Na-K ATPase in the outer medulla vs. age-matched WKY. ADH circulating levels were not different between young prehypertensive SHR and WKY, but the urine aquaporin2 (AQP2)/creatinine ratio and labeling of AQP2 in the collecting duct were increased. At 28–30 weeks, hypertensive SHR with moderate renal failure did not show any difference in urinary osmolarity, urine AQP2/creatinine ratio, tubule BGT-1, and alpha-1-Na-K ATPase as compared with WKY. These results suggest an increased sensitivity to ADH in prehypertensive female SHR. On this basis, a second series of experiments were set to study the role of ADH V1 and V2 receptors in the development of hypertension, and a group of female prehypertensive SHRs were treated from the 25th to 49th day of age with either V1 (OPC21268) or V2 (OPC 41061) receptor antagonists to evaluate the BP time course. OPC 41061-treated SHRs had a delayed development of hypertension for 5 weeks without effect in OPC 21268-treated SHRs. In prehypertensive female SHR, an increased renal ADH sensitivity is crucial for the development of hypertension by favoring a positive water balance. Early treatment with selective V2 antagonism delays future hypertension development in young SHRs.

Determining risk factors for triple whammy acute kidney injury

Concurrent use of a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as “triple whammy”. Diuretics and RAS inhibitors, such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker, are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common. The goals of this study are to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual’s susceptibility. To accomplish these goals, we utilize sex-specific computational models of long-term blood pressure regulation. These models include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron and the RAS and are parameterized separately for men and women. Hypertension is modeled as overactive renal sympathetic nervous activity. Model simulations suggest that low water intake, the myogenic response, and drug sensitivity may predispose patients with hypertension to develop triple whammy-induced AKI. Triple treatment involving an ACE inhibitor, furosemide, and NSAID results in blood pressure levels similar to double treatment with ACEI and furosemide. Additionally, the male and female hypertensive models act similarly in most situations, except for the ACE inhibitor and NSAID double treatment.

Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule.

Epidemiological and clinical observations have shown that potassium ingestion is inversely correlated with arterial hypertension prevalence and cardiovascular mortality. The higher the dietary potassium, the lower the blood pressure and mortality. This phenomenon is explained, at least in part, by the interaction between salt reabsorption in the distal convoluted tubule (DCT) and potassium secretion in the connecting tubule/collecting duct of the mammalian nephron: In order to achieve adequate K+ secretion levels under certain conditions, salt reabsorption in the DCT must be reduced. Because salt handling by the kidney constitutes the basis for the long‐term regulation of blood pressure, losing salt prevents hypertension. Here, we discuss how the study of inherited diseases in which salt reabsorption in the DCT is affected has revealed the molecular players, including membrane transporters and channels, kinases, and ubiquitin ligases that form the potassium sensing mechanism of the DCT and the processes through which the consequent adjustments in salt reabsorption are achieved.

Selective Renal Silencing of the Calcineurin Homologous Protein‐1 Decreases Blood Pressure in Balb/cJ Mice

Hypertension has high incidence and health care cost. Its treatments are often ineffective; therefore, we are in need of new strategies to prevent, limit or reverse hypertension. Long-term regulation of blood pressure (BP) has fundamental renal components; in particular, the causes of impaired renal Na+ handling and possible strategies to overcome disturbances in renal Na+ balance in hypertension are not well defined. Recently, we have shown that a Ca2+-binding protein, the Calcineurin Homologous Protein-1 (CHP1), is a regulatory binding partner of a key player in the control of Na+ homeostasis, the epithelial brush-border Na+/H+ exchanger-3 (NHE3). Here, we proposed that CHP1 expression controls BP as a regulatory co-factor of NHE3 transport. Indeed, selective renal silencing of Chp1 via renal subcapsular infusion of Chp1 siRNA in Balb/cJ mice significantly reduced NHE3 protein expression (-50%). Importantly, Chp1 siRNA treated mice had a reduced systolic blood pressure compared to scrambled siRNA treated mice (-30%) measured in anesthetized mice from the aorta and femoral artery, and in conscious mice using noninvasive tail-cuff method. Chp1 siRNA treated mice also had markedly reduced serum Na+ and increased urinary Na+ excretion compared to scrambled siRNA treated mice. Serum K+ and Cl- did not change while urinary K+ and Cl- excretion were increased in Chp1 siRNA treated mice. Glomerular Filtration Rate estimated by creatinine clearance was reduced in Chp1 treated mice possibly as consequence of tubuloglomerular feedback. This is the first animal model in mammals where the effect of a reduction in CHP1 protein expression in the kidney was studied. Our findings provide new insights into the action of CHP1 on renal tubular Na+ transport and propose CHP1 protein expression as a novel tool to significantly control blood pressure.

Higher cardiac vagal activity predicts lower peripheral resistance 6 years later in European but not African Americans.

African American (AA) individuals are at a greater risk for the development of cardiovascular complications, such as hypertension, compared with European Americans (EAs). Higher vagally mediated heart rate variability (HRV) is typically associated with lower blood pressure (BP) and total peripheral resistance (TPR). However, research has yet to examine the differential impact of HRV on longitudinal hemodynamic activity between AAs and EAs. We sought to rectify this in a sample of 385 normotensive youths (207 AAs, 178 EAs; mean age 23.16 ± 2.9 yr). Individuals participated in two laboratory evaluations spanning approximately 6 yr. Bioimpedance was used to assess HRV at time 1 and cardiac output at both time 1 and time 2. Mean arterial pressure (MAP) was measured at both time points via an automated BP machine. TPR was calculated as MAP divided by cardiac output. Results showed AAs to have higher BP and higher TPR at time 2 compared with EAs, independent of several important covariates. Also, higher HRV at time 1 significantly predicted both lower TPR and BP at time 2 among EAs only; these associations were attenuated and not significant in AAs. HRV did not significantly predict cardiac output at time 2 in the full sample or split by ethnicity. Our findings highlight that AAs show TPR mediated long-term increases in BP irrespective of resting HRV, providing a physiological pathway linking AAs with a greater risk for mortality and morbidity from hypertension and potentially other cardiovascular disease.NEW & NEWSWORTHY African Americans and European Americans differ in hemodynamics underlying long-term blood pressure regulation. Over 6 yr, African Americans show total peripheral resistance-mediated increases in blood pressure compared with European Americans. Higher heart rate variability predicts lower blood pressure and total peripheral resistance 6 yr later in European Americans but not African Americans.

The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension

The kidney is critical in the long-term regulation of blood pressure. Oxidative stress is one of the many factors that is accountable for the development of hypertension. The five dopamine receptor subtypes (D1R–D5R) have important roles in the regulation of blood pressure through several mechanisms, such as inhibition of oxidative stress. Dopamine receptors, including those expressed in the kidney, reduce oxidative stress by inhibiting the expression or action of receptors that increase oxidative stress. In addition, dopamine receptors stimulate the expression or action of receptors that decrease oxidative stress. This article examines the importance and relationship between the renal dopaminergic system and oxidative stress in the regulation of renal sodium handling and blood pressure. It discusses the current information on renal dopamine receptor-mediated antioxidative network, which includes the production of reactive oxygen species and abnormalities of renal dopamine receptors. Recognizing the mechanisms by which renal dopamine receptors regulate oxidative stress and their degree of influence on the pathogenesis of hypertension would further advance the understanding of the pathophysiology of hypertension.

A Modern View of the Interstitial Space in Health and Disease.

Increases in the volume of the interstitial space are readily recognized clinically as interstitial edema formation in the loose connective tissue of skin, mucosa, and lung. However, the contents and the hydrostatic pressure of this interstitial fluid can be very difficult to determine even in experimental settings. These difficulties have long obscured what we are beginning to appreciate is a dynamic milieu that is subject to both intrinsic and extrinsic regulation. This review examines current concepts regarding regulation of interstitial volume, pressure, and flow and utilizes that background to address three major topics of interest that impact IV fluid administration. The first of these started with the discovery that excess dietary salt can be stored non-osmotically in the interstitial space with minimal impact on vascular volume and pressures. This led to the hypothesis that, along with the kidney, the interstitial space plays an active role in the long-term regulation of blood pressure. Second, it now appears that hypovolemic shock leads to systemic inflammatory response syndrome principally through the entry of digestive enzymes into the intestinal interstitial space and the subsequent progression of enzymes and inflammatory agents through the mesenteric lymphatic system to the general circulation. Lastly, current evidence strongly supports the non-intuitive view that the primary factor leading to inflammatory edema formation is a decrease in interstitial hydrostatic pressure that dramatically increases microvascular filtration.

Formation of HETE-EAs and dihydroxy derivatives in mouse kidney tissue and analysis by high-performance liquid chromatography tandem mass spectrometry

The kidneys play an important role in the long-term regulation of blood pressure by control of salt and water balance in the body through various systems including the endocannabinoid system. The endocannabinoid system consists of the two major cannabinoid receptor agonists, anandamide (AEA) and 2-arachidonylglycerol (2-AG), their hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the cannabinoid receptors, CB1 and CB2. AEA can be converted into 12- and 15(S)-hydroperoxyeicosatetraenoic acid ethanolamides by 12-LOX and 15-LOX, respectively and can form epoxyeicosatrienoic acid- (EET-EAs) (5,6-, 8,9-, 11,12-, 14,15-) and hydroxyeicosatetraenoic acid- (HETE) ethanolamides. Furthermore, the EET-EAs produce a secondary metabolism by microsomal epoxide hydrolase to form the corresponding dihydroxyeicosatetraenoic acid-EAs (DiHETE-EA). Reference material was not available for DiHETE-EA. These metabolites were synthesized by incubation of the corresponding EET-EAs with mouse liver cytosol containing epoxide hydrolases. Presented is a solid phase extraction and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for the extraction and quantitation of AEA, 2-AG, their metabolites, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA), and the in vivo formation of the DiHETE-EAs in kidney after a single intravenous bolus administration of 20 mg/kg of anandamide in C57BL/6 J and FAAH KO mice.

A PF‐3845‐induced novel lipid fraction in mouse medullary interstitial cells causes diuresis and natriuresis via a CB1‐mediated pathway

The relationship between the endocannabinoid system in the renal medulla and the long‐term regulation of blood pressure is not understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase (FAAH), PF‐3845. Treatment of MMICs with PF‐3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. HPLC analyses of lipid extracts of MMIC culture medium revealed a 205nm‐absorbing peak that showed responsiveness to PF‐3845 treatment. The biologic activities of the PF‐3845‐induced product (PIP) isolated by HPLC were investigated in anesthetized, normotensive surgically‐instrumented mice. Intravenous and intramedullary infusions of PIP at low doses resulted in a vasodepressor, diuretic and natriuretic effects. Pharmacological and genetic ablation of cannabinoid 1 receptors resulted in the loss of the vasodepressor, diuretic and natriuretic effect of PIP. Radioactive binding assays showed that PIP competes for binding to CB1 receptors in the presence of a full agonist (CP 55,940). PIP did not elevate urine and sodium excretion in a genetic knockout mouse model of FAAH. A PIP‐induced decrease in blood pressure at high doses of PIP was similar between FAAH WT and FAAH KO mice. These data support a model whereby PF‐3845 treatment of MMICs results in increased secretion of a neutral lipid which acts directly to promote diuresis and natriuresis via a CB1‐mediated mechanism. The diuretic and natriuretic responses to PIP are eliminated by inhibition of FAAH, suggesting an undergoing sensitization to PIP in FAAH KO mice. Efforts to identify the structure of the PF‐3845‐induced lipid and its relationship to the previously proposed renomedullary antihypertensive lipids are ongoing.Support or Funding InformationThis work was supported by the National Institute of Diabetes and Digestive and Kidney Disorders grant [grant R01DK102539] and the National Institute on Drug Abuse [grant P30DA033934]. S.D. was supported by the National Institute on Drug Abuse [training grant T32DA007027].This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling.

Sex differences in blood pressure and the prevalence of hypertension are found in humans and animal models. Moreover, there has been a recent explosion of data concerning sex differences in nitric oxide, the renin-angiotensin-aldosterone system, inflammation, and kidney function. These data have the potential to reveal the mechanisms underlying male-female differences in blood pressure control. To elucidate the interactions among the multitude of physiological processes involved, one may apply computational models. In this review, we describe published computational models that represent key players in blood pressure regulation, and highlight sex-specific models and their findings.

Diuretic, Natriuretic, and Vasodepressor Activity of a Lipid Fraction Enhanced in Medium of Cultured Mouse Medullary Interstitial Cells by a Selective Fatty Acid Amide Hydrolase Inhibitor.

The relationship between the endocannabinoid system in the renal medulla and the long-term regulation of blood pressure is not yet understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured, and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase, PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide). Treatment of MMICs with PF-3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. High-performance liquid chromatography (HPLC) analyses of lipid extracts of MMIC culture medium revealed a 205-nm absorbing peak that showed responsiveness to PF-3845 treatment. The biologic activities of the PF-3845-induced product (PIP) isolated by HPLC were investigated in anesthetized, normotensive surgically instrumented mice. Intramedullary and intravenous infusion of PIP at low dose rates (0.5-1 area units under the peak/10 min) stimulated diuresis and natriuresis, whereas these parameters returned toward baseline at higher doses but mean arterial pressure (MAP) was lowered. Whereas intravenous bolus doses of PIP stimulated diuresis, the glomerular filtration rate, and medullary blood flow (MBF) and reduced or had no effect on MAP, an intraperitoneal bolus injection of PIP reduced MAP, increased MBF, and had no effect on urine parameters. These data support a model whereby PF-3845 treatment of MMICs results in increased secretion of a neutral lipid that acts directly to promote diuresis and natriuresis and indirectly through metabolites to produce vasodepression. Efforts to identify the structure of the PF-3845-induced lipid and its relationship to the previously proposed renomedullary antihypertensive lipids are ongoing.

Sex-specific long-term blood pressure regulation: Modeling and analysis

Hypertension is a global health challenge: it affects one billion people worldwide and is estimated to account for >60% of all cases or types of cardiovascular disease. In part because sex differences in blood pressure regulation mechanisms are not sufficiently well understood, fewer hypertensive women achieve blood pressure control compared to men, even though compliance and treatment rates are generally higher in women. Thus, the objective of this study is to identify which factors contribute to the sexual dimorphism in response to anti-hypertensive therapies targeting the renin angiotensin system (RAS). To accomplish that goal, we develop sex-specific blood pressure regulation models. Sex differences in the RAS, baseline adosterone level, and the reactivity of renal sympathetic nervous activity (RSNA) are represented. A novel aspect of the model is the representation of sex-specific vasodilatory effect of the bound angiotensin II type two receptor (AT2R-bound Ang II) on renal vascular resistance. Model simulations suggest that sex differences in RSNA are the largest cause of female resistance to developing hypertension due to the direct influence of RSNA on afferent arteriole resistance. Furthermore, the model predicts that the sex-specific vasodilatory effects of AT2R-bound Ang II on renal vascular resistance may explain the higher effectiveness of angiotensin receptor blockers in treating hypertensive women (but not men), compared to angiotensin converting enzyme inhibitors.

Abstract 115: Renal-Specific Expression of Human Grk4 R65L in Mice Lacking Grk4 Increases Blood Pressure

The genetic causes of salt (NaCl) sensitivity in humans are not well understood. The kidney is critical to the overall fluid and electrolyte balance and long-term regulation of blood pressure (BP). Therefore, the pathogenesis of salt sensitivity must involve a deficient renal NaCl handling. The renal paracrine inhibition of Na + transport by dopamine is impaired in salt-sensitive rats, mice, and humans due to decreased dopamine D1 receptor (D1R) function and not related to a primary defect of the D1R gene but rather due to its uncoupling from second messengers caused by activating variants of the human G protein-coupled receptor kinase type 4 (h GRK4 ) (R65L, A142V, and A486V). We have shown that global transgenic mice expressing hGRK4 R65L variant have salt-sensitive hypertension. To determine the role of the kidney in the salt-sensitivity of these mice, we developed a mouse model of kidney-specific expression of the R65L variant (KS hGRK4 R65L) by bilateral ureteral infusion of AAV vectors carrying the variant in GRK4 knockout mice. Mice infused with hGRK4 wild-type served as controls (KS hGRK4 WT). Systolic BP (SBP) was measured under anesthesia in the mice before and after infusion of the AAV vectors. SBP before AAV was similar in both groups. SBP post AAV increased in KS hGRK4 R65L (93±1 vs 117±4 mmHg, P<0.05, n=4) but not in KS hGRK4 WT (96±2 vs 105±6, n=5). Renal mRNA expressions of dopamine 1 (D1R, 0.81±0.01 vs 1.28±0.04, P<0.01), D3R (0.44±0.02 vs 1.27±0.07, P<0.01) and angiotensin AT1A (AT1A, 0.78±0.02 vs 1.02±0.02, P<0.01) receptors were decreased in renal cortex of KS hGRK4 R65L relative to KS hGRK4 WT. In addition, the expressions of Na + /K + ATPase (1.12±0.03 vs 1.0 ±0.007, P<0.05) and ENaC (1.4±0.14 vs 1.0±0.11, P<0.05) were increased while those of the proximal tubule Na + transporters NaPi2 (0.81±0.02 vs 1.04±0.02), SGLT2 (0.89±0.03 vs 1.07±0.05), and NBCe2 (0.50±0.07 vs 1.15±0.03) were decreased. Our results show that kidney specific expression of hGRK4 R65L increased SBP and produced changes in the expression of receptors and Na + transporters, pump, and channel but their roles in the increased SBP remain to be determined.

Modulation of mean arterial pressure and diuresis by renomedullary infusion of a selective inhibitor of fatty acid amide hydrolase.

The kidneys contribute to the control of body fluid and electrolytes and the long-term regulation of blood pressure through various systems, including the endocannabinoid system. Previously, we showed that inhibition of the two major endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, in the renal medulla increased the rate of urine excretion (UV) and salt excretion without affecting mean arterial pressure (MAP). The present study evaluated the effects of a selective FAAH inhibitor, N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidine carboxamide (PF-3845) on MAP and renal functions. Infusion of PF-3845 into the renal medulla of C57BL/6J mice reduced MAP during the posttreatment phases and increased UV at 15 and 30 nmol/min per gram kidney weight (g kwt), relative to the pretreatment control phase. Intravenous PF-3845 administration reduced MAP at the 7.5, 15, and 30 doses and increased UV at the 15 and 30 nmol⋅min-1⋅g-1 kwt doses. PF-3845 treatment elevated sodium and potassium urinary excretion and medullary blood flow. Homozygous FAAH knockout mice were refractory to intramedullary PF-3845-induced changes in MAP, but UV was increased. Both MAP and UV responses to intramedullary PF-3845 in C57BL/6J mice were diminished by pretreatment with the cannabinoid type 1 receptor-selective antagonist, rimonabant (3 mg/kg, ip) but not the cyclooxygenase 2-selective inhibitor, celecoxib (15 mg/kg, iv). Liquid chromatography-tandem mass spectrometry analyses showed increased anandamide in kidney tissue and 2-arachidonoyl glycerol in plasma after intramedullary PF-3845. These data suggest that inhibition of FAAH in the renal medulla leads to both a diuretic and blood pressure-lowering response mediated by elevated anandamide in kidney tissue or 2-arachidonoyl glycerol in plasma.