A diet enriched with mackerel (Scomber scombrus)-derived products improves the endothelial function in a senior population (Prevención de las Enfermedades Cardiovasculares: Estudio Santoña--PECES project).

BACKGROUND: Regular consumption of fish reduces cardiovascular risks. Here, we investigate if the consumption of products with mackerel (Scomber scombrus) with 8.82 g of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) content per 100 g of product improves parameters of endothelial function in a controlled population. MATERIALS AND METHODS: Subjects maintained a 12-week diet with products with mackerel. The population consisted of 58 senior subjects (12 withdrawals, 25 women), aged 82.08 +/- 8.13 years (Group A). Twenty-three senior subjects (13 women) on a regular diet were used as the control group (Group B). Subjects of Group A received 57 portions throughout 12 weeks (four to five portions a week of products with a mean EPA + DHA content of 2.5 g a day). A continuous follow-up and a final evaluation were performed to determine the level of consumption. Plasma samples were stored at -70 degrees C for a biochemical study. Endothelial function was analysed by reactive hyperemia with a mercury strain gauge plethysmography with measurement of blood flow in the forearm, both baseline and at the end of the 12-week diet. RESULTS: Endothelium-dependent vasodilatation significantly increased in Group A subjects (P < 0.001). No changes were found in Group B. The subgroup analyses showed that improvements were produced in Group A subjects without cardiovascular disease (P < 0.001). Nitrites/nitrates and von Willebrand factor plasma concentrations were higher in participants after the 12-week diet. CONCLUSIONS: The consumption of mackerel meat products improves endothelium-dependent, flow-mediated vasodilatation in a senior population. This finding might explain some of the cardioprotective effects of fish consumption.

Ischemic preconditioning and kidney transplantation: in vivo nitric oxide monitoring in a rat ischemia-reperfusion experimental model.

Direct nitric oxide measurement in live tissue would help us to understand its role in ischemia-reperfusion injury and its relationship to ischemic preconditioning (IP). We constructed four experimental groups of ischemia-reperfusion in the rat kidney: G1 were controls; G2, 1 hour of renal ischemia; G3 and G4: one or two 15/10 minute cycles, respectively, of IP prior to 1 hour of ischemia. Real-time in vivo nitric oxide measurements were compared with functional parameters of kidney damage at 24 hours. The peaks of nitric oxide production in the IP periods increased less in the rising curve of nitric oxide production during the 1 hour ischemia time. No improvement in the IP groups was observed based on serum creatinine levels at 24 hours.

Necesidad del manejo de la insuficiencia cardiaca congestiva por el internista y ventajas de la investigación clínica / Management of congestive heart by internist and advantages of clinic investigation

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Levels of plasma total adrenomedullin are related with two acute phase inflammatory reactants (fibrinogen and sialic acid) but not with markers of endothelial dysfunction in Type 1 diabetes Adrenomedullin and vascular risk factors in Type 1 DM.

Adrenomedullin (AM), an ubiquitous regulatory peptide with different actions, is known to be elevated in different clinical situations, including diabetes mellitus (DM), but its potential role in the pathogenesis of diabetic vascular complications is not clear. In the present study, we examined plasma total AM levels, and their association with different markers of endothelial dysfunction and with other established risk factors for cardiovascular diseases, in patients with Type 1 DM. We studied a total of 155 patients, 117 patients without any kind of vascular complications, 24 patients with retinopathy only, and 14 patients with retinopathy and microalbuminuria but normal renal function. None of them had clinical evidence of atherosclerotic disease. Compared with the control group (64 healthy participants), patients had raised fibrinogen, soluble E-selectin ((s)E-selectin), vascular cellular adhesion molecule (VCAM), angiotensin converting enzyme (ACE), and von Willebrand factor (vWf) (P<.001 in all cases), but plasma total AM, endothelin (ET), sialic acid, and homocysteine were not raised. In the diabetic group, AM levels correlated significantly with sialic acid (r=.16; P<.05), but a more significant correlation was found with fibrinogen (r=.30; P<.001). No correlation was found with the other parameters studied. In summary, plasma total AM levels seem to correlate with inflammatory markers but not with endothelial dysfunction markers in Type 1 diabetic patients without atherosclerotic disease.

Autoantibodies against oxidized LDL and serum total antioxidant status in active cyclists and ex-cyclists.

There is an apparent paradox between the benefits of aerobic exercise and the potentially deleterious effects of increased free radicals and decreased circulating antioxidants generated during exercise. To assess the oxidative/antioxidative status in competitive cyclists and ex-cyclists, we measured two markers not well studied in these situations, serum total antioxidant status (TAS) and antibodies against oxidized LDL (AuAb-ox-LDL) in 18 competitive male cyclists, 10 ex-competitive cyclists and 14 healthy males. AuAb-ox-LDL was evaluated by enzyme immunoassay, and serum TAS concentration was analyzed by spectrophotometry. Ex-cyclists had serum TAS levels statistically higher than the control group and cyclists group (p = 0.001 and p < 0.001, respectively). Active sportsmen showed significantly less AuAb-ox-LDL than healthy sedentary males, while there was a non-significant trend in the ex-cyclists to have lower AuAb-ox-LDL than the corresponding control group. AuAb-ox-LDL levels were not statistically different between the groups of active and previously active sporting men. There was a positive correlation between TAS and LDL-cholesterol in active cyclists under heavy training. In the ex-cyclist group, there was a negative correlation between serum TAS and the time elapsed since they had ended the competition. Competitive cycling decreases AuAb-ox-LDL levels, suggesting that it may decrease ox-LDL levels. After ending physical training, antioxidative status remains increased for at least one year, but the effect on AuAb-ox-LDL levels is lost.

Venous endothelial function in postmenopausal women after six months of tibolone therapy.

STUDY OBJECTIVE: To test venous endothelial function in long-term climateric therapy with tibolone. DESIGN: Measurement of dorsal hand-vein diameter by venous occlusion plethysmography during infusion of norepinephrine (NE), bradykinin (BK), NG-monomethyl L-arginine (L-NMMA) and sodium nitroprusside (SNP). SETTING: Plethysmography and Menopause Units. University Hospital Valdecilla. Santander. Spain. PATIENTS: Eleven postmenopausal women having continuous treatment with oral tibolone (2.5 mg/day) for 6 months. INTERVENTIONS: Three plethysmography studies were made: at baseline, and at three and six months of treatment. MAIN OUTCOME MEASURES: Dorsal hand-vein diameter measured by venous occlusion plethysmography during infusion of NE, BK, L-NMMA and SNP. RESULTS: (a) Baseline study: maximum dilation with BK was 54.2+/-10.2%. (b) Three-month study: BK dilation of 71.5+/-11.9%, with a significant increase of 17.3% (P=0.019) compared with baseline. (c) Six-month study: BK dilation of 77.5+/-11.9%, with a significant increase 23.3% (P=0.002) compared with baseline. Maximal vasodilation was reached with SNP in the three studies and L-NMMA infusion has a similar vasoconstrictor response in the three studies. CONCLUSIONS: Long-term climateric therapy with tibolone improves vein endothelium-dependent vasodilation suggesting a positive impact of this drug on endothelial function.

Venous endothelial function in postmenopausal women who are receiving long-term estrogen and progestagen therapy.

OBJECTIVE: To test venous endothelial function during long-term hormone replacement therapy (HRT) and after treatment withdrawal. DESIGN: Measurement of dorsal hand-vein diameter by venous occlusion plethysmography during infusion of norepinephrine, bradykinin, NG-monomethyl L-arginine, and sodium nitroprusside. SETTING: Plethysmography and menopause units, University Hospital Marqués de Valdecilla, Santander, Spain. PATIENT(S): Twenty postmenopausal women, of whom 10 were assigned to receive no hormone replacement therapy (HRT) for 6 months after plethysmography (group A) and 10 were assigned to receive HRT for 6 months (group B). After 6 months, HRT was administered to group A and withdrawn from group B for another 6 months. INTERVENTION(S): Plethysmography at baseline and at 6 and 12 months. MAIN OUTCOME MEASURE(S): Dorsal hand-vein diameter measured by venous occlusion plethysmography during infusion of norepinephrine, bradykinin, NG-monomethyl L-arginine, or sodium nitroprusside. RESULT(S): At 6 months, the maximum dilation obtained with bradykinin was 48.8 +/- 7.58% in group A and 76.7 +/- 12.9% in group B. At 12 months, maximum bradykinin dilation increased to 74.3 +/- 14.2% in group A and decreased to 54.0 +/- 15.9% in group B. CONCLUSION(S): Long-term HRT with estrogen plus progestin improves endothelium-dependent vasodilation, but this effect is lost in a relatively short time. Endothelial function in dorsal hand veins is an easy-to-use plethysmography model that can be used in serial studies.

[The Nobel Prize for nitric oxide. The unjust exclusion of Dr. Salvador Moncada]. / El Nobel para el óxido nítrico. La injusta exclusión del Dr. Salvador Moncada.

The 1998 Nobel Prize in Physiology and Medicine has been awarded jointly to North-American scientists, Dr Robert F. Furchgott, Louis J. Ignarro and Ferid Murad, for their discoveries in relation to "nitric oxide as a signalling molecule in the cardiovascular system". This has raised an important polemic because of the exclusion the South-American scientist, now nationalized British, Dr. Salvador Moncada. This short historical review examines some of the fundamental contributions to the knowledge in this field. It shows the sequence of the discoveries and the communication of them to the scientific community by the rewarded scientists and by Dr. Moncada. It is based on some fundamental publications in order to better understand this story, which does not coincide with the writing in 1996 by the Lasker Prize Committee, and which in 1998 was re-written again by the Nobel Committee of the Swedish Academy. More than 90 universities, academies and societies have acknowledged Dr. Moncada up to now with priority in the discovery of the fact that nitric oxide is released by endothelial cells, and the revealing of its metabolic way. More than 20,000 citations of their fundamental papers endorse in the scientific community his primacy in this field. Even Robert Furchgott, author of the brilliant discovery of the endothelium derived relaxing factor, that opened this field to the science, declared about the award of the 1998 Nobel Prize: "I feel that the Nobel Prize Committee could have made an exception this year and chosen a fourth person, Salvador Moncada (to share the prize)".

Effects of radiation on endothelial function.

PURPOSE: The response of endothelium to ionizing radiation was studied. METHODS AND MATERIALS: The abdominal aorta in different experimental groups of rats was irradiated, and the response of arterial rings from the irradiated segments to norepinephrine, acetylcholine (ACh), and nitroglycerin (NTG) was studied. Nonirradiated thoracic segments in the same experimental animals were used as as a control for comparisons. Two age-matched nonirradiated control groups were also studied. RESULTS: A poor endothelium-dependent vasodilator response was obtained with ACh in the irradiated rings and also in those not directly irradiated; the endothelium-independent vasodilator response to NTG was preserved during the first 3 days after irradiation. By 6 months, both the endothelium-dependent response and endothelium-independent response were impaired. CONCLUSIONS: Alterations in nitric oxide synthesis and/or release by the endothelium were observed during the early phase of radiation in irradiated and nonirradiated segments. In the delayed phase of radiation, endothelium-independent muscular relaxation was also affected.

Plasma adrenomedullin levels in type 1 diabetes. Relationship with clinical parameters.

OBJECTIVE: To assess the relationship between plasma adrenomedullin (AM) levels and the presence of microvascular complications in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: We measured plasma AM and cAMP levels in 103 type 1 diabetic patients (46 without complications, 24 with retinopathy only, 14 with microalbuminuria but normal kidney function, and 19 with renal insufficiency) and 41 matched healthy control subjects. RESULTS: Patients with renal insufficiency had higher levels of AM and cAMP than all other groups. Patients with only retinopathy showed a trend to have higher levels than patients without complications. There were no differences among all other groups. There was a significant correlation between AM and cAMP in the total diabetic group (rs = 0.36, P < 0.001) but not in the control group. In multiple regression analysis, plasma AM demonstrated significant relationships with creatinine clearance (beta = -0.31, P = 0.004) and duration of the disease (beta = 0.28, P = 0.008). CONCLUSIONS: Plasma AM and cAMP are increased in type 1 diabetic patients with renal insufficiency. Creatinine clearance (CrClc) and duration of the disease are related to plasma AM levels in these patients.

Age-related responses of vasoactive factors during acute exercise.

To evaluate the age-related response of vasoactive factors during acute exercise, young (n = 8, aged 23.6+/-2 years) and old (n = 13, aged 77+/-6 years) healthy volunteers performed a stress test using a treadmill, and blood samples were taken before and after exercise. There were neither basal (old people 77+/-53 vs. young people 67.6+/-40 pg/ml) nor peak exercise-related (old people 77+/-43 vs. young people 66.8+/-34 pg/ml) differences in plasma adrenomedullin (AM) between both groups. AM did not increase with exercise in either group. Regarding plasma cAMP, there were neither basal nor exercise related differences, but this nucleotide increased with exercise in both groups (old people p < 0.0001, young people p < 0.05). Plasma Atrial Natriuretic Peptide (ANP) was higher in basal (116.3+/-64 vs. 46.8+/-21 pg/ml, p < 0.003) and after exercise samples (150.2+/-76.5 vs. 68.7+/-29.5 pg/ml, p < 0.004) in old people as compared with young people. Old people showed an increase in ANP with exercise (p < 0.05), but in young people, though there was a trend to increase, it did not reach statistical significance. There were neither basal nor exercise related differences in plasma cGMP, but this nucleotide increased with exercise in both groups. Angiotensin II (AT-II) levels were lower in basal and after exercise samples in old people as compared with young people. AT-II levels did not increase with exercise in either group. These data suggest that, with increasing age, the vascular tree develops resistance to ANP and higher sensitivity to AT-II, while AM levels do not change. Exercise makes ANP changes more evident, while AM and AT-II are not modified.

Contribution of nitric oxide to exercise-induced changes in healthy volunteers: effects of acute exercise and long-term physical training.

Endothelium plays a central role in the regulation of regional blood flow through the release of certain vasoactive substances. We conducted this study to test whether an increase in the production of nitric oxide (NO) metabolites, atrial natriuretic peptide (ANP) and plasma and intraplatelet cyclic guanosine 3':5' monophosphate (cGMP) is involved in the adaptation to chronic exercise in physically trained people and in the vasodilatation induced by acute physical exercise. We studied one group of 10 trained athletes and another group of 10 untrained people. We measured plasma levels of nitrites, nitrates and cGMP and intraplatelet levels of cGMP, as an indicator of intracellular guanylate cyclase activity, and ANP before and after a maximal treadmill test. Resting cardiac rate (CR) and systolic blood pressure (SBP) were lower in the athlete group than in the control group (73.8 +/- 3.6 vs. 92 +/- 5.9; P < 0.02 and 110 +/- 2.58 vs. 118 +/- 3.27; P < 0.02 respectively). SBP did not show differences between groups after the exercise test. Diastolic blood pressure (DBP) at rest was lower in the athlete group (71 +/- 1.79 vs. 80.5 +/- 3.53; P < 0.03) and the decrease after maximal exercise was more pronounced in this group (64 +/- 2.67 vs. 74.5 +/- 3.2; P < 0.02). Basal plasma nitrites were 4.9 +/- 0.8 in the athlete group and 1.9 +/- 0.3 in the control group (P < 0.05). After exercise, test differences between groups remained (P < 0.05). Nitrates were significantly higher in the group of athletes and did not show exercise-related changes. Plasma levels of cGMP and ANP increased in both groups after the treadmill test, with no differences between groups. Among the athletes, cGMP increased from 1.11 +/- 0.1 to 2.6 +/- 0.4 (P < 0.001), whereas in the untrained group plasma cGMP rose from 1.14 +/- 0.09 to 1.86 +/- 0.2 (P < 0.01). There was a significant correlation between the increases in plasma cGMP and the atrial natriuretic peptide in both groups (r = 0.91, P < 0.0002, for athletes; and r= 0.68, P < 0.04, for control group). The intraplatelet concentration of cGMP did not show differences between groups and did not change after exercise. In conclusion, we have found increased basal levels of plasma nitrite and nitrate in trained subjects. Exercise does not produce differences in the increments of these metabolites. Therefore, we speculate the release of nitric oxide is not augmented by exercise in trained athletes.

Impaired vascular smooth muscle nitric oxide-dependent relaxation in human coronary arteries from "transplanted heart vasculopathy".

The long-term prognosis after heart transplant is mainly determined by the development of transplant vasculopathy. The pathogenic mechanism of transplant vasculopathy remain uncertain, although endothelial dysfunction has been postulated. The objective of this work is to evaluate the smooth muscle and endothelium nitric oxide relaxing mechanisms in coronary arteries from patients with transplant vasculopathy. We studied human coronary arteries obtained from heart transplant surgery specimens of patients with heart transplant vasculopathy, ischaemic cardiopathy or dilated cardiomyopathy. Rings from the coronary arteries were mounted on stainless steel hooks in 40 ml organ bath. The tissues were contracted with phenylephrine (approx. ED 80-90) and concentration-response curves were performed with glyceryltrinitrate and acetylcholine. Glyceryltrinitrate relaxed arterial rings from patients with dilated cardiomyopathy and ischaemic cardiopathy. Arterial rings from patients with heart transplant vasculopathy showed a lower response to glyceryltrinitrate. Acetylcholine induced dilatation of coronary arteries from dilated cardiomyopathy but increased the tension in coronary rings from heart transplant vasculopathy and inschaemic cardiopathy. In conclusion, there is a lower response to glyceryltrinitrate and a paradoxical response to acetylcholine in arteries from patients with transplant vasculopathy. The response to glyceryltrinitrate may be a meaningful tool in the early diagnosis of transplant vasculopathy.

Dose- and time-dependency of the dilator effects of the endothelin antagonist, BQ-123, in the human forearm.

AIMS: Endothelin-1 is a potent endogenous vasoconstrictor that acts on the endothelin A (ET[A]) receptor. The dose-response and time-course of the dilator effect of the ET(A) receptor antagonist, BQ-123, was investigated in the forearm of healthy volunteers. METHODS: Forearm blood flow was measured using mercury-in rubber strain gauge venous occlusion plethysmography. RESULTS: Following intra-arterial infusion of BQ-123 (50 nmol min-1) for 5 min, forearm blood flow increased by approximately 60% over the next 60 minutes; lower doses were without significant effect. The degree of dilatation was similar to that observed in previous studies using 20-fold larger doses. CONCLUSIONS: This study confirms that basal endothelin-1 has a role in the physiological regulation of vascular tone. It is possible that at low doses, BQ-123 might be a more sensitive pharmacological tool for the detection of abnormal endothelin-1 mediated constriction.