Angiotensin II-converting Enzyme Research Articles

Concomitant presence of endothelial nitric oxide 894T and angiotensin II‐converting enzyme D alleles are associated with diabetic nephropathy in a Kurdish population from Western Iran

The present study investigated the influence of insertion (I)/deletion (D) polymorphism of the angiotensin II-converting enzyme (ACE) gene in combination with endothelial nitric oxide (eNOS) G894T polymorphism on the predisposition to diabetic nephropathy (DN). Using polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) method, the ACE and eNOS polymorphisms were genotyped in 72 microalbuminuric, 68 macroalbuminuric and 72 normoalbuinuric type 2 diabetes mellitus (T2DM) patients from Western Iran. The presence of eNOS T or ACE D allele was not associated with increased risk of macroalbuminuria (odds ratio (OR) = 1.36, P = 0.27 and OR = 1.6, P = 0.062, respectively). However, in the presence of both alleles there was a trend towards increased risk of macroalbuminuria (fivefold, P = 0.05). Our study indicates that the concomitant presence of both ACE D and eNOS T alleles tends to be associated with an elevation risk of macroalbuminuria compared with the presence of each polymorphism alone. This risk could be attributed to the increasing activity of ACE and angiotensin II level in the presence of D allele and decreasing NO production in the presence of T allele accelerating diabetic nephropathy.

The Metabolic Syndrome, Oxidative Stress, Environment, and Cardiovascular Disease: The Great Exploration

The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome.

300 Dose comparison of angiotensin II-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure

300 Dose comparison of angiotensin II-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure

Feeding blueberry diets inhibits angiotensin II-converting enzyme (ACE) activity in spontaneously hypertensive stroke-prone rats

Feeding flavonoid-rich blueberries to spontaneously hypertensive stroke-prone rats (SHRSP) lowers blood pressure. To determine whether this is due to inhibition of angiotensin-converting enzyme (ACE) activity, as seen with other flavanoid-rich foods, we fed blueberries to SHRSP and normotensive rats and analyzed ACE activity in blood and tissues. After 2 weeks on a control diet, the hypertensive rats showed 56% higher levels of ACE activity in blood as compared with the normotensive rats (p < 0.05). Feeding a 3% blueberry diet for 2 weeks lowered ACE activity in the SHRSP (p < 0.05) but not the normotensive rats. ACE activity in plasma of SHRSP was no longer elevated at weeks 4 and 6, but blueberry feeding inhibited ACE in SHRSP after 6 weeks. Blueberry diets had no effect on ACE activity in lung, testis, kidney, or aorta. Our results suggest that dietary blueberries may be effective in managing early stages of hypertension, partially due to an inhibition of soluble ACE activity.

Regional vascular response to ProAngiotensin-12 (PA12) through the rat arterial system

ProAngiotensin-12 (PA12) is the most recent peptide to be identified as a functional component of the renin–angiotensin system (RAS). PA12 is reported to constrict rat coronary arteries and the aorta, dependent upon angiotensin II-converting enzyme 1 (ACE1) and chymase. The current study employed myography to determine the direct vascular effects of PA12 on a range of isolated rat arteries extending from the core to periphery. PA12 significantly constricted the descending thoracic aorta, right and left common carotid arteries, abdominal aorta and superior mesenteric artery, with little effect on the femoral and renal arteries. AngII was found to produce similar responses to PA12 when administered at the same dose. A potency gradient in response to PA12 was clearly apparent, with vessels in closest proximity to the heart responding with the greatest constriction; while constrictive potency was lost further form the heart. Inhibition of ACE1 and chymase both significantly attenuated PA12-induced vasoconstriction, with chymostatin displaying lesser potency. We postulate ACE1 primarily regulates RAS activity within the circulation, while chymase may have an important role in local, tissue-based RAS activity.

Phenotypic change and accumulation of smooth muscle cells in strictures in Crohn’s disease: relevance to local angiotensin II system

Intestinal stricture lesions in Crohn's disease are characterized as submucosal fibromuscular accumulation. There has been a controversy about whether the fibrogenic cells in stricture lesions in Crohn's disease originate from a smooth muscle cell or a fibroblast lineage. In the present study, we aimed to elucidate: (1) the origin of the fibrogenic cells in stricture lesions; and (2) the roles of the local angiotensin II system, including mast cell chymase, in stricture formation. Methanol-Carnoy's-fixed colonic tissues, obtained from the stricture sites of 18 patients with Crohn's disease, were analyzed by immunostaining for vimentin, smooth muscle actin (1A4 and CGA7), angiotensin II type-1 receptor, angiotensin II-converting enzyme, and mast cell tryptase and chymase. As controls, unaffected (normal) portions of 11 colonic tumor specimens were also investigated. Submucosal fibromuscular accumulation was seen in every stricture lesion. The majority of mesenchymal cells accumulated in the stricture lesions were moderately differentiated intestinal smooth muscle cells [vimentin(+), 1A4(+), and CGA7(+)]. Moreover, occasional intestinal smooth muscle cells in the muscular layers, adjacent to the site of the submucosal fibromuscular response, showed distinct positivity for vimentin, indicating phenotypic modulation toward an immature, or dedifferentiated state. These smooth muscle cells accumulated in the stricture lesions were positive for angiotensin II type-1 receptor. Abundant chymase-positive mast cells were distributed in these lesions. These results suggest that the proliferation and migration of moderately differentiated intestinal smooth muscle cells from the muscular layers are the major pathological mechanisms in stricture formation in Crohn's disease, and the angiotensin II system is involved in this process.

Bosentan for Digital Ulcers in Patients with Systemic Sclerosis: A Prospective 3-year Followup Study

To the Editor: Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease characterized by cutaneous and visceral fibrosis and widespread vascular pathology1. Digital ulcers (DU) are a major clinical problem in SSc, occurring in about one-third of patients2. DU cause local pain and functional impairment and have a negative effect on quality of life for patients with SSc2. Therapeutic agents potentially used for management of DU include calcium channel blockers, α-adrenergic inhibitors, angiotensin II-converting enzyme inhibitors, prostacyclin analogs, phosphodiesterase-5 inhibitor, and others2. Bosentan is a specific orally active dual endothelin receptor antagonist that has been used for the treatment of pulmonary hypertension (PH) and recently for DU3–5. The objective of our study was to examine the effectiveness and safety of bosentan for healing DU in patients with SSc over the long term. For a cohort of 110 patients with SSc, 30 patients with DU were identified. All patients fulfilled the American College of Rheumatology criteria for SSc6 and all were refractory to calcium channel antagonists, angiotensin II inhibitors, or sildenafil. … Address reprint requests to Prof. Drosos. E-mail: adrosos{at}cc.uoi.gr

Angiotensin II Type 2 Receptor Blockade Increases Bone Mass

Renin angiotensin system (RAS) regulates circulating blood volume and blood pressure systemically, whereas RAS also plays a role in the local milieu. Previous in vitro studies suggested that RAS may be involved in the regulation of bone cells. However, it was not known whether molecules involved in RAS are present in bone in vivo. In this study, we examined the presence of RAS components in adult bone and the effects of angiotensin II type 2 (AT2) receptor blocker on bone mass. Immunohistochemistry revealed that AT2 receptor protein was expressed in both osteoblasts and osteoclasts. In addition, renin and angiotensin II-converting enzyme were expressed in bone cells in vivo. Treatment with AT2 receptor blocker significantly enhanced the levels of bone mass, and this effect was based on the enhancement of osteoblastic activity as well as the suppression of osteoclastic activity in vivo. These results indicate that RAS components are present in adult bone and that blockade of AT2 receptor results in alteration in bone mass.

Prevention of Recurrent Lone Atrial Fibrillation by the Angiotensin-II Converting Enzyme Inhibitor Ramipril in Normotensive Patients

The aim of the present study was to verify whether angiotensin-II converting enzyme (ACE) inhibition is also effective in preventing relapses of lone atrial fibrillation (LAF), that is, in the absence of hypertension and/or heart disease. Several studies have shown that ACE inhibitors are effective in preventing atrial fibrillation (AF) relapses in patients with arterial hypertension or several forms of heart disease, that is, in the presence of clinical conditions that are recognized as causing a higher risk of atrial arrhythmias. Sixty-two patients admitted to the emergency department of our institution for a first-ever episode of LAF were enrolled in the study after excluding the presence of cardiac or extracardiac conditions known to be associated with an increased risk of AF, by medical history, physical examination, complete echocardiographic study, and the evaluation of blood pressure, thyroid function, urinary catecholamines, serum electrolytes, blood glucose, red blood cell count, and arterial blood gases. After cardioversion to sinus rhythm by intravenous propafenone, patients were randomized to either ramipril 5 mg/day (n = 31) or placebo (n = 31). Holter monitoring and clinical examination were performed every 3 months. After a 3-year follow-up, AF relapses were observed in 3 patients treated with ramipril and in 10 patients allocated to placebo (p < 0.03, Kaplan-Meier, log-rank test). During follow-up, none of the patients developed arterial hypertension or other cardiac or extracardiac condition known to be associated with increased risk of AF, that is, in all patients the diagnosis of LAF was confirmed. Ramipril is effective in preventing relapses of LAF.

Connexin40 regulates renin production and blood pressure

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.

Thiazide-Associated Glucose Abnormalities: Prognosis, Etiology, and Prevention

Thiazide diuretics have been recommended as the preferred class of antihypertensive (AHT) drugs for initial therapy and for inclusion in a regimen of multiple drugs.1 This recommendation is based on 4 decades of randomized clinical events trials with placebo (or usual care) comparators, meta-analyses of such trials, and active-controlled trials, including the very large Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT).2,3 In the latter, treatment beginning with the thiazide-like diuretic chlorthalidone reduced the risk for major coronary events (the primary outcome) similar to treatment based on representatives of newer drug classes (amlodipine, doxazosin, and lisinopril); diuretic-based treatment was more effective at preventing heart failure, and in some comparisons, other cardiovascular disease (CVD) events. However, in ALLHAT mean fasting blood glucose (FBG) and incident diabetes mellitus (IDM) were slightly but significantly increased in the chlorthalidone compared with the other arms.3 Although the design precluded distinguishing between a benefit of the alternate drugs (especially lisinopril) and an adverse effect of the diuretic, previous evidence suggested that thiazides can cause dysglycemia (impaired glucose tolerance, impaired fasting glucose, or diabetes).4 One point about the ALLHAT results that has not received enough emphasis is that if the calcium channel blocker is taken as metabolically neutral, the 4-year IDM rates in the diuretic and calcium channel blocker arms (11.6% and 9.8%, respectively) imply that 83% of IDM occurring in association with thiazide use is not because of the diuretic. Nevertheless, based on the assumption that there is a direct relationship between thiazide exposure and dysglycemia, several key questions need to be addressed: (1) What are the long-term morbidity/mortality consequences, if any? (2) What are the mechanisms? and (3) Are the changes preventable and/or reversible? The role of potassium may be important to addressing each of these issues. Evidence …

Angiotensin II Regulates Vascular and Endothelial Dysfunction: Recent Topics of Angiotensin II Type-1 Receptor Signaling in the Vasculature

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.

Noncardiovascular Illness as Barrier to Antihypertensive Treatment

Control rates of hypertension vary from one country to another, but in general, they are much lower than would be desirable. In the United States, the National Health and Nutrition Examination Survey1 showed that the awareness of the hypertensive population improved from 50% in the 1970s to 70% in the 1990s. Over the same time interval, the proportion of treated hypertensive patients with normalized blood pressure rose from 10% to 29%. Recent studies in Europe2 and other parts of the world3 confirmed that the rule of halves still exists and that the fractions of hypertensive patients with properly controlled blood pressure range from ≈5% to 45%.4,5 Patients with high blood pressure not carrying out recommended therapy is a pervasive phenomenon that contributes worldwide to the low control rates of hypertension. Adherence, in a more judgmental way, also termed compliance, is the extent to which a patient’s behavior coincides with the clinical prescription.6 It usually increases with higher education, affluence, social support, and the frequency and quality of the interactions with the care providers, but it diminishes with the number of tablets to be taken.7 Other frequently cited reasons for not filling prescriptions are the …

Chinese Herbal Medicine in the Treatment of Chronic Kidney Disease

Chronic kidney disease (CKD) is a worldwide public health issue with poor outcomes and high cost. There is growing evidence that some of the adverse outcomes of CKD can be prevented or delayed by early treatment using angiotensin II-converting enzyme inhibitors and angiotensin II-receptor blockers. A great amount of the world's population has been using traditional Chinese herbal medicine (TCHM) for treatment of CKD and has accumulated their experience for years. In this article, the knowledge and the therapeutic principles of traditional Chinese medicine in the treatment of CKD are briefly reviewed. The efficacy of several TCHMs, supported by either clinical evidence or experimental studies, is presented. The future direction for the study of Chinese herbal medicines in CKD is discussed.

Metformin prevents the impairment of endothelium-dependent vascular relaxation induced by high glucose challenge in rabbit isolated perfused kidneys

High glucose concentrations are involved in the development of diabetic-associated vascular complications. We have previously reported that acute high glucose challenge, corresponding to post-prandial glycemia levels observed in patients with type 2 diabetes, blunts ACh-induced endothelium-dependent relaxation of the renal circulation of non-diabetic rabbits. Isolated perfused kidneys from non-diabetic rabbits were acutely exposed (3 h) to normal (5.5 mM--control group) or high (15 mM) D-glucose concentrations in the presence or absence of a continuous infusion of metformin (20 or 100 microM). Renal vascular reactivity was evaluated with endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) vasodilating agents. ACh-induced maximal renal vasodilation was reduced by high glucose infusion (15 mM) in comparison to the control group (25+/-3% and 41+/-3% respectively; P<0.01), being restored to 41+/-4% and 43+/-2% by a simultaneous 3-h infusion of 20 or 100 microM of metformin respectively (P>0.05). Perfusion of the kidneys with the angiotensin II-converting enzyme inhibitor captopril (10 microM) also significantly prevented the deleterious effects of high glucose challenge in the renal circulation. The use of a continuous infusion of N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) did not affect the protective effect of metformin in the renal circulation (39+/-4%; P>0.05), while tetraethylammonium (TEA, 10 mM) partially blunted this effect (33+/-4, P<0.01). Renal vasodilation induced by SNP was not modified by simultaneous infusion of high glucose and/or metformin. It is concluded that the impairment of ACh-induced endothelium-dependent renal vasodilation observed after acute exposure to high glucose concentrations is abolished by metformin administration. These alterations of renal vascular reactivity can be accounted for, at least in part, by the activation of the renal renin-angiotensin system during hyperglycemia. The protective effects of metformin present some EDHF-dependent component and are not related to metabolic pathways dependent on nitric oxide.

The Role of Chymase in Vascular Remodeling and Tissue Fibrosis

Chymase generates angiotensin II which plays a crucial role in vascular remodeling. In clinical studies, an angiotensin II receptor blocker was successful in preventing restenosis after percutaneous coronary intervention, but an angiotensin II-converting enzyme inhibitor was not. In dog, chymase activity was significantly increased in vessels injured by a balloon catheter, and a chymase inhibitor and an angiotensin II receptor blocker were effective in preventing the vascular proliferation, but an angiotensin-converting enzyme inhibitor was ineffective. Chymase also activates matrix metalloproteinase-9, and their function may play an important role in development of atherosclerosis and aneurysmal aorta. In human atherosclerosis and aneurysmal aorta, chymase activity was significantly increased. In the experimental models, chymase activity and mRNA level were also significantly increased in atherosclerotic lesions and aneurysmal aorta, but chymase inhibitors prevented the vascular remodeling. On the other hand, chymase activates latent transforming growth factor-β-binding protein to transforming growth factor-β, and its function may be related in promoting tissue fibrosis. Chymase promotes activations of angiotensin II, matrix metalloproteinase-9 and transforming growth factor-β, and chymase inhibitors may promise to prevent vascular remodeling and tissue fibrosis.

Analysis of heart rate variability in hypertensive patients before and after treatment with angiotensin II-converting enzyme inhibitors.

To compare heart rate variability in normotensive and hypertensive individuals and to observe the behavior of the autonomic nervous system after treatment with angiotensin II-converting enzyme inhibitors. The study comprised 286 patients diagnosed with arterial hypertension (AH) for the first time and divided into 4 groups according to diastolic blood pressure (DBP) levels: group A -- DBP<90 mmHg; group B -- DBP 90-99 mmHg; group C -- DBP 100-109 mmHg; group D -- DBP>110 mmHg. Group A (110 healthy individuals) and group C (79 patients with moderate AH) underwent 24-hour Holter-ECG with analysis of heart rate variability in time domain (TD) and frequency domain (FD). The group C patients were treated with ACE inhibitors for 3 months, and, after this period, they underwent a new 24-hour Holter-ECG study for assessing heart rate variability, the values being compared with those of normotensive individuals. The SDNN and PNN50 parameters (TD), and the LF spectrum (FD) were significantly different in the 2 groups, with clearly reduced values in hypertensive individuals (P<0.05). Group C patients, after treatment with ACE inhibitors, showed a recovery in all variables of heart rate variability, achieving values close to those of normotensive individuals. Heart rate variability was reduced in hypertensive patients when compared with that in normotensive individuals, indicating a decrease in the baroreceptor reflex. A functional autonomic adjustment after the antihypertensive treatment with ACEI was observed, indicating recovery of parasympathetic tonus.

Low-dose angiotensin II receptor antagonists and angiotensin II-converting enzyme inhibitors alone or in combination for treatment of primary glomerulonephritis

The renin-angiotensin system is thought to be involved in the progression of chronic renal diseases of both diabetic and non-diabetic origin. It has been confirmed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) reduce urinary protein excretion and attenuate the development of renal injury. Clinical data comparing the renal effects of ACEIs and ARBs, either singly or in combination, are scarce and usually concern the use of standard or high doses. This was a prospective, randomized, 9-month study of the effects of low doses of losartan (25 mg; n = 18) versus enalapril (10 mg; n = 18) versus the combination of losartan (25 mg) and enalapril (10 mg) (n = 16) on proteinuria, kidney function and metabolic profile in 54 patients with biopsy-proven chronic glomerulonephritis, hypertension and normal or slightly impaired kidney function. The clinical evaluation and laboratory tests were performed before treatment (baseline) and after 3 and 9 months of therapy. After 3 months, significant decreases in proteinuria were observed in all groups: losartan, 22.6% (p = 0.02); enalapril, 43% (p = 0.012); and combined therapy, 63% (p = 0.001). This anti-proteinuric effect was even greater after 9 months of therapy: losartan, 44.2% (p = 0.02); enalapril, 49.6% (p = 0.02); and combined therapy, 51% (p = 0.003). There was no significant difference between losartan and enalapril with respect to their impact on proteinuria level. Proteinuria reduction was significantly greater in patients receiving combined therapy in comparison with losartan treatment after 3 months of therapy (p = 0.02). Creatinine clearance and serum creatinine were stable during the entire study period in all patients. No significant changes in lipids, serum uric acid or protein levels were observed. These results indicate that proteinuria is reduced by low doses of losartan or enalapril. The combination of these drugs seems to be beneficial and may offer an additional renoprotective effect. This needs to be confirmed in a study with a larger sample size.

Hypertension in menopausal women – a special case ,for special treatment?

After the menopause the consequences of hypertension in women change. Their risks of myocardial infarction and stroke rise steeply ,a rise that has been blamed in part on the loss of estrogen and the onsetof menopausal metabolic syndrome ,with endothelial dysfunction ,hyperlipidemia ,insulin resistance and derangement in coagulation. Hypertensive menopausal women have not had optimum treatment. They havepoorer prognoses than men of the same age. Their antihypertensive management therefore merits special attention. Hormone replacement ,aspirin prophylaxis and lipid-lowering drugs have their place. The antihypertensivedrug chosen should not worsen the metabolic syndrome: angiotensin-II converting enzyme (ACE) inhibitors are therefore among the first-line drugs. Few drugs have been specifically aimed at menopausal hypertensionand these are reviewed here.

Effect of doxazosin on the size of LDL particle in the type 2 diabetic patients with hypertension

Hypertension is common in patients with type 2 diabetes mellitus (DM), and contributes to the progression of its complications in patients with diabetes. Doxazosin is a selective α1-adrenoceptor-blocking anti-hypertensive agent and has a favorable impact upon lipid metabolism. We investigated the effect of doxazosin on the lipid metabolism in hypertensive patients with type 2 diabetes, especially low-density lipoprotein (LDL) particle size that is associated with many elements of the insulin resistance syndrome. Cross-sectional study ( n=19) was designed to determine whether doxazosin, administered with an angiotensin II-converting enzyme inhibitor (ACEI) and a Ca antagonist, affects LDL particle size. As a follow-up study ( n=6), lipid and glucose metabolism and LDL particle size were followed for 12 weeks before and after the initiation of doxazosin administration (1–4 mg/day). The average size of LDL particle was significantly larger in the patients treated with doxazosin (LDL-migration index (LDL-MI): 0.348±0.027) than those in the patient treated without doxazosin (0.378±0.035), although LDL cholesterol levels did not differ between the two groups. The plasma glucose and HbA1c levels remained unchanged. Lipid profile showed normolipemia throughout the period of the study. However, LDL particle size was demonstrated to become larger during the following period. Small LDL fraction (LDL3–7) diminished remarkably and large LDL (LDL1–2) increased on the polyacrylamide gel electrophoresis (PAGE) LDL system (LipoPrint). From this pilot study, it was concluded that doxazosin is a useful anti-hypertensive agent for hypertensive type 2 diabetic patients in improving the size of LDL particle.