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The aim of this study was to investigate the biodynamic effects of vulgarenol, a sesquiterpene isolated from Magnolia grandiflora flower petals and its possible mechanism on the Langendorff isolated and perfused heart model. Vulgarenol (5 µ m) caused a statistically significant decrease in coronary vascular resistance (15.21 ± 6.00 dyn s cm−5 vs 36.80 ± 5.01 dyn s cm−5, control group), increased nitric oxide release (223.01 ± 8.76 pmol/mL vs 61.00 ± 12.00 pmol/mL, control group) and cyclic guanosine monophosphate accumulation in left ventricular tissue samples (142.17 ± 8.41 pmol/mg of tissue vs 43.94 ± 5.00 pmol/mg of tissue, control group). Pre-treatment with 3 µ m gadolinium chloride hexahydrate, 100 µ m N ω-nitro- l-arginine methyl ester hydrochloride, and 10 µ m 1 H-[1,2,4]oxadiazolo[4,2- a]quinoxalin-1-one significantly abolished the vulgarenol-induced coronary vascular resistance decrease, nitric oxide increased release and cGMP accumulation in left ventricular tissue samples. The results support the fact that nitric oxide and cyclic guanosine monophosphate are likely involved in the endothelium-dependent coronary vasodilation. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Garlic ( Allium sativum ) possesses healing properties for diseases like systemic arterial hypertension, cancer and diabetes, among others. Its main component, allicin, binds to the Transient Receptor Potential Vanilloid Type 1 (TRPV1). In this study, we investigated TRPV1's involvement in the regulation of various molecules at the systemic and aortic levels in Wistar rats treated with bacterial lipopolysaccharide (LPS) and garlic to activate the receptor. The experimental groups were as follows: 1) Control, 2) LPS, 3) Garlic, and 4) LPS + Garlic. Using Uv-visible spectrophotometry and capillary zone electrophoresis, we measured the levels of nitric oxide (NO), biopterins BH2 and BH4, total antioxidant capacity (TAC) and oxidizing capacity (OXCA). We also analyzed molecules related to vascular homeostasis such as angiotensin Ang 1-7 and Ang II, as well as endothelin ET-1. In addition, we assessed the inflammatory response by determining the levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and galectin-3 (GTN-3). For cell damage assessment, we measured levels of malondialdehyde (MDA), malonate (MTO) and 8-hydroxy-2-deoxyguanosine (8HO2dG). The results showed that LPS influenced the NO pathway at both systemic and aortic levels by increasing OXCA and reducing TAC. It also disrupted vascular homeostasis by increasing Ang-II and ET-1, while decreasing Ang1-7 levels. IL-6, TNFα, GTN-3, as well as MDA, MTO, and 8HO2dG were significantly elevated compared to the control group. The expression of iNOS was increased, but TRPV1 remained unaffected by LPS. However, garlic treatment effectively mitigated the effects of LPS and significantly increased TRPV1 expression. Furthermore, LPS caused a significant decrease in calcitonin gene-related peptide (CGRP) in the aorta, which was counteracted by garlic treatment. Overall, TRPV1 appears to play a crucial role in regulating oxidative stress and the molecules involved in damage and inflammation induced by LPS. Thus, studying TRPV1, CGRP, and allicin may offer a potential strategy for mitigating inflammatory and oxidative stress in sepsis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

The transient vanilloid receptor potential type 1 (TRPV1) regulates neuronal and vascular functions mediated by nitric oxide (NO) and by the calcitonin gene-related peptide (CGRP). Here, we study the participation of TRPV1 in the regulation of myocardial injury caused by ischemia-reperfusion and in the control of NO, tetrahydrobiopterin (BH4), the cGMP pathway, CGRP, total antioxidant capacity (TAC), malondialdehyde (MDA) and phosphodiesterase-3 (PDE-3). Isolated hearts of Wistar rats perfused according to the Langendorff technique were used to study the effects of an agonist of TRPV1, capsaicin (CS), an antagonist, capsazepine (CZ), and their combination CZ+CS. The hearts were subjected to three conditions: (1) control, (2) ischemia and (3) ischemia-reperfusion. We determined cardiac mechanical activity and the levels of NO, cGMP, BH4, CGRP, TAC, MDA and PDE-3 in ventricular tissue after administration of CS, CZ and CZ+CS. Western blots were used to study the expressions of eNOS, iNOS and phosphorylated NOS (pNOS). Structural changes were determined by histological evaluation. CS prevented damage caused by ischemia-reperfusion by improving cardiac mechanical activity and elevating the levels of NO, cGMP, BH4, TAC and CGRP. TRPV1 and iNOS expression were increased under ischemic conditions, while eNOS and pNOS were not modified. We conclude that the activation of TRPV1 constitutes a therapeutic possibility to counteract the damage caused by ischemia and reperfusion by regulating the NO pathway through CGRP.

The potential transient vanilloid receptor type 1 (TRPV1) plays important functional roles in the vascular system. In the present study, we explored the role of the TRPV1 in the production of nitric oxide (NO), biopterines (BH4 and BH2), cyclic guanosine monophosphate (cGMP), malondialdehyde (MDA), phosphodiesterase-3 (PDE-3), total antioxidant capacity (TAC), and calcitonin gene-related peptide (CGRP) in the rat aorta. Wistar rats were divided into four groups: (1) control, (2) capsaicin (CS, 20 mg/kg), (3) capsazepine (CZ, 24 mg/kg), and (4) CZ + CS. Treatments were applied daily for 4 days before removing the thoracic aortas for testing of aortic tissue and endothelial cells. TRPV1 activation produced increases in BH4 14%, cGMP 25%, NO 29%, and TAC 59.2% in comparison to the controls. BH2 and MDA increased with CZ. CGRP shows a tendency to decrease with CZ. The analysis by immunocytochemistry confirmed that the TRPV1 is present in aortic endothelial cells. Aortic endothelial cells were obtained from healthy rats and cultured to directly explore the effects of CS and CZ. The activation of the TRPV1 (CS 30  μ M) produced increases in BH4 17%, NO 36.6%, TAC 56.3%, and CGRP 65%, when compared to controls. BH2 decreased with CZ + CS. CS effects were diminished by CZ in cells and in the tissue. We conclude that the TRPV1 is a structure present in the membrane of aortic endothelial cells and that it participates in the production of NO. The importance of the TRPV1 should be considered in vascular reactivity studies., Competing Interests: The authors declare no conflict of interests., (Copyright © 2021 Elvira Varela-López et al.)

The purpose of the present study was to analyze the actions of transient receptor potential vanilloid type 1 (TRPV1) agonist capsaicin (CS) and of its antagonist capsazepine (CZ), on cardiac function as well as endothelial biomarkers and some parameters related with nitric oxide (NO) release in L -N G -nitroarginine methyl ester ( L -NAME)-induced hypertensive rats. NO has been implicated in the pathophysiology of systemic arterial hypertension (SAHT). We analyzed the levels of nitric oxide (NO), tetrahydrobiopterin (BH4), malondialdehyde (MDA), total antioxidant capacity (TAC), cyclic guanosin monophosphate (cGMP), phosphodiesterase-3 (PDE-3), and the expression of endothelial nitric oxide synthase (eNOS), guanosine triphosphate cyclohydrolase 1 (GTPCH-1), protein kinase B (AKT), and TRPV1 in serum and cardiac tissue of normotensive (118±3 mmHg) and hypertensive (H) rats (165 ± 4 mmHg). Cardiac mechanical performance (CMP) was calculated and NO was quantified in the coronary effluent in the Langendorff isolated heart model. In hypertensive rats capsaicin increased the levels of NO, BH4, cGMP, and TAC, and reduced PDE-3 and MDA. Expressions of eNOS, GTPCH-1, and TRPV1 were increased, while AKT was decreased. Capsazepine diminished these effects. In the hypertensive heart, CMP improved with the CS treatment. In conclusion, the activation of TRPV1 in H rats may be an alternative mechanism for the improvement of cardiac function and systemic levels of biomarkers related to the bioavailability of NO.

Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPAR γ ) ligand, has been reported to act as insulin sensitizer and exert cardiovascular actions. In this work, we hypothesized that RGZ exerts a PPAR γ -dependent regulation of blood pressure through modulation of angiotensin-converting enzyme (ACE)-type 2 (ACE2)/angiotensin-(1-7)/angiotensin II type-2 receptor (AT 2 R) axis in an experimental model of high blood pressure. We carried on experiments in normotensive (Sham) and aortic coarctation (AoCo)-induced hypertensive male Wistar rats. Both sham and AoCo rats were treated 7 days with vehicle (V), RGZ (5 mg/kg/day), or RGZ+BADGE (120 mg/kg/day) post-coarctation. We measured blood pressure and vascular reactivity on aortic rings, as well as the expression of renin-angiotensin system (RAS) proteins. We found that RGZ treatment in AoCo group decreases blood pressure values and improves vascular response to acetylcholine, both parameters dependent on PPAR γ -stimulation. RGZ lowered serum angiotensin II (AngII) but increased Ang-(1-7) levels. It also decreased 8-hydroxy-2'-deoxyguanosine (8-OH-2dG), malondialdehyde (MDA), and improved the antioxidant capacity. Regarding protein expression of RAS, RGZ decreases ACE and angiotensin II type 1 receptor (AT 1 R) and improved ACE2, AT 2 R, and Mas receptor in AoCo rats. Additionally, an in silico analysis revealed that 5'UTR regions of RAS and PPAR γ share motifs with a transcriptional regulatory role. We conclude that RGZ lowers blood pressure values by increasing the expression of RAS axis proteins ACE2 and AT 2 R, decreasing the levels of AngII and increasing levels of Ang-(1-7) in a PPAR γ -dependent manner. The in silico analysis is a valuable tool to predict the interaction between PPAR γ and RAS.

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.

Numerous studies have supported a role for oxidative stress in the development of ischemic damage and endothelial dysfunction. Crataegus oxyacantha ( Co ) and Rosmarinus officinalis ( Ro ) extracts are polyphenolic-rich compounds that have proven to be efficient in the treatment of cardiovascular diseases. We studied the effect of extracts from Co and Ro on the myocardial damage associated with the oxidative status and to the production of different vasoactive agents. Rats were assigned to the following groups: (a) sham; (b) vehicle-treated myocardial infarction (MI) (MI-V); (c) Ro extract-treated myocardial infarction (MI- Ro ); (d) Co extract-treated myocardial infarction (MI- Co ); or (e) Ro+Co -treated myocardial infarction (MI- Ro+Co ). Ro and Co treatments increased total antioxidant capacity, the expression of superoxide dismutase (SOD)-Cu 2+ /Zn 2+ , SOD-Mn 2+ , and catalase, with the subsequent decline of malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels. The extracts diminished vasoconstrictor peptide levels (angiotensin II and endothelin-1), increased vasodilators agents (angiotensin 1-7 and bradikinin) and improved nitric oxide metabolism. Polyphenol treatment restored the left intraventricular pressure and cardiac mechanical work. We conclude that Ro and Co treatment attenuate morphological and functional ischemic-related changes by both an oxidant load reduction and improvement of the balance between vasoconstrictors and vasodilators., Competing Interests: The authors declare no conflict of interest.

Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1β, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.

We investigated whether fenofibrate, metformin, and their combination generate cardioprotection in a rat model of type 2 diabetes (T2D) and acute myocardial infarction (AMI). Streptozotocin-induced diabetic- (DB-) rats received 14 days of either vehicle, fenofibrate, metformin, or their combination and immediately after underwent myocardial ischemia/reperfusion (I/R). Fenofibrate plus metformin generated cardioprotection in a DBI/R model, reported as decreased coronary vascular resistance, compared to DBI/R-Vehicle, smaller infarct size, and increased cardiac work. The subchronic treatment with fenofibrate plus metformin increased, compared with DBI/R-Vehicle, total antioxidant capacity, manganese-dependent superoxide dismutase activity (MnSOD), guanosine triphosphate cyclohydrolase I (GTPCH-I) expression, tetrahydrobiopterin : dihydrobiopterin (BH4 : BH2) ratio, endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) bioavailability, and decreased inducible NOS (iNOS) activity. These findings suggest that PPARα activation by fenofibrate + metformin, at low doses, generates cardioprotection in a rat model of T2D and AMI and may represent a novel treatment strategy to limit I/R injury in patients with T2D.

Since the end of the XVIII century, digitalis glycosides were employed in heart failure. They were considered initially as diuretics and later as cardiotonic agents or as positive inotropics. At the present time there are varied groups of positive inotropic agents, which have a beneficial action on the failing human myocardium. For example, the beta adrenergics, the phosphodiesterase III inhibitors such as milrinone, or the sensibilizers of myocardial proteins to Ca++ such as levosimendan and omecamtiv mecarbil. However, following the opinion of distinguished cardiologists, in the case of heart failure associated to atrial fibrillation, digitalis cannot be substituted.

We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin-angiotensin system in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Male Wistar rats were treated with L-NAME (75.0 mg·(kg body mass)(-1)·day(-1), in their drinking water) for different durations (1-33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg(-1)·day(-1)) or celecoxib (1.0 mg·kg(-1)·day(-1)) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with L-NAME, and both peaked at 19-25 days. In addition, L-NAME increased renal 6-Keto-PGF(1α) (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF(1α) at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in L-NAME-induced hypertension.

Objective: Strengthen knowledge about the pathophysiology of aortic stenosis., Methods: Urinary levels of angiotensin-(1-7) and angiotensin II were compared between two samples: A) forty five patients with severe aortic stenosis, without systemic arterial hypertension and with normal kidney and normal left ventricular systolic function; B) control group: twenty one persons without cardiovascular disease., Null Hypothesis: there would be no difference between urinary levels., Results: The average of angiotensin-(1-7) urinary concentration in severe aortic stenosis patients was 2.102 pmol/mL and 5.591 pmol/mL for the control group. The average of Ang II was 0.704 pmol/mL and 0.185 pmol/mL respectively. Using t-Student test, we determine that the difference in urinary concentration of angiotensin-(1-7) [p=0.633] and the difference of angiotensin II (p=0.631), were statistically significant., Conclusion: documented a statistically significant difference in urinary levels angiotensin II and angiotensin-(1-7) within the group of patients with severe aortic stenosis.

We describe the procedure developed for the simultaneous detection and quantification of angiotensin II and angiotensin-(1-7), by capillary zone electrophoresis with UV detection by photodiode-array, at a wavelength of 200 nm, in the plasma and urine from hypertensive rats. Optimal separation was achieved with a 100mM boric acid+3mM tartaric acid+10 fM gold (III) chloride electrolyte solution at pH 9.80. The applied voltage was 30 kV and the capillary temperature was kept constant at 20 degrees C. The method was over the concentration range of 0.01-500 pmol/mL. All determination coefficients were higher or equal to 0.9985. Limits of detection and quantification for angiotensin II were 0.0110 pmol/mL (S/N=3) and 0.0195 pmol/mL (S/N=5), respectively. While for angiotensin-(1-7), the limits were 0.0112 pmol/mL (S/N=3) and 0.0193 pmol/mL (S/N=5), respectively. The present method offers a time-saving way to simultaneous determination of angiotensin II and angiotensin-(1-7), since it can be completed in 10 min, compared to other methodologies reported in the literature for capillary electrophoresis and liquid chromatography, which require more than 1h for analysis of complex matrices, such as plasma and urine. The procedure is illustrated by experiments that quantify simultaneously angiotensin II and angiotensin-(1-7) in plasma and urine from hypertensive and normotensive rats, with and without antihypertensive treatment. The levels of angiotensin II and angiotensin-(1-7) detected in the experimental model, resulted in a recovery of 99.00-106.01% and a reproducibility of less than 10%. The proposed analytical method is a use full tool for the simultaneous detection of angiotensin II and angiotensin-(1-7) implicated in vascular remodeling in pathologies such as hypertension., (Copyright (c) 2009 Elsevier B.V. All rights reserved.)

Purpose: The endothelial function is the cornerstone of several cardiovascular disease. In this trial we compared how the Nitric Oxide (NO) and Oxidative Stress (OS) serum levels, as surrogate markers of endothelial function, change in patients who received (or not) rosuvastatin during the first seven days of an acute coronary syndrome (ACS)., Methods: Twenty-two patients with ACS (age:66 +/- 9 years, gender: ten female and 12 male) were randomized in two groups. Patients in the first group (G1) received the conventional treatment for an ACS, plus placebo. The other group (G2) additionally received a daily oral dose of 40 mg of rosuvastatin. We measured the blood levels of nitrates and OS in both groups twice: at baseline (admission to Intensive care unit) and seven days after. The statistical analysis was performed using the paired t-test or the Chi2 test depending of the variables. Statistical significance was considered with a p < 0.05., Results: Groups (G1 and G2) differed statistically on age (G1=71 years +/- 10 vs. G2 63 +/- 9 years, p=0.04). After 7 days of the ACS onset, ON levels diminished on 21% (p=0.17) in G1, but raised on 24% in the group who re- ceived rosuvastatin (p=0.005), with statistically difference between groups (p=0.005). On the other hand, the OS, augmented statistically on both groups: G1 (17%, p<0.001) and G2 (13%, p<0.001), without any difference between groups (p=0.77)., Conclusion: The endothelial dysfunction in the first days of an ACS is accentuated, but with the use of rosuvastatina, the endothelial function improves. In contrast, the OS increase in both groups, without differences between groups.

We describe a capillary zone electrophoretic procedure with photodiode-array detection for the determination of the apoptogenic protein cytochrome c in cytosolic fractions and mitochondrial extracts from guinea pig hearts. Optimal separation was achieved with a 100mM phosphates electrolyte solution at pH 2.05. The applied voltage was 25kV and the capillary temperature was kept constant at 25+/-0.5 degrees C. The method was linear over the concentration range of 0.2-600pM. All determination coefficients were higher or equal to 0.9989. Limits of detection and quantitation were 0.06pM (S/N=3) and 0.21pM (S/N=10), respectively. The present method offers a time-saving way to determine cytochrome c since it can be completed in 12min, compared to a time scale of days for Western blotting methods, or hours for ELISA-based methods. The procedure is illustrated by experiments that quantify cytochrome c released under control conditions and in a digitalis intoxication experimental animal model, in which cytochrome c content was successfully determined and was found to be (mean+/-standard deviation): control cytosol (0.48+/-0.01pM), digitalis-intoxicated cytosol (0.85+/-0.01pM), control mitochondria (1.11+/-0.1pM) and digitalis-intoxicated mitochondria (0.75+/-0.02pM). Recovery results ranged from 98.4 to 110.2%. Hence, the proposed analytical method could be useful to elucidate the digitalis intoxication mechanism as well as the role of cytochrome c in mediating apoptosis.

Inflammatory status is involved in the pathophysiology of several cardiovascular disorders and in the genesis of high blood pressure. In this disease inflammation results from the activity of several hematological cells as well as the presence of chemotactic factors, immunological reactivity and hyperactivity of vasoconstrictor systems as that of the renin-angiotensin. Clinical evaluation of hypertension recommends secreening of several proinflammatory substances in hypertensive patients in order to evaluate their level of cardiovascular risk. Interleukin-6 and C reactive protein have been considered the most usual risk biomarkers. Interleukin 6 is a potent proinflammatory compound which participates in the acute fase of the tissular reaction to lesions associated to immunological, ischemic or oxidative stress. C reactive protein participates during inflammation activating the first component of complement with disorganization of the phospholipidic array of the endothelial sarcolemmal membrane and the consequent endothelial dysfunction related to the genesis of high blood pressure.

Vulgarenol, a sesquiterpene isolated from Magnolia grandiflora flower petals, decreased coronary vascular resistance in the Langendorff isolated and perfused heart model, when compared to the control group [(15.2 x 10(7) +/- 1.0 x 10(7)) dyn s cm(-5) vs. (36.8 x 10(7) +/- 1.2 x 10(7)) dyn s cm(-5)]. Our data suggest that this coronary vasodilator effect probably involved inducible and endothelial nitric oxide synthase overexpression (6.8 and 4.2 times over control, respectively), which correlated with increases in nitric oxide release [(223 +/- 9) pmol mL(-1) vs. (61 +/- 11) pmol mL(-1)] and in cyclic guanosine monophosphate production [(142 +/- 8) pmol mg(-1) of tissue vs. (44 +/- 10) pmol mg(-1) of tissue], as compared to control values. This effect was antagonized by 3 microm gadolinium(III) chloride, 100 microM N-nitro-L-arginine methyl ester, and 10 microM 1H-[1,2,4]oxadiazolo[4,2-a]quinoxalin-1-one. Hence, the vulgarenol-elicited coronary vasodilator effect could be mediated by the nitric oxide-soluble guanylyl cyclase pathway.

It has been suggested that dietary intake of flavonoids may reduce the risk of cardiovascular diseases. On the other hand, in vitro and in vivo studies shows that flavonoids has a vast array of biological activities. Our aim in this review is to put in evidence the effect of flavonoids on several enzymatic systems that could act as potential therapeutic targets, based on the reports of diverse research groups, leaders in the natural products research area, have published through the years, and with the goal of consolidating those results with the findings provided by some epidemiological studies, could support the introduction of these compounds into the clinic.

After prolonged periods of ischemia and energy depletion, the ischemic myocardial cell can be jeopardized by specific causes within the reperfusion period. These causes can be viewed as unwanted aspects of the recovery process itself limiting its efficiency. Three potential initial causes of immediate reperfusion injury, aside from oxygen radicals, have been experimentally investigated in detail, and are briefly discussed: 1. re-energization; 2. rapid normalization of tissue pH; and 3. rapid normalization of tissue osmolality. These potential causes are not entirely independent. Understanding of the basic causes has opened novel perspectives for specific interference with these serious pathomechanisms. The experimental results obtained in the last years encourage the development of therapeutic approaches to reduce infarct size by specific measures applied during the early phase of reperfusion. In the clinical setting, reperfusion therapy for acute myocardial infarction (AMI) has shown to reduce mortality, yet it may also have deleterious effects, including myocardial necrosis and no-reflow. Almost two decades ago, great hope arose from the description of ischemic preconditioning. Unfortunately, ischemic preconditioning is not feasible in the clinical practice because the coronary artery is already occluded at the time of hospital admission of the AMI patient. Recently, in the dog model, a phenomenon called "postconditioning" has been described. It has been reported previouly that reperfusion injury can be significantly reduced by modifying the conditions and the composition of the initial reperfusate. Whereas preconditioning is triggered by brief episodes of ischemia-reperfusion performed just before a prolonged coronary artery occlusion, postconditioning is induced by a comparable sequence of reversible ischemia-reperfusion, but it is applied "just after the prolonged" ischemic insult. Protection afforded by postconditioning is as potent as that provided by preconditioning. Unlike preconditioning, the experimental design of postconditioning allows direct application in the clinical practice, especially during PTCA. It has been reported very recently, that postconditioning patients with ST segment elevation AMI, during coronary angioplasty protects the human heart in this clinical scenario. Obtaining such a beneficial effect by a simple manipulation of reperfusion is of major potential clinical interest. Now more than ever, mechanistic and pharmacological research in the field of reperfusion injury appears to be necessary and clinically relevant.

The pharmacological effect of a Viscum album aqueous extract was evaluated on the Langendorff isolated and perfused heart model in normotense male guinea pig hearts. Coronary vascular resistance, left intraventricular pressure, nitric oxide release in the perfusion liquid, cyclic guanosine monophosphate production, and analysis of inducible and endothelial nitric oxide synthases expression by Western Blot in ventricular tissue were recorded in absence and presence of blockers and inhibitors, such as 3 microM gadolinium chloride, 100 microM N(omega)-nitro-L-arginine methyl ester and 10 microM 1H-[1,2,4]oxadiazolo[4,2-a]quinoxalin-1-one. V. album aqueous extract exerts a significant decrease in the coronary vascular resistance, which courses with significant increases in nitric oxide and cyclic guanosine monophosphate production. Analysis of the expression of both nitric oxide synthases revealed that this extract significantly induces the expression of both isoforms in guinea pig hearts. These effects were inhibited by the presence of blockers and inhibitors. The coronary vasodilation induced by the extract is mediated by the nitric oxide/soluble guanylyl cyclase pathway. In addition, this extract shows a positive inotropic effect which that is tyramine-mediated by means of beta1-adrenergic stimulation.

Objective: Based on a National Re-survey on Hypertension (HTA) and other cardiovascular risk factors performed in Mexico during 2003 and 2004 in the adult population with HTA, as identified in the 2000 National Survey of Health, this study was planed to determine: 1) morbidity and mortality rates; 2) the incidence and interrelation with other risk factors, such as overweight, obesity, dyslipidemia, nephropathy and diabetes; 3) the main risk factors associated to HTA involved in its complications, need for hospitalization and number of days; and, 4) the degree of therapeutical adhesion and the type of antihypertensive drugs used., Methods: The survey was of type III using the step by step method described by WHO. Sampling was weighed a priori taking into account a national prevalence average of HTA of 30.05% and its corresponding rate for each federal state. Permissible maximum error in the estimation = 0.28. Effect of design = 4.5; and, Rate of awaited answer (0.70)., Results: From the initial 14,567 interviewed patients, 1,165 (8%) subjects were considered non-hypertensive or false positives at the 2000 survey. From the 13,402 remaining patients, 335 died during the first 2 years of pursuit, which implies an annual mortality of approximately 1.15% in the hypertensive population. Thus, 13,067 survivors were subjected to the final analysis. The mean age at the re-survey was 45.6 +/- 12.6; 40.5% were men (n = 5,295). There was a statistically significant difference in height, but not in weight between both genders. The control HTA was raised 14.6% in the year 2000 and 19.2% in 2004. The prevalence of diabetes was duplicated from 16% to 30% (< .001). Fifty four percent of the whole population required hospitalization at least once during the period of study. The rates of overweight, obesity, and dyslipidemia rose significantly (p < 0.05) independently from age, federal state, and gender., Conclusion: RENAHTA shows the impact of hypertension on the morbidity and mortality during the 3.1 +/- 1.5 years of follow-up in Mexico. It alerts us on the need to reinforce the strategies of attention and prevention of this crucial risk factor and of screening the dynamic nonlinear interaction between the main cardiovascular risk factors in Mexico. New hypotheses are proposed for the metabolic syndrome.

Several extracts from diverse Magnolia grandiflora varieties were pharmacological evaluated in the cardiac muscle. From March to July, flowers and leaves from Magnolia grandiflora, native from the National Institute of Cardiology "Ignacio Chávez", from north, west, and orient zones from Mexico City, and from Puebla, Colima and Chiapas states were collected. They were separately processed and the extracts were obtained by maceration with ethanol-water (1:3 v/v) at 4 degrees C during two weeks. Qualitative analysis was accomplished with thin-layer, column and high-performance liquid chromatographies (HPLC). Functional and molecular analysis was made by specific chemical reactivity and by protonic magnetic resonance (RMN 1H). Pharmacological evaluation was completed in isolated and perfused male guinea pigs hearts. Extracts, fractions, and compounds were administrated by serial bolus in a gradual dose-response curves study in which left intraventricular pressure and coronary perfusion pressure were recorded, evaluating by such the positive inotropic and vasodilator effects of Magnolia grandiflora extracts. Vulgarenol and 2-p-hydroxyphenyl-2-hydroxy-ethylamine were isolated and identified, and the obtained results suggest that its positive inotropic and vasodilator effects are owed to these substances, being complemented by magnograndiolide and tyramine.

Nitric oxide and cytochrome P450 arachidonic acid metabolites participate in blood pressure regulation. The synthesis of these autacoids leads to arterial hypertension. However, it is not known whether there is an interaction between them. Therefore, we studied the modulatory effect of nitric oxide and cytochrome P450-arachidonic acid metabolites, their interaction on blood pressure, and the renal content of cytochrome P450. Male Wistar rats were divided: 1) control, 2) L-NAME (100 mg/kg/d p.o.), 3) L-NAME + SnCl2 (10 mg/kg/d i.p.), and 4) L-NAME + dexamethasone (1 mg/kg/d s.c.). We measured blood pressure and collected urine and blood for nitric oxide measurement. NO2 was quantified by HPLC. Blood pressure was: control, 97 +/- 7 mmHg; L-NAME, 151 +/- 4.6 mmHg; L-NAME + SnCl2, 133 +/- 3 mmHg, and L-NAME + dexamethasone 152 +/- 4.5 mmHg. Urine nitrite concentration was: 1) 1.832 +/- 0.32, 2) 1.031 +/- 0.23, 3) 1.616 +/- 0.33, and 4) 1.244 +/- 0.33 mumol/mL, while the concentration in blood was: 1) 0.293 +/- 0.06, 2) 0.150 +/- 0.05, 3) 0.373 +/- 0.13, and 4) 0.373 +/- 0.07 mumol/mL. L-NAME + SnCl2 decreased cytochrome P450 renal content, and L-NAME + dexamethasone showed a similar response. In conclusion, both, nitric oxide and CYP-arachidonic acid metabolites play a role in the regulation of blood pressure. Nitric oxide also partially regulates renal cytochrome P450 content.

The results of three clinical studies (OVERTURE, ENABLE and RENEWAL), in patients with cardiac failure, are analyzed from a pharmacological point of view. In the first one of these, the action of an Angiotensin Converting Enzyme inhibitor, that at the same time inhibits the neutral endopeptidase, is studied. In the second, a blockade for endothelin cellular receptors is studied and, in the third, a synthetic acceptor of the alpha-Tumoral Necrosis Factor is taken into account. In the OVERTURE study, the benefit action of the inhibition of the Angiotensin Converting Enzyme in patients suffering from cardiac failure is confirmed, without a major effect from the neutral endopeptidase derived from its simultaneous inhibition. The other two studies were suspended because of the major side effects. The drugs used in OVERTURE, ENABLE and RENEWAL studies are relevant efforts of molecular design that, without any question, will project into the future of the therapeutic approach of cardiac failure. It is convenient to point out that in the task of designing clinical studies considering cellular signaling systems, there are other venues warranting their use in pathological or natural functions.

In spite their reduced therapeutic index, digitalis-type drugs continue being used for treating diseases such as congestive heart failure and chronic atrial fibrillation. Thanks to the development of several methods, their structural determination has been feasible, so, structural modifications have been worked out to modulate their toxicity. Several reports realizes that efficacy for these digitalis-type drugs lies on the electronegativity centered on the steroidal moiety (D-ring) generated by either lactone and hydroxyl substituents attached to the steroidal moiety. In this work, we report how electronegativity, and so structural conformation, does modify their pharmacological properties, e.g., inotropism and safety margin. Thus, we evaluated a series of eleven drugs derived from digitoxigenin, named -OH, -Lac, D-01, D-02, D-03, D-07, D-14, D-15, D-20, D-21 and D-22, with groups that substitute both lactone and hydroxyl groups on the steroidal D-ring. Electronegativity and conformational energy were determined by Duhamm's method. The pharmacological evaluation for these drugs was accomplished in guinea pigs isolated hearts (according to the model proposed by Langendorff) and dog's isolated heart (as established by Starling's in vivo model). The results may suggest that digitalis-like action lies on the substituents attached to the D-ring. Positive inotropic effect and therapeutic index are related with increases in electronegativity as well with decreases in rotational and translational energies; therefore, these molecular properties have such importance for the digitalis efficacy.

Purpose: To determine the prevalence and interrelation of noncommunicable chronic diseases (NCCD), obesity, smoking, and proteinuria in the adult population (between 20 and 69 years of age) of Mexico, and their stratification according to age, gender, and geographical area., Method: During the year 2000, a probabilistic national survey was performed in 45,300 persons. The sample size was calculated to approach NCCD with a minimal estimated prevalence of 6%. The survey corresponds to type III of the step-by-step method described by WHO. Data were weighted for the distribution of the population and gender, according to the national survey of population and housing (National Institute of Statistics and Geography, INEGI)., Results: A total of 38,377 (98.8%) of individuals were included in the analysis; 69.4% were women. Average age for men was 39.4 +/- 12.9 and for women 38.6 +/- 13.0. National average prevalence for hypertension was 30.05%, for diabetes of 10.7%, for obesity of 24.4%, for abnormal capillary glucose of 12.7%, and for proteinuria of 9.2%. Prevalence for hypertension and diabetes were directly related with age, body mass index, and waist perimeter. The pyramidal distribution of the Mexican population determined that the greatest proportion of prevalence of NCCD was given by those under 54 years of age with a statistical significance (> 75%)., Conclusion: ENSA 2000 demonstrates the marked increase in NCCD prevalence in the Mexican population and alerts on the urgent need of national strategies to restrain this important public health problem. Strategies must be oriented towards an integrated approach of the NCCD, since their clinical and physiopathological interrelation is clearly demonstrated through ENSA 2000.

Unlabelled: The toxic effect of digitalis compounds at cell level produces an intracellular Ca2+ overload and a decrease in intracellular concentrations of K+. Since Ca2+ and K+ are critical modulators of life and death, the purpose of this study was to explore the cell death pathway activated through the ionic imbalance provoked by digitalis intoxication. We present results of cell toxicity in a study performed with ouabain acting on a HeLa cells culture and on guinea pig heart myocites under ouabain intoxication., Results: In tissue culture, ouabain produced inhibition of cell viability in a time and dose dependent manner. Through ethidium-bromide staining, nuclear condensation and fragmentation were observed. The electrophoretic analysis of nuclear DNA in agarose gel showed a degradation pattern characteristic of apoptosis. In histologic sections of guinea pig heart under ouabain intoxication (50-60% of lethal doses), in situ cell death was detected by in situ DNA TUNEL labeling. We conclude that the electrical and physiologic imbalance produced by toxic doses of ouabain activates mechanisms that cause cell death via apoptosis in heart myocites and fast growing cells.

High-risk patients, during anesthesia and after surgery present changes in pharmacokinetics (biotransformation reactions, renal clearance, drug interactions, etc.) modifying the usefulness of most drugs, cardiac inotropics included. This group of substances is formed by adrenergic agents, phospodiesterase inhibitors and digitalis compounds. Adrenergic agents are the catecholamines, adrenaline (A), noradrenaline (NA) and dopamine (D), plus dopaminergic agonists as dobutamine and pirbuterol. Phosphodiesterase inhibitors, as amrinone and milrinone, produce their inotropic action by preserving cyclic adenosine monophosphate (AMPc) from its intracellular catabolism. Recent studies on the utility of digitalis compounds demonstrated the valuable applicability of digoxin in chronic and acute heart failure. Another group of substances whose mechanism of action differs from that of the inotropics, offers future utility in high risk patients, they include: inhibitors of nitric oxide sintases, natriuretic atrial peptide inhibitors, Q-10 coenzyme, endothelin antagonists, and anti-tumoral necrosis factor.

Aims: Hypertension remains as a major cause of cardiovascular morbidity in México. The Health National Survey 2000 of México was performed to analyze the current status of the prevalence of some risk factors such as diabetes, hypertension (HTA), obesity, smoking, and proteinuria., Methods: A National Survey was carried out in México where 45,300 individuals between 20 to 69-y.o. were screened. The estimated sample size was calculated considering the total number of persons into the mentioned age; a minimal prevalence of 6% of the included risk factors, at a significance level of 0.05; a maximum relative error of 0.145, and a rate of response of at least 70%. Diagnosis of HTA was accepted in: previous medical diagnosis with prescription of antihypertensive drugs, or high blood pressure (> or = 140/90 mmHg) detected during the interview. Data were adjusted for the national distribution of age-groups and gender (established in 2000, INEGI)., Results: 38,377 (98.8%) individuals were correctly screened for blood pressure. The prevalence of hypertension in México was 30.05% (34.2% in men and 26.3% in women). The prevalence was directly related with age and gender. The percentage of mexicans with HTA after 50-y.o. is > 50%. The prevalence was greater in women after 50-y.o. Among persons with hypertension, treatment was detected in 46% and approximately 20% of them were controlled (< 140/90 mmHg). The percentage of mexicans with HTA who were unaware that they have high blood pressure was 61%. The total percentage of HTA controlled was 14.6%. The North states had the greater prevalence (approximately 34%) of HTA while South states had the lower prevalence (27%). The odds ratio (age/sex-adjusted) for HTA were: for diabetes 1.54(CI95%, 1.44-1.63); for obesity 2.3 (CI 95%, 2.22-2.43); for smoking 1.26 (CI 95%, 1.21-1.32). For proteinuria subjects, 40% had HTA., Conclusions: Around 15 millions of mexicans between 20 to 69-y.o. had hypertension, 60% of them are unaware. The prevalence of hypertension in México (30.05%) has increased. Among persons with hypertension -15% are controlled. The North of México has the higher prevalence of hypertension. Diabetes, smoking, and obesity increase the risk of hypertension. The 2000 National Survey of Health shows the epidemiological trend in several important chronic diseases in México and declare an urgent need of new strategies for detection, control and treatment of hypertension.

In order to explore the hypothesis about the existence of an adenylic component on ouabain effects on the atrioventricular node, we perform experiments on anesthetized and vagotomized dogs. Decremental propagation of impulses through atrioventricular conduction system was evaluated stimulating the right atria at frequencies from 3.5 to 5.0 per second. Aminophylline antagonized and dipyridamole synergized the atrioventricular decremental conduction induced by digitalis. The blockade of purinergic receptors produced by aminophylline and the inhibition of adenosine endocytosis by dipyridamole could explain these antagonic and synergistic interaction with ouabain, and constitute an experimental evidence favorable to the possibility of the existence of a purinergic component on the digitalis mechanism of action.