Browsing by Author "LEE, TSUNG-MING"

Abstract Objectives This study sought to examine whether distension of the urinary bladder, a physiological stimulus, could induce impaired coronary circulation in patients with early atherosclerosis. Background Distension of the urinary bladder reflexly causes an increase in sympathetic activity . The effect of such distension on the coronary circulation in patients with early atherosclerosis remains unknown. Methods To assess the effect of bladder distension on coronary dynamics, epicardial and microvascular responses were measured with intracoronary Doppler flow wire in 40 patients with early atherosclerosis (< 50% diameter stenosis ). Patients were randomized into two groups on the basis without (group 1, n = 20) or with (group 2, n = 20) pretreatment of 1 adrenergic receptor blocker (oral doxazosin 2 mg). Coronary flow velocity and quantitative coronary angiography were monitored at baseline, during urinary bladder distension, and after intracoronary nitroglycerin injection. Results In response to bladder distension, bladder distension significantly decreased coronary diameter at the stenotic segments (p < 0. 001), coronary blood flow (p < 0.001), and increased coronary resistance ( p < 0.001) compared with baseline values, in group 1 patients. In group 2 patients during bladder distension, angiographic variables did not show significant changes compared with baseline values. No significant differences were noted between the groups in the responses of angiographic variables after nitroglycerin administration . Conclusions The present study showed for the first time that urinary bladder distension caused vasoconstriction of coronary conduit and resistance vessels involved mechanisms related to 1-adrenoceptors. Pretreated administration of doxazosin had reversed the changes towards baseline. Vasoconstriction during bladder distension can be relieved after nitroglycerin administration, suggesting an unchanged responsiveness of vascular smooth muscle cells to such distension.

Add-on and withdrawal effect of pravastatin on proteinuria in hypertensive patients treated with AT₁ receptor blockers. Background. Although angiotensin receptor antagonists and 3-hydroxy-3- methylgultaryl coenzyme A (HMG- CoA) reductase inhibitors (statins) have been shown to attenuate proteinuria individually, it remains unclear whether proteinuria may be additionally improved by statin therapy in well -controlled hypertensive patients treated with angiotensin receptor antagonists–based regimen and whether withdrawal of chronic statin treatment may abrogate this beneficial effect in normolipidemic patients. Methods. A total of consecutive 82 proteinuric patients treated with antihypertensive agents, including losartan, were randomized 10 mg of pravastatin or placebo with a 6-month treatment. After completing 6 months of drug treatment, the pravastatin -treated patients were randomly assigned to continue ( N= 19 ) or withdraw ( N= 17) pravastatin for a further 6 months. Results. Subjects treated with pravastatin had significant further improvement of proteinuria at 6 months compared with placebo group (559 ± 251 mg/24 hours vs. 1262 ± 557 mg/24 hours) ( P < 0 .0001). Of 17 patients assigned to withdraw pravastatin, proteinuria returned to the pretreatment levels and was significantly higher than those who continued treatment. Multivariate analysis revealed that proteinuric improvement was significantly correlated with the continuous statin use. Urinary excretion of endothelin-1 (ET-1) is decreased in pravastatin-treated patients, but withdrawal of statin resulted in 27% up- regulation. The linear regression models in the initial statin-treated group showed that changes in urinary ET-1 correlated with urinary protein excretion ( r= 0.83, P < 0.0001). Conclusion. We conclude that pravastatin administration is associated with improved proteinuria probably by inhibiting urine ET-1 levels in patients with losartan-based treatment. However,... [ ABSTRACT FROM AUTHOR]

Both angiotensin receptor antagonists and 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to attenuate cardiomyocyte hypertrophy after myocardial infarction. Whether combination treatment may be superior to either drug alone on cardiomyocyte hypertrophy remains unclear. After ligation of the left anterior descending artery, rats were randomized to both, one, or neither of the angiotensin receptor antagonists olmesartan ( 0.01, 0.1, 1, and 2 mg(.)kg( -1.)day(-1)) and HMG-CoA reductase inhibitor pravastatin (5 mg(.)kg(-1.) day(-1)) for 4 wk. Each drug, when given alone, decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone when compared with vehicles. However, compared with either drug alone, combined olmesartan and pravastatin prevent cardiomyocyte hypertrophy to a larger extent, which was further confirmed by downregulation of the left ventricular atrial natriuretic peptide mRNA. The myocardial endothelin-1 levels at the border zone were 6.5-fold higher (P < 0.0001) in the vehicle group compared with the sham group, which can be inhibited after pravastatin administration. Combination treatment significantly attenuated cardiomyocyte hypertrophy in a dose-dependent manner, although tissue endothelin-1 levels remained stable in combination groups of different olmesartan doses. Measurements of the arrhythmic score mirrored those of cardiomyocyte hypertrophy. Dual therapy with pravastatin and olmesartan, which produced an additive reduction in cardiomyocyte hypertrophy and cardiac fibrosis after myocardial infarction through different mechanisms, decreases the propensity of the heart to arrhythmogenesis. Pravastatin administration provided favorable ventricular remodeling, probably through decreased tissue endothelin-1 level. In contrast, olmesartan-related attenuated cardiomyocyte hypertrophy is independent of endothelin-1 pathway.

Background: Traffic of potentially harmful cytosolic messengers through gap junctions might cause increased injury during ischemia. The present study was to determine whether the infarct size-reducing effect of adjunctive estradiol administration prior to reperfusion is associated with ail attenuated expression of connexin43 at the border of infarction in a canine model. Methods: Experiments were performed in 48 dogs (n = 16 each group), assigned to receive either vehicle (control group), 17beta- estradiol administered before coronary Occlusion (early group), or 3 min before coronary reperfusion following 60-min ischemia ( late group). Changes in the amount of phosphorylated connexin43 were measured by Western blot. Results: Infarct size was significantly larger in the control (38 +/- 7% of area at risk) than in the supplemented groups (16 +/ - 6% in the early group; 16 +/- 8% in the late group, P < 0.0001, both). Reperfusion caused a significant elevation in free radicals as measured by lucigenin-derived chemiluminescence. The rise of free radicals was significantly inhibited in animals treated with estrogen, either early or late. The amount of phosphorylated connexin43 was reduced, as assessed by Western blot in control hearts at the border zone. These changes were significantly enhanced by estrogen administration. The magnitude of infarct size positively correlated with the magnitude of phosphorylated connexin43 expression assessed by Western blot (r = 0.83, P < 0.0001). Confocal microscopy confirmed the changes of junctional complexes. Conclusions: This result demonstrated that the cardioprotective effect of estrogen as ail antioxidant may be associated with the reduced amount of phosphorylated myocardial connexin43 protein. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Diabetes is a state of increased oxidant stress and there is evidence that oxidation may play a role in the genesis of higher left ventricular mass. Gliclazide has been shown to possess free radical scavenging properties. We assessed whether gliclazide may have a beneficial effect on left ventricular mass via reducing 8-iso-prostaglandin F-2 alpha concentrations, a reliable marker of oxidant injury. A total of 41 patients were randomized into two groups. All patients had been taking glibenclamide for more than 3 months before being randomized to switch either an equipotent dose of gliclazide (n = 2 1) or to continue on glibenclamide (n = 20). Baseline characteristics were similar in both groups. At 6 months, gliclazide-treated patients showed a significant regression in left ventricular mass index compared with the glibenclamide- treated group (- 16% versus 3%, P = 0.003). Gliclazide patients had significantly lower plasma 8-iso-prostaglandin F-2 alpha compared with baseline (299 +/- 101 pg/ml versus 400 +/- 112 pg/ml, P = 0.001) and the glibenclamide-treated patients ( 299 +/- 101 pg/ml versus 388 +/- 114 pg/ ml, P = 0.01) after 6-month therapy. The magnitude of left ventricular mass index regression correlated univariately with the magnitude of inhibition of 8-iso-prostaglandin F-2 alpha formation (r= 0.74, P < 0.0001 ). Multivariate analysis revealed that regression of left ventricular mass index significantly correlated with the changes of 8-iso-prostaglandin F- 2 alpha (P < 0.0001, adjusted R-2 = 0.55). Our findings demonstrated for the first time that in addition to its primary hypoglycemia, gliclazide may have an additional effect on reducing left ventricular mass, possibly through attenuation of free radical formation. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

Summary: Epidemiologic studies have shown that hypercholesterolemia is associated with increased left ventricular (LV) mass. Free radicals have been shown to be increased in hyperlipidemic patients. This study sought to determine whether pravastatin administration can affect LV mass in patients with untreated total cholesterol >=240 mg/ dl by reducing 8-iso- prostaglandin F2[alpha] concentrations, a reliable marker of oxidant injury. Fifty patients were randomly assigned to one of two groups, one with (n = 25) and one without (n = 25) treatment with pravastatin (10 or 20 mg/d). A group of normolipidemic control subjects was used for comparison. Echocardiograms were performed at baseline and after 6 months of therapy. Hyperlipidemic patients showed significant increases in LV mass index at baseline compared with the normolipidemic control group (125 +/- 8 vs. 107 +/- 5 g/m2, p < 0.0001). Pravastatin treatment significantly reduced plasma total and low-density lipoprotein cholesterol levels, as well as increased high- density lipoprotein cholesterol. After 6 months of therapy with pravastatin, the magnitude of LV mass regression correlated with the magnitude of inhibition of free radical formation assessed by 8-iso-prostaglandin F2[alpha] formation (r = 0.67, p = 0.002). Multivariate analysis revealed that regression of LV mass was significantly correlated only with the changes in 8-iso-prostaglandin F2[ alpha] (p < 0.0001, adjusted R2 = 0.83). These findings demonstrated for the first time that in addition to its primary anti-lipidemia, pravastatin may have an additional effect of reducing LV mass-independent lipid- lowering effects, possibly through attenuation of free radical formation.

Cilostazol is a new phosphodiesterase inhibitor with anti- platelet and vasodilatory properties. Cilostazol and pentoxifylline are the only two drugs that have been approved for the treatment of patients with intermittent claudication. However, the mechanisms by which exercise tolerance is improved remain unclear. Vascular endothelial growth factor ( VEGF) is a potent endothelial mitogen that results in angiogenesis when overexpressed in human subjects . To assess the potential role of VEGF in the improvement in exercise tolerance, we investigated plasma levels of VEGF in 50 patients with intermittent claudication who were allocated randomly to groups receiving cilostazol (n = 17), pentoxifylline (n = 17) or placebo (n = 16). Patients given either cilostazol or pentoxifylline showed a significant improvements in maximal walking distance compared with the placebo group (34 m and 33 m respectively, compared with 5 m ; both P < 0.05). Neither cilostazol nor pentoxifylline increased the ankle- brachial index after treatment. Circulating VEGF levels were increased ( from 116±29 to 169±45 pg/ml; P = 0.002), and the levels of VEGF were correlated significantly with exercise tolerance in a positive direction ( r = 0.88, P = 0.004), in those patients treated with cilostazol that did not have diabetes mellitus. In contrast, VEGF levels remained stable after the administration of pentoxifylline. These findings suggest that VEGF may contribute to the cilostazol-related improvement in exercise tolerance in non-diabetic patients. However, pentoxifylline did not affect VEGF levels, although a similar improvement in maximal walking distance was achieved. Thus the mechanisms involved in the pentoxifylline -treated group were different from those in the cilostazol- treated group, and require further study.

We have demonstrated the effects of estrogen on modulation of ATP- sensitive K+ channels; however, the subcellular location of these channels is unknown. The purpose of the present study was to investigate the role of the sarcolmmal and mitochondrial ATP-sensitive K+ channels in a canine model of myocardial infaraction after stimulation with 17β- esreadial. Anesthetized dogs were subjected to 60 min of the left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Infarct size was markedly reduced in estradial-treated dog compared with controls (14± 6 versus 42 ±6 %, p < 0.0001), indication the effective dose of estradial administrated. Pretreatment with the mitochondrial ATP-sensitive K+ channel antagonist 5- hydroxydecanoate completely abolished estradial- induced cardioprotection. The sarcolemmal ATP-sensitive K+ channel antagonist 1-15-12-(5- chloro-o-anisamido) ethylmjethoxypheny) sulfonyl-3- methylthiourea (HMR 1098) did not significantly attenuate estradial- induecd infarct size limitation. in addition, estradial administration significantly reduced the incidence and duration of reperfusion-induced ventricular tachycardia and ventricular fibrillation. Although 5- hydroxydecanoate alone caused no sigificant effect on the incidence of reperfusion arrhythmias in the presence or absence of estradial, the administration of HMR 1098 abolished estrogen-in-duced improvment of reperfusion arrhythmias. Pretreatment with the estrogen-receptor antagonist faslodex(ICI 182, 780)did not alter estrogen-induced infarct- limiting and antiarrhythmic effects. These results demonstrate that estrogen is cardioprotective against infarct size and fatal reperfusion arrhythmias by different ATP-sensitive K+ channels for an estrogen receptor- independent mechanism. The infarct size- limiting and antiarrhythmic effects of estrogen were abolished by 5- hydroxydecanoate and HMR 1098, Suggesting that the effects may result from activation of the mitochondial and sarcolemmal ATP-sensitive K+ channels, respectively.

Distension of the urinary bladder causes an increase in efferent sympathetic activity, which can precipitate myocardial ischemia. Smoking has been shown to modulate activities of afferent nerves from the distended urinary bladder and to impair endothelial function in response to sympathetic activation. To assess the effect of bladder distension on coronary dynamics in smokers, we measured epicardial and microvascular responses in 24 patients with early atherosclerosis (< 50% diameter stenosis). Patients were classified into habitual smokers (group 1, n = 14 ) and nonsmokers (group 2, n = 10). Habitual smokers were randomized into two subgroups on the basis of the use of doxazosin, as follows: subgroup 1 A (n = 7), without administration of doxazosin before catheterization; subgroup 1B (n = 7), with dosing doxazosin. In response to bladder distension (mean intravesical pressure 21.5 mmHg), bladder distension significantly decreased coronary diameter at the stenotic segments, coronary blood flow, and increased coronary resistance compared with baseline values, in subgroup 1A patients. In subgroup 1B patients during bladder distension, coronary diameter, coronary blood flow, and coronary resistance did not show significant changes compared with baseline values. There were significant differences of coronary diameter at the stenotic segments, coronary blood flow, and of changes of coronary vascular resistance between subgroup 1A and group 2 during bladder distension, despite similar changes in rate-pressure product . The present study showed that urinary bladder distension caused an abnormal vasomotor response of epicardial vasoconstriction and a concomitant increased coronary resistance, which leads to reduction in coronary blood flow in patients with early atherosclerosis. Smoking may further impair the response, implying that smoking has exaggerated response to sympathetic stimulation of conduit and resistance vessels. The abnormal response was abolished by pretreated administration of doxazosin, suggesting that the involved mechanisms are related to alpha(1)-adrenoceptors.

Objectives The purpose of this study was to determine whether ATP- sensitive potassium (K-ATP) channel agonists exert a beneficial effect on the structural, functional, and molecular features of the remodeling heart in infarcted rats. Background Myocardial K-ATP channels have been implicated in the ventricular remodeling after myocardial infarction by inhibition of 70-kDa S6 (p70S6) kinase. Methods Male Wistar rats after induction of myocardial infarction were randomized to either vehicle, agonists of K- ATP channels nicorandil and pinacidil, an antagonist of KATP channels glibenclamide, or a combination of nicorandil and glibenclamide or pinacidil and glibenclamide for 4 weeks. To verify the role of p70S6 kinase in ventricular remodeling, rapamycin was also assessed. Results Significant ventricular hypertrophy was detected by increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Increased synthesis of p70S6 kinase messenger ribonucleic acid after infarction in vehicle-treated rats was confirmed by reverse transcription-polymerase chain reaction, consistent with the results of immunohistochemistry and Western blot for phosphorylated p70 S6 kinase. Rats in the nicorandil- and pinacidil- treated groups significantly attenuated cardiomyocyte hypertrophy and phosphorylated p70S6 kinase expression with similar potency, as compared with vehicle. The beneficial effects of nicorandil and pinacidil were abolished by administering either glibenclamide or 5-hydroxydecanoate. Addition of rapamycin attenuated ventricular remodeling and did not have additional beneficial effects compared with those seen in rats treated with either nicorandil or pinacidil alone. Conclusions Activation of K-ATP channels by either nicorandil or pinacidil can attenuate ventricular remodeling , probably through a p70S6 kinase-dependent pathway after infarction.

This study investigated whether selective endothelin (ET) type A (ETA) or nonselective ETA/ETB receptor blockade exerted antiarrhythmic effects through attenuated sympathetic reinnervation after infarction. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats received either vehicle, ABT-627 ( selective ETA receptor antagonist) , bosentan (nonselective ETA/ETB receptor antagonist), or hydralazine for 4 wk. The measurement of myocardial ET-1 levels at the remote zone revealed a significant increase in vehicle-treated infarcted rats compared with sham-operated rats, consistent with increased activities of ET-1 after infarction. Sympathetic nerve function changes assessed by the norepinephrine content of myocardium and the dialysate and plasma dihydroxyphenylglycol levels were parallel to ET-1 levels. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated protein 43, and neurofilament also confirmed the change of nerve function. This was accompanied with a significant upregulation of nerve growth factor protein expression and mRNA in the vehicle-treated infarcted rats, which reduced after the administration of either ETA or ETA/ETB blockade to a similar extent. The beneficial effects of ET receptor antagonists on sympathetic nerve function and structures were dissociated from their blood pressure-lowering effect because ET receptor antagonists and hydralazine reduced arterial pressure similarly. Arrhythmic severity during programmed stimulation in ET receptor antagonists-treated rats was significantly lower than that in vehicle-treated infarcted rats. Our data indicate that the ET system, especially via ETA receptors, plays an important role in attenuating sympathetic reinnervation after infarction. Independent of their hemodynamic effects, a chronic use of either ETA or ETA/ETB antagonists may modify the arrhythmogenic response to programmed electrical stimulation.

Background: Estrogen has an antioxidant potential which may contribute to its cardioprotective effect. We sought to determine whether estrogen administration can affect coronary vasomotor tone in patients after angioplasty by reducing 8-iso-prostaglandin (PG) F2?? concentrations, a bioactive product of lipid peroxidation. Methods: The study was designed to prospectively investigate 30 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n=15) or did have (group 2, n =15) intracoronary (i.c.) treatment with estrogen prior to coronary angioplasty. Results: There were no significant differences of collateral circulation assessed by intracoronary Doppler flow velocity during balloon inflations between the study groups. The diameters of the coronary artery at the dilated and distal segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 (both P<0.0001). The vasoconstriction was significantly blunted in group 2. The 8-iso-PGF2?? levels in plasma from the coronary sinus rose significantly from 194??45 to 390??97 pg/ml (P<0.0001, 95% confidence intervals=142???249 pg/ml) 15 min after angioplasty in group 1, which was attenuated after administering estrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and 8- iso-PGF2?? levels in group 1 (r=0.73, P=0.002) . Conclusions: 8-iso-PGF2? ? is released into the coronary circulation during angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. Estrogen administration attenuated vasoconstriction by reducing the 8-iso -PGF2?? levels. This finding may provide a new strategy to treat coronary vasoconstriction after angioplasty.

Syndrome X may exhibit myocardial ischemia and is associated with estrogen deficiency. We sought to assess the possible role of estrogen in modulating the characteristics of ventricular repolarization by measurement of QT interval and QT dispersion in patients with syndrome X. We prospectively used 12-lead electrocardiograms and echocardiograms to study 52 consecutive menopausal patients with syndrome X ( group subdivided into subgroup1a: 32 patients with dosing nicorandil, an ATP- sensitive K+ channel opener, and subgroup 1b: 20 patients without dosing nicorandil). For comparisons , a control group consisted of age- and echocardiographic left ventricular mass index-matched 20 healthy menopausal women. Baseline QT intervals and QT dispersion were similar between the 2 groups (subgroup1a and controls). After dosing estrogen, there were significant prolongation of maximal QTc intervals and reduction of QT or QTc dispersion compared with baseline in patients with syndrome X. The changes restored to baseline after nicorandil administration. Control subjects showed no changes in response to the administration of estrogen. Thus, estrogen modulates characteristics of ventricular repolarization, which appears to be mediated by blocking ATP-sensitive K+ channel. The effects of estrogen on QT intervals may be different between menopausal women with or without syndrome X.

Systemic markers of inflammation may be increased in patients after percutaneous coronary intervention. In the present study, we evaluated whether IP (ischaemic preconditioning) attenuated inflammation by activating KATP( ATP-sensitive potassium) channels in patients undergoing coronary angioplasty. Patients (n=36) undergoing angioplasty of a major left coronary artery were allocated randomly to one of four groups: a control group, a group receiving nicorandil (an agonist of KATP channels), an IP group or an IP group pretreated with glibenclamide (an antagonist of KATP channels). To measure the release of sCD40L, P-selectin and myeloperoxidase from the ischaemic region, blood samples were drawn simultaneously from the ascending aorta and the great cardiac vein before and 15 min after coronary angioplasty. At 15 min after angioplasty, a significant increase in sCD40L and P-selectin levels in the great cardiac vein in the control group was observed. IP- and nicorandil-treated patients did not show a significant change in sCD40L and P-selectin levels in response to angioplasty. However, the IP-induced attenuation of sCD40L and P-selectin release was abolished by administering glibenclamide. The change in myeloperoxidase levels mirrored those of sCD40L and P-selectin. The levels of inflammatory markers in the aorta remained stable throughout the study. Patients undergoing angioplasty had increased sCD40L and P- selectin levels in the ischaemic region. In conclusion, IP abolished angioplasty-induced myeloperoxidase release by preventing activated platelet-induced P-selectin release via a KATP-channel-initiated pathway. Therefore, in addition to its primary effect on cardioprotection, IP may also provide beneficial anti-inflammatory effects on the interaction between platelets and neutrophils.

Epidemiological studies showed that hypercholesterolemia was associated with a higher left ventricular mass. Myocardial ATP-sensitive potassium ( KATp) channels have been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on hypercholesterolemia-induced ventricular hypertrophy and whether the attenuated hypertrophic effect was via activation of myocardial KATp channels. In this study, we evaluated the hemodynamic, biochemical, and morphological responses to pravastatin in cholesterol-fed (1%) rabbits. Male New Zealand White rabbits were randomized to either vehicle, nicorandil (an agonist of KATp channels), pravastatin, glibenclamide (an antagonist of KATp channels), or a combination of nicorandil and glibenclamide or pravastatin and glibenclamide for 8 weeks. The left ventricular weight and left ventricular myocyte sizes increased 8 weeks after cholesterol-feeding in comparison to that in normocholesterolemic rabbits. Pravastatin administration significantly decreased the left ventricular weight by 12% and cardiomyocyte cell areas by 30 %. Hyperlipidemic rabbits in the nicorandil- and pravastatin -treated groups significantly attenuated cardiomyocyte hypertrophy, as compared with the vehicle-treated group ( 3162 +/- 1277 mum(2), 3372 +/- 228 mum(2) versus 4388 +/- 163 mum(2) in the vehicle group, both P < 0.0001, respectively). Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, pravastatin-induced beneficial effects were reversed by the addition of glibenclamide, implicating KATp channels as the relevant target. The results of the present study suggest a pathogenetic role of KATp channels in hypercholesterolemia- induced ventricular hypertrophy. The antihypertropic effects of pravastatin may be related to activation of KATp channels, and result in an amelioration of cardiomyocyte hypertrophy development by an atherogenic diet. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

We have demonstrated that myocardial ATP-sensitive potassium (KATP) channels are implicated in the development of cardiac hypertrophy in hyperlipidemic rabbits. We investigated the effect of pravastatin on development of ventricular hypertrophy in male normolipidemic Wistar rats with two-kidney, one-clip (2K1C) hypertension and whether the attenuated hypertrophic effect was via activation of KATP channels. Twenty-four hours after the left renal artery was clipped, rats were treated with one of the following therapies for 8 wk: vehicle, nicorandil (an agonist of KATP channels), pravastatin, glibenclamide (an antagonist of KATP channels), hydralazine, nicorandil plus glibenclamide, or pravastatin plus glibenclamide. Systolic blood pressure, relative left ventricular (LV) weight, and cardiomyocyte sizes significantly increased in vehicle-treated 2K1C rats compared with those in sham-operated rats. Treatment with either nicorandil or pravastatin significantly attenuated LV hypertrophy/ body weight compared with the vehicle, which was further confirmed by downregulation of LV atrial natriuretic peptide mRNA. Nicorandil-induced effects were abolished by administering glibenclamide. Similarly, pravastatin-induced beneficial effects were reversed by the addition of glibenclamide, implicating KATP channels as the relevant target. A dissociation between the effects of blood pressure and cardiac structure was noted because pravastatin and hydralazine reduced arterial pressure similarly. These results suggest a crucial role of cardiac KATP channel system in the development of ventricular hypertrophy in the 2K1C hypertensive rats. Pravastatin is endowed with cardiac antihypertrophic properties probably through activation of KATP channels, independent of lipid and hemodynamic changes.

Pravastatin has been shown, in an experimental model of ischemia reperfusion, to increase adenosine levels, which exert a potent and protective effect on the heart. The purpose of this study was to investigate whether pravastatin can provide cardioprotection by increased production of adenosine in patients undergoing coronary angioplasty, a clinical model of ischemia reperfusion. Thirty-five hyperlipidemic patients who underwent elective angioplasty for a major epicardial coronary artery were randomly allocated to either 3-month pravastatin or placebo before catheterization. In the placebo group, the mean ST-segment shift during the second balloon inflation was similar that observed during the first inflation, whereas in the preconditioned patients, the shift was significantly less, which is consistent with ischemic preconditioning. In the pravastatin-treated patients, the changes of ST-segment shift were similar between the first and second balloon inflations. In constrast, the patients who receive aminophylline developed higher ST-segment shifts during the first and second inflations than those in the pravastatin- treated group alone. Measurements of chest pain score and myocardial lactate extraction ratios during inflation mirrored those of the ST- segment shift. The present study demonstrates that administration of pravastatin results in a significant gain in tolerance to ischemia during angioplasty. The effect of pravastatin was abolished by aminophylline, suggesting that the cardioprotective effect of pravastatin may result from activation of adenosine receptors.

Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effects of 3-hydroxy- 3-methyglutaryl coenzyme A reductase inhibitor (statin) therapy on proteinuria in normolipidemic patients with well- controlled hypertension have not been studied. A total of 63 normolipidemic (total cholesterol <240 mg/dL) and proteinuric (300 to 3000 mg/d) patients with well-controlled blood pressure (<140/90 mm Hg) were randomized to receive either placebo (n=32) or pravastatin (10 mg/d; n=31) after a 3-month placebo period. Pravastatin lowered proteinuria after 6 months by 54% (P<0.0001). Creatinine clearance was stable throughout the study in the 2 groups. Despite unchanged plasma endothelin-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with improvement in urinary protein excretion in pravastatin-treated patients ( r=0.64, P=0.001) . The urinary excretion of retinol-binding protein decreased after pravastatin administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of IgG did not change significantly throughout the study in either group. Multivariate analysis revealed that proteinuria was only significantly correlated with statin use (P<0.0001, R-2 =0,66). Linear regression analysis in the statin-treated group did not show any correlation between changes in lipid profiles and proteinuria regression. Thus, in addition to their primary function of antilipidemia, the addition of pravastatin to treatment for well-controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and lipid-lowering effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.

BACKGROUND: Distension of the urinary bladder reflexly causes a change of coronary vasomotor response. The effect of such distension on the coronary circulation in hyperlipidemic patients, a condition with impaired endothelial function, remains unknown. HYPOTHESIS: We tested the hypothesis whether urinary bladder distension caused an exaggerated vasomotor response of epicardial and resistance vasoconstriction in hyperlipidemic patients. METHODS: Thirty patients with early atherosclerosis (< 50% diameter stenosis) were divided into three groups: Group 1 (n = 10): hyperlipidemia without doxazosin administration; Group 2 (n= 10): hyperlipidemia with pretreatment of alpha1-adrenergic receptor blocker (oral doxazosin 2 mg); and Group 3 (n = 10) : normolipidemia. A prospective analysis of the results of quantitative angiograms, intracoronary Doppler flow, and lactate concentrations from aortic root and coronary sinus was performed during distension of urinary bladder. RESULTS: Bladder distension significantly decre= 10): hyperlipidemia with pretreatment of alpha1- adrenergicreceptor blocker ( oral doxazosin 2 mg); and Group 3 (n = 10): normolipidemia. A prospective analysis of the results of quantitative angiograms, intracoronary Doppler flow, and lactate concentrations from aortic root and coronary sinus was performed during distension of urinary bladder. RESULTS: Bladder distension significantly decreased coronary diameter at the stenotic segments (p = 0. 004), coronary blood flow ( p = 0.05), and increased coronary resistance ( p = 0.006) compared with baseline values, in Group 1 patients. In Group 2 patients during bladder distension, coronary diameter, coronary blood flow , and coronary resistance showed no significant changes compared with baseline values. There were significant differences of stenotic coronary diameter ( p = 0.01) between Groups 1 and 3 during bladder distension despite similar changes in rate- pressure product. No significant differences were noted among the groups in the responses of coronary diametercoronary blood flow, and coronary resistance after nitroglycerin administration. CONCLUSIONS: The present study showed that urinary bladder distension caused an abnormal vasomotor response of epicardial vasoconstriction and that a concomitant increased coronary resistance involved mechanisms related to alpha1- adrenoceptors. Hyperlipidemia may further impair the response. Pretreated administration of doxazosin had reversed the changes toward baseline. Vasoconstriction during bladder distension can be relieved after nitroglycerin administration, suggesting an unchanged responsiveness of vascular smooth muscle cells to such distension.

Reactive cardiomyocyte hypertrophy after myocardial infarction (MI) is an important risk factor for arrhythmias. Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on ventricular hypertrophy during remodeling after MI and whether the attenuated hypertrophic effect was via reduced regional ET-I expression. After ligation of the anterior descending artery, male Wistar rats were randomized to either vehicle, pravastatin, mevalonate, or a combination of the two drugs for 4 weeks. Sham operation served as controls. Pravastatin decreased cardiomyocyte sizes isolated by enzymatic dissociation at the border zone. The myocardial ET-I levels at the border zone were 6.3-fold higher (P < 0.0001) in the vehicle group compared with sham group. The increased regional ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the localization of ET-I mainly in the cardiomyocytes. This was paralleled by a 9.8 +/- 2.3-fold upregulation of preproET-1 mRNA assessed by real-time quantitative reverse transcription-polymerase chain reaction in the vehicle-treated rats, which reduced after administering pravastatin. Cardiomyocyte sizes at the border zone correlated positively with regional ET-1 levels (P = 0 .001). Arrhythmic scores during programmed stimulation were significantly higher in the vehicle group than in the pravastatin- treated group (3.0 +/- 1.3 vs. 1.3 +/- 1.0, P < 0.0001). In contrast, pravastatin-induced effects were reversed by the addition of mevalonate, implicating 3- hydroxy-3-methyglutaryl-CoA reductase as the relevant target . The results of the present study suggest that the pravastatin administration after infarction can reduce the inducibility of ventricular arrhythmias as a result of attenuated cardiomyocyte hypertrophy probably through decreased tissue ET-1 level, which is linked to mevalonate metabolism.