Molecular mechanisms of insulin-induced sympathoexcitation

AJH–April 2002–VOL. 15, NO. 4, PART 2

ORALS: Novel Mechanisms Linking Obesity to Hypertension and Cardiovascular Disease

OR-1 ROSIGLITAZONE IMPROVES INSULIN SENSITIVITY AND LOWERS BLOOD PRESSURE IN HYPERTENSIVE PATIENTS Annaswamy Raji, Donald C. Simonson, Ellen W. Seely, Shannon A.R. Bekins, Gordon H. Williams. Endocrine- Hypertension, Brigham & Women’s Hospital, Boston, Massachusetts, United States. Insulin resistance is associated with essential hypertension (EH), although the pathophysiologic mechanisms underlying this relationship are not clear. This study was designed to evaluate insulin sensitivity (IS) in patients with EH, and to determine whether the insulin sensitizer rosiglitazone would decrease 24-hr ambulatory blood pressure (ABPM), improve IS, and reduce cardiovascular (CV) risk factors. Twenty-four non-diabetic subjects with EH (age⫽57⫾6yrs, BMI⫽30⫾5Kg.m-2, Fasting glucose⫽83⫾8mg/dl) were studied. After a 2-week washout phase off antihypertensive meds, all subjects had baseline ABPM, a euglycemic hyperinsulinemic clamp (40mU.m2.min-1), and blood tests including fasting insulin, lipid profile, liver function tests, PAI-1, and C-reactive protein (CRP). Subjects were then placed on rosiglitazone (4 mg PO qd, titrated to bid in 2 weeks) and their usual antihypertensive meds (but not ACE-Is) for 16 weeks. At the end of rosiglitazone treatment (including final 2 weeks off antihypertensive meds) there were significant decreases in mean 24-hr, nighttime, and daytime systolic and diastolic BP, and a significant improvement in IS (table 1). There was a highly significant correlation between the improvement in IS and the decline in systolic BP after rosiglitazone treatment (r⫽0.68, p⬍0.002). PAI-1 (16.7⫾1.5 vs 11.1⫾1.5 ng/ml, p⬍0.009) and CRP (0.27⫾0.06 vs 0.15⫾0.04 mg/ml, p⬍0.002) declined significantly. Total cholesterol(206⫾6 vs 186⫾7, p⬍0.0006), Triglycerides (134⫾16 vs 89⫾8 mg/dl, p⬍0.01), LDL (129⫾6 vs 122⫾8 mg/dl, p⫽0.18) and HDL (50⫾3 vs 46⫾3 mg/dl, p⬍0.02) all declined, with no change in the LDL/HDL ratio. Treatment with the insulin sensitizer rosiglitazone improves blood pressure, insulin sensitivity and markers for risk of cardiovascular disease in non-diabetic hypertensive patients. Insulin sensitizers may play a role in the treatment of hypertension and its associated cardiovascular risks. BP & Insulin Sensitivity Mean ⴞ SEM

0 Week

16 Week

P value

24hr Mean Systolic mmHg 24hr Mean Diastolic mmHg Night time (23hrs-6.00am) Systolic mmHg Night time (23hrs-6.00am) Diastolic mmHg Fasting Insulin (␮U/ml) Peripheral insulin Sensitivity-mg/kg/min

138 ⫾ 2 85 ⫾ 2 131 ⫾ 3 79 ⫾ 2 16 ⫾ 2 5.0 ⫾ 0.4

134 ⫾ 2 80 ⫾ 2 126 ⫾ 3 72 ⫾ 2 12 ⫾ 1 5.9 ⫾ 0.5

⬍0.01 ⬍0.0001 ⬍0.01 ⬍0.0001 ⬍0.01 ⬍0.001

Key Words: Rosiglitazone, Insulin Resistance, Hypertension

OR-2 ADENOVIRAL LEPTIN AS GENE THERAPY FOR OBESITY RELATED HYPERTENSION Weiguo Zhang, Sabine Telemaque-Potts, Paul R. Anderson, Zhongyun Wang, Jie An, Chris B. Newgard, Ronald G. Victor. The Donald W Reynolds Cardiovascular Clinical Research Center, The University of Texas Southwestern Medical Center, Dallas, TX, United States. Leptin has been postulated as an important hormone linking obesity with sympathetic activation and hypertension. In a rat model of dietary obesity moderate hyperleptinemia by adenoviral gene transfer has been shown to reverse all the other features of the metabolic syndrome including insulin resistance and glucose intolerance. To determine if leptin improves or worsens hypertension in this model, we measured blood pressure with intraarterial catheters in young male Wistar rats that had been fed for 6 weeks with normal chow or with a 45% fat diet and then infused with adenoviruses containing the leptin gene (AdCMV-lep), or as a control, © 2002 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.

1A

the ␤-galactosidase gene (AdCMV-␤GAL). Compared with lean rats, fat-fed rats had a higher mean arterial pressure (MAP): 104⫾2 vs 94⫾1 mmHg (p⬍.05). In the fat-fed rats treated with AdCMV-lep, plasma leptin levels were two-fold higher than with fat feeding alone (39.1⫾8.1 vs 18.8⫾4.8 ng/ml, p⬍.05) and blood pressure was indistinguishable from that in the lean rats (90⫾3 vs 94⫾1 mmHg), whereas AdCMV␤GAL was without effect. To more closely simulate a fast-food Western diet, we performed additional experiments in young male Wistar rats fed a high salt diet (8% NaCl) ad libitum, which resulted in a doubling of daily caloric intake and a marked increase in body weight accompanied by hyperinsulinemia and hypertriglyceridemia. By measuring blood pressure continuously with radiotelemetry in these rats, we observed a robust hypertension: 24h MAP increased progressively over 6 weeks from 87⫾2 to 107⫾5 mmHg (p⬍.01, n⫽9). This hypertension and the associated metabolic derangements were caused largely by increased caloric intake because both were greatly attenuated in a separate group of rats fed the same high salt diet but with caloric intake restricted to a normal value. Most importantly, in the rats fed high salt diet ad libitum, AdCMV-lep administration completely normalized the hyperinsulinemia and hypertriglyceridemia and partially corrected the hypertension: MAP fell from 107⫾5 to 101⫾5 mmHg, p⬍.01). From these data, we conclude that in two dietary models of obesity, adenoviral leptin therapy certainly does not exacerbate hypertension but rather exerts a modest antihypertensive effect. Key Words: Obesity, Leptin, Diet

OR-3 MOLECULAR MECHANISMS OF INSULIN-INDUCED SYMPATHOEXCITATION Kamal Rahmouni, Donald A. Morgan, Wei Zhou, Allyn L. Mark, William G. Haynes. Hypertension Genetics SCOR and Internal Medicine, University of Iowa and VAMC, Iowa City, IA, United States. Insulin receptors are present in the brain regions that control energy homeostasis and cardiovascular function, and central nervous system (CNS) insulin acts to increase sympathetic neural outflow. Insulin signaling in blood vessels and skeletal muscle depends on activation of diverse mechanisms including mitogen activated protein kinase (MAPK) and phosphoinositol kinase (PI3K). We hypothesized that MAPK and PI3K mediate CNS sympathetic responses to insulin. We assessed sympathetic nerve activity (SNA) to brown adipose tissue (BAT), lumbar, kidney and adrenal glands in anesthetized (methohexital sodium/chloralose) Sprague-Dawley rats after intracerebroventricular (icv) administration of insulin (500 mU) in presence or absence of selective inhibitors of MAPK (PD98059, 5 mcg) or PI3K (LY294002, 5 mcg). ICV administration of insulin increased SNA to BAT (282⫹/-27%, n⫽20, P⬍0.001 vs vehicle), lumbar (274⫹/-24%, n⫽7, P⬍0.001), kidney (85⫹/-16%, n⫽9, P⬍0.001) and adrenal (93⫹/-19%, n⫽10, P⬍0.01). ICV administration of the MAPK inhibitor PD98059 blocked the insulin-induced increase in BAT SNA (47⫹/-13%, n⫽20, P⬍0.001 vs insulin alone), but PD98059 did not affect the insulin-mediated increases in SNA to other tissues. In contrast, icv administration of the PI3K inhibitor LY294002 attenuated the lumbar SNA (119⫹/-20, n⫽14, P⬍0.05 vs insulin alone) response to insulin. ICV LY294002 did not affect the insulin-induced increase in SNA to other tissues. Our data demonstrate that contrasting molecular mechanisms are involved in regional sympathoactivation by insulin. The increase in SNA to thermogenic tissue is mediated by MAPK while the sympathoexcitatory effect of insulin to hindlimb is mediated by PI3K. However, none of these signaling pathways appear to be involved in insulin-mediated sympathoexcitation to the kidney and adrenal gland. Exploration of these CNS pathways may offer insights into central mechanisms of obesity and hypertension. Key Words: Insulin, Sympathetic Nerve Activity, MAP Kinase and PI3 Kinase 0895-7061/02/$22.00