2022
DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment
Wilson JR, Garner EM, Mashayekhi M, Hubers SA, Bustamante C, Kerman SJ, Nian H, Shibao CA, Brown NJ. DPP4 (Dipeptidyl Peptidase-4) Inhibition Increases Catecholamines Without Increasing Blood Pressure During Sustained ACE (Angiotensin-Converting Enzyme) Inhibitor Treatment. Hypertension 2022, 79: 827-835. PMID: 35045722, PMCID: PMC8917054, DOI: 10.1161/hypertensionaha.121.18348.Peer-Reviewed Original ResearchMeSH KeywordsAdultAngiotensin Receptor AntagonistsAngiotensin-Converting Enzyme InhibitorsAngiotensinsAprepitantBlood PressureCardiovascular AgentsCatecholaminesCross-Over StudiesDiabetes Mellitus, Type 2Dipeptidyl Peptidase 4HumansNorepinephrineRamiprilRenin-Angiotensin SystemSitagliptin PhosphateValsartanConceptsDPP4 inhibitionBlood pressureACE inhibitionDouble-blind crossover studyAcute ACE inhibitionBlood pressure armNK1 receptor blockerACE inhibitor treatmentOral diabetes medicationsCalcium channel blockersType 2 diabetesEffects of DPP4Aldosterone systemCardiovascular complicationsDiabetes medicationsReceptor blockersCardiovascular effectsCrossover therapyHeart failureHypotensive effectCrossover studyChannel blockersDPP4 inhibitorsHeart rateInhibitor treatment
2018
DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition
Hubers SA, Wilson JR, Yu C, Nian H, Grouzmann E, Eugster P, Shibao CA, Billings FT, Jafarian Kerman S, Brown NJ. DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition. Hypertension 2018, 72: 712-719. PMID: 29987109, PMCID: PMC6202157, DOI: 10.1161/hypertensionaha.118.11498.Peer-Reviewed Original ResearchConceptsNPY infusionPlacebo-controlled crossover studyAngiotensin-converting enzyme inhibitorAldosterone system inhibitionDose-dependent vasoconstrictionIntra-arterial enalaprilatAngiotensin receptor blockersForearm blood flowHigh-risk patientsOrder of treatmentReceptor blockersVasoconstrictor effectVasoconstrictor responsesCardiovascular effectsRenin-AngiotensinBrachial arteryHeart failureNorepinephrine releaseCrossover studyEndogenous NPYY1 receptorCrossover treatmentSystem inhibitionY2 receptorsDPP4 inhibition
2014
Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans
Luther JM, Byrne LM, Yu C, Wang TJ, Brown NJ. Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans. The Journal Of Clinical Endocrinology & Metabolism 2014, 99: e1895-e1902. PMID: 25029426, PMCID: PMC4184066, DOI: 10.1210/jc.2014-2122.Peer-Reviewed Original ResearchConceptsHigh sodium dietHigh sodium intakeInsulin sensitivity indexSodium intakeInsulin secretionAldosterone systemAldosterone infusionInsulin sensitivityAcademic clinical research centerAcute insulin secretory responseLow dietary sodium intakeDecrease insulin secretionC-peptide responsePlasma renin activityDietary sodium intakeLow sodium dietSystolic blood pressureClinical Research CenterInsulin secretory responseAcute insulin responseHigh-risk individualsImpairs insulin secretionGlucose-stimulated insulinIncident diabetesNormotensive volunteers
2012
Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery*
Pretorius M, Murray KT, Yu C, Byrne JG, Billings FT, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Mishra V, Body SC, Brown NJ. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery*. Critical Care Medicine 2012, 40: 2805-2812. PMID: 22824930, PMCID: PMC3588582, DOI: 10.1097/ccm.0b013e31825b8be2.Peer-Reviewed Original ResearchConceptsAcute renal failureAngiotensin-converting enzyme inhibitorMineralocorticoid receptor blockadePostoperative atrial fibrillationMineralocorticoid receptor antagonistsAtrial fibrillationPlacebo groupSpironolactone groupRenal failureCardiac surgeryReceptor blockadeReceptor antagonistEnzyme inhibitorsDouble-blind placebo-controlled studyAngiotensin-converting enzyme inhibitionPrevalence of hypotensionElective cardiac surgeryPlacebo-controlled studyRenin-angiotensin systemNormal sinus rhythmEnzyme inhibitionRamipril groupSpironolactone useHospital stayPrimary endpointPolymorphisms in the serum- and glucocorticoid-inducible kinase 1 gene are associated with blood pressure and renin response to dietary salt intake
Rao AD, Sun B, Saxena A, Hopkins PN, Jeunemaitre X, Brown NJ, Adler GK, Williams JS. Polymorphisms in the serum- and glucocorticoid-inducible kinase 1 gene are associated with blood pressure and renin response to dietary salt intake. Journal Of Human Hypertension 2012, 27: 176-180. PMID: 22648267, PMCID: PMC3463709, DOI: 10.1038/jhh.2012.22.Peer-Reviewed Original ResearchMeSH KeywordsAdultBiomarkersBlood PressureChi-Square DistributionEuropeFemaleGene FrequencyGenetic Predisposition to DiseaseHumansHypertensionImmediate-Early ProteinsLinear ModelsLinkage DisequilibriumLogistic ModelsMaleMiddle AgedPhenotypePolymorphism, Single NucleotideProtein Serine-Threonine KinasesReninRenin-Angiotensin SystemSodium Chloride, DietaryUnited StatesWhite PeopleConceptsDietary salt intakeBlood pressureSalt intakeSingle nucleotide polymorphismsHigher systolic blood pressureMeasurement of BPAldosterone system activityRAA system activitySystem activitySystolic blood pressureSalt-sensitive hypertensionSGK1 gene variantGlucocorticoid-inducible kinase 1Non-significant trendNormotensive populationRenin responseEpithelial sodium channelHuman hypertensionGenotype statusStudy populationDistal nephronHypertensionAdditive genetic modelSodium channelsGene variantsAldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II–induced cardiac, renal, and vascular injury
Luther JM, Luo P, Wang Z, Cohen SE, Kim HS, Fogo AB, Brown NJ. Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II–induced cardiac, renal, and vascular injury. Kidney International 2012, 82: 643-651. PMID: 22622494, PMCID: PMC3434275, DOI: 10.1038/ki.2012.170.Peer-Reviewed Original ResearchMeSH KeywordsAldosteroneAngiotensin IIAnimalsAortaBiomarkersBlood PressureCytochrome P-450 CYP11B2Disease Models, AnimalFibrosisGene Expression RegulationHeart DiseasesInflammationKidney DiseasesKidney GlomerulusMiceMice, 129 StrainMice, Inbred C57BLMineralocorticoid Receptor AntagonistsMyocardiumReceptors, MineralocorticoidRenin-Angiotensin SystemSodium Chloride, DietarySpironolactoneTime FactorsVascular DiseasesConceptsMineralocorticoid receptor antagonismAbsence of aldosteroneAldosterone deficiencyAngiotensin IIReceptor antagonismMineralocorticoid receptorKnockout miceAldosterone synthase knockout (AS(-/-)) miceMineralocorticoid receptor antagonist spironolactonePlasminogen activator inhibitor-1 mRNA expressionAldosterone synthase inhibitionMineralocorticoid receptor activationPrevents angiotensin IIAngiotensin II treatmentSynthase knockout miceBlood urea nitrogenWild-type miceWild-type littermatesMineralocorticoid antagonismAntagonist spironolactoneAortic remodelingRenal injuryEndogenous aldosteroneGlomerular hypertrophyGlomerular injury
2011
The renin–angiotensin–aldosterone system and glucose homeostasis
Luther JM, Brown NJ. The renin–angiotensin–aldosterone system and glucose homeostasis. Trends In Pharmacological Sciences 2011, 32: 734-739. PMID: 21880378, PMCID: PMC3223326, DOI: 10.1016/j.tips.2011.07.006.Peer-Reviewed Original ResearchConceptsAldosterone systemΒ-cellsGlucose-stimulated insulin secretionIncidence of diabetesLarge clinical trialsInduces Insulin ResistanceCultured β-cellsPancreatic β-cellsRAAS inhibitionAng IIAngiotensin IIInsulin resistanceHeart diseaseClinical trialsDiabetes progressionMineralocorticoid receptorPharmacological strategiesInsulin secretionGlucose homeostasisPancreatic isletsOxidative stressDiabetesIndependent mechanismsGlucose transportCellular level
2008
Male–female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population
Schoenhard JA, Asselbergs FW, Poku KA, Stocki SA, Gordon S, Vaughan DE, Brown NJ, Moore JH, Williams SM. Male–female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population. Human Genetics 2008, 124: 479-488. PMID: 18953568, PMCID: PMC2770717, DOI: 10.1007/s00439-008-0573-x.Peer-Reviewed Original ResearchConceptsPlasminogen activator inhibitor-1PAI-1 levelsTissue-type plasminogen activatorRenin polymorphismPAI-1 4G/5G polymorphismRenin-angiotensin systemDiastolic blood pressurePopulation-based sampleActivator inhibitor-1Large-scale population-based samplePAI-1 expressionBlood pressureTotal cholesterolThromboembolic diseasePlasma levelsRisk factorsCardiovascular diseaseD polymorphismMetabolic parametersG polymorphismFibrinolytic systemGene polymorphismsThrombus formationCaucasian subjectsGhanaian populationAldosterone and Vascular Inflammation
Brown NJ. Aldosterone and Vascular Inflammation. Hypertension 2008, 51: 161-167. PMID: 18172061, DOI: 10.1161/hypertensionaha.107.095489.Peer-Reviewed Original Research
2007
Aldosterone and end-organ damage
Marney AM, Brown NJ. Aldosterone and end-organ damage. Clinical Science 2007, 113: 267-278. PMID: 17683282, DOI: 10.1042/cs20070123.Peer-Reviewed Original ResearchConceptsMR antagonismBlood pressureEndothelial functionMyocardial infarctionGlucose homeostasisRapid non-genomic effectsEnd-organ damageImpairs endothelial functionNon-genomic effectsNon-genomic pathwaysResistant hypertensionAldosterone concentrationEndothelial dysfunctionRenal injuryDiabetic patientsMetabolic syndromeSleep apnoeaSubsequent fibrosisMR activationSodium retentionCardiac fibrosisCardiovascular remodellingBody of evidenceAldosteronePatients
2006
Endogenous NO Regulates Plasminogen Activator Inhibitor-1 During Angiotensin-Converting Enzyme Inhibition
Brown NJ, Muldowney JA, Vaughan DE. Endogenous NO Regulates Plasminogen Activator Inhibitor-1 During Angiotensin-Converting Enzyme Inhibition. Hypertension 2006, 47: 441-448. PMID: 16432054, DOI: 10.1161/01.hyp.0000202478.79587.1a.Peer-Reviewed Original ResearchMeSH KeywordsAdultAldosteroneAngiotensin-Converting Enzyme InhibitorsArginineDouble-Blind MethodDrug CombinationsEnzyme InhibitorsFemaleFibrinolysisHemodynamicsHumansInfusions, IntravenousMaleMiddle AgedNG-Nitroarginine Methyl EsterNitric OxideNitric Oxide SynthasePlasminogen Activator Inhibitor 1ProdrugsRamiprilReference ValuesRenin-Angiotensin SystemConceptsPlasminogen activator inhibitor-1Plasminogen activator inhibitor-1 antigenActivator inhibitor-1Salt-replete subjectsL-arginineFibrinolytic balanceInhibitor-1Angiotensin-Converting Enzyme InhibitionNO precursor L-argininePlasminogen activator inhibitor antigenTissue-type plasminogen activator antigenEffect of angiotensinPrecursor L-argininePlasminogen activator antigenNO synthase inhibitorEnzyme inhibitionT-PA activityRenin activityD-dimerInhibitor antigenNormal subjectsSynthase inhibitorEnzyme inhibitorsT-PAAntigen
2005
Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia
Ma J, Albornoz F, Yu C, Byrne DW, Vaughan DE, Brown NJ. Melanocortin-4 Receptor–Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia. Hypertension 2005, 46: 326-332. PMID: 15998706, DOI: 10.1161/01.hyp.0000174327.53863.86.Peer-Reviewed Original ResearchMeSH KeywordsAdultCross-Over StudiesDiureticsDouble-Blind MethodElectrolytesFemaleFibrinolysisHemodynamicsHumansHydrochlorothiazideHypertensionMaleMiddle AgedMineralocorticoid Receptor AntagonistsPlasminogen Activator Inhibitor 1PotassiumReceptors, MineralocorticoidRenin-Angiotensin SystemSodium Chloride Symporter InhibitorsSpironolactoneTriamtereneConceptsPAI-1 antigenMineralocorticoid receptor antagonismHypertensive subjectsPAI-1 responseTissue-type plasminogen activatorAldosterone systemNormotensive subjectsFibrinolytic balanceReceptor antagonismMelanocortin 4 receptor-deficient micePlasminogen activator inhibitor-1 (PAI-1) concentrationsEffect of spironolactoneReceptor-deficient miceEffect of triamtereneBlood pressureSerum potassiumTreatment groupsEffects of activationSpironolactonePAI-1Plasminogen activatorAntigenTriamtereneRegression analysisSubjects
2004
Uric acid and the state of the intrarenal renin-angiotensin system in humans
Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ, Brown NJ, Williams GH, Hollenberg NK, Fisher ND. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney International 2004, 66: 1465-1470. PMID: 15458439, DOI: 10.1111/j.1523-1755.2004.00909.x.Peer-Reviewed Original ResearchConceptsIntrarenal renin-angiotensin systemRenin-angiotensin systemSerum uric acid concentrationBody mass indexHigh-density lipoproteinUric acid concentrationRenal vascular responsePlasma renin activityAng IIRPF responseExperimental hyperuricemiaBlood pressureVascular responsesUric acidRenal plasma flow responsePara-aminohippuric acid clearanceHigh sodium balanceIntrarenal RAS activityRenal vascular responsivenessExogenous angiotensin IISerum high-density lipoproteinSerum uric acidMultivariable regression analysisPlasma flow responseRenin activity
2003
Effect of Combined AT1 Receptor and Aldosterone Receptor Antagonism on Plasminogen Activator Inhibitor-1
Sawathiparnich P, Murphey LJ, Kumar S, Vaughan DE, Brown NJ. Effect of Combined AT1 Receptor and Aldosterone Receptor Antagonism on Plasminogen Activator Inhibitor-1. The Journal Of Clinical Endocrinology & Metabolism 2003, 88: 3867-3873. PMID: 12915681, DOI: 10.1210/jc.2003-030374.Peer-Reviewed Original ResearchMeSH KeywordsAdultAngiotensin Receptor AntagonistsBenzimidazolesBiphenyl CompoundsDiureticsElectrolytesFemaleFibrinolysisFurosemideHemodynamicsHumansMaleMineralocorticoid Receptor AntagonistsPlasminogen Activator Inhibitor 1Potassium ChlorideReceptor, Angiotensin, Type 1Renin-Angiotensin SystemSingle-Blind MethodSpironolactoneTetrazolesConceptsMean arterial pressureAldosterone receptor antagonismAng IIReceptor antagonismPAI-1Angiotensin II type 1Coadministration of spironolactoneEffects of candesartanFurosemide-induced increasePresence of candesartanAldosterone receptor antagonistsEndogenous Ang IIPlasminogen activator inhibitor-1PAI-1 antigenActivator inhibitor-1PAI-1 productionPlasminogen activator inhibitorAldosterone systemNormotensive subjectsArterial pressureAngiotensin IIAT1 receptorFibrinolytic variablesReceptor antagonistCandesartanEplerenone
Brown NJ. Eplerenone. Circulation 2003, 107: 2512-2518. PMID: 12756192, DOI: 10.1161/01.cir.0000071081.35693.9a.Peer-Reviewed Original ResearchConceptsAldosterone receptor antagonistsReceptor antagonistMineralocorticoid receptor-dependent mechanismSelective aldosterone receptor antagonistAldosterone receptor antagonismRole of aldosteroneCongestive heart failureTreatment of hypertensionReceptor-dependent mechanismAntiandrogenic side effectsRenal injuryHeart failureReceptor antagonismCardiovascular toxicityClinical trialsSide effectsAnimal studiesEplerenoneAldosteroneAntagonistHypertensionPatientsSpironolactoneInjuryMortality
2002
ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism
Brown NJ, Kumar S, Painter CA, Vaughan DE. ACE Inhibition Versus Angiotensin Type 1 Receptor Antagonism. Hypertension 2002, 40: 859-865. PMID: 12468570, DOI: 10.1161/01.hyp.0000040264.15961.48.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin Receptor AntagonistsAngiotensin-Converting Enzyme InhibitorsAntihypertensive AgentsBlood GlucoseBlood PressureDiureticsDose-Response Relationship, DrugDrug Therapy, CombinationFemaleHumansHydrochlorothiazideHypertensionInsulinInsulin ResistanceLosartanMaleMiddle AgedPlasminogen Activator Inhibitor 1RamiprilReceptor, Angiotensin, Type 1Renin-Angiotensin SystemSodium Chloride Symporter InhibitorsTissue Plasminogen ActivatorTreatment OutcomeConceptsPlasminogen activator inhibitor-1PAI-1 antigenAngiotensin type 1 receptor antagonismPlasma PAI-1 antigenAT1 receptor antagonismReceptor antagonismACE inhibitionAddition of ramiprilAngiotensin receptor antagonismWeeks of hydrochlorothiazideEffects of losartanPlasma PAI-1Activator inhibitor-1Aldosterone systemHypertensive subjectsBlood pressureFibrinolytic variablesMyocardial infarctionTPA antigenRisk factorsTreatment periodLosartanTPA activityAntigenInhibitor-1The Renin-Angiotensin-Aldosterone System and Fibrinolysis in Progressive Renal Disease
Brown NJ, Vaughan DE, Fogo AB. The Renin-Angiotensin-Aldosterone System and Fibrinolysis in Progressive Renal Disease. Seminars In Nephrology 2002, 22: 399-406. PMID: 12224047, DOI: 10.1053/snep.2002.34725.Peer-Reviewed Original ResearchMeSH KeywordsDisease ProgressionFibrinolysisHumansKidney DiseasesPlasminogen Activator Inhibitor 1Renin-Angiotensin SystemConceptsPlasminogen activator inhibitor-1Renal diseaseAldosterone systemProgressive renal diseaseFinal common pathwayActivator inhibitor-1Extracellular matrix accumulationPAI-1 expressionInitiating injuryRenal failureRenin-AngiotensinInterstitial fibrosisClinical managementMajor physiologic inhibitorAnimal modelsProduction of plasminFibrosisMatrix accumulationPlasminogen activatorPhysiologic inhibitorInhibitor-1Common pathwayDiseaseInjuryRAAS
2001
Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen
Brown N, Murphey L, Srikuma N, Koschachuhanan N, Williams G, Vaughan D. Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen. Arteriosclerosis Thrombosis And Vascular Biology 2001, 21: 1071-1077. PMID: 11397722, DOI: 10.1161/01.atv.21.6.1071.Peer-Reviewed Original ResearchConceptsPAI-1 4G/5G genotypePAI-1 antigen concentrationsPAI-1 antigenHigh salt intakeLow salt intakeSalt intakeG genotypeAntigen concentrationThrombotic cardiovascular eventsPlasma renin activityPAI-1 expressionPAI-1 geneAldosterone systemCardiovascular eventsCardiovascular morbidityRenin activityPharmacological therapyEssential hypertensionSerum triglyceridesEffects of activationG polymorphismG homozygotesG groupAntigenIntake
1999
Comparative Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Antagonism on Plasma Fibrinolytic Balance in Humans
Brown N, Agirbasli M, Vaughan D. Comparative Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Antagonism on Plasma Fibrinolytic Balance in Humans. Hypertension 1999, 34: 285-290. PMID: 10454455, DOI: 10.1161/01.hyp.34.2.285.Peer-Reviewed Original ResearchMeSH KeywordsAdultAldosteroneAngiotensin IIAngiotensin Receptor AntagonistsAngiotensin-Converting Enzyme InhibitorsAntihypertensive AgentsBlood PressureData Interpretation, StatisticalDiet, Sodium-RestrictedFemaleFibrinolysisHeart RateHumansIsoquinolinesLosartanMalePlasminogen Activator Inhibitor 1QuinaprilReninRenin-Angiotensin SystemTetrahydroisoquinolinesTissue Plasminogen ActivatorConceptsPlasminogen activator inhibitor-1PAI-1 antigenTissue plasminogen activatorACE inhibitorsFibrinolytic balanceAldosterone systemAngiotensin II type 1 receptor antagonismAngiotensin II type 1 receptor antagonistAngiotensin-Converting Enzyme InhibitionType 1 receptor antagonistPlasma PAI-1 antigenPAI-1 antigen concentrationsAntigen concentrationEquivalent hypotensive dosesPlasma fibrinolytic balancePlasma renin activityAngiotensin II formationLow salt intakePAI-1 activityClass of drugsTPA antigen concentrationsActivator inhibitor-1Enzyme inhibitionLosartan treatmentQuinapril treatment
1998
Effect of Activation and Inhibition of the Renin-Angiotensin System on Plasma PAI-1
Brown N, Agirbasli M, Williams G, Litchfield W, Vaughan D. Effect of Activation and Inhibition of the Renin-Angiotensin System on Plasma PAI-1. Hypertension 1998, 32: 965-971. PMID: 9856958, DOI: 10.1161/01.hyp.32.6.965.Peer-Reviewed Original ResearchMeSH KeywordsAdultAldosteroneAngiotensin-Converting Enzyme InhibitorsCatecholaminesCircadian RhythmCreatinineDiet, Sodium-RestrictedFibrinolysisHemodynamicsHumansHydrocortisoneIsoquinolinesMalePlasminogen Activator Inhibitor 1QuinaprilReninRenin-Angiotensin SystemSodiumSupine PositionTetrahydroisoquinolinesTissue Plasminogen ActivatorConceptsLow salt intakeRenin-angiotensin systemPAI-1 antigenPlasma renin activitySalt intakeACE inhibitionMyocardial infarctionTPA antigenFibrinolytic systemPAI-1Plasminogen activator inhibitor-1 activityTissue-type plasminogen activator antigenPAI-1 antigen concentrationsPAI-1 antigen levelsThrombotic cardiovascular eventsHigh salt intakeLeft ventricular dysfunctionRecurrent myocardial infarctionPlasminogen activator antigenInhibitor-1 activityPlasma PAI-1PAI-1 activityConcomitant ACE inhibitionCardiovascular eventsRenin activity