Faraci, Frank M., and Donald D. Heistad. Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels. Physiol. Rev. 78: 53–97, 1998. — Several new concepts have emerged in re...

Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels

In this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.

Pathophysiology of endothelin in the cardiovascular system

The present review summarises the potential nutritional and physiological functions of betaine as a feed additive in relation to performance criteria in livestock production. Betaine, the trimethyl derivative of the amino acid glycine, is a metabolite of plant and animal tissues. In plants, betaine is particularly synthesised and accumulated as an osmoprotectant against salt and temperature stress. In animals, betaine is the product of choline oxidation or it originates from nutritional sources. Over the past decades, numerous studies have been carried out to investigate the potential effects of betaine supplementation on animal performance. Due to its chemical structure, betaine shows the characteristics of a dipolar zwitterion resulting in osmoprotective properties. Promoting effects on the intestinal tract against osmotic stress occurring during diarrhoea or coccidiosis have been reported following betaine supplementation in pigs and poultry. There is also some evidence that dietary betaine may improve the digestibility of specific nutrients. As a product of choline oxidation, betaine is involved in transmethylation reactions of the organism. Betaine as a methyl donor provides its labile methyl groups for the synthesis of several metabolically active substances such as creatine and carnitine. Supplementation with betaine may decrease the requirement for other methyl donors such as methionine and choline. There is also some evidence for enhanced methionine availability after dietary supplementation of betaine resulting in improved animal performance. Alterations in the distribution pattern of protein and fat in the body have been reported following betaine supplementation. A more efficient use of dietary protein may result from a methionine-sparing effect of betaine, but also direct interactions of betaine with metabolism-regulating factors have to be considered. Though the mode of action of betaine as a carcass modifier remains open, there is, however, growing evidence that betaine could have a positive impact both on animal performance and carcass quality.

/pdf/potential-nutritional-and-physiological-functions-of-betaine-2g8iwy17q1.pdf

Potential nutritional and physiological functions of betaine in livestock

Complex barriers separate immune-privileged tissues from the circulation. Here, we propose that cell entry to immune-privileged sites through barriers composed of tight junction-interconnected endothelium is associated with destructive inflammation, whereas border structures comprised of fenestrated vasculature enveloped by tightly regulated epithelium serve as active and selective immune-skewing gates in the steady state. Based on emerging knowledge of the central nervous system and information from other immune-privileged sites, we propose that these sites are endowed either with absolute endothelial-based barriers and epithelial gates that enable selective and educative transfer of trafficking leukocytes or with selective epithelial gates only.

Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates.

The capacity of endothelin-1 to induce severe reductions in cerebral blood flow and ischaemic neuronal damage was assessed in anaesthetised rats. Endothelin-1 (25 microliters of 10(-7)-10(-4) M) was applied to the adventitial surface of an exposed middle cerebral artery and striatal blood flow assessed by the hydrogen clearance technique. Endothelin-1 induced severe dose-dependent reductions in cerebral blood flow (e.g., minimum CBF at 10(-5) M of 9 +/- 11 ml 100 g-1 min-1 compared to 104 +/- 22 ml 100 g-1 min-1 with vehicle, p < 0.05), which persisted for at least 60 min at each concentration of endothelin-1. Application of endothelin-1 to the middle cerebral artery produced dose-dependent ischaemic brain damage (e.g., volume of damage of 65 +/- 34 mm3 at 10(-5) M compared to 0.22 +/- 0.57 mm3 for vehicle, p < 0.01). These data demonstrate that endothelin-1 is capable of reducing blood flow to pathologically low levels and provide a new model of controlled focal ischaemia followed by reperfusion.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1993.34

Endothelin-1-Induced Reductions in Cerebral Blood Flow: Dose Dependency, Time Course, and Neuropathological Consequences

A considerable quantity of endothelin-like immunoreactivity was demonstrated as present in the CSF of patients with subarachnoid hemorrhage. The endothelin levels in the CSF raised from 0.4 +/- 0.2 (Mean +/- SD) pmol/L at Day 0-1 to 2.2 +/- 0.6 pmol/L at Day 6 and the levels decreased gradually. The result suggest that endothelin may contribute the generation of vasospasm often observed in subarachnoid hemorrhage.

Increased endothelin concentration in CSF from patients with subarachnoid hemorrhage.

A radioimmunoassay method for endothelin was developed. Antisera raised against endothelin 1 showed significant crossreaction with endothelin 2 and 3 (45 and 13%, respectively). Considerable endothelin immunoreactivity was shown to be present in the cerebrospinal fluid of patients with a subarachnoid hemorrhage, ranging from 0.3 pmol/l cerebrospinal fluid to 4.5 pmol/l cerebrospinal fluid, though no endothelin immunoreactivity was observed in the cerebrospinal fluid of controls and patients with cerebral infarction, subdural haematoma or brain tumours. Endothelin immunoreactivity was also observed in two out of five cerebrospinal fluid samples from patients with cerebral bleeding. Reverse phase high performance liquid chromatography showed that the main immunoreactive component in cerebrospinal fluid appeared to elute at the same position. There was, however, an immunoreactive component which eluted at the same position as endothelin 3. These results may support the idea that endothelin immunoreactivity in the cerebrospinal fluid originate mainly from endothelial and neural tissues and that endothelin may contribute to the generation of the vasospasm often observed in subarachnoid hemorrhage, a conclusion based on the exceptionally high endothelin immunoreactivity in cerebrospinal fluid observed in patients with subarachnoid haemorrhage.

Endothelin immunoreactivity in cerebrospinal fluid of patients with subarachnoid haemorrhage.

A peptide, 7B2, originally isolated from pituitary, is present in endocrine tumors, with high concentrations in pancreatic islet tumors. Plasma from most of these patients showed very high immunoreactivity to 7B2 (IR-7B2). To assess whether or not there is any alteration in circulating 7B2 concentrations due to age, sex, etc., we measured concentrations in plasma in 96 fasting healthy subjects, ages three months to 91 years; in patients with various other conditions, including pregnancy; and in cord blood. The response of circulating IR-7B2 to oral glucose was also evaluated. We found particularly high IR-7B2 concentrations in cord blood. Postnatally the concentrations were lower and decreased gradually with age to values for adults [15.6 (SE 2.9) pmol/L], increasing again significantly (P less than 0.01) in persons older than 70 years [37.1 (SE 32) pmol/L]. There was no significant sex-related difference in values for plasma. For the pathological conditions studied, we observed significantly supranormal values in patients with chronic renal failure [175.1 (SE 35.9) pmol/L]. Some of the pregnant patients in their third trimester also showed high values. A small but significant increase in plasma IR-7B2 was observed after a glucose load, both in control subjects and diabetics. Perhaps the kidney plays a major role in 7B2 degradation.

Circulating concentrations of immunoreactive peptide 7B2 in certain pathophysiological conditions, and response to oral glucose load.

We investigated the possible relation between neuropeptides and cerebral vasoconstriction in samples of ventricular or cisternal cerebrospinal fluid from 14 patients with subarachnoid hemorrhage. Neuropeptide Y, calcitonin gene-related peptide, atrial natriuretic peptide, and pituitary polypeptide 7B2 were present in the cerebrospinal fluid of these patients. Concentrations of calcitonin gene-related peptide and 7B2 were not significantly different from those in control subjects, but that of atrial natriuretic peptide was significantly lower. Although the mean concentration of neuropeptide Y was not significantly higher than control, consecutive determinations showed an increase 6-11 days after the onset of subarachnoid hemorrhage. An initially high 7B2 concentration decreased gradually, although half the patients showed a second increase greater than 10 days after the onset. Considering the well-recognized vasoconstrictive effect of neuropeptide Y, it is possible that this increase in its concentration in the cerebrospinal fluid plays a role in the pathogenesis of the cerebral vasospasm that is often seen after subarachnoid hemorrhage.

https://www.ahajournals.org/doi/pdf/10.1161/01.STR.20.12.1680

Increased neuropeptide Y concentrations in cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage.

The influence of glycine, the simplest amino acid, on pituitary function has been investigated in the present study. Different doses (4, 8, or 12 g) of glycine were intravenously infused over 15 or 30 min in normal subjects. Serum levels of GH (growth hormone) and Prl (prolactin) were measured before and after the infusion, and also blood sugar levels were determined. The dose of 4 or 8 g glycine induced a significant increase in serum GH (P less than 0.05 or P less than 0.001, respectively); however, a more pronounced and significant increase in serum GH levels was observed after infusion at a dose of 12 g glycine (P less than 0.001). It was clearly observed that the dose-dependent GH release to intravenous glycine occurred in normal subjects. On the contrary, serum Prl level was not changed significantly, and blood sugar level was transiently, but significantly (P less than 0.05), increased after the infusion of 12 g glycine. The present data suggest that glycine might play an important role in the control of hypothalamic-pituitary function.

Hitoshi Suzuki

Papers

Increased endothelin concentration in CSF from patients with subarachnoid hemorrhage.

Endothelin immunoreactivity in cerebrospinal fluid of patients with subarachnoid haemorrhage.

Circulating concentrations of immunoreactive peptide 7B2 in certain pathophysiological conditions, and response to oral glucose load.

Increased neuropeptide Y concentrations in cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage.

Glycine stimulates growth hormone release in man