Sepsis involves a heterogeneous class of syndromes, and septic shock, a severe form of sepsis, is associated with the development of progressive damage in multiple organs. The present study examined the time-dependent alterations of endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF) levels in liver tissue in a septic rat model. Healthy male Wistar rats aged 15 weeks received 15 mg/kg lipopolysaccharide (LPS) and were sacrificed at different time points (1, 3, 6, and 10 hrs after treatment). Rats that did not receive LPS were considered to be controls. A 28-fold increase in the ET-1 level was observed in liver tissue 10 hrs after LPS administration. VEGF was also altered in hepatic tissue in a time-dependent manner. A gradual increase of VEGF expression in liver tissue after LPS administration was observed. Expression of Flt-1, the vascular permeability receptor of VEGF, was also increased in liver tissue after LPS administration. ET-1 is a potent vasoconstrictor and, therefore, may play a role in the regulation of hepatic perfusion in a sepsis model. On the other hand, VEGF may be involved in capillary leakage in liver tissue after LPS administration. The present findings suggest that there might be a loss of balance between the ET-1 and VEGF levels in the septic liver at different time points, which could contribute to the pathogenesis of acute liver injury in endotoxemia.
Systemic arterial compliance (C) and vascular resistance (R) regulate effective arterial elastance (Ea), an index of artery load. Increases in Ea during exercise are due primarily to reductions of C and maintain optimal ventricular-arterial coupling. Because C at rest and left ventricular functional reserve are greater in endurance-trained (ET) compared with sedentary control (SC) humans, we hypothesized that reductions of C and increases in Ea are greater in ET than SC individuals. The aim of this study was to investigate C, R, and Ea during exercise in ET and SC humans. C, R, Ea, and cardiac cycle length (T) were measured at rest and during exercise of 40, 60, and 80% maximal oxygen uptake using Doppler ultrasonography in 12 SC and 13 ET men. C decreased in an exercise intensity-dependent manner in both groups, but its reductions were greater in the ET than SC subjects. Consequently, although C at rest was greater in the ET than SC group, the intergroup difference in C disappeared during exercise. Exercise-related changes in R/T were relatively slight and R/T was lower in the ET than the SC group, both at rest and during exercise. Although Ea at rest was lower in the ET than SC group, there were no intergroup differences in Ea at 40, 60, or 80% maximal oxygen uptake. We conclude that the reductions of C from rest to exercise are more marked in ET than SC humans. This may be related to the exercise-associated disappearance of the difference in Ea between ET and SC humans.
Case A 57‐year‐old woman was transferred to our emergency department by ambulance with cardiopulmonary arrest caused by massive genital bleeding. Cardiopulmonary resuscitation, including massive transfusion, was carried out and the return of spontaneous circulation was achieved. A giant uterine tumor was considered the source of the bleeding. Although hysterectomy was necessary to achieve definitive hemostasis, the patient was unable to tolerate the operation because of hemodynamic instability, acidosis, and coagulopathy. Therefore, we undertook vaginal gauze packing and uterine artery embolization to attain temporary hemostasis, which resulted in hemodynamic stabilization. Abdominal hysterectomy for definitive hemostasis was carried out 10 h after the embolization. Outcome The patient made a good post‐surgical recovery without any complications. Conclusion In treating hemorrhagic shock due to uterine leiomyoma, damage‐control resuscitation may be useful as a bridge prior to definitive hemostasis through hysterectomy.
We have previously reported that production of endothelin (ET)-1 is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET-1 in the left ventricle(LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore, we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-1 production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.
Vascular tone is regulated through the actions of locally produced agents. Among the vasoconstrictors, the most potent agent is endothelin (ET), which exerts its vasoconstrictor actions principally through ET type A (ET(A)) receptors. Of the vasodilators, nitric oxide (NO) seems to be the most important contributor to the acute regulation of vascular tone. Vasculopathy is an important feature of diabetes mellitus (DM). Endogenous ET-mediated vasoconstrictor tone is augmented in diabetic states, and conflicting results persist concerning the NO system in diabetes. The present study investigated the expressions of inducible NO synthases (iNOS) and endothelial NOS (eNOS) in the heart of diabetic animals and the effects of a selective ET(A) receptor antagonist on these alterations. Type I diabetes was induced by intraperitoneal injection of streptozotocin (65 mg/kg) in Sprague-Dawley rats, while control (Con) rats received only citrate buffer. After 1 week, the streptozotocin-administered rats were randomly divided into two groups: the selective ET(A) receptor antagonist-administered group (DM+TA-0201, 1 mg/kg/day, by osmotic minipump for 2 weeks) and the DM+vehicle group (comprising the diabetic rats that received saline). The random blood glucose level was 405 +/- 103 mg/dl in DM animals, and this level was unchanged by ET antagonism. Body weight was more greatly decreased in DM rats than in Con rats, but the left ventricle to body weight ratio was increased in the DM group and was unaffected by ET antagonism. Protein expressions of eNOS and iNOS were assessed in the left ventricular tissues. eNOS expression was significantly increased in DM heart and was greatly inhibited by the treatment with ET antagonist. The expression of iNOS was also increased in early DM heart but was reversed by the ET antagonist. Thus, endothelin antagonism might be beneficial for DM heart by reversing the upregulated eNOS and iNOS expressions.
Regular aerobic exercise reduces aortic stiffness. However, the mechanisms by which chronic exercise lowers arterial stiffness are not known. PURPOSE To determine the molecular mechanisms underlying aerobic exercise training-induced reduction of aortic stiffness, the alteration of gene expression by aerobic exercise training was measured with the microarray technique. METHODS and RESULTS The differences in expression levels of 3,800 genes in the abdominal aorta of sedentary control (8 weeks old) and exercise-trained rats (8 weeks old) were compared by the microarray analysis. Rats in the training group exercised on a treadmill for 4 weeks (60 min at 30 m/min, 5 days/week). Aortic pulse wave velocity (PWV) was significantly lower in the exercise-trained group than in the control group. Of the 323 genes that displayed differential expression (upregulation of 206 genes and downregulation of 117 genes), a total of 29 genes (24 upregulated and 5 downregulated genes) were identified as potential candidate genes that may be involved in vasodilation and arterial destiffening. Among these genes, we focused on prostaglandin EP2 receptor, prostaglandin EP4 receptor, C-type natriuretic peptide (CNP), and endothelial nitric oxide synthase (eNOS) genes because these genes have documented impacts on arterial function as mediators for vasodilatation. Using real-time quantitative PCR, we confirmed the results of microarray analysis that prostaglandin EP2 receptor, prostaglandin EP4 receptor, CNP, and eNOS genes were differentially expressed. The mRNA expression of prostaglandin EP2 receptor, prostaglandin EP4 receptor, CNP, and eNOS in the abdominal aorta was significantly higher in the trained group than in the control group. Furthermore, there were modest correlations between arterial stiffness and levels of these factors. Differential expression of eNOS gene was further verified at protein level by using Western blot analysis. CONCLUSIONS These results suggest that aerobic exercise training induces the altered expression in several genes including prostaglandin, CNP, and nitric oxide in the aorta and that these molecular changes may contribute, at least in part, to the beneficial effect of exercise training on aortic stiffness. Supported by grants from the Ministry of Education, Science, Sports and Culture of Japan (16500391) and the National Institutes of Health (AG20966).
