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Direct effect of leptin on endothelial function and their changes in patients with essential hypertension
AJH–April 2002–VOL. 15, NO. 4, PART 2
P-439 DIRECT EFFECT OF LEPTIN ON ENDOTHELIAL FUNCTION AND THEIR CHANGES IN PATIENTS WITH ESSENTIAL HYPERTENSION Y. Yao, A.Q. Ma, G.R. Wu, X. Tian, Y.T. Xi. Cardiovascular Medicine, NO.1 Hosptial of Xi’an Jiaotong University, Xi’an, Shaanxi, China. Objective: By observing the change of serum leptin and endothelial function in essential hypertension (EH) patients,as well as the direct effect of leptin on human umbilical vein endothelial cells (HUVEC),we speculate the possible change mechanism of both serum leptin and endothelial function in patients with EH. Subjects and Methods: 34 patients with EH and 30 mormotensive subjects matched for age and sex were involved,We tested their serum leptin endothelin-1(ET-1) and nitric oxide(NO).Then we observed the direct effect of leptin on NO and ET-1 secretion from HUVEC;and Whether tyrosine kinase inhibitor genestein and PI 3-kinase inhibitor wortmannin could disturb above effects. Results: (1) Patients with EH had high serum leptin and ET-1.(2)Serum leptin was significantly positively correlated with ET-1 and SBP. (3)High concentration of leptin had direct effect of promoting the NO secretion from HUVEC;the effect was blocked by either genestein(tyrosine kinase inhibitor) and wortmannin(PI 3-kinase inhibitor). (4) Leptin had no direct effect on ET-1 secretion from HUVEC. Conclusions: (1) Patients with EH had leptin resistance and endothelial dysfunction. (2)Either tyrosine kinase or PI 3-kinase may be the possible leptin post-receptor signal transduction effector molecule and abnormal post-receptor signaling transduction of leptin was the cause of both high serum leptin and endothelial dysfunction in EH. Key Words: Leptin, Essential Hypertension, Nitric Oxide
P-440 ATTENUATED RENAL SYMPATHETIC NERVE RESPONSES TO STIMULATION OF MELANOCORTIN SYSTEM IN ABSENCE OF LEPTIN RECEPTORS Kamal Rahmouni, William G. Haynes, Donald A. Morgan, Allyn L. Mark. Hypertension Genetics SCOR and Internal Medicine, University of Iowa and VAMC, Iowa City, IA, United States. We have previously shown the importance of melanocortin-4 receptors in the control of renal sympathetic nerve outflow by leptin. The sympathoexcitatory effect of leptin was absent in melanocortin-4 receptor knockout mice. Here we examine whether absence of leptin receptors (in db/db mice) alters sympathetic response to melanocortin-4 receptor stimulation. Each mouse received an intracerebroventricular (icv) cannula one week before the study. Arterial pressure, heart rate and renal sympathetic nerve activity (RSNA) were recorded under anesthesia (Xylaxine/Ketamine) at baseline and during 4 hours after icv injection. The effects of icv administration of leptin and melanocortin-4 receptor agonist (MTII) were compared in leptin deficient (db/db) mice and their wild-type controls (C57BL/KsJ). At baseline, mean arterial pressure and RSNA were higher (P⫽0.0005 and P⬍0.0001, respectively) in the db/db mice (91⫹/-1 mmHg and 1.8⫹/-0.1 volts*sec/min, n⫽48) as compared to their littermate controls (84⫹/-1, 1.3⫹/-0.03, n⫽49). As expected, icv administration of leptin (2 mcg) increased RSNA by 297⫹/-97% (n⫽7, P⬍0.01) in wild-type mice, but leptin did not affect RSNA in the db/db mice (n⫽5). ICV injection of melanocortin-4 receptor agonist MTII (2 mcg) increased RSNA in the wild-type mice by 291⫹/-67% (n⫽7, P⬍0.001) but not in the db/db mice. A ten fold higher dose (20 mcg) of MTII was required to increase RSNA (170⫹/-40%, n⫽7, P⫹/-0.01) in db/db mice. In contrast, the rise in RSNA induced by icv insulin (20 mcU) was of the same magnitude in the wild-type controls (157⫹/-39%, n⫽6, P⬍0.01) and db/db mice (142⫹/-15%, n⫽6, P⬍0.01). Our data demonstrate that in absence of leptin receptors the sympathoexcitatory effects of melanocortin-4 receptor stimulation are attenuated. These findings confirm an
POSTERS: Obesity, Insulin Resistance, Diabetes
191A
important physiologic interaction of leptin and melanocortin system in regulation of sympathetic nerve activity. Key Words: Leptin, Sympathetic Nerve Activity, Melanocortin System
P-441 THE DEGREE OF ALBUMINURIA IS A FUNCTION OF LEFT VENTRICULAR HYPERTROPHY IN HYPRETENSIVE DIABETICS AND IS INDEPENDENT OF THE LEVEL OF BLOOD PRESSURE OR SYSTOLIC FUNCTION OF THE LEFT VENTRICLE Abdul-Majeed Salmasi, Ewart Jepson, Mark Dancy. Cardiology, Central Middlesex Hospital, London, United Kingdom. The degree of albuminuria is a risk factor for cardiovascular events in patients with or without diabetes mellitus. We investigated the relation between left ventricular mass index (LVMI) and degree of albuminuria in 17 normotensive normalbuminuric diabetics (NOR), 11 hypertensive microalbuminuric diabetics (MIC) and 20 hypertensive macroalbuminuric diabetics (MAC) who were age and sex matched. Left ventricular ejection fraction (LVEF), LVMI and diastolic function of the left ventricle (LV) were derived from echocardiography. LV diastolic function was assessed by measuring the E/A ratio (peak velocity of early/atrial filling waves of the transmitral flow) Table shows that LVMI was higher in MAC than MIC or NOR. There was higher number of patients with LV hypertrophy (LVH) and LV diastolic dysfunction in MAC than MIC or NOR. LVMI was not related to LVEF. Blood pressure (BP) was not different between MAC and MIC but was significantly higher than NOR. This study suggests that high degree of albuminuria in hypertensive diabetics is associated with high value for LVMI and high incidence of LVH independent of blood pressure level or systolic LV function. LVH is associated with LV diastolic dysfunction. The degree of albuminuria may predict level of LVMI and LVH which are associated with LV diastolic dysfunction. This may explain why albuminuria is a risk factor for cardiovascular events in diabetics.
Systolic BP Diastolic BP LVMI* LVH* LVEF E/A* E/A ⬍ 1*
NOR (n ⴝ 17)
MIC (n ⴝ 10)
MAC (n ⴝ 20)
119.9 ⫾ 6.6 78.3 ⫾ 7.0 90.0 ⫾ 31.8 3 (17) 0.6 ⫾ 0.07 1.2 ⫾ 0.3 1 (6)
148.7 ⫾ 5.6 93.0 ⫾ 4.2 115.6 ⫾ 32.5 5 (50) 0.56 ⫾ 0.1 1.1 ⫾ 0.1 1 (10)
146.3 ⫾ 4.4 92.5 ⫾ 4.9 132.3 ⫾ 55.4 13 (65) 0.56 ⫾ 0.09 0.93 ⫾ 0.34 9 (45)
(* p⬍0.01. Figures between brackets represent percentage ineach group)
Key Words: Diabetes, Left Ventricular Hypertrophy, Albuminuria
P-442 INSULIN RESISTANCE IN HYPERTENSIVE SUBJECTS: CORRELATION BETWEEN REAVENS TEST AND HOMA MODEL. EFFECT OF DOXAZOSIN Eladio Ramos, Jose L. Griera, Jose Contreras, Aparicio Maravi, Josefina Olivan, Ramon Perez-Cano. Unidad de Hipertension, Hospital Virgen Macarena, Sevilla, Spain. Insulin resistance (IR) is a feature of essential hypertension. Most of methods to measure it are expensive and time-consuming, so that they aren’t feasible to use in large populations. Homeostasis Model Assessment (HOMA) model is a newly used method that allows an easy and not expensive assessment of IR. We have studied IR using Reaven’s test (Insulin Supression Test with Somatostatin, to calculate Steady State Plasma Glucose -SSPG- as the mean plasma glucose after a 120 min. infusion of 350 mg/h of somatostatin, 25 mU/m2/min of insulin and 6 mg/Kg/min of glucose) as well as with HOMA model [Insulin (U/ml) x Glucose (mmol/l) / 22.5] in a group of 11 hypertensive subjects (HT)
P-439 DIRECT EFFECT OF LEPTIN ON ENDOTHELIAL FUNCTION AND THEIR CHANGES IN PATIENTS WITH ESSENTIAL HYPERTENSION Y. Yao, A.Q. Ma, G.R. Wu, X. Tian, Y.T. Xi. Cardiovascular Medicine, NO.1 Hosptial of Xi’an Jiaotong University, Xi’an, Shaanxi, China. Objective: By observing the change of serum leptin and endothelial function in essential hypertension (EH) patients,as well as the direct effect of leptin on human umbilical vein endothelial cells (HUVEC),we speculate the possible change mechanism of both serum leptin and endothelial function in patients with EH. Subjects and Methods: 34 patients with EH and 30 mormotensive subjects matched for age and sex were involved,We tested their serum leptin endothelin-1(ET-1) and nitric oxide(NO).Then we observed the direct effect of leptin on NO and ET-1 secretion from HUVEC;and Whether tyrosine kinase inhibitor genestein and PI 3-kinase inhibitor wortmannin could disturb above effects. Results: (1) Patients with EH had high serum leptin and ET-1.(2)Serum leptin was significantly positively correlated with ET-1 and SBP. (3)High concentration of leptin had direct effect of promoting the NO secretion from HUVEC;the effect was blocked by either genestein(tyrosine kinase inhibitor) and wortmannin(PI 3-kinase inhibitor). (4) Leptin had no direct effect on ET-1 secretion from HUVEC. Conclusions: (1) Patients with EH had leptin resistance and endothelial dysfunction. (2)Either tyrosine kinase or PI 3-kinase may be the possible leptin post-receptor signal transduction effector molecule and abnormal post-receptor signaling transduction of leptin was the cause of both high serum leptin and endothelial dysfunction in EH. Key Words: Leptin, Essential Hypertension, Nitric Oxide
P-440 ATTENUATED RENAL SYMPATHETIC NERVE RESPONSES TO STIMULATION OF MELANOCORTIN SYSTEM IN ABSENCE OF LEPTIN RECEPTORS Kamal Rahmouni, William G. Haynes, Donald A. Morgan, Allyn L. Mark. Hypertension Genetics SCOR and Internal Medicine, University of Iowa and VAMC, Iowa City, IA, United States. We have previously shown the importance of melanocortin-4 receptors in the control of renal sympathetic nerve outflow by leptin. The sympathoexcitatory effect of leptin was absent in melanocortin-4 receptor knockout mice. Here we examine whether absence of leptin receptors (in db/db mice) alters sympathetic response to melanocortin-4 receptor stimulation. Each mouse received an intracerebroventricular (icv) cannula one week before the study. Arterial pressure, heart rate and renal sympathetic nerve activity (RSNA) were recorded under anesthesia (Xylaxine/Ketamine) at baseline and during 4 hours after icv injection. The effects of icv administration of leptin and melanocortin-4 receptor agonist (MTII) were compared in leptin deficient (db/db) mice and their wild-type controls (C57BL/KsJ). At baseline, mean arterial pressure and RSNA were higher (P⫽0.0005 and P⬍0.0001, respectively) in the db/db mice (91⫹/-1 mmHg and 1.8⫹/-0.1 volts*sec/min, n⫽48) as compared to their littermate controls (84⫹/-1, 1.3⫹/-0.03, n⫽49). As expected, icv administration of leptin (2 mcg) increased RSNA by 297⫹/-97% (n⫽7, P⬍0.01) in wild-type mice, but leptin did not affect RSNA in the db/db mice (n⫽5). ICV injection of melanocortin-4 receptor agonist MTII (2 mcg) increased RSNA in the wild-type mice by 291⫹/-67% (n⫽7, P⬍0.001) but not in the db/db mice. A ten fold higher dose (20 mcg) of MTII was required to increase RSNA (170⫹/-40%, n⫽7, P⫹/-0.01) in db/db mice. In contrast, the rise in RSNA induced by icv insulin (20 mcU) was of the same magnitude in the wild-type controls (157⫹/-39%, n⫽6, P⬍0.01) and db/db mice (142⫹/-15%, n⫽6, P⬍0.01). Our data demonstrate that in absence of leptin receptors the sympathoexcitatory effects of melanocortin-4 receptor stimulation are attenuated. These findings confirm an
POSTERS: Obesity, Insulin Resistance, Diabetes
191A
important physiologic interaction of leptin and melanocortin system in regulation of sympathetic nerve activity. Key Words: Leptin, Sympathetic Nerve Activity, Melanocortin System
P-441 THE DEGREE OF ALBUMINURIA IS A FUNCTION OF LEFT VENTRICULAR HYPERTROPHY IN HYPRETENSIVE DIABETICS AND IS INDEPENDENT OF THE LEVEL OF BLOOD PRESSURE OR SYSTOLIC FUNCTION OF THE LEFT VENTRICLE Abdul-Majeed Salmasi, Ewart Jepson, Mark Dancy. Cardiology, Central Middlesex Hospital, London, United Kingdom. The degree of albuminuria is a risk factor for cardiovascular events in patients with or without diabetes mellitus. We investigated the relation between left ventricular mass index (LVMI) and degree of albuminuria in 17 normotensive normalbuminuric diabetics (NOR), 11 hypertensive microalbuminuric diabetics (MIC) and 20 hypertensive macroalbuminuric diabetics (MAC) who were age and sex matched. Left ventricular ejection fraction (LVEF), LVMI and diastolic function of the left ventricle (LV) were derived from echocardiography. LV diastolic function was assessed by measuring the E/A ratio (peak velocity of early/atrial filling waves of the transmitral flow) Table shows that LVMI was higher in MAC than MIC or NOR. There was higher number of patients with LV hypertrophy (LVH) and LV diastolic dysfunction in MAC than MIC or NOR. LVMI was not related to LVEF. Blood pressure (BP) was not different between MAC and MIC but was significantly higher than NOR. This study suggests that high degree of albuminuria in hypertensive diabetics is associated with high value for LVMI and high incidence of LVH independent of blood pressure level or systolic LV function. LVH is associated with LV diastolic dysfunction. The degree of albuminuria may predict level of LVMI and LVH which are associated with LV diastolic dysfunction. This may explain why albuminuria is a risk factor for cardiovascular events in diabetics.
Systolic BP Diastolic BP LVMI* LVH* LVEF E/A* E/A ⬍ 1*
NOR (n ⴝ 17)
MIC (n ⴝ 10)
MAC (n ⴝ 20)
119.9 ⫾ 6.6 78.3 ⫾ 7.0 90.0 ⫾ 31.8 3 (17) 0.6 ⫾ 0.07 1.2 ⫾ 0.3 1 (6)
148.7 ⫾ 5.6 93.0 ⫾ 4.2 115.6 ⫾ 32.5 5 (50) 0.56 ⫾ 0.1 1.1 ⫾ 0.1 1 (10)
146.3 ⫾ 4.4 92.5 ⫾ 4.9 132.3 ⫾ 55.4 13 (65) 0.56 ⫾ 0.09 0.93 ⫾ 0.34 9 (45)
(* p⬍0.01. Figures between brackets represent percentage ineach group)
Key Words: Diabetes, Left Ventricular Hypertrophy, Albuminuria
P-442 INSULIN RESISTANCE IN HYPERTENSIVE SUBJECTS: CORRELATION BETWEEN REAVENS TEST AND HOMA MODEL. EFFECT OF DOXAZOSIN Eladio Ramos, Jose L. Griera, Jose Contreras, Aparicio Maravi, Josefina Olivan, Ramon Perez-Cano. Unidad de Hipertension, Hospital Virgen Macarena, Sevilla, Spain. Insulin resistance (IR) is a feature of essential hypertension. Most of methods to measure it are expensive and time-consuming, so that they aren’t feasible to use in large populations. Homeostasis Model Assessment (HOMA) model is a newly used method that allows an easy and not expensive assessment of IR. We have studied IR using Reaven’s test (Insulin Supression Test with Somatostatin, to calculate Steady State Plasma Glucose -SSPG- as the mean plasma glucose after a 120 min. infusion of 350 mg/h of somatostatin, 25 mU/m2/min of insulin and 6 mg/Kg/min of glucose) as well as with HOMA model [Insulin (U/ml) x Glucose (mmol/l) / 22.5] in a group of 11 hypertensive subjects (HT)