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(Hypertension. 1996;28:219-223.)
© 1996 American Heart Association, Inc.
Articles |
Attenuation of Hypertension by Insulin-Sensitizing Agents
Correspondence to Theodore A. Kotchen, MD, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226.
Key Words: insulin resistance • hyperinsulinism • insulin
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Introduction |
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Epidemiological and clinical evidence document an association between hypertension and resistance to insulin-stimulated glucose uptake.1 Insulin-resistant individuals also tend to have increased plasma concentrations of triglycerides and low-density lipoprotein cholesterol and decreased concentrations of high-density lipoprotein cholesterol. These associations have been observed in individuals with type II diabetes and in obese people. In addition, depending on methodologies and criteria for its definition, insulin resistance is present in 16% to 40% of nonobese individuals with essential hypertension and in normotensive individuals who are at increased risk for developing hypertension.1 2 Insulin resistance may be associated with salt sensitivity of blood pressure.3 4 5
Insulin resistance has also been observed in both genetic and acquired rat models of hypertension, eg, the Dahl salt-sensitive (Dahl S) rat, spontaneously hypertensive rat (SHR), Milan hypertensive rat, and rats with sucrose or fructose feeding.1 However, insulin-stimulated glucose uptake is normal in both the one-kidney, one clip hypertensive rat and the two-kidney, one clip hypertensive rat, suggesting that insulin resistance is not an invariable consequence of elevated arterial pressure.6 7
Although a number of putative mechanisms have been proposed, it is unclear whether insulin resistance and/or hyperinsulinemia actually cause hypertension.1 Insulin itself is a vasodilator, and in normal subjects, insulin infusions along with sufficient glucose to prevent hypoglycemia cause vasodilation, not vasoconstriction.8 Individuals with insulinoma do not have an increased prevalence of hypertension,9 although in this situation hyperinsulinemia is primary and is not due to insulin resistance.
In a variety of circumstances, increasing insulin sensitivity and/or reversal of hyperinsulinemia is associated with a concomitant reduction of arterial pressure. For example, blood pressure may be lowered and insulin-stimulated glucose uptake may be augmented by increased physical activity and in obese individuals by weight loss.10 11 12 Somatostatin infusion has been reported to reduce plasma insulin concentrations and lower blood pressure in rats with hypertension induced by a high fructose intake and in obese, hyperinsulinemic, hypertensive humans.13 14 Feeding guar gum to both obese hypertensive subjects and to lean normotensive subjects reportedly increases insulin sensitivity and lowers blood pressure.15 However, the effects of exercise, weight loss, somatostatin, and guar gum on blood pressure may not be specifically related to their effects on insulin resistance and/or hyperinsulinemia. To further clarify the relationship between insulin resistance and hypertension, we and others have recently evaluated the effects of oral hypoglycemic agents on arterial pressure in different models of hypertension (Table
).
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Antihypertensive Effects of Insulin-Sensitizing Agents |
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Thiazolidinedione Derivatives
Thiazolidinedione derivatives increase the insulin sensitivity of target tissues without stimulating endogenous insulin secretion.43 Although relatively little is known about the mechanism, increased insulin sensitivity appears to be due to an effect of the thiazolidinediones on postreceptor binding steps in the transduction of the insulin response.
We have recently shown that one of these agents, pioglitazone, attenuates the development of hypertension in both the Dahl S rat and the one-kidney, one clip Sprague-Dawley rat.16 In Dahl S rats, reduction of blood pressure is due to a reduction of total peripheral resistance. Pioglitazone, or other thiazolidinedione derivatives, also decreases both blood pressure and plasma triglyceride concentrations in obese Zucker rats,17 fructose-fed Sprague-Dawley rats,18 19 20 SHR,21 22 23 and obese insulin-resistant rhesus monkeys.24 In apparent contrast, in a single recent report, treatment with CS-045 (a thiazolidinedione derivative) failed to lower blood pressure in the SHR despite improvement of insulin resistance.44
The capacity of thiazolidinediones to prevent hypertension is not invariably associated with their capacity to increase insulin sensitivity. Studies with the euglycemic insulin clamp have shown that pioglitazone prevents hypertension without affecting insulin sensitivity in the one-kidney, one clip Sprague-Dawley rat, a model of hypertension not associated with insulin resistance.45
Limited data are available about the effect of thiazolidinediones on blood pressure in humans. In an uncontrolled study of 18 patients with type II diabetes and mild hypertension, blood pressure decreased modestly after 8 weeks of treatment with troglitazone.25 In a separate study, after 12 weeks of treatment, this same agent improved glucose tolerance (but had no effect on plasma cholesterol or triglyceride concentrations) in 18 obese subjects with either impaired or normal glucose tolerance and decreased systolic (5±2 mm Hg) and diastolic (4±2 mm Hg) pressures (P=.04); insulin sensitivity and blood pressure did not change in a separate placebo group.26
Metformin
Although chemically unrelated to the thiazolidinediones, biguanides also improve glucose tolerance without stimulating endogenous insulin secretion.46 These agents act by suppressing hepatic glucose output and also by increasing insulin-mediated glucose disposal. Metformin, a biguanide, increases insulin sensitivity and lowers arterial pressure in the SHR; raising plasma insulin levels in metformin-treated SHR to those observed in untreated SHR reportedly reverses the effect of metformin on blood pressure.27 28 In contrast, we have recently reported that metformin does not alter the development of hypertension in either the Dahl S or one-kidney, one clip Sprague-Dawley rat.45
Limited and somewhat conflicting data are available about the effect of metformin on blood pressure in humans. In studies with small numbers of patients, several of which were uncontrolled, metformin has been reported to increase insulin sensitivity and decrease blood pressure in nonobese hypertensive men,29 in obese diabetic and nondiabetic hypertensive women,30 31 in normotensive patients with non-insulin-dependent diabetes,32 and in women with the polycystic ovary syndrome.33 In several of these studies, metformin was also associated with a reduction in body weight, raising the possibility that a putative effect on blood pressure was a consequence of weight loss. In contrast, metformin has been reported not to decrease blood pressure in nondiabetic hypertensive34 and diabetic35 patients.
Additional Agents That Increase Insulin Sensitivity and/or Lower Plasma Lipid Concentrations
Vanadyl sulfate and bismaltolato(oxo)vanadium (an organic vanadium compound) prevent the development of hypertension in the SHR but do not affect blood pressure in normotensive Wistar-Kyoto rats.36 37 These agents decrease plasma insulin concentrations by enhancing sensitivity to insulin, and restoration of plasma insulin to pretreatment levels reverses their antihypertensive effects. Etomoxir, an agent that inhibits fatty acid oxidation, also increases insulin action and decreases blood pressure in the SHR.38
In contrast, blood pressure is not lowered by sulfonylureas and acarbose, two different classes of hypoglycemic drugs. Unlike the thiazolidinedione derivatives and metformin, the sulfonylureas stimulate endogenous insulin secretion in addition to increasing sensitivity to insulin in peripheral tissues.47 48 Although the acute administration of glyburide lowers blood pressure in normal dogs,49 long-term administration of glyburide increases plasma insulin concentrations and diastolic pressure in female but not in male stroke-prone SHR.50 Glybenclamide also does not lower blood pressure in the SHR.51 In a clinical study in normotensive or mildly hypertensive diabetic patients on antihypertensive drugs, glipizide treatment was associated with increased insulin sensitivity but not with improved blood pressure control compared with insulin.52 Acarbose is an oral hypoglycemic agent that acts by blunting polysaccharide digestion in the gastrointestinal tract. In the SHR, treatment with acarbose lowers plasma insulin levels but has no effect on blood pressure.53
Clofibrate and benfluorex are antilipidemic agents that lower elevated serum lipid concentrations by reducing the very-low-density lipoprotein fraction rich in triglycerides. Clofibrate attenuates the development of hypertension in Dahl S rats,39 and benfluorex increases insulin sensitivity and lowers both blood pressure and plasma triglyceride concentrations in fructose-fed Wistar rats.40 Benfluorex also reduces both plasma insulin concentrations and blood pressure in middle-aged and elderly hypertensive men.41 Lovastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase) prevents the development of hypertension in the Dahl S rat,42 although in apparent contrast, this same agent has also been reported to increase blood pressure in the SHR and normotensive Wistar-Kyoto rat.54
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Antihypertensive Mechanisms of Insulin-Sensitizing Agents |
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Attenuation of hypertension by insulin-sensitizing agents and lipid-lowering agents may be related to their effects on vascular structure, function, or both. Insulin is a potent mitogen, and increased peripheral resistance associated with hypertension is partly due to accelerated growth (hyperplasia or hypertrophy) of vascular smooth muscle in small arteries and arterioles. We have recently reported that pioglitazone inhibits proliferation of rat renal afferent arteriolar smooth muscle cells in response to stimulation by insulin and other mitogens.16 Similarly, troglitazone inhibits mitogen-stimulated signal transduction in vascular smooth muscle.55 Lovastatin also inhibits proliferation of rat mesangial cells and rat aortic smooth muscle cells, possibly because of decreased production of mevalonate.56 Metformin has been reported to inhibit proliferation of human57 but not of rat58 vascular smooth muscle cells.
Alternatively, insulin-sensitizing agents may decrease peripheral resistance by affecting vascular contractility. Both augmented vasoconstriction and impaired endothelium-dependent vasodilation have been described in association with insulin resistance and hypercholesterolemia.59 60 61 62 63 64 65 66 67 In Dahl S rats, pretreatment with pioglitazone inhibits in vivo pressor responses to both norepinephrine and angiotensin II.68 Additionally, in vitro, in the presence of insulin, pioglitazone inhibits pressor responses of aortic strips to norepinephrine and phenylephrine and augments acetylcholine-induced, but not nitroprusside-induced, vasodilation.68 69 On the basis of these observations, we have hypothesized that pioglitazone attenuates hypertension by modulating the effect of insulin on vascular function, resulting in both blunted vasoconstriction and augmented endothelium-dependent vasodilation.
Increases of intracellular free calcium contribute to agonist-induced vasoconstriction, mitogen-stimulated cell growth, and insulin resistance.70 71 Conceivably, the capacities of thiazolidinediones (and possibly other insulin-sensitizing agents) to decrease the pressor responsiveness to vasoconstrictor agents, to inhibit mitogen-stimulated growth of vascular smooth muscle, and to increase insulin sensitivity may all be mediated by alterations of intracellular calcium. Ciglitazone (a thiazolidinedione derivative) abolishes sustained elevations of intracellular calcium induced by platelet-derived growth factor in A172 human glioblastoma cells.23 Metformin also decreases vasopressin- and thrombin-stimulated increases of intracellular calcium in SHR aortic smooth muscle cells.72 Furthermore, pioglitazone attenuates inward current through voltage-dependent calcium channels, by an action on L-type calcium channels, and inhibits agonist-mediated (norepinephrine, vasopressin, potassium chloride) calcium uptake by vascular smooth muscle.73 74
Another potential mechanism by which these agents may decrease blood pressure in vivo may be related to their capacities to decrease circulating glucose and lipid concentrations. In the streptozotocin-induced diabetic rat, poor glycemic control results in an elevation of arterial pressure within 1 to 4 days.75 Glucose, advanced glycosylation end products, and low-density lipoprotein cholesterol may themselves, or by their capacity to generate oxygen free radicals, contribute to impaired endothelium-dependent vasodilation.76 Protein kinase C may play a role in glucose-induced vascular smooth muscle dysfunction.77 Studies in animal models of both diabetes and hypercholesterolemia support augmented nitric oxide inactivation by oxygen-derived free radicals as a cause of endothelial dysfunction. Treatment with antioxidants normalizes impaired endothelium-dependent relaxation in arterioles exposed to hyperglycemia in vitro and in vivo in both animal models and individuals with diabetes.76
It has recently been suggested that clofibrate alters renal tubular function, favoring natriuresis.39 Cytochrome P-450 metabolites of arachidonic acid play a role in the regulation of renal tubular function. In the Dahl S rat, chloride reabsorption is increased in the loop of Henle, and cytochrome P-450 
-hydroxylation of arachidonic acid is reduced in microsomes prepared from the outer renal medulla. Treatment with clofibrate induces -hydroxylation of fatty acids by P-450 in the kidney and prevents hypertension. However, it remains to be determined whether clofibrate affects chloride transport in the loop and the capacity of the kidney to excrete sodium. Nevertheless, this is an attractive hypothesis because insulin resistance is associated with salt sensitivity of blood pressure. Perhaps relevant to this hypothesis is the recent observation that CS-045 increases urinary sodium excretion in the obese Zucker rat.17
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Summary and Hypotheses |
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The observation that pharmacologically diverse insulin-sensitizing agents and lipid-lowering drugs decrease blood pressure lends credence to the hypothesis that insulin resistance causes an elevation of arterial pressure. However, these agents may lower blood pressure by different mechanisms (Fig 1
). On the basis of the physiological and metabolic effects of these drugs, we hypothesize that hypertension induced by insulin resistance may be mediated by one or more of the following: (1) stimulation of vascular smooth muscle growth and possibly renal sodium retention by compensatory hyperinsulinemia; (2) augmented vasoconstriction in response to norepinephrine and angiotensin II, possibly as a consequence of enhanced calcium influx across vascular muscle membranes; and (3) impaired endothelium-dependent vasodilation as a consequence of hyperglycemia and hyperlipidemia.
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Finally, other than thiazide diuretics and ß-blockers, which decrease insulin sensitivity, insulin sensitivity is increased by several different classes of antihypertensive agents, including calcium antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, and peripheral 
-adrenergic antagonists.78 79 The capacity of these drugs to increase insulin sensitivity may be a consequence of vasodilation and hence increased blood flow to insulin-sensitive tissues.
On the basis of these observations, it is tempting to speculate that some common mechanism contributes to both vasoconstriction and resistance to insulin-stimulated glucose uptake, eg, increased intracellular free calcium concentrations in vascular smooth muscle and in insulin-sensitive tissues (Fig 2). A cycle may be established by which insulin resistance results in vasoconstriction and vasoconstriction in turn results in decreased blood flow to insulin-sensitive tissues and hence insulin resistance. Conceivably, the cycle may be interrupted by pharmacological agents that increase insulin sensitivity or alternatively by agents that increase blood flow to insulin-sensitive tissues as their primary action.
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Whatever mechanisms may be involved, the observation that a single agent may have the capacity to increase insulin sensitivity and attenuate the development of hypertension is potentially of considerable clinical significance. Furthermore, sufficient data may be available from animal studies to justify a controlled clinical trial of the effects of insulin-sensitizing agents, particularly thiazolidinediones, on blood pressure in hypertensive insulin-resistant humans.
Received April 3, 1996; first decision April 10, 1996; accepted April 10, 1996.
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References |
|---|
|
TopIntroductionAntihypertensive Effects of...Antihypertensive Mechanisms of...Summary and HypothesesReferences |
|---|
1. O'Shaughnessy IM, Kotchen TA. Epidemiologic, physiologic, and clinical implications of hypertension and insulin resistance. Curr Opin Cardiol. 1993;8:757-764.
2. Lind L, Berne C, Lithell H. Prevalence of insulin resistance in essential hypertension. J Hypertens. 1995;13:1457-1462.[Medline] [Order article via Infotrieve]
3. Sharma AM, Schorr U, Distler A. Insulin resistance in young salt-sensitive normotensive subjects. Hypertension. 1993;21:270-273.
4. Bigazzi R, Bianchi S, Baldari G, Campese VM. Clustering of cardiovascular risk factors in salt-sensitive patients with essential hypertension: role of insulin. Am J Hypertens. 1996;9:24-32.[Medline] [Order article via Infotrieve]
5. Zavaroni I, Coruzzi P, Bonini L, Luigi G, Mossini L, Musiari L, Gasparini P, Fantuzzi M, Reaven GM. Association between salt sensitivity and insulin concentrations in patients with hypertension. Am J Hypertens. 1995;8:855-858.[Medline] [Order article via Infotrieve]
6.
Kotchen TA, Zhang HY, Covelli M, Blehschmidt N. Insulin resistance and blood pressure in Dahl rats and in one-kidney, one-clip hypertensive rats. Am J Physiol. 1991;261:E692-E697.
7.
Buchanan TA, Siopos GF, Madrilejo N, Liu C, Campese VM. Hypertension without peripheral insulin resistance in spontaneously hypertensive rats. Am J Physiol. 1992;262:E14-E19.
8.
Anderson EA, Mark AL. The vasodilator action of insulin: implications for the insulin hypothesis of hypertension. Hypertension. 1993;21:136-141.
9. Sawicki PT, Heinemann L, Starke A, Berger M. Hyperinsulinaemia is not linked with blood pressure elevation in patients with insulinoma. Diabetologia. 1992;35:649-652.[Medline] [Order article via Infotrieve]
10.
American Heart Association. Nonpharmacological approaches to the control of high blood pressure. Hypertension. 1986;8:444-467.
11. Rocchini AP, Key J, Bondie D, Chico R, Moorhead C, Katch V, Martin R. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med. 1989;231:580-585.
12. Su H-Y, Sheu WH, Chin HML, Jeng CY, Chen YDI, Reaven GM. Effect of weight loss on blood pressure and insulin resistance in normotensive and hypertensive obese individuals. Am J Hypertens. 1995;8:1067-1071.[Medline] [Order article via Infotrieve]
13.
Reaven GM, Ho H, Hoffman BB. Somatostatin inhibition of fructose induced hypertension. Hypertension. 1989;14:117-120.
14. Carretta R, Fabris B, Fischetti F, Constantini M, DeBiasi F, Muiesan S, Bardelli M, Vran F, Campanacci L. Reduction of blood pressure in obese hyperinsulinaemic hypertensive patients during somatostatin infusion. J Hypertens. 1989;7(suppl 6):S196-S197.
15.
Landin K, Holm G, Tengborn L, Smith U. Guar gum improves insulin sensitivity, blood lipids, blood pressure, and fibrinolysis in healthy men. Am J Clin Nutr. 1992;56:1061-1065.
16.
Dubey RK, Zhang HY, Reddy SR, Boegehold MA, Kotchen TA. Pioglitazone attenuates hypertension and inhibits growth of renal arteriolar smooth muscle in rats. Am J Physiol. 1993;265:R726-R732.
17. Yoshioka S, Nishino H, Shiraki T, Ikeda K, Koike H, Okuno A, Wada M, Fujiwara T, Hosikoshi H. Antihypertensive effects of CS-045 treatment in obese Zucker rats. Metabolism. 1993;42:75-80.[Medline] [Order article via Infotrieve]
18. Kaufman LN, Peterson MM, DeGrange LM. Pioglitazone prevents diet induced hypertension in rats. Diabetes. 1993;42:47A. Abstract.
19. Meehan WP, Buchanan TA, Hseuh W. Effects of pioglitazone treatment in fructose-fed rats. Hypertension. 1993;22:452. Abstract.
20. Lee MK. The effect of CS-045 to prevent insulin resistance and hypertension in high fructose fed rats. In: Abstracts of the 75th Annual Meeting of the Endocrine Society; June 9-12, 1993; Las Vegas, Nevada; p 493.
21. Lardinois CK, Grinsell J, Michaels JR. Pioglitazone attenuates basal and postprandial insulin concentrations and decreases blood pressure in spontaneously hypertensive rats. Am J Hypertens. 1994;7:53A. Abstract.
22. Morgan DA, Mark AL. Ciglitazone lowers arterial pressure independent of increased insulin sensitivity in spontaneously hypertensive rats. Am J Hypertens. 1993;6:2A. Abstract.
23.
Pershadsingh HA, Szollosi J, Benson S, Hyun WC, Feuerstein BG, Kurtz TW. Effect of ciglitazone on blood pressure and intracellular calcium metabolism. Hypertension. 1993;21:1020-1023.
24. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman RN, Mejlasson MD. Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure in obese, insulin-resistant rhesus monkeys. Diabetes. 1994;43:204-211.[Abstract]
25. Ogihara T, Rakugi H, Ikegami H, Mikami H, Masuo K. Enhancement of insulin sensitivity by troglitazone lowers blood pressure in diabetic hypertensives. Am J Hypertens. 1995;8:316-320.[Medline] [Order article via Infotrieve]
26.
Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994;331:1188-1193.
27. Morgan DA, Ray CA, Balon TW, Mark AL. Metformin increases insulin sensitivity and lowers arterial pressure in spontaneously hypertensive rats. Clin Res. 1992;40:740A. Abstract.
28.
Verma S, Bhanot S, McNeill JH. Metformin decreases plasma insulin levels and systolic blood pressure in spontaneously hypertensive rats. Am J Physiol. 1994;267:H1250-H1253.
29. Landin K, Tengborn L, Smith U. Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med. 1991;229:181-187.[Medline] [Order article via Infotrieve]
30. Giugliano D, DeRosa N, DiMario G, Marfella R, Acampora R, Buoninconti R, D'Onofrio F. Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive obese women. Diabetes Care. 1993;16:1387-1390.[Abstract]
31. Giugliano D, Quatraro A, Consol G, Minei A, Ceriello A, DeRosa N. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993;44:107-112.[Medline] [Order article via Infotrieve]
32. Chan JCN, Tomilson B, Critchley JA, Cockran CS, Walden RJ. Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. Diabetes Care. 1993;16:1035-1038.[Abstract]
33. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43:647-654.[Medline] [Order article via Infotrieve]
34. Dorella M, Datos V, Campagnolo M, Giusto M, Ceolotto B, Palatini P, Semplicini A, DelPrato S. Metformin treatment in non-diabetic hypertensive patients. Diabetes. 1993;42:58A. Abstract.
35. Ngai DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care. 1993;16:621-629.[Abstract]
36.
Bhanot S, McNeill JH. Vanadyl sulfate lowers plasma insulin and blood pressure in spontaneously hypertensive rats. Hypertension. 1994;24:625-632.
37. Bhanot S, Bryer-Ash M, Cheung A, McNeill JH. Bis(malto-lato)oxovanadium(IV), attenuates hyperinsulinemia and hypertension in spontaneously hypertensive rats. Diabetes. 1994;43:857-861.[Abstract]
38. Swislocki A, Eason T. Glucose tolerance and blood pressure are improved in the spontaneously hypertensive rat by ethyl-2-(6-(4-chlorophenoxy)-hexyl)oxirane-2-carboxylate (etomoxir), an inhibitor of fatty acid oxidation. Am J Hypertens. 1994;7:739-744.[Medline] [Order article via Infotrieve]
39.
Roman RJ, Ma Y-H, Frohlich B, Markham B. Clofibrate prevents the development of hypertension in Dahl salt-sensitive rats. Hypertension. 1993;21:985-988.
40. Storlien LH, Oakes ND, Pan DA, Kusunoki M, Jenkins AB. Syndromes of insulin resistance in the rat: inducement by diet and amelioration with benfluorex. Diabetes. 1993;42:457-462.[Abstract]
41. Nestler JE, Beer NA, Jakubowicz DA, Colombo C, Beer RM. Effects of insulin reduction with benfluorex on serum DHEA, DHEA sulfate, and blood pressure in middle-aged and elderly men. J Clin Endocrinol Metab. 1995;80:700-706.[Abstract]
42.
Donnell MP, Kasiske BL, Katz SA, Schmitz PG, Keane WF. Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats. Hypertension. 1992;20:651-658.
43. Hofmann CA, Colca JR. New oral thiazolidinedione antidiabetic agents act as insulin sensitizers. Diabetes Care. 1992;12:1075-1078.
44. Katayama S, Abe M, Kashiwabara H, Kosegawa I, Ishii J. Evidence against a role of insulin in hypertension in spontaneously hypertensive rats: CS-045 does not lower blood pressure despite improvement of insulin resistance. Hypertension. 1994;23(part 2):1071-1074.
45.
Zhang HY, Reddy SR, Kotchen TA. Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity. Hypertension. 1994;24:106-110.
46.
Bailey C, Turner RC. Metformin: review article. N Engl J Med. 1996;334:574-579.
47. Elkeles RS, Heding LG, Palsey RB. The long-term effects of chlorpropamide on insulin, C-peptide and proinsulin secretion. Diabetes Care. 1982;5:427-429.[Abstract]
48. Smith RJ. Effects of the sulfonylureas on muscle glucose homeostasis. Am J Med. 1990;89(suppl 2A):38S-44S.
49. Ballagi-Pordany G, Koltai MZ, Aranyl Z, Pogatsa G. Direct effect of hypoglycemic sulphonylureas on the cardiovascular system of dogs. Diabetes Res Clin Pract. 1991;11:47-52.[Medline] [Order article via Infotrieve]
50.
Peuler JD, Johnson BAB, Phare SM, Sowers J. Sex-specific effects of an insulin secretagogue. Hypertension. 1993;22:214-220.
51. Morgan DA, Mark AL. Contrasting effects of a biguanide and a sulfonylurea on arterial pressure in spontaneously hypertensive rats. Hypertension. 1993;22:452. Abstract.
52. Levy J, Vandenberg M, Grunberger G. Insulin versus glipizide treatment in patients with non-insulin-dependent diabetes mellitus: effects on blood pressure and glucose tolerance. Am J Hypertens. 1995;8:445-453.[Medline] [Order article via Infotrieve]
53. Lardinois CK, Sare JS, Michaels JR, Gonzalez R, Starich GH. Acarbose attenuates basal and postprandial insulin levels but fails to lower blood pressure in spontaneously hypertensive rats. Am J Hypertens. 1994;7:53A. Abstract.
54.
Roullet RJ, Xue H, Papu AJ, Roullet C, Holcomb S, McCarron DA. Mevalonate availability and cardiovascular functions. Proc Natl Acad Sci U S A. 1993;90:11728-11732.
55. Law RE, Xi XP, Hseuh WA. Troglitazone inhibits insulin, EGF, and PDGF mitogenic signal transduction in A10 vascular smooth muscle and mesangial cells. Hypertension. 1995;26:553. Abstract.
56. Donnell MP, Kasiske BL, Kim Y, Alturn D, Keane WF. Lovastatin inhibits proliferation of rat mesangial cells. J Clin Invest. 1993;91:83-87.
57. Bunting CE, Koschinsky T, Rutter R, Gries FA. Metformin inhibits the growth of human vascular cells: a new potentially antiatherogenic drug effect. Diabetologia. 1986;29:523A. Abstract.
58. Peuler JD, Phare SM, Iannucci AR, Hodorek MJ. Differential inhibitory effects of antidiabetic drugs on arterial smooth muscle cell proliferation. Am J Hypertens. 1996;9:188-192.[Medline] [Order article via Infotrieve]
59. Andrews HE, Brackdorfer KR, Dunn RC, Jacobs M. Low density lipoproteins inhibit endothelium-dependent relaxation in rabbit aorta. Nature. 1987:327:237-239.
60. Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau V. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990;86:228-234.
61. Laakso M, Edelman SV, Brechtel G, Baron AD. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: a novel mechanism for insulin resistance. J Clin Invest. 1990;85:1844-1852.
62. Soltis EE, Katovich MJ. Reduction in aortic smooth muscle beta-adrenergic responsiveness results in enhanced norepinephrine responsiveness in the Dahl salt-sensitive rat. Clin Exp Hypertens A. 1991;13:117-132.[Medline] [Order article via Infotrieve]
63. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM. Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet. 1992;340:1430-1432.[Medline] [Order article via Infotrieve]
64. Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein (a) level. J Clin Invest. 1994;93:50-55.
65. Standley PR, Rose KA, Sowers JR. Increased basal arterial smooth muscle glucose transport in the Zucker rat. Am J Hypertens. 1995;8:48-52.[Medline] [Order article via Infotrieve]
66. Vollenweider P, Randin D, Tappy L, Jequier E, Nicold P, Scherrer U. Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. J Clin Invest. 1994;93:2365-2371.
67. Zanchi A, Delacretaz E, Taleb V, Gaillard R, Jeanrenaud B, Brunner HR, Waeber B. Endothelial function of the mesenteric arteriole and mechanical behavior of the carotid artery in rats with insulin resistance and hypercholesterolemia. J Hypertens. 1995;13:1463-1470.[Medline] [Order article via Infotrieve]
68.
Kotchen TA, Zhang HY, Reddy SR, Hoffman RG. Effect of pioglitazone on vascular reactivity in vivo and in vitro. Am J Physiol. 1996;270:R660-R666.
69. Bourghli M, Sowers JR, Peuler JD. Direct and insulin-related attenuating effects of pioglitazone on aortic vascular contractility. Am J Hypertens. 1994;7:71A. Abstract.
70. Draznin B, Sussman KE, Eckel RH, Kao M, Yost T, Sherman NA. Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J Clin Invest. 1988;82:1848-1852.
71.
Postnov YV, Orlov SN. Ion transport across plasma membranes in primary hypertension. Physiol Rev. 1985;65:904-945.
72. Balla RC, Toth KF, Tan E, Mathias E, Sharma RV. Vascular effects of metformin: possible mechanisms for its antihypertensive action in spontaneously hypertensive rats. Am J Hypertens. In press.
73.
Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD. Effects of pioglitazone in calcium channels in vascular smooth muscle. Hypertension. 1994;24:170-175.
74. Buchanan TA, Meehan WP, Jeng YY, Yang D, Chan TM, Nadler JL, Scott S, Rude RK, Hseuh WA. Blood pressure lowering by pioglitazone: evidence for a direct vascular effect. J Clin Invest. 1995;96:354-360.
75. Brands MW, Hopkins TE. Poor glycemic control induces hypertension in diabetes mellitus. Hypertension. 1996;27(part 2):735-739.
76. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest. 1996;97:22-28.[Medline] [Order article via Infotrieve]
77. Williams B. Glucose-induced vascular smooth muscle dysfunction: the role of protein kinase C. J Hypertens. 1995;13:477-486.[Medline] [Order article via Infotrieve]
78. Lithell HDL. Effects of antihypertensive agents on insulin, glucose, and lipid metabolism. Diabetes Care. 1991;14:203-209.[Abstract]
79. Navarro-Cid J, Maeso R, Perez-Vizcaino F, Cachofeiro V, Ruilope LM, Tamargo J, Lahera V. Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. Hypertension. 1995;26(part 2):1074-1078.
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