Purinergic component in the coronary vasodilatation to acetylcholine after ischemia-reperfusion in perfused rat hearts.

To determine the involvement of purinergic receptors in coronary endothelium-dependent relaxation, the response to acetylcholine (1 × 10(-8) to 3 × 10(-7)M) was recorded in isolated rat hearts perfused according to the Langendorff procedure before and after 30 min of ischemia and 15 min of reperfusion and after the inhibition of nitric oxide synthesis with L-NAME (10(-4)M), in the absence and presence of the antagonist of purinergic P2X receptors, PPADS (3 × 10(-6)M), and of the antagonist of purinergic P2Y receptors, Reactive Blue 2 (3 × 10(-7)M). In control conditions, the relaxation to acetylcholine was not altered by PPADS or Reactive Blue 2. The relaxation to acetylcholine was reduced after ischemia-reperfusion, and, in this condition, it was further reduced by treatment with PPADS or Reactive Blue 2. Likewise, the relaxation to acetylcholine was reduced by L-NAME, and reduced further by Reactive Blue 2 but not by PPADS. These results suggest that the relaxation to acetylcholine may be partly mediated by purinergic receptors after ischemia-reperfusion, due to the reduction of nitric oxide release in this condition.

Early in vivo detection of denervation-induced atrophy by luminescence transient nanothermometry.

Denervation induces skeletal muscle atrophy due to the loss of control and feedback with the nervous system. Unfortunately, muscle atrophy only becomes evident days after the denervation event when it could be irreversible. Alternative diagnosis tools for early detection of denervation-induced muscle atrophy are, thus, required. In this work, we demonstrate how the combination of transient thermometry, a technique already used for early diagnosis of tumors, and infrared-emitting nanothermometers makes possible the in vivo detection of the onset of muscle atrophy at short (<1 day) times after a denervation event. The physiological reasons behind these experimental results have been explored by performing three dimensional numerical simulations based on the Pennes' bioheat equation. It is concluded that the alterations in muscle thermal dynamics at the onset of muscle atrophy are consequence of the skin perfusion increment caused by the alteration of peripheral nervous autonomous system. This work demonstrates the potential of infrared luminescence thermometry for early detection of diseases of the nervous system opening the venue toward the development of new diagnosis tools.

Time-dependent dual effect of NLRP3 inflammasome in brain ischaemia.

BACKGROUND: Inflammasomes are cytosolic multiprotein complexes which, upon assembly, activate the maturation and secretion of the inflammatory cytokines IL-1ß and IL-18. However, participation of the NLRP3 inflammasome in ischaemic stroke remains controversial. Our aims were to determine the role of NLRP3 in brain ischaemia, and explore the mechanism involved in the potential protective effect of the neurovascular unit. METHODS: WT and NLRP3 knock-out mice were subjected to ischaemia by middle cerebral artery occlusion (60 min) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: We identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1ß and TNF-α), NLRP3 inflammasome components (NLRP3 and pro-caspase-1), protease expression (MMP9), and endothelial adhesion molecules (ICAM and VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junction proteins (ZO-1 and Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration. CONCLUSIONS: These findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischaemia with potential clinical translation.

Nitric oxide-mediated relaxation to lactate of coronary circulation in the isolated perfused rat heart.

The objective of this study was to analyze the effects of lactate on coronary circulation. Rat hearts were perfused in a Langendorff preparation, and the coronary response to lactate (3-30 mM) was recorded after precontracting coronary vasculature with 11-dideoxy-1a,9a-epoxymethanoprostaglandin F2α (U46619), in the presence or the absence of the inhibitor of nitric oxide synthesis, N-omega-nitro-l-arginine methyl ester (l-NAME, 10 M), the blocker of Ca-dependent potassium channels, tetraethylammonium (TEA, 10 M), or the blocker of adenosine triphosphate-sensitive potassium channels, glybenclamide (10 M). The effects of lactate were also studied in isolated segments of rat coronary arteries that were precontracted with U46619, with or without endothelium. In perfused hearts, lactate induced concentration-dependent coronary vasodilatation and a reduction in myocardial contractility (left ventricular developed pressure and dP/dt) without altering the heart rate. Coronary vasodilatation in response to lactate was reduced by l-NAME but unaffected by TEA or glybenclamide. The effects of lactate on myocardial contractility were unchanged by l-NAME, TEA, or glybenclamide. In isolated coronary artery segments, lactate also produced relaxation, an effect attenuated by removing the endothelium. Together these findings suggest that lactate exerts coronary vasodilatory effects through the release of endothelial nitric oxide, independently of potassium channels. These findings may be relevant for the regulation of coronary circulation when lactate levels are elevated.

Supplementation with a Carob (Ceratonia siliqua L.) Fruit Extract Attenuates the Cardiometabolic Alterations Associated with Metabolic Syndrome in Mice.

The incidence of metabolic syndrome (MetS) is increasing worldwide which makes necessary the finding of new strategies to treat and/or prevent it. The aim of this study was to analyze the possible beneficial effects of a carob fruit extract (CSAT+®) on the cardiometabolic alterations associated with MetS in mice. 16-week-old C57BL/6J male mice were fed for 26 weeks either with a standard diet (chow) or with a diet rich in fats and sugars (HFHS), supplemented or not with 4.8% of CSAT+®. CSAT+® supplementation reduced blood glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-c), insulin, and interleukin-6 (IL-6). In adipose tissue and skeletal muscle, CSAT+® prevented MetS-induced insulin resistance, reduced macrophage infiltration and the expression of pro-inflammatory markers, and up-regulated the mRNA levels of antioxidant markers. Supplementation with CSAT+® prevented MetS-induced hypertension and decreased the vascular response of aortic rings to angiotensin II (AngII). Moreover, treatment with CSAT+® attenuated endothelial dysfunction and increased vascular sensitivity to insulin. In the heart, CSAT+® supplementation reduced cardiomyocyte apoptosis and prevented ischemia-reperfusion-induced decrease in cardiac contractility. The beneficial effects at the cardiovascular level were associated with a lower expression of pro-inflammatory and pro-oxidant markers in aortic and cardiac tissues.

Ultrafast photochemistry produces superbright short-wave infrared dots for low-dose in vivo imaging.

Optical probes operating in the second near-infrared window (NIR-II, 1,000-1,700 nm), where tissues are highly transparent, have expanded the applicability of fluorescence in the biomedical field. NIR-II fluorescence enables deep-tissue imaging with micrometric resolution in animal models, but is limited by the low brightness of NIR-II probes, which prevents imaging at low excitation intensities and fluorophore concentrations. Here, we present a new generation of probes (Ag2S superdots) derived from chemically synthesized Ag2S dots, on which a protective shell is grown by femtosecond laser irradiation. This shell reduces the structural defects, causing an 80-fold enhancement of the quantum yield. PEGylated Ag2S superdots enable deep-tissue in vivo imaging at low excitation intensities (<10 mW cm-2) and doses (<0.5 mg kg-1), emerging as unrivaled contrast agents for NIR-II preclinical bioimaging. These results establish an approach for developing superbright NIR-II contrast agents based on the synergy between chemical synthesis and ultrafast laser processing.

Effects of endothelin-1 on the relaxation of rat coronary arteries.

To analyze the effects of endothelin-1 on the b-adrenergic response of the coronary circulation, 2-mm-long segments of coronary arteries from rats were prepared for isometric tension recording in organ baths. The relaxation to isoproterenol (3 x 10(-8) M), field electrical stimulation (4 Hz, 0.1-millisecond duration, 10 seconds), acetylcholine (3 x 10(-8) M), and sodium nitroprusside (10(-9) M) was recorded in arteries precontracted with U46619 (10(-7) to 5 x 10(-7) M) before and after treatment with endothelin-1 (3 3 10210 and 1029 M). The relaxation to isoproterenol was increased by treatment with endothelin-1 and with the endothelin ET(B) antagonist BQ788 (10(-6) M) but not with the endothelin ET(A) antagonist BQ123 (10(-6) M) or with the blocker of protein kinase C chelerythrine (10(-5) M). In the presence of BQ788, BQ123, or chelerythrine, endothelin-1 did not modify the relaxation to isoproterenol. Treatment with endothelin-1 did not modify the relaxation to electrical stimulation, acetylcholine, or sodium nitroprusside. These results suggest that endothelin-1 may potentiate coronary beta-adrenergic vasodilatation, at least in part due to stimulation of endothelin ET(A) receptors and activation of protein kinase C.

Response to endothelin-1 in arteries from human colorectal tumours: role of endothelin receptors.

To examine the reaction of tumour arteries to endothelin-1, we obtained arteries supplying blood flow to colorectal tumours from patients, as well as mesenteric arteries supplying the normal colon tissue from the same patients and mesenteric arteries from patients without a colorectal tumour pathology. The contraction in response to endothelin-1 and the relaxation produced by bradykinin was recorded in each of these arteries. Accordingly, the sensitivity to endothelin-1 but not the maximal response, was higher in the arteries supplying colorectal tumours than in mesenteric arteries supplying normal colon or in mesenteric arteries from patients with no tumour pathology. The contraction produced by endothelin-1 was not modified by exposure to L-NAME or meclofenamate in arteries supplying both the tumour and the normal colon. The endothelin ET(A) andET(B) receptors were expressed similarly in arteries supplying the tumour or normal colon. However, the antagonist of the endothelin ET(B) receptors BQ788 (10(-6) M) decreased the contractions in the arteries supplying the tumour but not in those supplying the normal colon. By contrast, the antagonist of endothelin ET(A) receptors BQ123 (10(-6) M) reduced the contraction equally in both these types of arteries. Likewise, in arteries precontracted with U46619, the relaxation in response to bradykinin was similar in all three types of arteries. Together, these results suggest that the arteries supplying human colorectal tumours are more sensitive to endothelin-1, which could be due to the enhanced activity of endothelin ET(B) receptors in the absence of any change in the modulatory effect of nitric oxide or prostanoids in the arterial response to this peptide.

Endothelin-1 potentiation of coronary artery contraction after ischemia-reperfusion.

Hearts from Sprague-Dawley rats were perfused at constant flow and then exposed to 30 min global zero-flow ischemia followed by 15 min reperfusion. After ischemia-reperfusion, coronary arteries were dissected from the heart and segments 2 mm long were prepared for isometric tension recording in organ baths. Stimulation of the arteries with 5-hydroxytryptamine (10(-6) M) produced contraction, which was potentiated by treatment with endothelin-1 (3x10(-10); 10(-9) M). This potentiation was lower in the arteries from hearts after ischemia-reperfusion (for 3x10(-10) M, 15+/-5%; P>0.05; for 10(-9) M, 37+/-7%, P<0.01, n=5) than after control (for 3x10(-10) M, 34+/-4%; P<0.01; for 10(-9) M, 50+/-6%, P<0.01, n=5), and the potentiation was reduced by the inhibitor of nitric oxide synthesis l-NAME (10(-4) M), the antagonist of endothelin ET(A) receptors BQ123 (10(-6) M) and the antagonist of endothelin ET(B) receptors BQ788 (10(-6) M), but not by the cyclooxygenase inhibitor meclofenamate (10(-5) M). These results suggest that endothelin-1 at low concentrations potentiates coronary vasoconstriction, and this effect is reduced after ischemia-reperfusion, mediated by endothelin ET(A) and ET(B) receptors and dependent on nitric oxide release.

Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids.

Apelin effects were examined in human splanchnic arteries from liver donors (normal arteries) and from liver recipients. Segments 3 mm long were obtained from mesenteric arteries taken from liver donors (normal arteries), and from hepatic arteries taken from cirrhotic patients undergoing liver transplantation (liver recipients), and the segments were mounted in organ baths for isometric tension recording. In arteries under resting conditions, apelin (10(-10)-10(-6) M) caused no effect in any of the arteries tested. In arteries precontracted with the thromboxane A(2) analogue U46619 (10(-7)-10(-6) M), apelin (10(-10)-10(-6) M) produced concentration-dependent relaxation that was lower in hepatic than in mesenteric arteries, whereas sodium nitroprusside (10(-8)-10(-4) M) produced a similar relaxation in both types of arteries. The inhibitor of nitric oxide synthesis N(w)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) diminished the relaxation to apelin in mesenteric but not in hepatic arteries. The inhibitor of cyclooxygenase meclofenamate (10(-5) M) did not affect the relaxation provoked by apelin in both types of arteries. Therefore, apelin may produce relaxation in normal human splanchnic arteries, and this relaxation may be mediated in part by nitric oxide without involvement of prostanoids. This relaxation as well as the role of nitric oxide may be decreased in splanchnic arteries from cirrhotic patients.

Adrenergic response of splanchnic arteries from cirrhotic patients: role of nitric oxide, prostanoids, and reactive oxygen species.

Peripheral and splanchnic vasodilatation in cirrhotic patients has been related to hyporesponsiveness to vasoconstrictors, but studies to examine the vascular adrenergic response provide contradictory results. Hepatic arteries from cirrhotic patients undergoing liver transplantation and mesenteric arteries from liver donors were obtained. Segments 3 mm long from these arteries were mounted in organ baths for testing isometric adrenergic response. The concentration-dependent contraction to noradrenaline (10(-8) to 10(-4) M) was similar in hepatic and mesenteric arteries, and prazosin (alpha 1-adrenergic antagonist, 10(-6) M), but not yohimbine (alpha 2-adrenergic antagonist, 10(-6) M), produced a rightward parallel displacement of this contraction in both types of arteries. Phenylephrine (alpha 1-adrenergic agonist, 10(-8) to 10(-4) M) and clonidine (alpha 2-adrenergic agonist, 10(-8) to 10(-4) M) also produced concentration-dependent contractions that were comparable in hepatic and mesenteric arteries. The inhibitor of cyclooxygenase meclofenamate (10(-5) M), but not the inhibitor of nitric oxide synthesis N(w)-nitro-l-arginine methyl ester (l-NAME, 10(-4) M), potentiated the response to noradrenaline in hepatic arteries; neither inhibitor affected the response to noradrenaline in mesenteric arteries. Diphenyleneiodonium (DPI; 5 x 10(-6) M), but neither catalase (1000 U/ml) nor tiron (10(-4) M), decreased the maximal contraction for noradrenaline similarly in hepatic and mesenteric arteries. Therefore, it is suggested that, in splanchnic arteries from cirrhotic patients, the adrenergic response and the relative contribution of alpha 1- and alpha 2-adrenoceptors in this response is preserved, and prostanoids, but not nitric oxide, may blunt that response. Products dependent on NAD(P)H oxidase might contribute to the adrenergic response in splanchnic arteries from control and cirrhotic patients.

Endothelium-dependent relaxation of isolated splanchnic arteries from cirrhotic patients: Role of reactive oxygen species.

AIM: To examine the endothelium-dependent relaxation of splanchnic arteries during cirrhosis as well as the role of reactive oxygen species in this relaxation using hepatic arteries from cirrhotic patients undergoing liver transplantation and mesenteric arteries from liver donors. METHODS: Arterial segments 3 mm long were mounted in organ baths for isometric tension recording and precontracted with the thromboxane A(2) analog U46619 (10(-7)-10(-6) M). RESULTS: The relaxation to acetylcholine (10(-8)-10(-4) M), but not to sodium nitroprusside (10(-8)-10(-4) M) was lower in hepatic arteries. The inhibitor of nitric oxide synthesis, N(omega)-nitro-l-arginine methyl ester (l-NAME, 10(-4) M), the inhibitor of cyclooxygenase, meclofenamate (10(-5) M), or l-NAME (10(-4) M) + meclofenamate (10(-5) M) diminished the relaxation to acetylcholine only in mesenteric arteries. l-NAME (10(-4) M) + meclofenamate (10(-5) M) combined with charybdotoxin (10(-7) M) + apamine (10(-6) M) inhibited the relaxation toacetylcholine in both types of arteries, and this inhibition was greater than with l-NAME + meclofenamate. The scavenger of hydrogen peroxide, catalase (1000 U/mL), the superoxide dismutase mimetic, tiron (10(-2) M) or the inhibitor of NAD(P)H oxidase, diphenyleneiodonium (5 x 10(-6) M), but not the inhibitor of superoxide dismutase, diethyldithiocarbamate (10(-3) M) potentiated the acetylcholine-induced relaxation only in hepatic arteries. l-NAME did inhibit the relaxation to acetylcholine in hepatic arteries pretreated with catalase or tiron. CONCLUSIONS: Cirrhosis may decrease endothelial release and/or bioavailability of nitric oxide and prostacyclin in splanchnic arteries, which might be caused partly by increased production of reactive oxygen species.

Effects of age and caloric restriction in the vascular response of renal arteries to endothelin-1 in rats.

Cardiovascular alterations are the most prevalent cause of impaired physiological function in aged individuals with kidney being one the most affected organs. Aging-induced alterations in renal circulation are associated with a decrease in endothelium-derived relaxing factors such as nitric oxide (NO) and with an increase in contracting factors such as endothelin-1(ET-1). As caloric restriction (CR) exerts beneficial effects preventing some of the aging-induced alterations in cardiovascular system, the aim of this study was to analyze the effects of age and caloric restriction in the vascular response of renal arteries to ET-1 in aged rats. Vascular function was studied in renal arteries from 3-month-old Wistar rats fed ad libitum (3m) and in renal arteries from 8-and 24-month-old Wistar rats fed ad libitum (8m and 24m), or subjected to 20% caloric restriction during their three last months of life (8m-CR and 24m-CR). The contractile response to ET-1 was increased in renal arteries from 8m and 24m compared to 3m rats. ET-1-induced contraction was mediated by ET-A receptors in all experimental groups and also by ET-B receptors in 24m rats. Caloric restriction attenuated the increased contraction to ET-1 in renal arteries from 8m but not from 24m rats possibly through NO release proceeding from ET-B endothelial receptors. In 24m rats, CR did not attenuate the aging-increased response of renal arteries to ET-1, but it prevented the aging-induced increase in iNOS mRNA levels and the aging-induced decrease in eNOS mRNA levels in arterial tissue. In conclusion, aging is associated with an increased response to ET-1 in renal arteries that is prevented by CR in 8m but not in 24m rats.

In Vivo Ischemia Detection by Luminescent Nanothermometers.

There is an urgent need to develop new diagnosis tools for real in vivo detection of first stages of ischemia for the early treatment of cardiovascular diseases and accidents. However, traditional approaches show low sensitivity and a limited penetration into tissues, so they are only applicable for the detection of surface lesions. Here, it is shown how the superior thermal sensing capabilities of near infrared-emitting quantum dots (NIR-QDs) can be efficiently used for in vivo detection of subcutaneous ischemic tissues. In particular, NIR-QDs make possible ischemia detection by high penetration transient thermometry studies in a murine ischemic hindlimb model. NIR-QDs nanothermometers are able to identify ischemic tissues by means of their faster thermal dynamics. In addition, they have shown to be capable of monitoring both the revascularization and damage recovery processes of ischemic tissues. This work demonstrates the applicability of fluorescence nanothermometry for ischemia detection and treatment, as well as a tool for early diagnosis of cardiovascular disease.

Goat cerebrovascular reactivity to ADP after ischemia-reperfusion. Role of nitric oxide, prostanoids and reactive oxygen species.

To analyze the cerebrovascular effects of ischemia-reperfusion, cerebrovascular reactivity to ADP was studied after inducing 60-min occlusion followed by 60-min reperfusion of the left middle cerebral artery (MCA) in anesthetized goats. In 12 goats, at the end of reperfusion, left MCA resistance was decreased by 19%, and reactive hyperemia to 5- and 10-s occlusions as well as the cerebral vasodilatation to ADP (0.03-0.3 microg) but not to sodium nitroprusside (0.3-3 microg) was decreased. In 28 animals, killed at the end of reperfusion, segments 3-mm long were obtained from the left (ischemic) and right (control) MCA, prepared for isometric tension recording, and precontracted with the thromboxane A2 analogue U46619. The relaxation to ADP (10(-8) to 10(-5) M) but not to sodium nitroprusside (10(-8) to 10(-4) M) was lower in ischemic arteries. L-NAME (inhibitor of nitric oxide synthesis, 10(-4) M), charybdotoxin (10(-7) M)+apamin (10(-6) M) (blockers of KCa), or catalase (1000 U/ml) reduced the relaxation to ADP only in control arteries. Charybdotoxin+apamin further augmented the L-NAME-induced reduction in the relaxation to ADP in control arteries. The inhibitor of cyclooxygenase meclofenamate (10(-5) M) increased the relaxation to ADP only in ischemic arteries. The superoxide dismutase mimetic tiron (10(-2) M) increased the ADP-induced relaxation only in ischemic arteries. Therefore, it is suggested that ischemia-reperfusion produces cerebrovascular endothelial dysfunction, which may be associated with decreased nitric oxide bioavailability, decreased release of an EDHF, and increased production of vasoconstrictor prostanoids. All these alterations may be related in part with an increased production of superoxide anion.

Vasoconstrictor prostanoids may be involved in reduced coronary reactive hyperemia after ischemia-reperfusion in anesthetized goats.

To examine coronary vasodilator reserve after ischemia-reperfusion, reactive hyperemia was determined during reperfusion after partial and total, brief and prolonged ischemia. To this, left circumflex coronary artery flow was electromagnetically measured, and partial (60 min) or total (15 and 60 min) occlusions of this artery were induced, followed in each case by 60-min reperfusion in anesthetized goats untreated and treated with N(W)-nitro-l-arginine methyl ester (l-NAME) or meclofenamate. In untreated and treated animals, coronary flow was decreased during reperfusion after the three types of ischemia. In hyperemic responses to 5- and 10-s coronary occlusions, repayment of debt decreased during reperfusion after the three types of ischemia in untreated animals, and this decrease was not affected by l-NAME. This decrease during reperfusion after partial and total, 60-min ischemia, but not after total, 15-min ischemia, reversed with meclofenamate. Peak hyperemic flow/control flow ratio decreased only during reperfusion after total 60-min occlusion in untreated animals and it was normalized by meclofenamate. These results show that ischemia-reperfusion reduces hyperemic response (vasodilator reserve); this diminution being dependent on duration and severity of ischemia. The hyperemic responses reduction during reperfusion after prolonged ischemia, but not after brief ischemia may be related at least in part to increased production of vasoconstrictor prostanoids.

Effects of antagonists for endothelin ET(A) and ET(B) receptors on coronary endothelial and myocardial function after ischemia-reperfusion in anesthetized goats.

To compare the effects of antagonists for endothelin ET(A) and ET(B) receptors on the action of ischemia-reperfusion on endothelial and myocardial function, 30 min of partial or total occlusion followed by 60 min of reperfusion of the left circumflex coronary artery was induced in anesthetized goats treated with intracoronary administration of saline (vehicle), BQ-123 (endothelin ET(A) receptors antagonist) or BQ-788 (endothelin ET(B) receptors antagonist). During reperfusion after partial occlusion, coronary vascular conductance and left ventricle dP/dt were decreased after saline or BQ-788, and they normalized after BQ-123. In these three groups of animals, the coronary effects of acetylcholine (3-100 ng) and sodium nitroprusside (1-10 microg) during reperfusion were as under control. During reperfusion after total occlusion, coronary vascular conductance and left ventricle dP/dt were decreased after saline, and they normalized after BQ-123 or BQ-788. In these three groups of animals, the coronary effects of acetylcholine but not those of sodium nitroprusside during reperfusion were decreased after saline, and they reversed after BQ-123 or BQ-788. Therefore, selective antagonists of endothelin ET(B) and ET(A) receptors may produce similar protection of coronary vasculature and myocardium against reperfusion after severe ischemia. Selective antagonists of endothelin ET(B) receptors, contrarily to those of endothelin ET(A) receptors, may be ineffective to protect coronary vasculature and myocardium against reperfusion after mild ischemia.

Uso de Solución Hipertónica en pacientes con insuficiencia cardiaca aguda como terapia adyuvante a altas dosis de diuréticos / Use of Hypertonic Solution in patients with acute heart failure as adjunctive therapy to high-dose diuretics

Resumen La insuficiencia cardíaca aguda descompensada (ICAD) es una causa común de hospitalización, con repercusiones significativas en los sistemas de salud. El manejo agudo se basa en la reducción de la volemia con diuréticos de asa, sin embargo, un porcentaje de pacientes presenta resistencia o no logra la respuesta clínica esperada con este tratamiento. Una de las medidas que ha comprobado ser efectiva en este contexto, es el uso de solución salina hipertónica (SSH) en conjunto con dosis altas de diuréticos de asa, como medida terapéutica temida por sus posibles repercusiones sobre la función renal y posible sobrecarga de sodio. Objetivos: Determinar si el uso de solución salina hipertónica en pacientes con falla cardiaca aguda e hipervolemia genera un deterioro de la función renal. Determinar la respuesta del Pro-BNP ante el uso de la solución salina hipertónica en pacientes con falla cardiaca aguda como marcador de respuesta terapéutica. Determinar si el uso de solución salina hipertónica aumenta la diuresis sin generar cambios importantes en el sodio. Se muestran datos de pacientes con insuficiencia cardiaca aguda descompensada, que tras no presentar mejoría con altas dosis de diurético de asa en bolo, se les aplicó la solución hipertónica como adyuvante a este tratamiento. Se toma un total de 26 pacientes analizando datos generales clínicos y de laboratorio, se valoran curvas con la respuesta diurética y por parámetros de laboratorio a las 48 y 72 horas. El uso de solución salina hipertónica consigue un aumento de más de un 200% de la diuresis en 24 horas, con un descenso del Pro BNP de más de un 60% a las 48 horas, sin mostrar un cambio importante en los niveles de creatinina, nitrógeno ureico y sodio. Se requirió reposición de potasio en la totalidad de los pacientes. Se concluye que la infusión de furosemida más solución hipertónica es efectiva tanto en disminuir niveles de NT Pro-BNP en los pacientes, como en generar un aumento en el volumen de diuresis. La principal complicación fue la hipokalemia, sin cambios considerables en el valor de sodio, creatinina y nitrógeno ureico séricos.

Abstract Uso de Solución Hipertónica en pacientes con insuficiencia cardiaca aguda como terapia adyuvante a altas dosis de diuréticos Acute decompensated heart failure (AHF) is a common cause of hospitalization, with significant repercussions on health systems. Acute management is based on the reduction of blood volume with loop diuretics; however, a percentage of patients show resistance or do not achieve the expected clinical response with this treatment. One of the measures that has proven to be effective in this context is the use of hypertonic saline (HSS) in conjunction with high doses of loop diuretics, as a therapeutic measure feared due to its possible repercussions on kidney function and possible sodium overload. Objetives: To determine if the use of hypertonic saline in patients with acute heart failure and hypervolemia leads to a deterioration in renal function. To determine the response of Pro-BNP to the use of hypertonic saline in patients with acute heart failure as a marker of therapeutic response. Determine if the use of hypertonic saline increases urine output without causing significant changes in sodium. Data are shown from patients with acute decompensated heart failure, who after not presenting improvement with high doses of bolus loop diuretic, the hypertonic solution was applied as an adjunct to this treatment. A total of 26 patients are taken analyzing general clinical and laboratory data, curves with the diuretic response and by laboratory parameters are evaluated at 48 and 72 hours. The use of hypertonic saline solution achieves an increase of more than 200% in diuresis in 24 hours, with a decrease in Pro BNP of more than 60% at 48 hours, without showing a significant change in creatinine levels, urea nitrogen and sodium. Potassium replacement was required in all patients. It is concluded that the infusion of furosemide plus hypertonic solution is effective both in reducing levels of NT Pro-BNP in patients, and in generating an increase in the volume of diuresis. The main complication was hypokalemia, without significant changes in serum sodium, creatinine, and urea nitrogen.

Mechanisms of the protective effects of urocortin on coronary endothelial function during ischemia-reperfusion in rat isolated hearts.

1 Urocortin is a vasodilator peptide related to corticotrophin-releasing factor, which may protect endothelial function during coronary ischemia-reperfusion (I-R). The aim of this study was to study the mechanisms of this protective effect. 2 Hearts from Sprague-Dawley rats were isolated and perfused at constant flow and then exposed to 15 min global zero-flow ischemia, followed by 15 min reperfusion. The relaxation to acetylcholine (10 nM-10 microM) was recorded after pre-constriction of the coronary vasculature with U46619 (100-300 nM) in ischemic-reperfused or time-control hearts. 3 After I-R, the coronary relaxation to acetylcholine was reduced and this reduction was attenuated by treatment with urocortin (10 pM), administered before ischemia and during reperfusion. 4 This urocortin-induced improvement of the relaxation to acetylcholine was not modified by tetraethylammonium (10 mM), blocker of Ca2+ dependent-potassium channels; glibenclamide (10 microM), blocker of K(ATP) channels; N(w)-nitro-L-arginine methyl ester (L-NAME, 100 microM), blocker of nitric oxide synthesis; or meclofenamate (10 microM), blocker of cyclooxygenase, but it was abolished by chelerythrine (3 microM), blocker of protein kinase C (PKC). 5 These results suggest that urocortin may protect coronary endothelial function during I-R by activation of PKC.

Enhanced response of pig coronary arteries to endothelin-1 after ischemia-reperfusion. Role of endothelin receptors, nitric oxide and prostanoids.

To analyse the coronary effects of endothelin-1 after ischemia-reperfusion, the left anterior descending coronary artery of anesthetized pigs was subjected to 30-min occlusion followed by 60-min reperfusion. Then, rings distal (ischemic arteries) and proximal (control arteries) to the occlusion were taken from this artery and prepared for isometric tension recording. The sensitivity of the contraction in response to endothelin-1 (3 x 10(-10)-3 x 10(-7) M) and the endothelin ET(B) receptor agonist IRL-1620 (3 x 10(-10)-3 x 10(-7) M) was greater in ischemic vessels. The endothelin ET(A) receptor antagonist BQ-123 (10(-7)-3 x 10(-6) M) decreased the sensitivity of the response to endothelin-1 similarly in ischemic and control arteries. The endothelin ET(B) receptor antagonist BQ-788 (10(-6) M), endothelium removal or the inhibitor of nitric oxide synthesis N(omega)-nitro-L-arginine methyl ester (L-NAME 10(-4) M) potentiated the response to endothelin-1 and IRL-1620 in control arteries only. The cyclooxygenase inhibitor meclofenamate (10(-5) M) augmented the maximal response to endothelin-1 in control arteries, and reduced it in ischemic arteries. In precontracted arteries, IRL-1620 (3 x 10(-11)-3 x 10(-10) M) relaxed control but not ischemic arteries, and L-NAME or meclofenamate abolished this relaxation. Therefore, ischemia-reperfusion increases the coronary vasoconstriction in response to endothelin-1 probably due to impairment of endothelin ET(B) receptor-induced release of nitric oxide and prostacyclin, augmentation of the contractile response to activation of endothelin ET(B) receptors, and increased release of vasoconstrictor prostanoids.