Management of hypertension in chronic heart failure.

Chronic heart failure (CHF) is associated with frequent hospitalizations and high mortality. It affects more than 5 million individuals in the USA, and another 660,000 new cases are diagnosed each year; overall, heart failure (HF) now accounts for 7% of all deaths from cardiovascular disease. Hypertension (HTN) increases the risk of development of HF and it precedes it in 75% of cases. HF patients are nearly evenly divided between those with reduced left ventricular (LV) function or systolic dysfunction and those with preserved LV systolic function or diastolic dysfunction. The management of HTN in patients with CHF is challenging. Drugs such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor blockers, hydralazine and nitrates, which have shown mortality benefit in CHF and exert antihypertensive effects, should be used as first-line agents to control HTN in CHF. In addition, antihypertensive drugs such as alpha-receptor blockers that can increase mortality in HF should be avoided. The dihydropyridine group of calcium channel blockers are good antihypertensive medications with a neutral effect on mortality in patients with CHF. These may be used in CHF patients with refractory HTN. In patients with HF with reduced ejection fraction, HTN is treated differently in comparison to patients with HF with normal ejection fraction. This article reviews the treatment of essential HTN in patients at risk for developing HF, in the presence of HF and the latest developments in treatment that might benefit both HTN and HF management.

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice.

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1alpha levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS-/- and iNOS-/- mice. Male C57BL/6 wild-type (WT), eNOS-/-, and iNOS-/- mice received 10 mg.kg(-1).day(-1) Pio (Pio+) or water alone (Pio-) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4+/-1.4% vs. 39.0+/-1.1%; P<0.001), as well as in the eNOS-/- (32.0+/-1.6% vs. 44.2+/-1.9%; P<0.001) and iNOS-/- (18.0+/-1.2% vs. 45.5+/-2.3%; P<0.001) mice. The protective effect of Pio in eNOS-/- mice was smaller than in the WT (P<0.001) and iNOS-/- (P<0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS-/- mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS-/- and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF1alpha levels and cPLA2 and COX2 activity in the WT, eNOS-/-, and iNOS-/- mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.

Caffeinated coffee blunts the myocardial protective effects of statins against ischemia-reperfusion injury in the rat.

PURPOSE: We asked whether caffeinated coffee (CC) blunts the infarct size (IS)-limiting effects of atorvastatin (ATV). BACKGROUND: Adenosine receptor activation is essential for mediating the IS-limiting effects of statins. Caffeine is a nonspecific adenosine receptor blocker, and thus drinking CC may block the myocardial protective effects of statins. METHODS: Rat received 3-day ATV (10 mg/kg/day) or water by oral gavage once daily. Drinking water was replaced by water + sugar (7.5 g/100 ml), CC with sugar, or decaffeinated coffee (DC) with sugar. On the 4th day, rats were anesthetized and underwent 30 min of coronary artery occlusion and 4 h reperfusion. Area at risk was assessed by blue dye and infarct size by TTC. RESULTS: Body weight and area at risk was comparable among groups. IS was 25.1 +/- 3.9% of the area at risk in the control group. In rats not receiving ATV, CC (25.5 +/- 3.1%) and DC (34.0 +/- 2.8%) did not affect IS. IS was significantly reduced by ATV in the water + sugar (11.7 +/- 0.7%, p = 0.015) and DC (11.5 +/- 1.0%; p < 0.001) groups, but not in the CC group (32.3 +/- 3.0%; p = 0.719). ATV increased myocardial levels of Ser-473 phosphorylated Akt in the water + sugar and DC groups, but not in the CC group. CONCLUSIONS: CC, but not DC, abrogated the IS-limiting effects of ATV by blocking the adenosine receptors and preventing the phosphorylation of Akt. CC did not affect IS in rats not receiving ATV.

The cardioprotective effect of a statin and cilostazol combination: relationship to Akt and endothelial nitric oxide synthase activation.

BACKGROUND: Atorvastatin (ATV) protects against ischemia-reperfusion by upregulating Akt and subsequently, endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177. However, when given orally, high doses of ATV (10 mg/kg/d) are needed to achieve maximal protective effect in the rat. Protein kinase A (PKA) also phosphorylates eNOS at Ser-1177. As PKA activity depends on cAMP, cilostazol (CIL), a phosphodiesterase type III inhibitor, may stimulate NO production by activating PKA. HYPOTHESIS: CIL and ATV may have synergistic effects on eNOS phosphorylation and myocardial infarct size (IS) reduction. METHODS: Sprague-Dawley rats received 3-day oral pretreatment with: (1) water; (2) low dose ATV (2 mg/kg/d); (3) CIL (20 mg/kg/d): (4) ATV+CIL. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts explanted for immunoblotting without being subjected to ischemia. Area at risk (AR) was assessed by blue dye and IS by triphenyl-tetrazolium-chloride. RESULTS: Body weight and the size of AR were comparable among groups. There were no significant differences among groups in mean blood pressure and heart rate. CIL, but not ATV, reduced IS. IS in the ATV+CIL group was significantly smaller than the other three groups (P < 0.001 for each comparison). ATV, CIL and their combination did not affect total eNOS expression. ATV at 2 mg/kg/d did not affect Ser-1177 P-eNOS levels, whereas CIL increased it (258 +/- 15%). The level of myocardial P-eNOS levels was highest in the ATV+CIL group (406 +/- 7%). CONCLUSIONS: ATV and CIL have synergistic effect on eNOS phosphorylation and IS reduction. By increased activation of eNOS, CIL may augment the pleiotropic effects of statins.

The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation.

Statins activate phosphatidylinositol-3-kinase, which activates ecto-5'-nucleotidase and phosphorylates 3-phosphoinositide-dependent kinase-1 (PDK-1). Phosphorylated (P-)PDK-1 phosphorylates Akt, which phosphorylates endothelial nitric oxide synthase (eNOS). We asked if the blockade of adenosine receptors (A(1), A(2A), A(2B), or A(3) receptors) could attenuate the induction of Akt and eNOS by atorvastatin (ATV) and whether ERK1/2 is involved in the ATV regulation of Akt and eNOS. In protocol 1, mice received intraperitoneal ATV, theophylline (TH), ATV + TH, or vehicle. In protocol 2, mice received intraperitoneal injections of ATV, U0126 (an ERK1/2 inhibitor), ATV + U0126, or vehicle; 8 h later, hearts were assessed by immunoblot analysis. In protocol 3, mice received intraperitoneal ATV alone or with 8-sulfophenyltheophylline (SPT); 1, 3, and 6 h after injection, hearts were assessed by immunoblot analysis. In protocol 4, mice received intraperitoneal ATV alone or with SPT, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (CSC), alloxazine, or MRS-1523; 3 h after injection, hearts were assessed by immunoblot analysis. ATV increased P-ERK, P-PDK-1, Ser(473) P-Akt, Thr(308) P-Akt, and P-eNOS levels. TH blocked ATV-induced increases in P-ERK, Ser(473) P-Akt, Thr(308) P-Akt, and P-eNOS levels without affecting the induction of P-PDK-1 by ATV. U0126 blocked the ATV induction of Ser(473) P-Akt and Thr(308) P-Akt while attenuating the induction of P-eNOS. A detectable increase in P-ERK, Ser(473) P-Akt and P-eNOS was seen 3 and 6 h after injection but not at 1 h. DPCPX, CSC, and alloxazine partially blocked the ATV induction of P-ERK, Ser(473) P-Akt, and P-eNOS. In conclusion, blockade of adenosine A(1), A(2A), and A(2B) receptors but not A(3) receptors inhibited the induction of Akt and eNOS by statins. Adenosine was required for ERK1/2 activation by statins, which resulted in Akt and eNOS phosphorylation.

Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) by atorvastatin is mediated by 15-deoxy-delta-12,14-PGJ2.

Several studies suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Atorvastatin (ATV) increases myocardial levels of prostaglandins (PG) by upregulating and activating cytosolic-phospholipase-A(2) and cycloxygenase-2 (COX2). We investigated whether ATV activates PPAR-gamma via 15-deoxy-delta-12,14-PGJ(2) (15DPGJ(2)) an endogenous ligand of PPAR-gamma and a product of PGD(2), and to compare the effects of pioglitazone (PIO), a known direct PPAR-gamma activator, to that of ATV. First we measured myocardial 15DPGJ(2) levels in the rat heart after a 3-day pretreatment with oral ATV (10 mg/(kg d)), PIO (10 mg/(kg d)), ATV+PIO, ATV+COX1 inhibitor, and ATV+COX2 inhibitor. We also assessed in human umbilical venous endothelial cells (HUVEC) whether ATV and PIO activate PPAR-gamma via 15DPGJ(2) using siRNA targeted to PGD(2) synthase. Both 15DPGJ(2) levels and PPAR-gamma activation were assessed. ATV and PIO increased myocardial 15DPGJ(2) levels in the rat myocardium and HUVEC. siRNA inhibited this increase in both groups. Both ATV and PIO augmented PPAR-gamma activation while co-treatment with siRNA completely blocked the ATV effect but only partially inhibited the PIO effect. In conclusion, both ATV and PIO activate PPAR-gamma and increase myocardial 15DPGJ(2) levels. Activation of PPAR-gamma by ATV is mediated solely by 15DPGJ(2), whereas PIO activates PPAR-gamma both directly and indirectly via 15DPGJ(2).

Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination.

Atorvastatin (ATV) limits infarct size (IS) by activating Akt and ecto-5-nucleotidase, which generates adenosine. Activated Akt and adenosine activate endothelial nitric oxide synthase (eNOS). When given orally, high doses (10 mg/kg) are needed to achieve full protection. We determined whether dipyridamole (DIP), by preventing the reuptake of adenosine, has a synergistic effect with ATV in reducing myocardial IS. In this study, rats received 3-days of the following: water, ATV (2 mg.kg(-1).day(-1)), DIP (6 mg.kg(-1).day(-1)), or ATV + DIP. In addition, rats received 3-days of the following: aminophylline (Ami; 10 mg.kg(-1).day(-1)) or Ami + ATV + DIP. Rats underwent 30 min of myocardial ischemia followed by 4 h of reperfusion (IS protocol), or hearts were explanted for immunoblotting. As a result, IS in the controls was 34.0 +/- 2.8% of the area at risk. ATV (33.1 +/- 2.1%) and DIP (30.5 +/- 1.5%) did not affect IS, whereas ATV + DIP reduced IS (12.2 +/- 0.5%; P < 0.001 vs. each of the other groups). There was no difference in IS between the Ami alone (48.1 +/- 0.8%) and the Ami + ATV + DIP (45.8 +/- 2.9%) group (P = 0.422), suggesting that Ami completely blocked the protective effect. Myocardial adenosine level in the controls was 30.6 +/- 3.6 pg/microl. ATV (51.0 +/- 4.9 pg/microl) and DIP (51.5 +/- 6.8 pg/microl) caused a small increase in adenosine levels, whereas ATV + DIP caused a greater increase in adenosine levels (66.4 +/- 3.1 pg/microl). ATV and DIP alone did not affect myocardial Ser473 phosphorylated-Akt and Ser1177 phosphorylated-eNOS levels, whereas ATV + DIP significantly increased them. In conclusion, low-dose ATV and DIP had synergistic effects in reducing myocardial IS and activation of Akt and eNOS. This combination may have a potential benefit in augmenting the eNOS-mediated pleiotropic effects of statins.