Ben R. Clower

Endothelin-A Receptor Antagonism Attenuates the Hypertension and Renal Injury in Dahl Salt-Sensitive Rats

The aim of this study was to examine the role of endothelin-A (ET(A)) receptors in mediating the hypertension and renal injury associated with high salt intake in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of chronic selective ET(A) antagonist (A-127722) treatment at a dose of 10 mg/kg/d on arterial pressure, renal function, and morphology in DS and Dahl salt-resistant (DR) rats placed on a high sodium (8% NaCl) diet (HSD) for 3 weeks. Placement of DS rats (n=13) on HSD for 3 weeks caused a progressive increase in systolic pressure (from 118+/-3 to 186+/-15 mm Hg). The increase in systolic pressure was significantly attenuated (from 125+/-4 to 167+/-12 mm Hg) in DS rats treated with A-127722 (n=13). Mean arterial pressure (MAP) measured directly at the end of the study was also significantly lower by 18 mm Hg (P<.02) in the DS rats treated with A-127722. The slope of the chronic pressure-natriuresis curve was shifted to the right in DS rats and to the left by chronic ET(A) receptor blockade in DS rats. The hypertension in DS rats was associated with marked proteinuria (from 4.1+/-1.1 to 74.3+/-5.3 mg/24 h/100 g body weight) that was significantly attenuated (from 5.7+/-1.2 to 55.2+/-6.5 mg/24 h/100 g body weight) in DS rats treated with A-127722. The percentage of glomeruli displaying fibrosis, hypercellularity, and hyalinization was also significantly reduced after treatment with A-127722 in DS rats. Arterial pressure, protein excretion, renal hemodynamics, and morphologic structure were not significantly changed in response to ET(A) receptor blockade in DR rats placed on HSD. These data indicate that endothelin-A receptor activation may play a role in the exacerbation of hypertension and development of renal injury in DS rats.

The angiopathy of subarachnoid hemorrhage: angiographic and morphologic correlates.

In patients with subarachnoid hemorrhage, particularly hemorrhage due to aneurysmal rupture, there was a positive significant relation between angiographic vessel constriction and vessel pathology (angiopathy). Furthermore, there was a positive relationship between post-hemorrhage survival time and the severity of angiopathy. Factors such as age, sex, operations, steroid and CSF pressure seemed to have little affect on angiopathy following hemorrhage. Pathological changes were primarily limited to the involved major cerebral vessels themselves, with their branches rarely being affected. While intramural vascular hemorrhage was a common pathological feature in vessels showing severe pathology, the mere presence of blood surrounding an artery seemed to have little influence on vessel alterations.

Bilirubin produces apoptosis in cultured bovine brain endothelial cells

Blood components such as oxyhemoglobin are believed to cause cerebral vasospasm by inducing contraction and cell death in cerebral arteries. We have observed previously that oxyhemoglobin produces apoptotic changes in cultured endothelial cells. This study was undertaken to explore if bilirubin, a bi-product of hemoglobin degradation, will produce similar cytotoxicity in endothelial cells. Cultured bovine brain microvascular endothelial cells were incubated in four concentrations of bilirubin (10, 25, 50, and 100 microM) for varying times (6, 12, and 24 h). Control cells were incubated in saline or vehicle (NaOH solution, <0.01% of 0.01 N) for similar time periods. The cultured cells were then observed microscopically for evidence of cellular alterations. Bilirubin (10-100 microM) produced apoptosis that appeared time-dependent but not clearly concentration-dependent. Biochemical markers for apoptosis such as DNA fragmentation and PARP cleavage were induced by bilirubin. We conclude that endothelial cells may undergo apoptosis after exposure to bilirubin.

Optison (FS069) disrupts the blood-brain barrier in rats.

Optison is a new echocardiographic contrast agent, designed for IV injection, that is very useful in delineating cardiac structures during ultrasound examination. Because Optison could be a valuable adjunct in the diagnosis and evaluation of congenital heart disease, this study was undertaken to assess its effects on the blood-brain barrier when introduced directly in the cerebral circulation, as might occur with some congenital lesions. In this study, Sprague-Dawley rats were anesthetized, and Optison, at various dosages, was injected into the carotid artery. After this, Evans blue dye, a marker for blood-brain barrier disruption, was injected at different time intervals. Gross and histologic examination of the animals’ brains revealed disruption of the blood-brain barrier that appeared to be Optison-dosage-dependent. Although the mechanism for this disruption is unclear, it may be related to the use of octofluoropropane gas used in the Optison as a contrast medium. Further studies are necessary to determine the pathologic consequences of Optison’s effects on the blood-brain barrier. Implications Optison appears to disrupt the blood-brain barrier when introduced directly into the cerebral arterial circulation. This may be related to the octafluoropropane gas used in Optison as a contrast medium. Optison should be used with caution when the possibility of a right-to-left shunt exists.

Stroke: anatomy of a catastrophic event.

Subarachnoid hemorrhage (SAH) resulting from the rupture of a cerebral aneurysm represents one major cause of stroke. SAH may be followed by a spontaneous severe contraction of major cerebral arteries, a condition referred to as cerebral vasospasm. Vasospasm may result in brain ischemia or actual tissue death. This constrictive vascular state is devastating, remains largely untreatable, and is a major cause of morbidity and mortality in SAH patients. Approximately 30,000 Americans are affected by this condition each year. The overall death rates are 25%, and significant neurological complications occur in 50% of individuals who survive the initial bleed. This report highlights some of the important aspects of this vascular disease. Anat. Rec. (New Anat.) 253:58‐63, 1998.

The angiopathy of subarachnoid hemorrhage I. Role of vessel wall catecholamines.

Subarachnoid hemorrhage (SAH) due to rupture of the right middle cerebral artery (RMCA) produced specific anatomical and biophysiological responses in the involved feline vessels. The RMCA showed morphological alterations that became progressively more severe with time and were widespread within the cerebral vascular tree. SAH also resulted in an acute depletion of vessel catechola- mlne levels which remained depressed over a 30 day period. When the cerebral vessels of cats were severely depleted of catecholamines (using reserpine) prior to induced SAH, morphological alterations were signifi- cantly reduced both in severity and in degree of spread within the cerebral vascular network. The results of this study suggest that the concentration of noreplnephrine within the vessel at the time of hemorrhage plays a significant role in the production of the angiopathy that follows SAH. Stroke Vol 15, No 2, 1984

Excitotoxin-induced myocardial necrosis

The excitotoxins, kainic acid and N-methyl-D-aspartic acid (NMDA), were injected bilaterally into the paraventricular hypothalamus of rats. Kainic acid elicited pressor responses, tachycardia and sudden cardiac death in Nembutal-anesthetized rats. Injections of NMDA caused cardiovascular stimulation on cessation of halothane anesthesia. Intramyocardial hemorrhage, hyaline myocardial necrosis and predominantly mononuclear inflammation were evident 48 h following NMDA. Labetalol pretreatment did not protect from nor did i.v. NMDA cause these changes. Intrahypothalamic excitotoxin injections cause deleterious myocardial changes.

Constrictive structural elements in human cerebral arteries following aneurysmal subarachnoid haemorrhage

Histoimmunological, histochemical, and histological studies were conducted on cerebral arteries from four living patients with a recent aneurysmal subarachnoid haemorrhage. There appeared to be a correlation between the severity of vasospasm and the magnitude of pathological findings. Large myofibroblast cells and type V collagen within the medial layer were abundant in arteries showing marked vasospasm, but were less conspicuous in those showing milder involvement. Intracranial arteries from patients who died from non-cerebral causes did not demonstrate these changes. In ruptured vessels, there was also a positive fluorescence for actin-myosin filaments in layers of the arterial wall other than the media. It is postulated that the intimal and adventitial actin-myosin, myofibroblasts and type V collagen may contribute to cerebral vasospasm by holding the damaged vessel in a contracted phase during the healing period.

Toxicity of cryoprotective agents at 30

The toxicity of four cryoprotective agents (glycerol, dimethylsulfoxide, dextran, magnesium ion) as a function of time was assessed at 30° on isolated rabbit atria. Glycerol, 2·0 M, in Ringer solution killed all atria in less than 30 min. Atria tolerated 2·1 M dimethylsulphoxide in Ringer for 1 hr, 0·7 M glycerol in Ringer for 4 hr, 6% (w/v) dextran in saline for 6 hr and 6·6 times 10−2 M magnesium chloride in Ringer for 8 hr. After washing out the cryoprotective agents the tissue was examined histologically and for its response to isoprenaline, MJ‐1999 [4,2‐(isopropylamino‐10‐hydroxyethyl)methanesulphonilide, a β‐blocking agent] and isoprenaline and ouabain. These tests were the more sensitive indicators of functional integrity.

Inverse relationship between potassium intake and coronary artery disease in the cholesterol-fed rabbit

We tested the hypothesis that a low level of dietary potassium intake would exacerbate the severity of vascular lesion formation in rabbit coronary arteries during high cholesterol intake. Two groups of nine rabbits were studied for 6 weeks while eating a diet containing 2% cholesterol and 0.9% sodium. The normal potassium group consumed a diet containing 1.5% potassium and the low potassium group consumed a diet containing 0.4% potassium. After 6 weeks the animals were killed, the hearts were removed, and blood samples were withdrawn from the abdominal aorta immediately before removing the heart. The hearts were sectioned and slides were prepared and fixed with hematoxylin and eosin. The numbers of normal and abnormal vessels, and those with foam cells in the subintima, were counted in selected sections. Plasma potassium concentration in the normal and low potassium intake groups averaged 4.27 +/- 0.27 mmol/L and 3.90 +/- 0.11 mmol/L, respectively. No differences between the groups were observed in plasma cholesterol or body weight gain. The percentages of abnormal arteries in the groups were 4.20 +/- 0.35 in the normal intake group and 6.36 +/- 0.50 in the low intake group, 51% greater in the normal intake group (P < .001). These results support the hypothesis that low potassium intake exacerbates the severity of subintimal lesion development in the coronary arteries.