Innervation and functional changes in mesenteric perivascular calcitonin gene-related peptide- and neuropeptide Y-containing nerves following topical phenol treatment

We have previously shown that age-related reduction of innervation and function in mesenteric perivascular calcitonin gene-related peptide-containing vasodilator nerves takes place in spontaneously hypertensive rats. The present study was performed to investigate innervation and functional changes in perivascular calcitonin gene-related peptide- and adrenergic neuropeptide Y-containing nerves after topical treatment with phenol, which damages nerve fibers, around the rat superior mesenteric artery. Under pentobarbital-Na anesthesia, 8-week-old Wistar rats underwent in vivo topical application of phenol (10% phenol in 90% ethanol) or saline (sham rats) to the superior mesenteric artery proximal to the bifurcation of the abdominal aorta. After the treatment, the animals were subjected to immunohistochemistry of the 3rd branch of small arteries proximal to the intestine and to vascular responsiveness testing on day 3 through day 14. The innervation levels of calcitonin gene-related peptide-like immunoreactivity containing fibers and neuropeptide Y-like immunoreactivity containing fibers were markedly reduced on day 3 to day 14 and on day 5 to day 14 after the treatment, compared with those in sham-operated rats, respectively. In perfused mesenteric vascular beds isolated from phenol-treated rats, adrenergic nerve-mediated vasoconstriction and calcitonin gene-related peptide nerve-mediated vasodilation in response to periarterial nerve stimulation (2-12 Hz) were significantly decreased on day 3 and day 7. Neurogenic release of norepinephrine in phenol-treated rats on day 7 was significantly smaller that that in sham-operated rats. Nerve growth factor content in the mesenteric arteries of phenol-treated rats was significantly lower than that in sham-operated rats. Administration of nerve growth factor using osmotic mini-pumps for 7 days after the phenol treatment resulted in greater density of calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity fibers than in phenol-treated rats and restored decreased vascular responses to periarterial nerve stimulation. These results suggest that topical phenol-treatment of the mesenteric artery effectively induces functional denervation of perivascular nerves, which can be prevented or reversed by nerve growth factor treatment.     

壳聚糖硫酸盐催化合成环扁桃酯

以扁桃酸和3,3,5-三甲基环己醇为原料,甲苯为溶剂,壳聚糖硫酸盐为催化剂制得环扁桃酯,最佳反应条件为:扁桃酸、3,3,5-三甲基环己醇、甲苯和壳聚糖硫酸盐投料比为1:1:2.86:9.1(mol:mol:mol:g),反应时间8h,收率约84%.     

The NO donor SIN-1 improves intestinal-arterial P(CO(2)) gap in experimental endotoxemia: an animal study

BACKGROUND: Dysfunction of the microcirculation is a prominent feature of sepsis and endotoxemia. Recently, it has been shown that microcirculatory alterations are completely reversed by local or systemic application of vasodilators in severely septic patients. Therefore, we investigated the influence of vasodilator therapy on microcirculatory dysfunction of the ileum during endotoxic shock in a prospective, controlled animal study. METHODS: After baseline measurements, shock was induced in 12 domestic pigs by lipopolysaccharide via the mesenteric vein until the mean arterial pressure fell below 60 mmHg. After 30 min in shock, six animals were resuscitated with either fluid alone (control) or fluid and 2 microg/kg/min of the vasodilator 3-morpholino-sydnonimine (SIN-1). The systemic and regional hemodynamics and oxygenation parameters, tonometric ileal P(CO(2)) and microvascular oxygen pressures (muP(O(2))) (by oxygen-dependent Pd-porphyrin phosphorescence) were measured simultaneously. RESULTS: The ileal-arterial P(CO(2)) gap increased during shock and the ileal mucosal and serosal muP(O(2)) decreased concurrently. SIN-1 in addition to fluid resuscitation significantly improved the ileal-arterial P(CO(2)), whereas fluid alone failed to decrease the P(CO(2)) gap. The SIN-1-induced improvement in the P(CO(2)) gap was accompanied by an increase in serosal muP(O(2)) above shock levels. Mucosal muP(O(2)) was resuscitated to baseline levels in both groups. CONCLUSION: The application of the vasodilator SIN-1 in addition to fluid resuscitation improves the ileal-arterial P(CO(2)) gap and mucosal muP(O(2)), together with a moderate increase in serosal muP(O(2)), after endotoxic shock. This finding is consistent with the concept that vasodilators may correct pathologic flow distribution within the intestinal wall.     

The apelinergic system: a promising therapeutic target

Importance of the field: Apelin is a bioactive peptide known as the ligand of the G-protein-coupled receptor APJ. In recent years, there has been a growing body of evidence regarding the importance of apelin and APJ in the pathophysiology of cardiovascular, metabolic and gastrointestinal diseases, brain signalling, HIV infection and tumor angiogenesis. Therefore, the apelinergic system is involved in the pathogenesis of several diseases that represent a major burden to our society.

Areas covered in this review: The goal of this paper is to give an up-to-date review of existing information on apelin/APJ since the discovery of apelin in 1998, with particular focus on their involvement in the regulation of human body systems and potential therapeutic applications.

What the reader will gain: An overview of the most important physiological functions of the apelinergic system and the diseases that may benefit in the future from its modulation as a therapeutic target.

Take home message: Today, the established biological effects of apelin involve major cardiovascular actions, neoangiogenesis, immunologic modulation and insulinemia control as well as body fluid and glucose homeostasis. However, the physiological and pathophysiological role of endogenous apelin is still unsettled and a better and profound knowledge of this system in humans is necessary for the development of novel apelinergic-based therapeutic targets.     

Factors, fiction and endothelium-derived hyperpolarizing factor

1. The principal mediators of vascular tone are neural, endothelial and physical stimuli that result in the initiation of dilator and constrictor responses to facilitate the control of blood pressure. Two primary vasodilatory stimuli produced by the endothelium are nitric oxide (NO) and prostaglandins. An additional endothelium-dependent vasodilatory mechanism is characterized as the hyperpolarization-mediated relaxation that remains after the inhibition of the synthesis of NO and prostaglandins. This mechanism is due to the action of a so-called endothelium-derived hyperpolarizing factor (EDHF) and is dependent on either the release of diffusible factor(s) and/or to a direct contact-mediated mechanism. 2. Most evidence supports the concept that 'EDHF' activity is dependent on contact-mediated mechanisms. This involves the transfer of an endothelium-derived electrical current, as an endothelium-derived hyperpolarization (EDH), through direct heterocellular coupling of endothelial cells and smooth muscle cells via myoendothelial gap junctions (MEGJ). However, there is a lack of consensus with regard to the nature and mechanism of action of EDHF/EDH (EDH(F)), which has been shown to vary within and between vascular beds, as well as among species, strains, sex and during development, ageing and disease. 3. In addition to actual heterogeneity in EDH(F), further heterogeneity has resulted from the less-than-optimal design, analysis and interpretation of data in some key papers in the EDHF literature; with such views being perpetuated in the subsequent literature. 4. The focus of the present brief review is to examine what factors are proposed as EDH(F) and highlight the correlative structural and functional studies from our laboratory that demonstrate an integral role for MEGJ in the conduction of EDH, which account for the heterogeneity in EDH(F), while incorporating the reported diffusible mechanisms in the regulation of this activity. Furthermore, in addition to the reported heterogeneity in the nature and mechanism of action of EDH(F), the contribution of experimental design and technique to this heterogeneity will be examined.     

尼莫地平的合成改进

间硝基苯甲醛和乙酰乙酸2-甲氧基乙酯在乙酸酐-浓硫酸催化下缩合得到2-(3-硝基亚苄基)乙酰乙酸2-甲氧基乙酯,再在浓盐酸催化下与3-氨基丁烯酸异丙酯在乙醇中闭环得到尼莫地平,总收率80%.     

Nitric oxide modulates acetylcholine‐induced vasodilatation in the hepatic arterial vasculature of the dual‐perfused rat liver

The role of nitric oxide in the modulation of hepatic arterial vascular reactivity was investigated in an isolated dual‐perfused rat liver preparation. Twelve male Wistar rats (200–250 g) were anaesthetized with sodium pentobarbitone (60 mg kg^–1 i.p.). The livers were then excised and perfused in vitro through hepatic arterial and portal venous cannulae at constant flow rates. Concentration‐dependent dose–response curves to acetylcholine (10^–8–10^–5 M ), sodium nitroprusside (10^–6–5 × 10^–4 M ), and adenosine triphosphate (ATP) (10^–8–10^–5 M ) in the hepatic artery were constructed after the tone was raised by addition of methoxamine (3 μM L^–1). Acetylcholine‐induced vasodilatation in the hepatic artery was significantly attenuated with inhibition of nitric oxide synthase by using N^G‐nitro‐L ‐arginine methyl ester (30 μM ), E_max=51.7 ± 2.8 vs. 32.5 ± 3.1 mmHg, before vs. after N^G‐nitro‐L ‐arginine methyl ester, respectively. ATP‐induced hepatic arterial vasoconstriction which was significantly enhanced with L ‐NAME, E_max=94.0 ± 9.3 vs. 127.0 ± 8.0 mmHg, before vs. after N^G‐nitro‐L ‐arginine methyl ester, respectively. Sodium nitroprusside‐induced hepatic arterial vasodilatation remained unchanged with N^G‐nitro‐L ‐arginine methyl ester, E_max=57.0 ± 3.4 vs. 57.0 ± 4.1, before vs. after N^G‐nitro‐L ‐arginine methyl ester, respectively. The data from the present study suggest that acetylcholine‐induced vasodilatation in the intrahepatic arterial vasculature of the rat liver is at least, in part, mediated by the release of nitric oxide. In addition, ATP‐induced hepatic arterial vasoconstriction is also modulated by the release of nitric oxide (*P < 0.05, Student’s paired t‐test).     

Regulation of hemodynamics in major salivary glands by parasympathetic vasodilation

Background

Since salivary fluid is created from blood plasma, hemodynamics in the salivary glands play an important role in the production of saliva. Trigeminal sensory input induces both salivary secretion and reflex parasympathetic vasodilation in salivary glands. This glandular vasodilation is thought to be important for the regulation of glandular hemodynamics due to the rapidity with which blood flow is increased. This review article summarizes recent research on the involvement of parasympathetic vasodilation in regulating hemodynamics in the salivary gland.