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Additive effects of AT1 receptor blockade with valsartan and ace inhibition in patients with heart failure
A
1997–VOL. 10, NO. 4, PART 2
SPECIAL SYMPOSIA 241A
Saturday May 31, Ballroom A, 5:30 pm Calcium Antagonists in 1997: Emerging Perspectives and Future Directions Newer PharmacologicStrategies for Retarding Progression of
Wednesday May 28, Ballroom A, 6:00 am The Role of Angiotensin II in Cardiovascular Disease
Renal Disease. Murray Epstein, M.D., Nephrology Sect., VA MedicalCenter.,Univ.Miami SchoolMedicine,Miami,FL End-stagereml disease(ESRD) is a major public health problem in the United States. The most important strategy to protect the kidney from hypertensivedamage is the effective control of blood pressure. Nevertheless, some classes of arttihypertensivemedication might confer a greater effect in slowing progression of renal disease despite similar levels of blcqdpressurereduction.Experimentalstudiessuggestthat ACEiehibitors, end possibly calcium antagonists,may preferentially retardthe progressionof renal disease.Tltemajorityoftrialshave
BC Ber~* University of Washington, Department of
assessedthe effectsof ACE-irrhibitors in patientswithIDDM. Recently,investigators havestudiedtherenalprotectiveeffectsof ACE inhibitors and calcium antagonists in patients with nondiabetic renal disease. Calcium antagonists have diverse properties, independentof their renal microcirculatoryeffects, that might afford renal protection. A prospective, randomized study by Zuchclli et al. sts~estcd that crdciumantagonistsand
ACEinhibitorsmaybe eqdly protective.Recently,Rossirrget al. wmparcd the effkcts of the long-acting dihydropyridine, nisoldipine, with those of art ACE inhibitor,lisinopril,on proteinrrria and on the decline of GFRin 49 hypertensive IDDM
patients. There was a striking dissociationbetwemrthe antiproteinuric effectsandthe effectsonGFR.Atbmnirruria was reducedby 47 YO in the lisinoprilgroup vs. no decrementin the nisoldipine group. In marked contrast, the decline in GFR appearedto be lesssteepinthenisoldipine groupaa comparedto the Iisinoprilgroup.Theseobservationsclearlydemonstratethat a dihydropyridine, presumably operating through meebarrisrm independent of their renal rnicrocirculatory effects, is renoprotcctive.In summary,the available results are consistent withthe formulationthat ACE inhibitorsand caIcimnentagoNsts act in a wmplementarymanner to attenuate the progressionof chronicrenalfaihr*.
Wednesday May 28, Ballroom A, 6:00 am The Role of Angiotensin II in Cardiovascular Disease ADDITIVEEFFECTSOFATI RXEPTOR BLOCKADEWITHVALSARTANANDACE INHIBITIONINPATIENTSWITHHEARTFAILURE JN Ccdut,for the Vsl-HelT Investigators,Universityof MimeMinneapolis,MitmesotaUSA ChronicACEinhibitortheqy favorablyaffectsthe courseof heartfailure(f-W)by improvingdepressedleft ventricrderfunction(presumablyas a resultof some regressionof left verttictderremedelirtg)endreducirtg the mortalityrate. Whetherthis actionresultsfmrn inhibitionof sngiotensirrII generation,enbamementof bredykirrirtactivityor someotherecdortrermins controversial If rmgiotensinII levelswerereducedto ineffectivelevelsbyACEinhibition,thenan ATI antagonistwouldnotbe expectedto exertrmadditional hemc+rtamic orneurohormortelefffxt. In orderto test the possibilityof continuedartgioterrsinII activity,83 patientswidsHF on chmrricACEinhibitortherapywere givenlisinoprifandthenchallengedwithplacebo, valsarferr80mg bid orvalaartart 160mg bid for 28 days. Invasivehernodynernicrneasuremetrtson Day 1andDay 28 cmfmned thatan ATI antagonistaddedto an ACE inhibitorproducesfurthcrreductionof arterkdpressure andpuhnonarycapillarypressureandftrrtherinhibition of aldosterone,therefotedetnonsfrstingthatfmtctionelly effectiveangiotensinII levelspersistdespitechronic ACEirtbibitortherapy. llrepoterttief forlong-terrn efficseyon mortalityendmorbidityof valsartatraddedto ACEinhibitionis the subjectof a newinternationaltrial, Val-HelT.
Key Words:
VASCULAR ACTIONS OF ANGIOTENSIN 11 Medicine,Divisionof Cardiology,Seattle,WA. AngiotensinH regulates vascular smooth muscle cell (VSMC) growth and contractility by binding to specific receptorsandstimulatingirtfracelhdersigtseflingevents.The signaltransductionevents stimulatedby engiotensinII arc similar to those stimulatedby growth factors and include activation of phospholipase C, inositol trisphosphate fortnation,cafciummobilization,activationof proteinkinase C, induction of proto-oncogenes, and protein tyrosine phosphorylation.However, aetgiotensinII causes VSMC hypertrophyrather than VSMC proliferation suggesting importantdifferencesin signal events. Our laboratory has characterizedprotein kinases activated by artgiotensinIL Mitogen-activated protein kinases (MAPK) are serinethreonineproteinkinases that are activatedby artgiotensin II. Potential substrates for MAPK related to cell growth includepp90rsk,CPLA2,and the transcriptionfactors c-jun and p62TcF.We have foundsignificantdifferencesin SHR and WKY VSMC in tbe activation and inactivation of MAPK and other angiotensin II stimulated kinases, suggesting a role for this pathway in hypertension. Upstreamregulatorsof MAPKincludeseverefkirtaaessuch as the MAP/ERK kinase or MEK, tbe MEK kinase (MEKK), Raf-1, and pp60c-src. Recent data suggest art importrmtrole for pp60c-srcin angiotensinII sigttafevents relatedto cell growthas well as differencesin regulationof Raf-1 by angiotensinII and PDGF. Different domains of the artgiotensin11receptor are likely to be involved in activation of specific components of these signal transduction pathways. These results suggest that future therapiesmaybe capableof both tissue-specificand signef transductionpathway-specificmodificationof angiotertsinII cellularresponses. KeyWorde: engiotensinII, smoothmusclecell, hypcrtrophy,signaltransduction Wednesday May 28, Ballroom A, 8:30 am Two Dialogues on Treating Hypertension THE RATIONALEFOR COMBINATIONTHERAPIESVS. SINGLE ENTITIESIN HYPERTENSION. M&We ir*. Universityof MarylandSchcolof Medicine,Baltimore,MD. The rationalebehindcombimtiontherapyrelates to the fact that when two different classes of agents are combined, they may provide additivityor even synergythroughdifferentatrtihypertensivemechanisms. Lowerdosesof two dregs whichprovidesimiku blued pressure reduction as higher doses of one drug may enhance tolerability and improve compliance. Investigativeefforts have been undertakento explore tixeddose combimtiorrsof drugs that do trot includediuretics. The first nondiureticfixed-dosecombinationsof drugsthat dn trotincludediuretics. The first non-diureticfixed-dosecombimtimtsare an ACE inhibitor-calcium antagonistcombimtionor a beta blocker-calciumantagonistcombimtion. The rationalefor an ACE irdribitor-calcirrm srrtagonistcombimtionis based on the fact that both dregs reduce vasnconstrictionthrough different mechanisms.TheACE inhibitorlargelyattenuatesvasucmrstriction through augmentationof vascdilatnrykinius and reductionof the vasocortsrrictive effect of arrgioreminII, whereas the calcium antagonists, through attenuatingtrarrsmembrmteflux of calcium, inhibits calcium-mediated electromechanicalcouplingin contractiletissue in responseto numerous stimuli. Moreover,hotbclsssesofdmgs facilitatesalt and water excretion by the kidneythroughdifferentmechanisms. The ACE inhibitorrestores the renal-adrenalresponseto salt Iosding,whereasthe calciumantagonist possesses intrinsic natriuretic properties through pcmrly described mechanismsof inhibitingrenal tubrdsrsalt and water reabsoqtion. The combinationof a beta blncker and dihydmpyridinecalcium antagonistis logicaldueto differentarnifrypertertsive mechsrrismsof these drugs without risk forcsrdiacconductionabnormalities. Of interest, there is evidencein these clinicaltrials that ACE inhibitorsmay offset one of the major side effectsassociatedwithcalciumantagonisttherapy: pedaledema. Although the studies are small and the obsemationssubjective, there is consistent evidencethat the combinationmay providean opportunityto reduce the Iikeliboodof this commonclinical problem. There ia also evidence of reducedcalciumantagonist-associatedconstipationand headachewith this type of drug combinationlikely since lower doses of this agent is used in combinationwithACE inhibitors. However,there is no publishedevidence that calcium antagonists reduce the cough associated with the ACE inhibitor. Key Words: ACE inhibitor, calcium antagonist, combination, efficacy, side effects
1997–VOL. 10, NO. 4, PART 2
SPECIAL SYMPOSIA 241A
Saturday May 31, Ballroom A, 5:30 pm Calcium Antagonists in 1997: Emerging Perspectives and Future Directions Newer PharmacologicStrategies for Retarding Progression of
Wednesday May 28, Ballroom A, 6:00 am The Role of Angiotensin II in Cardiovascular Disease
Renal Disease. Murray Epstein, M.D., Nephrology Sect., VA MedicalCenter.,Univ.Miami SchoolMedicine,Miami,FL End-stagereml disease(ESRD) is a major public health problem in the United States. The most important strategy to protect the kidney from hypertensivedamage is the effective control of blood pressure. Nevertheless, some classes of arttihypertensivemedication might confer a greater effect in slowing progression of renal disease despite similar levels of blcqdpressurereduction.Experimentalstudiessuggestthat ACEiehibitors, end possibly calcium antagonists,may preferentially retardthe progressionof renal disease.Tltemajorityoftrialshave
BC Ber~* University of Washington, Department of
assessedthe effectsof ACE-irrhibitors in patientswithIDDM. Recently,investigators havestudiedtherenalprotectiveeffectsof ACE inhibitors and calcium antagonists in patients with nondiabetic renal disease. Calcium antagonists have diverse properties, independentof their renal microcirculatoryeffects, that might afford renal protection. A prospective, randomized study by Zuchclli et al. sts~estcd that crdciumantagonistsand
ACEinhibitorsmaybe eqdly protective.Recently,Rossirrget al. wmparcd the effkcts of the long-acting dihydropyridine, nisoldipine, with those of art ACE inhibitor,lisinopril,on proteinrrria and on the decline of GFRin 49 hypertensive IDDM
patients. There was a striking dissociationbetwemrthe antiproteinuric effectsandthe effectsonGFR.Atbmnirruria was reducedby 47 YO in the lisinoprilgroup vs. no decrementin the nisoldipine group. In marked contrast, the decline in GFR appearedto be lesssteepinthenisoldipine groupaa comparedto the Iisinoprilgroup.Theseobservationsclearlydemonstratethat a dihydropyridine, presumably operating through meebarrisrm independent of their renal rnicrocirculatory effects, is renoprotcctive.In summary,the available results are consistent withthe formulationthat ACE inhibitorsand caIcimnentagoNsts act in a wmplementarymanner to attenuate the progressionof chronicrenalfaihr*.
Wednesday May 28, Ballroom A, 6:00 am The Role of Angiotensin II in Cardiovascular Disease ADDITIVEEFFECTSOFATI RXEPTOR BLOCKADEWITHVALSARTANANDACE INHIBITIONINPATIENTSWITHHEARTFAILURE JN Ccdut,for the Vsl-HelT Investigators,Universityof MimeMinneapolis,MitmesotaUSA ChronicACEinhibitortheqy favorablyaffectsthe courseof heartfailure(f-W)by improvingdepressedleft ventricrderfunction(presumablyas a resultof some regressionof left verttictderremedelirtg)endreducirtg the mortalityrate. Whetherthis actionresultsfmrn inhibitionof sngiotensirrII generation,enbamementof bredykirrirtactivityor someotherecdortrermins controversial If rmgiotensinII levelswerereducedto ineffectivelevelsbyACEinhibition,thenan ATI antagonistwouldnotbe expectedto exertrmadditional hemc+rtamic orneurohormortelefffxt. In orderto test the possibilityof continuedartgioterrsinII activity,83 patientswidsHF on chmrricACEinhibitortherapywere givenlisinoprifandthenchallengedwithplacebo, valsarferr80mg bid orvalaartart 160mg bid for 28 days. Invasivehernodynernicrneasuremetrtson Day 1andDay 28 cmfmned thatan ATI antagonistaddedto an ACE inhibitorproducesfurthcrreductionof arterkdpressure andpuhnonarycapillarypressureandftrrtherinhibition of aldosterone,therefotedetnonsfrstingthatfmtctionelly effectiveangiotensinII levelspersistdespitechronic ACEirtbibitortherapy. llrepoterttief forlong-terrn efficseyon mortalityendmorbidityof valsartatraddedto ACEinhibitionis the subjectof a newinternationaltrial, Val-HelT.
Key Words:
VASCULAR ACTIONS OF ANGIOTENSIN 11 Medicine,Divisionof Cardiology,Seattle,WA. AngiotensinH regulates vascular smooth muscle cell (VSMC) growth and contractility by binding to specific receptorsandstimulatingirtfracelhdersigtseflingevents.The signaltransductionevents stimulatedby engiotensinII arc similar to those stimulatedby growth factors and include activation of phospholipase C, inositol trisphosphate fortnation,cafciummobilization,activationof proteinkinase C, induction of proto-oncogenes, and protein tyrosine phosphorylation.However, aetgiotensinII causes VSMC hypertrophyrather than VSMC proliferation suggesting importantdifferencesin signal events. Our laboratory has characterizedprotein kinases activated by artgiotensinIL Mitogen-activated protein kinases (MAPK) are serinethreonineproteinkinases that are activatedby artgiotensin II. Potential substrates for MAPK related to cell growth includepp90rsk,CPLA2,and the transcriptionfactors c-jun and p62TcF.We have foundsignificantdifferencesin SHR and WKY VSMC in tbe activation and inactivation of MAPK and other angiotensin II stimulated kinases, suggesting a role for this pathway in hypertension. Upstreamregulatorsof MAPKincludeseverefkirtaaessuch as the MAP/ERK kinase or MEK, tbe MEK kinase (MEKK), Raf-1, and pp60c-src. Recent data suggest art importrmtrole for pp60c-srcin angiotensinII sigttafevents relatedto cell growthas well as differencesin regulationof Raf-1 by angiotensinII and PDGF. Different domains of the artgiotensin11receptor are likely to be involved in activation of specific components of these signal transduction pathways. These results suggest that future therapiesmaybe capableof both tissue-specificand signef transductionpathway-specificmodificationof angiotertsinII cellularresponses. KeyWorde: engiotensinII, smoothmusclecell, hypcrtrophy,signaltransduction Wednesday May 28, Ballroom A, 8:30 am Two Dialogues on Treating Hypertension THE RATIONALEFOR COMBINATIONTHERAPIESVS. SINGLE ENTITIESIN HYPERTENSION. M&We ir*. Universityof MarylandSchcolof Medicine,Baltimore,MD. The rationalebehindcombimtiontherapyrelates to the fact that when two different classes of agents are combined, they may provide additivityor even synergythroughdifferentatrtihypertensivemechanisms. Lowerdosesof two dregs whichprovidesimiku blued pressure reduction as higher doses of one drug may enhance tolerability and improve compliance. Investigativeefforts have been undertakento explore tixeddose combimtiorrsof drugs that do trot includediuretics. The first nondiureticfixed-dosecombinationsof drugsthat dn trotincludediuretics. The first non-diureticfixed-dosecombimtimtsare an ACE inhibitor-calcium antagonistcombimtionor a beta blocker-calciumantagonistcombimtion. The rationalefor an ACE irdribitor-calcirrm srrtagonistcombimtionis based on the fact that both dregs reduce vasnconstrictionthrough different mechanisms.TheACE inhibitorlargelyattenuatesvasucmrstriction through augmentationof vascdilatnrykinius and reductionof the vasocortsrrictive effect of arrgioreminII, whereas the calcium antagonists, through attenuatingtrarrsmembrmteflux of calcium, inhibits calcium-mediated electromechanicalcouplingin contractiletissue in responseto numerous stimuli. Moreover,hotbclsssesofdmgs facilitatesalt and water excretion by the kidneythroughdifferentmechanisms. The ACE inhibitorrestores the renal-adrenalresponseto salt Iosding,whereasthe calciumantagonist possesses intrinsic natriuretic properties through pcmrly described mechanismsof inhibitingrenal tubrdsrsalt and water reabsoqtion. The combinationof a beta blncker and dihydmpyridinecalcium antagonistis logicaldueto differentarnifrypertertsive mechsrrismsof these drugs without risk forcsrdiacconductionabnormalities. Of interest, there is evidencein these clinicaltrials that ACE inhibitorsmay offset one of the major side effectsassociatedwithcalciumantagonisttherapy: pedaledema. Although the studies are small and the obsemationssubjective, there is consistent evidencethat the combinationmay providean opportunityto reduce the Iikeliboodof this commonclinical problem. There ia also evidence of reducedcalciumantagonist-associatedconstipationand headachewith this type of drug combinationlikely since lower doses of this agent is used in combinationwithACE inhibitors. However,there is no publishedevidence that calcium antagonists reduce the cough associated with the ACE inhibitor. Key Words: ACE inhibitor, calcium antagonist, combination, efficacy, side effects