Influencia de la diabetes experimental sobre la reactividad de las arterias basilar, carótida y renal de conejo a la endotelina-1

RESUMEN Las complicaciones vasculares de la diabetes son principal causa de morbi-mortalidad del paciente diabético. Se ha estudiado la influencia de la diabetes experimental sobre la reactividad de las arterias basilar, carótida y renal a la endotelina-1 utilizando un modelo que permite el registro de la tensión isométrica desarrollada por los diferentes segmentos arteriales. Las conclusiones obtenidas han sido: 1. La diabetes experimental modifica la respuesta vascular a la endotelina-1 de forma dependiente del lecho vascular estudiado. 2. La diabetes induce hiperrreactividad de la arteria basilar de conejo a la endotelina-1 a través de al menos tres mecanismos: (1) menor modulación inhibitoria endotelial de esta respuesta, incluyendo la alteración de la actividad de los receptores endotelinérgicos ET-B endoteliales; (2) menor sensibilidad al óxido nítrico de las células del músculo liso vascular; y (3) mayor participación de los receptores endotelinérgicos ET-A y ET-B musculares que median vasoconstricción. 3. La diabetes induce hiperrreactividad de la arteria carótida de conejo a la endotelina-1 a través de al menos tres mecanismos: (1) mayor actividad de los receptores ET-A musculares; (2) alteración de la liberación de óxido nítrico mediada por la activación de los receptores ET-B y (3) mayor producción de tromboxano A2. 4. La hiperrreactividad de las arterias basilar y carótida a la endotelina-1 observada en la diabetes podría ser un factor condicionante del mayor riesgo de enfermedad cerebrovascular del paciente diabético 5. La diabetes induce cambios complejos en los mecanismos reguladores de la respuesta de la arteria renal a la endotelina-1: (1) aumento del NO endotelial; (2) alteración del balance de prostanoides vasoconstrictores (COX-1) y vasodilatadores (COX-2) en favor de estos últimos; (3) disminución del cociente entre prostanoides vasoconstrictores y vasodilatadores liberados tras la activación de los receptores ETA , predominando esta disminución sobre el aumento de dicho cociente tras la activación de los receptores ETB. La suma de todos estos cambios tiene como resultado una disminución de la sensibilidad de la arteria renal a la endotelina-1. 6. Deberían valorarse las posibles implicaciones vasculares del uso terapéutico de fármacos inhibidores de la COX-1 y COX-2 y de fármacos relacionados con la endotelina-1 en el manejo del paciente. __________________________________________________________________________________________________Vascular diabetes complications are the main cause of morbidity and mortality in the diabetic patient. The influence of alloxan-induced diabetes on the reactivity of rabbit basilar, carotid and renal arteries to endothelin-1 was examined by using a model in which isometric tension developed by the arterial segments is recorded. The conclusions obtained from this study are: 1. Experimental diabetes modifies the vascular response to endothelin-1 in a different way depending on the vascular bed. 2. Diabetes induces specific hyperreactivity of rabbit basilar artery to endothelin-1. The authors conclude that at least three causes could contribute to this hyperreactivity: 1) the lower endothelial inhibitory modulation of this response, including impaired activity of the endothelial endothelin ETB receptors which mediate vasodilatation through NO release; 2) the lower sensitivity to NO in the vascular smooth muscle cells; and 3) the greater participation of muscular endothelin ETA and ETB receptors that mediate vasoconstriction. 3. Diabetes induces hyperreactivity of the rabbit carotid artery to ET-1 by a mechanism that at least includes: 1) enhanced activity of muscular ETA receptors; 2) impairment of ETB receptors mediated NO release; and 3) enhancement of the production of thromboxane A2. 4. The hyperreactivity of the basilar and carotid bed to endothelin-1 could contribute to the greater susceptibility to cerebrovascular diseases of diabetic patients. 5. Diabetes induces complexes changes in the regulatory mechanisms that regulate the contractile response of the rabbit renal artery to endothelin-1: 1) enhancement of endothelial NO; 2) altered balance between vasoconstrictor (COX-1) and vasodilator (COX-2) prostanoids in favour of the last ones; and 3) decreased ratio between vasoconstrictor and vasodilator prostanoids released after activation of endothelin ETA receptors predominating on the increased ratio after activation of endothelin ETB receptors. The sum of these changes results in a decrease in the sensitivity of the renal artery to this peptide. 6. The possible vascular implications for the use of COX-inhibitors and endothelin-1 related drugs should be considered in diabetic patients

Different role of endothelin ETA and ETB receptors and endothelial modulators in diabetes-induced hyperreactivity of the rabbit carotid artery to endothelin-1

The influence of diabetes on regulatory mechanisms and specific receptors implicated in the contractile response of isolated rabbit carotid arteries to endothelin-1 was examined. Endothelin-1 induced a concentration-dependent contraction that was greater in arteries from diabetic rabbits than in arteries from control rabbits. Endothelium removal or NG-nitro-L-arginine enhanced contractions in response to endothelin-1 only in control arteries, without modifying the endothelin-1 response in diabetic arteries. Indomethacin, furegrelate (thromboxane A2 inhibitor), or cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123; endothelin ETA receptor antagonist) inhibited the contractions in response to endothelin-1, the inhibition being greater in diabetic arteries than in control arteries. 2,6-Dimethylpiperidinecarbonyl-g-methyl-Leu-Nin- (methoxycarbonyl)-D-Trp-D-Nle (BQ-788; endothelin ETB receptor antagonist) enhanced the contraction elicited by endothelin-1 in control arteries and displaced to the right the contractile curve for endothelin-1 in diabetic arteries. In summary, diabetes induces hyperreactivity of the rabbit carotid artery to endothelin-1 by a mechanism that at least includes: (1) enhanced activity of muscular endothelin ETA receptors; (2) impairment of endothelin ETB receptor-mediated nitric oxide (NO) release; and (3) enhancement of the production of thromboxane A2

Contribution of endothelin receptors and cyclooxygenase-derivatives to the altered response of the rabbit renal artery to endothelin-1 in diabetes

The influence of diabetes on regulatory mechanisms and specific receptors implicated in the response of isolated rabbit renal artery to endothelin-1 was examined. Endothelin-1 induced a concentration-dependent contraction that was less potent in arteries from diabetic rabbits than in arteries from control rabbits. Endothelium removal or NG-nitro-L-arginine (L-NOARG) enhanced contractions to endothelin-1 either in control and diabetic arteries. Indomethacin inhibited endothelin-1-induced response in control arteries, but enhanced it in diabetic arteries. In contrast to that observed in rubbed and in L-NOARG treated arteries, in the presence of indomethacin the contractile action of endothelin-1 was higher in diabetic arteries than in control arteries. Nimesulide enhanced endothelin-1 contractions both in control and diabetic arteries. Cyclo-(D-Asp-Pro-DVal-Leu-D-Trp) (BQ-123, endothelin ETA receptor antagonist), attenuated endothelin-1 vasoconstriction in control rabbits, while vasoconstriction resulted increased in diabetic rabbits. 2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle (BQ-788, endothelin ETB receptor antagonist), enhanced the contractile response in control rabbit arteries without modifying this response in diabetic rabbits. In summary, diabetes decreases the sensitivity of the rabbit renal artery to endothelin-1 by decreasing the ratio between vasoconstrictor and vasodilator prostanoids released after activation of endothelin ETA receptors

Mechanisms underlying diabetes enhancement of endothelin-1-induced contraction in rabbit basilar artery

The influence of alloxan-induced diabetes on the reactivity of rabbit basilar artery to endothelin-1 was examined. Endothelin-1 induced concentration-dependent contraction of basilar arteries that was higher in diabetic than in control rabbits. Endothelium removal produced a higher enhancement of the endothelin-1-induced contraction in control than in diabetic rabbits. NG-nitro-L-arginine (L-NOArg) enhanced the maximal contraction induced by endothelin-1 in control rabbits and potentiated this response in diabetic rabbits. Endothelin ETA receptor antagonist, cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), inhibited endothelin-1-induced contraction in both rabbit groups. Endothelin ETB receptor antagonist, 2,6-Dimethylpiperidinecarbonyl-g-Methyl Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle (BQ-788), enhanced endothelin-1-induced contraction in control rabbits and decreased the potency of endothelin-1 in diabetic rabbits. Sodium nitroprusside-induced relaxation of basilar arteries was lower in diabetic than in control rabbits. These results suggest that mechanisms underlying rabbit basilar artery hyperreactivity to endothelin-1 include decreased endothelial modulation of endothelin-1-induced contraction, with impaired endothelial endothelin ETB receptor activity; decreased sensitivity to nitric oxide (NO) in vascular smooth muscle; and enhanced participation of muscular endothelin ETA and ETB receptors

Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study

Background: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. Methods: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. Results: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). Conclusions: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.The work was supported by Internal Funds KU Leuven (STG-18-00379), the European Research Area Net for Cardiovascular Diseases (JTC2017-046-PROACT), the Ministerio de Ciencia e Innovación of Spain (PID2019-108973RB-C21 and C22 and PCIN2017-117), the Generalitat Valenciana of Spain (GV/2020/048), and GUTMOM (INTIMIC-085) from the EU Joint Programming Initiative Healthy Diet Healthy Life (HDHL).S

LDL particle size and composition and incident cardiovascular disease in a South-European population: The Hortega-Liposcale Follow-up Study.

The association of low-density lipoprotein (LDL) particle composition with cardiovascular risk has not been explored before. The aim was to evaluate the relationship between baseline LDL particle size and composition (proportions of large, medium and small LDL particles over their sum expressed as small-LDL %, medium-LDL % and large-LDL %) and incident cardiovascular disease in a population-based study. Methods: Direct measurement of LDL particles was performed using a two-dimensional NMR-technique (Liposcale®). LDL cholesterol was assessed using both standard photometrical methods and the Liposcale® technique in a representative sample of 1162 adult men and women from Spain. Results: The geometric mean of total LDL particle concentration in the study sample was 827.2 mg/dL (95% CI 814.7, 839.8). During a mean follow-up of 12.4 ± 3.3 years, a total of 159 events occurred. Medium LDL particles were positively associated with all cardiovascular disease, coronary heart disease (CHD) and stroke after adjustment for traditional risk factors and treatment. Regarding LDL particle composition, the multivariable adjusted hazard ratios for CHD for a 5% increase in medium and small LDL % by a corresponding decrease of large LDL % were 1.93 (1.55, 2.39) and 1.41 (1.14, 1.74), respectively. Conclusions: Medium LDL particles were associated with incident cardiovascular disease. LDL particles showed the strongest association with cardiovascular events when the particle composition, rather than the total concentration, was investigated. A change in baseline composition of LDL particles from large to medium and small LDL particles was associated with an increased cardiovascular risk, especially for CHD

PS-BPP03-3: CARDIOVASCULAR RISK AND METABOLIC CHARACTERIZATION OF METABOLICALLY HEALTHY OBESITY CLASSIFIED BY THE NEWLY PROPOSED DEFINITION: A PROSPECTIVE STUDY

Objective: The varying definition of metabolic health is responsible for the debate about whether metabolically healthy obesity (MHO) is associated with increased cardiovascular risk. An empirically derived definition of metabolic health has been newly proposed to identify individuals with obesity but without excess mortality risk. This study aimed to evaluate the association of MHO classified by the new definition with cardiovascular events and to reveal the metabolic characterization of MHO. Design and method: We classified 1331 Flemish people (mean age: 51.3 years; women: 50.3%) by their metabolic health status (systolic blood pressure \u3c 130 mmHg, waist-to-hip ratio \u3c 0.95 for women or 1.03 for men, and absence of antihypertensives and diabetes) and obesity status (body mass index \u3e = 25 kg/m2). Plasma 44 metabolites were measured by nuclear magnetic resonance spectroscopy at baseline. Hazard ratios (HRs), odds ratios, and 95% confidence intervals (95% CI) were calculated using Cox proportional hazard regressions and logistic regressions, accounting for sex, age, sex, smoking, alcohol, and physical activity. Results: During 5.6 years of follow-up, 111 cardiovascular events and 33 diabetes incidents occurred. MHO was not associated with cardiovascular events (HR 1.61, 95% CI: 0.49–5.27) compared with metabolically healthy normal weight. The HRs were 3.19 (95% CI: 1.07–9.53) and 3.27 (95% CI: 1.15–9.32) for metabolically unhealthy normal weight and obesity, respectively. Individuals with metabolic health had a lower risk of diabetes (HR: 0.22, 95%CI: 0.06–0.77). Compared with metabolically unhealthy obesity, MHO was associated with eight metabolites, including six with positive association (2-aminobutyrate, 4-aminobutyrate, alanine, leucine, 4-hydroxybutyrate, and acetate) and two with negative association (valerate and lactate). Metabolites positively associated with MHO showed inverse associations with diabetes risk, while metabolites negatively associated with MHO showed positive associations with diabetes risk. The associations of these metabolites with MHO reversed their directions compared with metabolically healthy normal weight. None of the eight metabolites was associated with cardiovascular events. Conclusion: This new definition of metabolic health can be replicated to stratify cardiovascular risk for individuals with or without obesity. The metabolic characterization of MHO was not completely ‘healthy’, which might help to identify novel targets for intervention

Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study

Background A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. Methods This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure \u3c 130 mmHg, no antihypertensive drugs, waist-to-hip ratio \u3c 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI \u3c 25, 25–30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. Results Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7–13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73–6.28] for normal weight, 2.50 [95% CI: 1.34–4.66] for overweight, and 3.42 [95% CI: 1.81–6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36–3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10–1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). Conclusions Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention

Time course of changes on systolic blood pressure and heart rate.

<p>Effects of either microparticles (MPs Shh+) or cyclopamine on systolic blood pressure (A). MPs Shh+ treatment abolished angiotensin II (Ang II)-induced hypertension. This effect was prevented by cyclopamine (B). Heart rate did not show differences between any groups (C). ***<i>P</i><0.001. Results are given as means ± SE of 8-10 mice for each group. The variability of the responses is so small that the error bars cannot be observable with this size of symbols. The dashed line indicate the time at which the mice received the osmotic pump in the absence or presence of Ang II, the arrows indicate the time at which the mice received MPs Shh+ or vehicle by i.v. injection.</p

Vascular response of small mesenteric arteries to flow.

<p>Flow-induced dilation obtained in small mesenteric arteries from mice receiving saline (control, CTL), microparticles alone (MPs Shh+), angiotensin II (ANG II), and the combination of ANG II plus MPs Shh+. Results are given as means ± SE of 6-11 mice for each group. **<i>P</i> < 0.01 and ***<i>P</i> < 0.001.</p