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Ovariectomy enhanced salt-induced hypertension and platelet aggregation in DAHL salt-sensitive rats
AJH-APRIL 1996-VOL. 9, NO.4, PART 2
E9
POSTERS: Experimental Models 39A
Eto
Lead-Induced Hypertension is Related to Accumulation of Reactivs Oxygen Species. H.C.Gonick*, Y.Ding, Z.Ni, r. Oveisi, N.D. Vaziri*. Depts. of Medicine, univeraity of california, Irvine, CA, and CedarS-Sinai Medical Center, Los Angeles,CA. Administration of 100 ppm lead acetate daily for 3 mo. to Sprague-Dawley rats caused an elevation of intra-arterial mean blood preasure (MBP) while treatment with 2, 3-dimercaptoBuccinic acid (DMSA), a thiol-containing chelator of lead and scavenger Of free radicals (0.5' daily for 2 weeks), reduced MBP toward normal (10S±2.4(SEM) DIIlI Hg, Controls, (C), VB 149±1.9, Lead-treated (L), p<0.001, va 124±1.4, Lead + DMSA-tr.ated (D), p<0.0011 C vs D, p-O.OOS). Animal. from each group (n-71 were anesthetized with Inactin., then infuBed sequentially in 30 minute intervals with saline, L-arginine (Arg), L-arginine + superoxide dismutase (SOD), saline, nitroprusside (SNP). Infusion of Arg (bolus of 300 mg followed by 10 mg/kg/min) caused a fall in MBP in all animals, which was significantly greater in L than in other groups (AHBP-Sl.8±S.8D11l1 Hg, L, vs 30.0±3.6, C, p<0.01). The addition of SOD (37,000 U. bolus followed by 1200 U/min) to the Arg infUsion failed to alter MBP. Infusion of SNP (15~g/kg/min) caused a similar fall in M8P in all groups (7l±4.8, C, vs 8S±6.0, L. vs 67±4.2, D. p-NS). MeaBurements of plasma and urinary nitric oxide (NO) by chemiluminescence analyzer and CGMP by RIA were similar in C and L groups. ABBay of malondialdshyde-thiobarbituric acid adduct (MeATBA) by HPLC, as a measurs of lipid peroxidation (and hence of reactive oxygen species), was elevated in L. reduced in D (1.87±0.20~M, C, vs J.59!.O.43, L, p
OVARIECTOMY AGGRAVATED HYPERTENSION AND ENHANCED PlATELET AGGREGATION IN DAHL·IWAI SALT·SENSITIVE RATS ~, Y OMo. K Ostuka. T Suzawa. Y Kato, H Suzuk", and T Saruta,
Kelo Unrverslty, TOkyo. Japan 'The renal Disease & DialYSIS Csnter, SMsma Medlcsl School, Saltama, Japan We have demonstrated that ovariectomy enhanced the gsnetlcal salt-senSitivity by blunllng pressurs natriureSIS relabonshlp. which precsded the development of overt hypertensIon in female DahHwai salt sensltlvs(DS) rats. In thiS study. the effsct of ovariectomy snd estrogen replacement on blood pressure and platelel aggregation were ,nvesl'gated n OS rats. At the 8ge of 12 weeks OS rats were ovariectomized or sham operated and were fed 0.3% or 8% NaCI diet 17~-estradlol was admlnrstsred sUbcutansously only ,n ovariectomized rats fed high sslt diet. EIght weeks later we ,nvesllgated the blood pressure end platslet aggregahon ,"duced by collagen (3ug/ml) SYStOliC blood pressure was measured by tall cuff method The ovareclomlzed rats attained greater weights compared With sham-operaled rats The Increase," body weight was suppressed by estrogen supplement Sail loadIng Increased blood pressure. snd ovariectomy also aggravated hypertension Hogh salt d'et Significantly Increased heart weight to body weight ratlo(HVBW) . Blood prassurs was correlated With HVBW(r: 445. P=.022) snd Inversely wllh uterus weight to body weight rstlo(UVBW, r: -0.309, p: 043) Platelet aggregation was Significantly enhanCed by sail loading. and ovariectomy also aggravated platelet aggregallon Estrogen supplsmenl to ovanectomized ralS rsduced platelet aggregallon In conclUSion ovariectomy aggravatsd hypenenslon and snhanced platelet sggregallon on Dahl-Iwal salt sensitive rats Thess results suggest that sslrogen sppears to play sn Inhibitory role on lhe development of hypertension and p'atelet a9gregation
o3"kNaCI (Ll BW20W(g)
8%NaCI (H)
Sham
OVX
Sham
OVX
OVX + EST
256±5
266±10
256±4
264±10
214,=16
Key Words: Lead toxicity, reactive oxygen species, nitric oxide, DMSA.
138±4 149±3$ 158±2#~ 174±5'~ 160-21 0.34±0.00 0.34±0.02 D.38±00211\1 039±D.Oll1\1 047=003 UtW/BW 0.17±000 0.11±0.02' 0.17-t0.00 o.10±OOl+ 025=002 Aggregal1Ol1l%) 12±2 <11+31 64+6' 70" 11$ 4O:e9t Values are means ± SEM. Each group n: 4 'p<.01 vs sham/L Sp< 05 vs shamlL 11 p<.Ol vs OVXIL 'p< 01 vs shamlH ;p<.05 vs OVX/H Key Words: ovanectomy. sstrogen, plalelet sggrsgatlon, Dahl-Iwal salt-sensltlvs rats
Ell
E12
EHECTS OF TRANDOI./\I'RII., VERAPAMII. MW THEIR ASSOCIATION ON ARTERIAl. STRUCTURE ANI> FUNCTION IN SPONTANEOUSI.Y HYPERTENSIVE RATS A Ilcnclos' I' LacoUey, M Klrchengasl " M Safar' I NSERM lJ~~7 Parl~ France and /I Knoll AG I.udwigshafen, (;cmlany. Among antihyperlenslve drug.s, anglolonsln converling enryme inhlblLors (ACEI) and calcium channel blockers (CCll) seem 10 he more eHicaclous ,n Ihe p"cvcntion or regression of hypertension Induced structural and functional .Jllerallons of ldrgc dltcrlcs However IL Is nol known whether comblnallon of lhese drugs has synergisllc effecls on arteridl pararnelers The aim of this sludy was lo evaluale the efrcels of 4 monlhs trealrnent with the "Chi Trandolapril Oran) 0.3 mg/kg/d, the CCll Verapaml1 (Ver) .'i0 mgfkg/d, and their assoclaUon Ver Tran on large arteries struclure and mechanical properlles tn SH Rs. Trealmenls were mixed In animals food and slarted when rals ,",'Ore 4 week old WKYand SHR conlrol rals received l-1acebo (PI) for the same period lnlra arterial blood pressure IIlP) was evaluated III conscious animals. In viva carotid arlery distensibillly (1l1s1 mmHg- 1 1O-3) Were delennlned In Ihe systollc·dlastollc range of Ill' using an echotracklng syslern In aneslhe!l7ed dnlmals ThoraCIC aorla media lhickness (Aolh lUll) and collagen conlenl (AoColI 10'1I2 /mm) were evalualed by hislo morphomelric Image analysis. 'n,e resulls of Ihe studied paramelers arc shown I n TahI e Ver Tran Ver PI SH~ PI WKY n:ll n=15 n=15 l'ran nell n:15 164t7 169t17 143tH' 119t7' 133t9' MIlP 103t6' 120t9 95t5· 99t7' AoTh 90t5'. 14Htl' lZ.3tZ· 11.SH', 17hZ AaCoIl Uhl' 2.3tl.0 29tl.2 Dist 33tt.4 56!1 8' 41ltl.7'
DIFFERENTIAL EFFECTS OF NITRIC OXIDE SYNTIIASE INHmlTORS ON BLOOD PRESSURE AND KIDNEV FUNCTION IN PREGNANT RATS. SS Greenbel'J, Do Powers, V Gao, T Freemao, J. XIe, XF Zbao, J OUYllJlll. 8118, M Given,
mean tSD, , p
SBP(mmHg) HW/BW
T Nolan and TO Giles*. Dept. of MedKine and Obstetrks IU1d GynecolOllY, Loolslsna State University. New Orleans, LA. Decreased prodllct/oo of nitric: oxide (NO) bas been sUUested as contributinl to the hypertellliion of pre-eclampsia. We Investigated thk possibility In prepsnt nils. Pregnant rats were treated from gestational day 13 to 20 with the NOS inhibitors aminoguanidine (AG, 0.1 mg/m1), LNAME (I mglml) or with 7-nltrolndazoie (7Nl, 25 mg/kg) sdded to the drinking water. Two additional group of rats was given daily dclses of LNIO (10 mg/kg, Ip) or LNlL (10 JDg/kg, Ip). Cootrol anImais received regular drinking water. Food and water intake and urinary euretioo of sodium, creatinine, uric: add, protein and nitrate and nitrite (RNI) wert measured daily. Maternal blood and
urine cbemistrles, blood pressure and cardiac fUllction and tissue arginine were measured at term. LNAME, but not LNIO, LNlL, AG or 7N1 raised arterial pregure despite the ability of each inhibitor to inhibit plasma and urine RNl. Of the five inhibitors only AG produced diuresis and natriuresis. Each of the inhibitors escept 7N1 decreased creatinine cIearan« and the fractional euretioo of 1Ddiwn. LNlO and LNlL produced hyperuricemia secondary Co Impairment of uric acid ncretioo. The data suggest that chrooic inhibition of nitric oxide synthesis is insufficient Co cause sustained hyperteosioo iD pregnant rats. Moreover, the different effects of these inhibitors on retW and cardioYascuIar functioo suggest that these C:OlIlpouods have phannac:oIogIc: lIl:tivitles In additioo Co that of NOS inhlbitloo.
pregnancy, NO synthase Inhibitors, Ytypenenslon, nnal functioo
Ke Worrl~'
E9
POSTERS: Experimental Models 39A
Eto
Lead-Induced Hypertension is Related to Accumulation of Reactivs Oxygen Species. H.C.Gonick*, Y.Ding, Z.Ni, r. Oveisi, N.D. Vaziri*. Depts. of Medicine, univeraity of california, Irvine, CA, and CedarS-Sinai Medical Center, Los Angeles,CA. Administration of 100 ppm lead acetate daily for 3 mo. to Sprague-Dawley rats caused an elevation of intra-arterial mean blood preasure (MBP) while treatment with 2, 3-dimercaptoBuccinic acid (DMSA), a thiol-containing chelator of lead and scavenger Of free radicals (0.5' daily for 2 weeks), reduced MBP toward normal (10S±2.4(SEM) DIIlI Hg, Controls, (C), VB 149±1.9, Lead-treated (L), p<0.001, va 124±1.4, Lead + DMSA-tr.ated (D), p<0.0011 C vs D, p-O.OOS). Animal. from each group (n-71 were anesthetized with Inactin., then infuBed sequentially in 30 minute intervals with saline, L-arginine (Arg), L-arginine + superoxide dismutase (SOD), saline, nitroprusside (SNP). Infusion of Arg (bolus of 300 mg followed by 10 mg/kg/min) caused a fall in MBP in all animals, which was significantly greater in L than in other groups (AHBP-Sl.8±S.8D11l1 Hg, L, vs 30.0±3.6, C, p<0.01). The addition of SOD (37,000 U. bolus followed by 1200 U/min) to the Arg infUsion failed to alter MBP. Infusion of SNP (15~g/kg/min) caused a similar fall in M8P in all groups (7l±4.8, C, vs 8S±6.0, L. vs 67±4.2, D. p-NS). MeaBurements of plasma and urinary nitric oxide (NO) by chemiluminescence analyzer and CGMP by RIA were similar in C and L groups. ABBay of malondialdshyde-thiobarbituric acid adduct (MeATBA) by HPLC, as a measurs of lipid peroxidation (and hence of reactive oxygen species), was elevated in L. reduced in D (1.87±0.20~M, C, vs J.59!.O.43, L, p
OVARIECTOMY AGGRAVATED HYPERTENSION AND ENHANCED PlATELET AGGREGATION IN DAHL·IWAI SALT·SENSITIVE RATS ~, Y OMo. K Ostuka. T Suzawa. Y Kato, H Suzuk", and T Saruta,
Kelo Unrverslty, TOkyo. Japan 'The renal Disease & DialYSIS Csnter, SMsma Medlcsl School, Saltama, Japan We have demonstrated that ovariectomy enhanced the gsnetlcal salt-senSitivity by blunllng pressurs natriureSIS relabonshlp. which precsded the development of overt hypertensIon in female DahHwai salt sensltlvs(DS) rats. In thiS study. the effsct of ovariectomy snd estrogen replacement on blood pressure and platelel aggregation were ,nvesl'gated n OS rats. At the 8ge of 12 weeks OS rats were ovariectomized or sham operated and were fed 0.3% or 8% NaCI diet 17~-estradlol was admlnrstsred sUbcutansously only ,n ovariectomized rats fed high sslt diet. EIght weeks later we ,nvesllgated the blood pressure end platslet aggregahon ,"duced by collagen (3ug/ml) SYStOliC blood pressure was measured by tall cuff method The ovareclomlzed rats attained greater weights compared With sham-operaled rats The Increase," body weight was suppressed by estrogen supplement Sail loadIng Increased blood pressure. snd ovariectomy also aggravated hypertension Hogh salt d'et Significantly Increased heart weight to body weight ratlo(HVBW) . Blood prassurs was correlated With HVBW(r: 445. P=.022) snd Inversely wllh uterus weight to body weight rstlo(UVBW, r: -0.309, p: 043) Platelet aggregation was Significantly enhanCed by sail loading. and ovariectomy also aggravated platelet aggregallon Estrogen supplsmenl to ovanectomized ralS rsduced platelet aggregallon In conclUSion ovariectomy aggravatsd hypenenslon and snhanced platelet sggregallon on Dahl-Iwal salt sensitive rats Thess results suggest that sslrogen sppears to play sn Inhibitory role on lhe development of hypertension and p'atelet a9gregation
o3"kNaCI (Ll BW20W(g)
8%NaCI (H)
Sham
OVX
Sham
OVX
OVX + EST
256±5
266±10
256±4
264±10
214,=16
Key Words: Lead toxicity, reactive oxygen species, nitric oxide, DMSA.
138±4 149±3$ 158±2#~ 174±5'~ 160-21 0.34±0.00 0.34±0.02 D.38±00211\1 039±D.Oll1\1 047=003 UtW/BW 0.17±000 0.11±0.02' 0.17-t0.00 o.10±OOl+ 025=002 Aggregal1Ol1l%) 12±2 <11+31 64+6' 70" 11$ 4O:e9t Values are means ± SEM. Each group n: 4 'p<.01 vs sham/L Sp< 05 vs shamlL 11 p<.Ol vs OVXIL 'p< 01 vs shamlH ;p<.05 vs OVX/H Key Words: ovanectomy. sstrogen, plalelet sggrsgatlon, Dahl-Iwal salt-sensltlvs rats
Ell
E12
EHECTS OF TRANDOI./\I'RII., VERAPAMII. MW THEIR ASSOCIATION ON ARTERIAl. STRUCTURE ANI> FUNCTION IN SPONTANEOUSI.Y HYPERTENSIVE RATS A Ilcnclos' I' LacoUey, M Klrchengasl " M Safar' I NSERM lJ~~7 Parl~ France and /I Knoll AG I.udwigshafen, (;cmlany. Among antihyperlenslve drug.s, anglolonsln converling enryme inhlblLors (ACEI) and calcium channel blockers (CCll) seem 10 he more eHicaclous ,n Ihe p"cvcntion or regression of hypertension Induced structural and functional .Jllerallons of ldrgc dltcrlcs However IL Is nol known whether comblnallon of lhese drugs has synergisllc effecls on arteridl pararnelers The aim of this sludy was lo evaluale the efrcels of 4 monlhs trealrnent with the "Chi Trandolapril Oran) 0.3 mg/kg/d, the CCll Verapaml1 (Ver) .'i0 mgfkg/d, and their assoclaUon Ver Tran on large arteries struclure and mechanical properlles tn SH Rs. Trealmenls were mixed In animals food and slarted when rals ,",'Ore 4 week old WKYand SHR conlrol rals received l-1acebo (PI) for the same period lnlra arterial blood pressure IIlP) was evaluated III conscious animals. In viva carotid arlery distensibillly (1l1s1 mmHg- 1 1O-3) Were delennlned In Ihe systollc·dlastollc range of Ill' using an echotracklng syslern In aneslhe!l7ed dnlmals ThoraCIC aorla media lhickness (Aolh lUll) and collagen conlenl (AoColI 10'1I2 /mm) were evalualed by hislo morphomelric Image analysis. 'n,e resulls of Ihe studied paramelers arc shown I n TahI e Ver Tran Ver PI SH~ PI WKY n:ll n=15 n=15 l'ran nell n:15 164t7 169t17 143tH' 119t7' 133t9' MIlP 103t6' 120t9 95t5· 99t7' AoTh 90t5'. 14Htl' lZ.3tZ· 11.SH', 17hZ AaCoIl Uhl' 2.3tl.0 29tl.2 Dist 33tt.4 56!1 8' 41ltl.7'
DIFFERENTIAL EFFECTS OF NITRIC OXIDE SYNTIIASE INHmlTORS ON BLOOD PRESSURE AND KIDNEV FUNCTION IN PREGNANT RATS. SS Greenbel'J, Do Powers, V Gao, T Freemao, J. XIe, XF Zbao, J OUYllJlll. 8118, M Given,
mean tSD, , p
SBP(mmHg) HW/BW
T Nolan and TO Giles*. Dept. of MedKine and Obstetrks IU1d GynecolOllY, Loolslsna State University. New Orleans, LA. Decreased prodllct/oo of nitric: oxide (NO) bas been sUUested as contributinl to the hypertellliion of pre-eclampsia. We Investigated thk possibility In prepsnt nils. Pregnant rats were treated from gestational day 13 to 20 with the NOS inhibitors aminoguanidine (AG, 0.1 mg/m1), LNAME (I mglml) or with 7-nltrolndazoie (7Nl, 25 mg/kg) sdded to the drinking water. Two additional group of rats was given daily dclses of LNIO (10 mg/kg, Ip) or LNlL (10 JDg/kg, Ip). Cootrol anImais received regular drinking water. Food and water intake and urinary euretioo of sodium, creatinine, uric: add, protein and nitrate and nitrite (RNI) wert measured daily. Maternal blood and
urine cbemistrles, blood pressure and cardiac fUllction and tissue arginine were measured at term. LNAME, but not LNIO, LNlL, AG or 7N1 raised arterial pregure despite the ability of each inhibitor to inhibit plasma and urine RNl. Of the five inhibitors only AG produced diuresis and natriuresis. Each of the inhibitors escept 7N1 decreased creatinine cIearan« and the fractional euretioo of 1Ddiwn. LNlO and LNlL produced hyperuricemia secondary Co Impairment of uric acid ncretioo. The data suggest that chrooic inhibition of nitric oxide synthesis is insufficient Co cause sustained hyperteosioo iD pregnant rats. Moreover, the different effects of these inhibitors on retW and cardioYascuIar functioo suggest that these C:OlIlpouods have phannac:oIogIc: lIl:tivitles In additioo Co that of NOS inhlbitloo.
pregnancy, NO synthase Inhibitors, Ytypenenslon, nnal functioo
Ke Worrl~'