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H+ antiport in the pathophysiology of essential hypertension
14A ASHABSTRACTS
Thursd~ 5118, Rendezvous Trianon, 5:00 pm-7:OO pm Theme I: AlteredCellular Ion Regulation in Hypertension 1011 Tranlport and tbe cytollkeleton In lIypertenlloa: a genetic Ua1l. BIanchi G. Choir of Nephrology. UnIversity of Milan. S, RalTaele HospItal. Milan. Italy Comparisons of Milan hypertensIve straIn of rats (MHS) with Its control normotensIve straIn (MNSJ for measurements of renal funcllon In whole antmal and Isolated organ, blood pressure after kidney cross transplantations. Ion transport across plasma membrane In tubular cells and erythrocytes or jlarentat straIns and gcnelle crosses. were all consistent with the hypothesIs that u fustcr Ion transport ncross the plasma membrane could be respllnslblt' for, al least. a portlon of the blood pressure IBP) difference between the twc strains, 1"11e Ion transport dUTerence In erythrocytes dlsappcarcs after removal of the membrane skeleton and cross-tmmuntzauon studies showed an lmmunochemtcal dIfference In u membrane skeleton protein subsequently fdentlned as adduetn. The genes coding for a and ~ adducln In MHS and MNS were sequenced and an one poInt mutation In each subunit causIng an nmtnoacld substitution was detected /Y and F In a subunit and R und Q In ~ respectively ro.' MHS and MNS genes). AnlJlysls of all f2 gcneratton demonstrated that tJ,.y MHS allele segregated wl~h a slllnlOcant Increment In blood pressure and lower kidney wclght and that thl!l OP elTect was modulated by presence of the R allele In the /3 subunit. lsolatlon of congcnlc substrains differing only by these alleles Is In progress to test possible assocIation between the adducln polymorphIsm. the Ion transport and the renal functional abnormahucs responsible (or the blood pressure dIfferences between MHS and MNS rats, 1'0 evaluate possible association between the aadducln locus and hypertension in man. a case control study Was carried out In 190 hypertensives and 126 controls by measurlng four mulll· allelic markers surrounding the a·adducln locus located In 4 p 16.3. '111<: maximum association (X2=13.3) occurred for the 04S95 marker whfr.h maps closest (20 RbI to adductn, while association or the other markers with blood pressure decreases as their dtstunec from the adductn locus Increases. Therefore the membrane skeleton protein adduem may be tnvulvcd tnhlond pressure regulation both In rat and In man.
AIR-APRIL 1995-VOL.8, NO.4, PART 2
Thursda~ 5/18, Rendezvous Trianon, 5:00 pm-7:00 pm Theme I: Altered Cellular Ion Regulation in Hypertension
CirCUlating InhibItor. of the Na Pump, Na/Ca Exchange, Dnd Hypertension. Mordecai P. Blaustein. Physiol. Dept., Univ. of Maryland, Baltimore, MO Excessive dietary Na, and a tendency to Na retention and blood volume expansion invariably lead to hypertension. Tha. missing link between Na and hypertension may be a new adrenocortical hormone that is a ouabain isomer. Chronic parenteral administration of exogenous (piant) ouabain induces hyportension in rats. Lowlevels "f ouabain Influence cell metabolism mainlyby raising cytosolic Na+ slightly. This also tends to raise cvtcsoflc Ca2+, via Nalea exchange, but most of the entering Ca is sequestered in the sercoplesrnlc reticulum (SRI of vascular smooth muscle (VSMI cells and the endoplasmic reticulum (EAI of other cell types. Because the SR/ER concentrates Ca, it acts as an amplifier: very small changes in cvtosolle Ca 2+ areassociated with large changes in stored Ca. This may be a consequence of the co-localization of the Na pump and Na/Cs exchanger molecules in plasmalemmal microdomains that overlie subplasmalemmal SR/ER. The SRIER is a majorsource of "activator" Co in most cells, including V5M. rhus, cell responsiveness is directly influenced by the relative SR/ER Ca content. These mechanisms provide a logical link between dietary salt and hypertension: t Na retention ... t endogenous ouabain .... t cvtosolic Na+ ... t cvtoslic Ca 2+ (via Ne/Ca exchange) ... t t SRfER Ca ... t t cell responsiveness. In VSM cells and sympathetic neurons, this leads to increased vascular tone and peripheral vascular resistance.' andtherebyelevates blood pressure. Key Words: End~gen~uB ouabain, Na/Ca exchange. Na pump. ssrcoptasrmc reticulurn
Thunlday,. 5/18, Rendezvous Trianon, 5:00 pm-7:00 pm ThemeI:AlteredCellularIon Regulation in Hypertension
Thursday, 5/18, Trianon Ballroom, 5:00 pm-6:00 pm Theme II: Should DihydropyridinesBeUsedfor FirstLineTreatment?
THE LINKS BETWEEN CELLULAR Ca2+ AND THE Na+lft ANTIPORT IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION. A. Aviv·, UMDNl·Nl Medical School, Newark, NJ. Essential hypertension is marked by dysfunctional regulation (dysregulation) of Ca 2+ and Na" at the cellular level. Since essential hypertension is a polygenic disorder, ionic dysregulation may independently arise from primary abnormalities in regulatory pathways of Ca2+ and Na". Alternatively, primary abnormalities resulting from the regulation of one of these ions may beexpressed by secondary (adaptive) alterations in the regulations of the other ion. Understanding the links between the regulatory elements of cellular Ca2+ and Na" is therefore the key to deciphering the underlying etiology of dysfunctional Ca 2+ and Na" regulatioP.i in essential hypertension. Moreover, the distinction between primary vs secondary ionic dysregulation is a crucial step in elucidating the genetic origin of essential hypertension, Recent studies have shown that the activity of the Na+lIt antiport (NHE-I) is enhanced in a subset of patients with essential hypertension and thatthisphenotype is maintained in immortalized Iymphoblasts from these patients, Primary abnormalities (i.e., mutations) in the NHE-I gene have been ruled out in essential hypertension. Thus, a higher Na+/H+ antiport activity in essential hypertension probably reflects alterations in the cellular regulation of this transport system. A number of systems participate in the control of the activity of the Na+/H+ antiport, including Ca2+ dependent protein kinases and calmodulin. These systems are closely linked tc cellular Ca2+ regulation. It is therefore logical to conclude that altered Na+lft antiport activity is the signature of Ca2+ dysregulation in essential hypertension, Key Words: Sodium, calcium, ion transport, essential hypertension
SHOULD DIHYDROPYRIDINES BE USED FOR FIRST UNE TREATMENT? Murray Epstein, M.D" Nephrology Section, VA Medical center lind Unlv. of Miami School of Medicine, MIami, FL. calcium antagonists have assumed a very important role as antihypertensive agents. In addition to efficacy, their metabolic neutrality (including the fact that they do not exacerba.e dyslipidemia) commends their use. An increasing bodyofevidence is acetuing tosuggestlhal calcium anlagonists may have renal protective effeds, which is anadditional factor favoring their use intreat;ng hypertension. Despite their inability to lower glomerular capillary pressure directly, calcium antagonists lessen injury in many experimental models ofrenal disease. by retarding renal growth and countervailing or attenuating the mitogenic effects of diverse growth factors (Kidney lnt 1992;41:S66-S72), Nevertheless, concerns have arisen recently regarding potential adverse effects of dihydropyridines. Thus, controversy exists about whether or not calcium antagonists exacerbate proteinuria, and secondly, whether some ch~mical subclasses are more apt to induce this. Wehave critically reviewed (Arch Int Med 1994;154:1185-1202) the available reports and noted that theresults vary markedly, precluding rigorous inferences. A recent rigorous short-term study characterizing the effects of nifedipine on glomerular hemodynamics, sieving function, and protein excretion disclosed that nifedipine has no effect on albuminuria and glomerular barrier function but inhibits proximal tubular function. A wide experience indicates that calcium antagonists can beused s~fely in a broad range of patients, both black~ and whites, and with commonly encountered concomitant disorciers including COPO, diabetes, periphtiral vascular disease, and abnonnal lipid profiles. At this juncture, with the current state ofknowledge one mt1'I condude that C3lcium antagonists are very important agents forfirst line monotherapy for hypertension, Key Words: Dihydropyridines, Hypertension
calcium
antagonists,
Thursd~ 5118, Rendezvous Trianon, 5:00 pm-7:OO pm Theme I: AlteredCellular Ion Regulation in Hypertension 1011 Tranlport and tbe cytollkeleton In lIypertenlloa: a genetic Ua1l. BIanchi G. Choir of Nephrology. UnIversity of Milan. S, RalTaele HospItal. Milan. Italy Comparisons of Milan hypertensIve straIn of rats (MHS) with Its control normotensIve straIn (MNSJ for measurements of renal funcllon In whole antmal and Isolated organ, blood pressure after kidney cross transplantations. Ion transport across plasma membrane In tubular cells and erythrocytes or jlarentat straIns and gcnelle crosses. were all consistent with the hypothesIs that u fustcr Ion transport ncross the plasma membrane could be respllnslblt' for, al least. a portlon of the blood pressure IBP) difference between the twc strains, 1"11e Ion transport dUTerence In erythrocytes dlsappcarcs after removal of the membrane skeleton and cross-tmmuntzauon studies showed an lmmunochemtcal dIfference In u membrane skeleton protein subsequently fdentlned as adduetn. The genes coding for a and ~ adducln In MHS and MNS were sequenced and an one poInt mutation In each subunit causIng an nmtnoacld substitution was detected /Y and F In a subunit and R und Q In ~ respectively ro.' MHS and MNS genes). AnlJlysls of all f2 gcneratton demonstrated that tJ,.y MHS allele segregated wl~h a slllnlOcant Increment In blood pressure and lower kidney wclght and that thl!l OP elTect was modulated by presence of the R allele In the /3 subunit. lsolatlon of congcnlc substrains differing only by these alleles Is In progress to test possible assocIation between the adducln polymorphIsm. the Ion transport and the renal functional abnormahucs responsible (or the blood pressure dIfferences between MHS and MNS rats, 1'0 evaluate possible association between the aadducln locus and hypertension in man. a case control study Was carried out In 190 hypertensives and 126 controls by measurlng four mulll· allelic markers surrounding the a·adducln locus located In 4 p 16.3. '111<: maximum association (X2=13.3) occurred for the 04S95 marker whfr.h maps closest (20 RbI to adductn, while association or the other markers with blood pressure decreases as their dtstunec from the adductn locus Increases. Therefore the membrane skeleton protein adduem may be tnvulvcd tnhlond pressure regulation both In rat and In man.
AIR-APRIL 1995-VOL.8, NO.4, PART 2
Thursda~ 5/18, Rendezvous Trianon, 5:00 pm-7:00 pm Theme I: Altered Cellular Ion Regulation in Hypertension
CirCUlating InhibItor. of the Na Pump, Na/Ca Exchange, Dnd Hypertension. Mordecai P. Blaustein. Physiol. Dept., Univ. of Maryland, Baltimore, MO Excessive dietary Na, and a tendency to Na retention and blood volume expansion invariably lead to hypertension. Tha. missing link between Na and hypertension may be a new adrenocortical hormone that is a ouabain isomer. Chronic parenteral administration of exogenous (piant) ouabain induces hyportension in rats. Lowlevels "f ouabain Influence cell metabolism mainlyby raising cytosolic Na+ slightly. This also tends to raise cvtcsoflc Ca2+, via Nalea exchange, but most of the entering Ca is sequestered in the sercoplesrnlc reticulum (SRI of vascular smooth muscle (VSMI cells and the endoplasmic reticulum (EAI of other cell types. Because the SR/ER concentrates Ca, it acts as an amplifier: very small changes in cvtosolle Ca 2+ areassociated with large changes in stored Ca. This may be a consequence of the co-localization of the Na pump and Na/Cs exchanger molecules in plasmalemmal microdomains that overlie subplasmalemmal SR/ER. The SRIER is a majorsource of "activator" Co in most cells, including V5M. rhus, cell responsiveness is directly influenced by the relative SR/ER Ca content. These mechanisms provide a logical link between dietary salt and hypertension: t Na retention ... t endogenous ouabain .... t cvtosolic Na+ ... t cvtoslic Ca 2+ (via Ne/Ca exchange) ... t t SRfER Ca ... t t cell responsiveness. In VSM cells and sympathetic neurons, this leads to increased vascular tone and peripheral vascular resistance.' andtherebyelevates blood pressure. Key Words: End~gen~uB ouabain, Na/Ca exchange. Na pump. ssrcoptasrmc reticulurn
Thunlday,. 5/18, Rendezvous Trianon, 5:00 pm-7:00 pm ThemeI:AlteredCellularIon Regulation in Hypertension
Thursday, 5/18, Trianon Ballroom, 5:00 pm-6:00 pm Theme II: Should DihydropyridinesBeUsedfor FirstLineTreatment?
THE LINKS BETWEEN CELLULAR Ca2+ AND THE Na+lft ANTIPORT IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION. A. Aviv·, UMDNl·Nl Medical School, Newark, NJ. Essential hypertension is marked by dysfunctional regulation (dysregulation) of Ca 2+ and Na" at the cellular level. Since essential hypertension is a polygenic disorder, ionic dysregulation may independently arise from primary abnormalities in regulatory pathways of Ca2+ and Na". Alternatively, primary abnormalities resulting from the regulation of one of these ions may beexpressed by secondary (adaptive) alterations in the regulations of the other ion. Understanding the links between the regulatory elements of cellular Ca2+ and Na" is therefore the key to deciphering the underlying etiology of dysfunctional Ca 2+ and Na" regulatioP.i in essential hypertension. Moreover, the distinction between primary vs secondary ionic dysregulation is a crucial step in elucidating the genetic origin of essential hypertension, Recent studies have shown that the activity of the Na+lIt antiport (NHE-I) is enhanced in a subset of patients with essential hypertension and thatthisphenotype is maintained in immortalized Iymphoblasts from these patients, Primary abnormalities (i.e., mutations) in the NHE-I gene have been ruled out in essential hypertension. Thus, a higher Na+/H+ antiport activity in essential hypertension probably reflects alterations in the cellular regulation of this transport system. A number of systems participate in the control of the activity of the Na+/H+ antiport, including Ca2+ dependent protein kinases and calmodulin. These systems are closely linked tc cellular Ca2+ regulation. It is therefore logical to conclude that altered Na+lft antiport activity is the signature of Ca2+ dysregulation in essential hypertension, Key Words: Sodium, calcium, ion transport, essential hypertension
SHOULD DIHYDROPYRIDINES BE USED FOR FIRST UNE TREATMENT? Murray Epstein, M.D" Nephrology Section, VA Medical center lind Unlv. of Miami School of Medicine, MIami, FL. calcium antagonists have assumed a very important role as antihypertensive agents. In addition to efficacy, their metabolic neutrality (including the fact that they do not exacerba.e dyslipidemia) commends their use. An increasing bodyofevidence is acetuing tosuggestlhal calcium anlagonists may have renal protective effeds, which is anadditional factor favoring their use intreat;ng hypertension. Despite their inability to lower glomerular capillary pressure directly, calcium antagonists lessen injury in many experimental models ofrenal disease. by retarding renal growth and countervailing or attenuating the mitogenic effects of diverse growth factors (Kidney lnt 1992;41:S66-S72), Nevertheless, concerns have arisen recently regarding potential adverse effects of dihydropyridines. Thus, controversy exists about whether or not calcium antagonists exacerbate proteinuria, and secondly, whether some ch~mical subclasses are more apt to induce this. Wehave critically reviewed (Arch Int Med 1994;154:1185-1202) the available reports and noted that theresults vary markedly, precluding rigorous inferences. A recent rigorous short-term study characterizing the effects of nifedipine on glomerular hemodynamics, sieving function, and protein excretion disclosed that nifedipine has no effect on albuminuria and glomerular barrier function but inhibits proximal tubular function. A wide experience indicates that calcium antagonists can beused s~fely in a broad range of patients, both black~ and whites, and with commonly encountered concomitant disorciers including COPO, diabetes, periphtiral vascular disease, and abnonnal lipid profiles. At this juncture, with the current state ofknowledge one mt1'I condude that C3lcium antagonists are very important agents forfirst line monotherapy for hypertension, Key Words: Dihydropyridines, Hypertension
calcium
antagonists,