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The cardioprotective effects of estrogen are mediated by receptors expressed in vascular cells. Here we show that 27-hydroxycholesterol (27HC), an abundant cholesterol metabolite that is elevated with hypercholesterolemia and found in atherosclerotic lesions, is a competitive antagonist of estrogen receptor action in the vasculature. 27HC inhibited both the transcription-mediated and the non-transcription-mediated estrogen-dependent production of nitric oxide by vascular cells, resulting in reduced estrogen-induced vasorelaxation of rat aorta. Furthermore, increasing 27HC levels in mice by diet-induced hypercholesterolemia, pharmacologic administration or genetic manipulation (by knocking out the gene encoding the catabolic enzyme CYP7B1) decreased estrogen-dependent expression of vascular nitric oxide synthase and repressed carotid artery reendothelialization. As well as antiestrogenic effects, there were proestrogenic actions of 27HC that were cell-type specific, indicating that 27HC functions as an endogenous selective estrogen receptor modulator (SERM). Taken together, these studies point to 27HC as a contributing factor in the loss of estrogen protection from vascular disease.

Duchenne muscular dystrophy (DMD) is an inherited disease that causes striated muscle weakness. Recently, we showed therapeutic effects of the combination of lisinopril (L), an angiotensin converting enzyme (ACE) inhibitor, and spironolactone (S), an aldosterone antagonist, in mice lacking dystrophin and haploinsufficient for utrophin (utrn(+/-);mdx, het mice); both cardiac and skeletal muscle function and histology were improved when these mice were treated early with LS. It was unknown to what extent LS treatment is effective in the most commonly used DMD murine model, the mdx mouse. In addition, current standard-of-care treatment for DMD is limited to corticosteroids. Therefore, potentially useful alternative or additive drugs need to be both compared directly to corticosteroids and tested in presence of corticosteroids. We evaluated the effectiveness of this LS combination in the mdx mouse model both compared with corticosteroid treatment (prednisolone, P) or in combination (LSP). We tested the additional combinatorial treatment containing the angiotensin II receptor blocker losartan (T), which is widely used to halt and treat the developing cardiac dysfunction in DMD patients as an alternative to an ACE inhibitor. Peak myocardial strain rate, assessed by magnetic resonance imaging, showed a negative impact of P, whereas in both diaphragm and extensor digitorum longus (EDL) muscle contractile function was not significantly impaired by P. Histologically, P generally increased cardiac damage, estimated by percentage area infiltrated by IgG as well as by collagen staining. In general, groups that only differed in the presence or absence of P (i.e. mdx vs. P, LS vs. LSP, and TS vs. TSP) demonstrated a significant detrimental impact of P on many assessed parameters, with the most profound impact on cardiac pathology.

Cucurbitacin I is a naturally occurring triterpenoid derived from Cucurbitaceae family plants that exhibits a number of potentially useful pharmacological and biological activities. However, the therapeutic impact of cucurbitacin I on the heart has not heretofore been reported. To evaluate the functional role of cucurbitacin I in an in vitro model of cardiac hypertrophy, phenylephrine (PE)-stimulated cardiomyocytes were treated with a sub-cytotoxic concentration of the compound, and the effects on cell size and mRNA expression levels of ANF and β-MHC were investigated. Consequently, PE-induced cell enlargement and upregulation of ANF and β-MHC were significantly suppressed by pretreatment of the cardiomyocytes with cucurbitacin I. Notably, cucurbitacin I also impaired connective tissue growth factor (CTGF) and MAPK signaling, pro-hypertrophic factors, as well as TGF-β/Smad signaling, the important contributing factors to fibrosis. The protective impact of cucurbitacin I was significantly blunted in CTGF-silenced or TGF-β1-silenced hypertrophic cardiomyocytes, indicating that the compound exerts its beneficial actions through CTGF. Taken together, these findings signify that cucurbitacin I protects the heart against cardiac hypertrophy via inhibition of CTGF/MAPK, and TGF- β/Smad-facilitated events. Accordingly, the present study provides new insights into the defensive capacity of cucurbitacin I against cardiac hypertrophy, and further suggesting cucurbitacin I's utility as a novel therapeutic agent for the management of heart diseases.

Considering the reduced ability of cardiac fibroblasts to release adenosine and increased ability of interstitial adenosine uptake during diabetes mellitus, the present study investigated the effect of adenosine preconditioning and the existence of cross-talk with opioid receptor activation in the diabetic rat heart subjected to ischemia–reperfusion (I/R). Langendorff-perfused normal and streptozotocin (65 mg/kg, i.p. , once)-administered diabetic (after 8-weeks) rat hearts were subjected to 30-min global ischemia and 120-min reperfusion. Myocardial infarct size using triphenyltetrazolium chloride staining, markers of cardiac injury such as lactate dehydrogenase (LDH) and creatine kinase (CK-MB) release, coronary flow rate (CFR) and myocardial oxidative stress were assessed. The diabetic rat heart showed high degree of I/R injury with increased LDH and CK-MB release, high oxidative stress and reduced CFR as compared to the normal rat heart. The adenosine preconditioning (10 μM) afforded cardioprotection against I/R injury in the normal rat heart that was prevented by naloxone (100 μM) pre-treatment. Conversely, adenosine preconditioning-induced cardioprotection was abolished in the diabetic rat heart. However, co-administration of dipyridamole (100 μM), adenosine reuptake inhibitor, markedly restored the cardioprotective effect of adenosine preconditioning in the diabetic rat heart, and this effect was also abolished by naloxone pre-treatment. The reduced myocardial availability of extracellular adenosine might explain the inability of adenosine preconditioning to protect the diabetic myocardium. The pharmacological elevation of extracellular adenosine restores adenosine preconditioning-mediated cardioprotection in the diabetic myocardium by possibly involving opioid receptor activation.

This study compares the role of endothelial factors in α‐adrenoceptor contractile responses in mesenteric resistance (MRA) and superior (SMA) mesenteric arteries from ouabain‐treated (8.0 μg day−1, 5 weeks) and untreated rats. The role of the renin–angiotensin system was also evaluated. Ouabain treatment increased systolic blood pressure. In addition, ouabain reduced the phenylephrine response in SMA but did not alter noradrenaline responses in MRA. Endothelium removal or the nitric oxide synthase (NOS) inhibitor (L‐NAME, 100 μM) increased the responses to α‐adrenergic agonists in both vessels. After ouabain treatment, both endothelial modulation and the L‐NAME effect were increased in SMA, while only the L‐NAME effect was increased in MRA. Endothelial NOS expression remained unaltered after ouabain treatment. Indomethacin (10 μM) similarly reduced the noradrenaline contraction in MRA from both groups; in contrast, in SMA, indomethacin only reduced phenylephrine‐induced contractions in segments from untreated rats. Co‐incubation of L‐NAME and indomethacin leftward shifted the concentration–response curves for noradrenaline more in MRA from ouabain‐treated rats; tetraethylammonium (2 mM) shifted the noradrenaline curves further leftward only in MRA from untreated rats. Losartan treatment prevents the development of hypertension but not all vascular changes observed after ouabain treatment. In conclusion, a rise in endothelial NO and impaired prostanoid participation might explain the reduction in phenylephrine‐induced contraction in SMA after ouabain treatment. An increase in the modulatory effect of endothelial NO and impairment of endothelium‐dependent hyperpolarizing factor effect might explain why the ouabain treatment had no effect on noradrenaline responses in MRA. British Journal of Pharmacology (2004) 143, 215–225. doi:10.1038/sj.bjp.0705919

Pharmacological concentrations of androgens are known to elicit a rapid positive inotropism in isolated left atrium of male rats. Upon short-term exposure to androgens, an increase in intracellular cAMP levels has been observed, though delayed with respect to the time course of contraction, suggesting that other mechanisms may participate in initiating the contraction. Therefore, the interaction of positive inotropism elicited by ouabain, an inhibitor of Na + -K + -ATPase, and androgens was studied in isolated left atrium of rat. Androgens antagonized ouabain-elicited positive inotropism and increased the basal tone. Vanadate, an inhibitor of the Ca 2+ pump, produced a similar effect as androgens on ouabain-elicited positive inotropism. Therefore, androgens might interact with the Ca 2+ pump and this may explain the increase in basal tone. The conjugation of 5α-dihydrotestosterone with bovine serum albumin produced the same effect, suggesting an extracellular interaction of androgens inhibiting the Na + -K + -ATPase that could increase intracellular Ca 2+ via the Na + -Ca 2+ exchange.

We evaluated the role of the inositol 1,4,5-triphosphate (IP(3)) receptor-mediated Ca(2+) release on the positive inotropic effects of alpha-adrenergic stimulation using a novel, potent, selective membrane-permeable blocker of IP(3) receptor, xestospongin C. Guinea-pig papillary muscle permeabilized with saponin exhibited spontaneous oscillatory contractions in solution buffered with pCa(2+) 6.5 by a low concentration of EGTA. The oscillatory activity was increased by adding 100 microM IP(3) and abolished by 1 microM ryanodine or 30 microM cyclopiazonic acid. Xestospongin C (3 microM) inhibited the IP(3)-induced increase in the oscillatory contractions without affecting basal oscillations. In intact papillary muscle, xestospongin C (3 microM) inhibited the positive inotropic effects of phenylephrine, resulting in a rightward and downward shift of the concentration-response curve for phenylephrine. On the contrary, xestospongin C did not affect the concentration-response curve for phenylephrine obtained in the presence of ryanodine (1 microM). On the other hand, xestospongin C affected neither basal contractions nor the positive inotropic effects of a high extracellular Ca(2+) concentration (3.2 mM) or that of isoprenaline (1 and 10 nM). These results suggest that the IP(3)-mediated increase in Ca(2+) release is involved in the positive inotropic effects of alpha-adrenergic stimulation in the guinea-pig cardiac muscle.

Background The presence and role of endogenous digoxin-like cardiotonic steroids (CTS) in humans is controversial. This study utilises a novel pipeline to quantify CTS and examines their interaction with digoxin within a randomised trial. Methods The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial randomised patients with permanent AF and symptoms of heart failure to low-dose digoxin or beta-blocker therapy; clinicaltrials.gov NCT02391337. Circulating CTS were detected and quantified using a new ultra-high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS) pipeline. Results All 160 participants of the RATE-AF trial were included, with mean age 76 years (SD 8) and 46% women. Endogenous CTS detected and quantified in baseline samples included digoxigenin and digitoxigenin, plus low or unquantifiable levels of ouabain, telocinobufagin, cinobufagin, marinobufagenin, bufalin, cinobufotalin, dihydroouabain, and ouabagenin. Compared to beta-blockers, patients randomised to digoxin had better functional outcomes at 12 months for heart failure (− 0.57 New York Heart Association class, 95% CI − 0.82 to − 0.32; p  < 0.001) and atrial fibrillation (odds ratio 2.24 for a two-class improvement in modified European Heart Rhythm Association class, 95% CI 1.43–3.84; p  < 0.001), with lower NT-pro-B-type natriuretic peptide (geometric mean ratio 0.78, 95% CI 0.61 to 0.99; p  = 0.006). No interactions were observed for any baseline CTS with each outcome. Digoxin was associated with fewer adverse events (odds ratio 0.16, 95% CI 0.07–0.34; p  < 0.001), again without any interaction from circulating CTS. Digoxin levels by LC–MS/MS were strongly correlated with measurement by a clinical immunoassay ( r  = 0.87; p  < 0.001), and treatment with digoxin did not affect CTS concentrations at 6-month follow-up. Conclusions A range of CTS are detected in the circulation of patients with atrial fibrillation and heart failure. Within this randomised trial but limited by low circulating levels, CTS do not appear to interact with the ability of digoxin to improve wellbeing compared to conventional first-line treatment with beta-blockers. Graphical Abstract

Background and Objective As a β-adrenoceptor antagonist (β-blocker), esmolol can reduce cardiac output and the phosphodiesterase III inhibitor milrinone has been shown to improve heart contractility in patients with septic shock. This study was performed to assess the effects of esmolol combined with milrinone in patients with severe sepsis. Methods This prospective randomized study was conducted in patients with severe sepsis in the intensive care unit of the Jiangxi Provincial People’s Hospital (Nanchang, Jiangsu, China) between June 2013 and June 2014. Patients were randomly divided into control (C), milrinone (M), and milrinone–esmolol (ME) groups. The primary outcome was the rate of controlling the heart rate (HR) to achieve target levels. Secondary outcomes included the 28-day survival rate and changes in hemodynamic variables, organ function variables, myocardial injury markers, and the serum levels of proinflammatory factors. Result A total of 90 patients with severe sepsis were included in this study (30 per group). The HR in the ME group was lower than in the M and C groups after 12 h. The rate of successful HR control during the first 96 h was significantly higher in the ME group (60.0 vs. 33.3 % in the M group, vs. 26.7 % in the C group). Also, patients in the ME group had higher 28-day overall survival compared with the M (Log rank statistic = 5.452; P  = 0.020) and C groups (Log rank statistic = 10.206; P  = 0.001). Additionally, several variables showed significant improvement in the ME group 96 h after treatment compared with the M and C groups ( P  < 0.05). Conclusion Combination therapy with milrinone and esmolol could improve cardiac function and the 28-day survival rate in patients with severe sepsis.

Ischemia reperfusion (IR) injury may be attenuated through succinate dehydrogenase (SDH) inhibition by dimethyl malonate (DiMAL). Whether SDH inhibition yields protection in diabetic individuals and translates into human cardiac tissue remain unknown. In isolated perfused hearts from 24 weeks old male Zucker diabetic fatty (ZDF) and age matched non-diabetic control rats and atrial trabeculae from patients with and without diabetes, we compared infarct size, contractile force recovery and mitochondrial function. The cardioprotective effect of a 10 minutes DiMAL administration prior to global ischemia and ischemic preconditioning (IPC) was evaluated. In non-diabetic hearts exposed to IR, DiMAL 0.1 mM reduced infarct size compared to IR (55 ± 7% vs. 69 ± 6%, p < 0.05). Mitochondrial respiration was reduced by DiMAL 0.6 mM compared to sham and DiMAL 0.1 mM (p < 0.05). In diabetic hearts an increased concentration of DiMAL (0.6 mM) was required for protection compared to IR (64 ± 13% vs. 79 ± 8%, p < 0.05). Mitochondrial function remained unchanged. In trabeculae from humans without diabetes, IPC and DiMAL improved contractile force recovery compared to IR (43 ± 12% and 43 ± 13% vs. 23 ± 13%, p < 0.05) but in patients with diabetes only IPC provided protection compared to IR (51 ± 15% vs. 21 ± 8%, p < 0.05). Neither IPC nor DiMAL modulated mitochondrial respiration in patients. Cardioprotection by SDH inhibition is possible in human tissue, but depends on diabetes status. The narrow therapeutic range and discrepancy in respiration between experimental and human studies may limit clinical translation.