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Age-related attenuation of endothelium-mediated vasodilation in perfused mesenteric bed of fischer 344 rats
AlH-APRIL 1996-VOL. 9, NO.4, PART 2
54A ASH XI ABSTRACTS
HI7
HIS
IN VIVO RELATIONSIDP BETWEEN ENDOTHELIN AND INSULIN. ROLE OF HYPER-INSULINAEMIA AND INSULINRESISTANCE.
MEDIATED VASODILAnON IN PERFUSED MESENTERIC
G Andronico MT Mangano, L. Ferrara. 0 Lamanna, G. Mule and G. Cerasola' - Chair of Intemal Medicine and Hypertension Centre University ofPalenno Italy Since endothelin production is stimulated in vitro by insulin. we perfonned this study to evaluate in vivo relationships between endothelin and insulin plasma levels during a glucose load We studied 28 subjects, 17 with nonnal glucose tolerance (NOT) and J I with impaired glucose tolerance (lOT). Ten of the subjects in study were nonnotensive and 18 with mild 10 moderate hypertension Age, sex and body mass index were comparable among the groups. After a two weeks period of washout they underwent oral glucose tolerance test, blood was drawn at 0 (basal), 90 and 120 minules after the load for glucose, insulin, C-peptide of insulin and endothelin 1·2 determination Values are expressed as means ± SEM For statistical analysis we used Student's t test and, where appropriated, the rank Speannan's correlation test A value of p less than 0.05 was considered significant Basal endothelin in all the subjects under study was correlated with basal insulin (rho: 0.41 - p: 0.014); moreover it was negatively related with the glucose/insulin ratio (rho -0.39 - P 0019) that has been considered as an insulin-sensitivity index, and positively with Ihe insulinlC-peptide ratio (rho 048 - P 0 005) considered as hepatic insulin-resistance index. The relalionship between basal endothelin and IDsulin values was also found ID each of glucose tolerance group (NOT' rho' 046 - p: 0032, IGT rho' 055 - P 0039). At 120 minutes after the glucose load, mean plasma values of endothelin were higher (IS 1 ± 3.3 vs 105 ± I 5 at 0', pg/mL) tlus difference was not significant because the high vanability of data, however the per cent increase of endothelin at 120' was positively related to the per cent increase of IDsulin (rho 041 - P 0 015) Between nonnoten.ive and hypertensive groups there were not significant differences in studIed endothelin parameters Our results appear to conlimt that, even in VIVO, insulin modulates circulating endothelin levels Key Words:
HI9 SODIUM LOAD, ATRIAL NATRIURETIC PEPTIDE AND LEFT VENTRICULAR MASS IN SALT SENSITIVE AL SALT RESISTANT HYPERTENSIVE PATIENTS.N Martell, A Galgo, C FernAndez-Pinilla. J Moya, A FernAndezCruz, MLuque-Otero*. Hypertension Unit. Hospital Universitario San Carlos. Madrid. Spain. Ther aim of this study was to establish the role of atrial natriuretic peptide (ANP) in the saltsensitivity of essential hypertensives (EH) and its relation with the left ventrlcular mass (LVM) . 18 EH (13 males) were studied after a run-in period of 4 weeks without antihypertensIve drugs and on their usual unrestricted diet. An echocardiogram was perfomed at the end of thIS period. Then the patients followed a 4 -week period of salt depletion (LNa) and another 4-week period of salt repletion (HNa). 24h urinary sodium (UNa), ANP measurements and 24h ABPM were done in the last day of each period. Saltsensitivity was defined as an increase of ~lOt In 24h MBP when going from LNa to HNA.
Bean! t. LVMI
19!m')
Sal t - .enel.
\1. ve.
0 52t8 lUi3.
! SS)
20th MBP (mm Hg)
lIN.
LN. ANP lpg/mil lIN.
LN.
UNa fmmol/24h) HNa LN.
lO?t? 93:1:6+
58tta 25t12 .. 28J,7t45.5
127, ttl1, 5.,.
ENDOTHEUUM-
BED OF FISCHER 344 RATS. AS 0 Adeagbo. Dept. of Physiol.lBiophys., and Center for Applied Microcirculatory Research, Univ. of Louisville, Louisville, KY. Acetylcholine (ACh) induced vasodilation of rat perfused mesenteric bed is resistant to blockade by nitro-Larginine methyl ester (L-NAME), and is due to the release of endothelium-derived hyperpolarizing factor (EDHF). We tested the hypothesis that a distortion in the balanced production and release of endothelium-derived nitric oxide (NO) and hyperpolarizing factor (EDHF) contributes to the changes in responsiveness of rat mesenterIC vascular bed to ACh at advanced age. Arterial beds, isolated under pentobarbitone (60 mglkg) anesthesia, were perfused (5ml/mm) with PSS (with/without 100 J-LM L-NAME), maintained at 37"C and saturated with 5 % CO, and 95 % O2 gas mixture. Perfusion pressures were measured with a Statham pressure transducer (model MX 23P) coupled to a Grass polygraph. ACh initiated dose-dependent dilations of pre-constricted vascular beds and the responses decreased significantly with age. At 10 pmol, dilator responses were 85.3±5.7%, 52.3±4.4%, and 20.8±6.3% for vessels from 2-, 16- and 29-month old rats respectively. ACh responses were not altered by 100 I'M LNAME (a NO synthase inhibitor) in vessels from the 2-month old rats, but were reduced significantly to 8.0±O.9% and O.8±O.6% in vessels from 16- and 29-month old rats respectively. Vasodilation initiated by 3 runol cromakalim (a K+ channel opener) in vessels from the three age categorIes were not significantly different indicating that the impairment in ACh response at old age occurred at endothelial, rather than at vascular smooth muscle K + channel level. These data suggest either that NO predominantly accounts for ACh vasodilation at old age, or that the proportIOn of the vasodIlator response mediated by EDHF decreased with age. [Support. Am. Heart Assoc. - KY Affiliate). Key Words' Aging, perfused mesenteric bed. endothelium-
mediated hyperpolarization
Endothelin, Insuhn-resistance, Glucose load
age
AGE-RELATED ATTENUATION OF
"S~aluti...Lre£!'!.l+",.",t.!!n"t .....:-,-,1S",RJ.,1
.Jill110!20
101t' 96::1: 9
25tlS-
latl O
316.5i89,0
1S8, 31;20. 6+
+ peO.OS •• compared w1.th HNa; .. peO.OS •• compared wlth SS.
A negative significant correlation between the percentual increase of ANP from LNa to HNa and LVMI is SS was found (r- -0.5. p<0.05). OUr results show that the effect of HNa diet on plasma ANP levels is greater in SS than in SR. The negative relationship between the increase of ANP from LNa to HNa and the LVMI in SS confirm previous findings of our group and could explaIn the similar LVMI observed in both groups. Key Words: atrial natriuretic peptide, sodium, salt-sensitivity, leCt ventricular .ass
54A ASH XI ABSTRACTS
HI7
HIS
IN VIVO RELATIONSIDP BETWEEN ENDOTHELIN AND INSULIN. ROLE OF HYPER-INSULINAEMIA AND INSULINRESISTANCE.
MEDIATED VASODILAnON IN PERFUSED MESENTERIC
G Andronico MT Mangano, L. Ferrara. 0 Lamanna, G. Mule and G. Cerasola' - Chair of Intemal Medicine and Hypertension Centre University ofPalenno Italy Since endothelin production is stimulated in vitro by insulin. we perfonned this study to evaluate in vivo relationships between endothelin and insulin plasma levels during a glucose load We studied 28 subjects, 17 with nonnal glucose tolerance (NOT) and J I with impaired glucose tolerance (lOT). Ten of the subjects in study were nonnotensive and 18 with mild 10 moderate hypertension Age, sex and body mass index were comparable among the groups. After a two weeks period of washout they underwent oral glucose tolerance test, blood was drawn at 0 (basal), 90 and 120 minules after the load for glucose, insulin, C-peptide of insulin and endothelin 1·2 determination Values are expressed as means ± SEM For statistical analysis we used Student's t test and, where appropriated, the rank Speannan's correlation test A value of p less than 0.05 was considered significant Basal endothelin in all the subjects under study was correlated with basal insulin (rho: 0.41 - p: 0.014); moreover it was negatively related with the glucose/insulin ratio (rho -0.39 - P 0019) that has been considered as an insulin-sensitivity index, and positively with Ihe insulinlC-peptide ratio (rho 048 - P 0 005) considered as hepatic insulin-resistance index. The relalionship between basal endothelin and IDsulin values was also found ID each of glucose tolerance group (NOT' rho' 046 - p: 0032, IGT rho' 055 - P 0039). At 120 minutes after the glucose load, mean plasma values of endothelin were higher (IS 1 ± 3.3 vs 105 ± I 5 at 0', pg/mL) tlus difference was not significant because the high vanability of data, however the per cent increase of endothelin at 120' was positively related to the per cent increase of IDsulin (rho 041 - P 0 015) Between nonnoten.ive and hypertensive groups there were not significant differences in studIed endothelin parameters Our results appear to conlimt that, even in VIVO, insulin modulates circulating endothelin levels Key Words:
HI9 SODIUM LOAD, ATRIAL NATRIURETIC PEPTIDE AND LEFT VENTRICULAR MASS IN SALT SENSITIVE AL SALT RESISTANT HYPERTENSIVE PATIENTS.N Martell, A Galgo, C FernAndez-Pinilla. J Moya, A FernAndezCruz, MLuque-Otero*. Hypertension Unit. Hospital Universitario San Carlos. Madrid. Spain. Ther aim of this study was to establish the role of atrial natriuretic peptide (ANP) in the saltsensitivity of essential hypertensives (EH) and its relation with the left ventrlcular mass (LVM) . 18 EH (13 males) were studied after a run-in period of 4 weeks without antihypertensIve drugs and on their usual unrestricted diet. An echocardiogram was perfomed at the end of thIS period. Then the patients followed a 4 -week period of salt depletion (LNa) and another 4-week period of salt repletion (HNa). 24h urinary sodium (UNa), ANP measurements and 24h ABPM were done in the last day of each period. Saltsensitivity was defined as an increase of ~lOt In 24h MBP when going from LNa to HNA.
Bean! t. LVMI
19!m')
Sal t - .enel.
\1. ve.
0 52t8 lUi3.
! SS)
20th MBP (mm Hg)
lIN.
LN. ANP lpg/mil lIN.
LN.
UNa fmmol/24h) HNa LN.
lO?t? 93:1:6+
58tta 25t12 .. 28J,7t45.5
127, ttl1, 5.,.
ENDOTHEUUM-
BED OF FISCHER 344 RATS. AS 0 Adeagbo. Dept. of Physiol.lBiophys., and Center for Applied Microcirculatory Research, Univ. of Louisville, Louisville, KY. Acetylcholine (ACh) induced vasodilation of rat perfused mesenteric bed is resistant to blockade by nitro-Larginine methyl ester (L-NAME), and is due to the release of endothelium-derived hyperpolarizing factor (EDHF). We tested the hypothesis that a distortion in the balanced production and release of endothelium-derived nitric oxide (NO) and hyperpolarizing factor (EDHF) contributes to the changes in responsiveness of rat mesenterIC vascular bed to ACh at advanced age. Arterial beds, isolated under pentobarbitone (60 mglkg) anesthesia, were perfused (5ml/mm) with PSS (with/without 100 J-LM L-NAME), maintained at 37"C and saturated with 5 % CO, and 95 % O2 gas mixture. Perfusion pressures were measured with a Statham pressure transducer (model MX 23P) coupled to a Grass polygraph. ACh initiated dose-dependent dilations of pre-constricted vascular beds and the responses decreased significantly with age. At 10 pmol, dilator responses were 85.3±5.7%, 52.3±4.4%, and 20.8±6.3% for vessels from 2-, 16- and 29-month old rats respectively. ACh responses were not altered by 100 I'M LNAME (a NO synthase inhibitor) in vessels from the 2-month old rats, but were reduced significantly to 8.0±O.9% and O.8±O.6% in vessels from 16- and 29-month old rats respectively. Vasodilation initiated by 3 runol cromakalim (a K+ channel opener) in vessels from the three age categorIes were not significantly different indicating that the impairment in ACh response at old age occurred at endothelial, rather than at vascular smooth muscle K + channel level. These data suggest either that NO predominantly accounts for ACh vasodilation at old age, or that the proportIOn of the vasodIlator response mediated by EDHF decreased with age. [Support. Am. Heart Assoc. - KY Affiliate). Key Words' Aging, perfused mesenteric bed. endothelium-
mediated hyperpolarization
Endothelin, Insuhn-resistance, Glucose load
age
AGE-RELATED ATTENUATION OF
"S~aluti...Lre£!'!.l+",.",t.!!n"t .....:-,-,1S",RJ.,1
.Jill110!20
101t' 96::1: 9
25tlS-
latl O
316.5i89,0
1S8, 31;20. 6+
+ peO.OS •• compared w1.th HNa; .. peO.OS •• compared wlth SS.
A negative significant correlation between the percentual increase of ANP from LNa to HNa and LVMI is SS was found (r- -0.5. p<0.05). OUr results show that the effect of HNa diet on plasma ANP levels is greater in SS than in SR. The negative relationship between the increase of ANP from LNa to HNa and the LVMI in SS confirm previous findings of our group and could explaIn the similar LVMI observed in both groups. Key Words: atrial natriuretic peptide, sodium, salt-sensitivity, leCt ventricular .ass