Secretion of medullipin I by the kidney requires oxygen.

OBJECTIVE: To test the hypothesis that the secretion of medullipin I by the kidney involves an oxidative step. DESIGN: Medullipin I is secreted by kidney renomedullary interstitial cells and is converted to medullipin II by the liver. Medullipin I can be derived from the kidney in the renal venous effluent by perfusing normal rat kidneys with 95% O2- 5% CO2 at an elevated pressure (180 mmHg). To evaluate whether the secretion of medullipin I involves an oxidative step normal rat kidneys were perfused at an elevated pressure in the presence of O2, in the absence of O2 and after treatment of the kidneys with a powerful antioxidant. METHODS: Normal rat kidneys were perfused with 5% albumin bubbled with O2-CO2 at 180 mmHg. This was the control procedure for each of the three approaches. In approach (1), the kidneys were perfused with 5% albumin bubbled with N2. In approach (2), the kidneys were perfused with 'blood' treated with carbon monoxide. In approach (3), the kidneys were treated with the antioxidant butylated hydroxytoluene then perfused with 5% albumin bubbled with O2-CO2. Each perfusate was tested for medullipin I activity by rapid intravenous injection into the SHR. RESULTS: All three approaches, which exclude the action of molecular O2, prevented the secretion of medullipin I by the kidneys. CONCLUSION: The secretion of medullipin I by the kidneys involves an oxidative step.     

Lipomedullipinoma: A Source of Hypermedullipinemia

Previously we reported a case of persistent hypotension associated with hypermedullipinemia (Blood Pressure 1992; 1:138-148). The hypermedullipinemia appeared to result from the autonomous secretion of medullipin I (Med I) by renomedullary interstitial cells (RIC's) in the patient's remaining endstage kidney. The patient subsequently died. At autopsy, the remaining kidney contained a yellow mass (1×1 ×0.5 cm) consisting of adipocytes and RIC's, termed a lipomedullipinoma. This mass was extracted and chromatographed by procedures known to yield Med I. Med I was identified following these procedures. Renal tissue outside the yellow mass failed to yield Med I. It appears that the hypermedullipinemia of this case resulted from autonomous, hypersecretion of Med I by the lipomedullipinoma.     

The renal antihypertensive endocrine function: its relation to cytochrome P-450

Unclipping the Goldblatt hypertensive rat lowers the blood pressure by cells in the renal papilla, the renomedullary interstitial cells (RIC), secreting a hormone that is part of a vasodilator system. A vasodilator, termed medullipin I, can be extracted from the renal papilla. Medullipin I and the renal venous effluent following unclipping have identical biologic properties. Medullipin I appears to be the agent secreted by the kidney following unclipping. Both medullipin I and the renal venous effluent must traverse the liver to be active. Medullipin I is converted in the liver to its active form, medullipin II. The blood pressure-lowering effect of both medullipin I and the renal venous effluent after unclipping are blocked by SKF 525A, the inhibitor of cytochrome P-450. The relation of the kidney to the liver was tested using the rate of decline of the blood pressure after unclipping as an index of the endocrine antihypertensive function of the kidney--acceleration of the decline being considered as increased function, decrease of the decline as decreased function. Five compounds: BW755C, phenobarbital, ketoconazole, eicosatetraynoic acid (ETYA) and butylated hydroxytoluene (BHT), and two manipulations: uretero-caval anastomosis (UCA) and removal of the liver from the circulation were used followed by unclipping. BW755C, inhibitor of both cyclo-oxygenase and lipoxygenase, potentiated the antihypertensive function to a maximum. It is reasoned that inhibition of the first two pathways of arachidonic acid metabolism potentiates the third pathway, the cytochrome P-450 pathway.(ABSTRACT TRUNCATED AT 250 WORDS)     

The vasodepressor function of the kidney: further characterization of medullipin and a second hormone designated angiolysin.

The objective of this study was to further characterize the antihypertensive properties of medullipin and a second hormone designated angiolysin physiologically. Angiolysin and medullipin were tested in coronary and aortic rings from cows, sheep, pigs, mice and rats. In vivo animal experiments were performed using spontaneously hypertensive rats. Medullipin was successfully separated from another antihypertensive agent at the polar end of the polarity continuum. It is an extremely potent vasodilator. With the methods available today, it is not possible to make a galenical preparation of medullipin for in vivo analysis. The newly discovered antihypertensive agent is another extremely potent vasodilator, even stronger than medullipin, and was therefore named angiolysin. The vasodilatory activity of both medullipin and angiolysin persisted for hours, on rat and mouse aortae, and on the coronary arteries of pigs, cows and sheep. Both substances exerted their effects even in animal rings that were precontracted with 100 mmol/l K+. Angiolysin reduced the resting tension in blood vessels from mice and rats even without precontraction. A single injection of angiolysin resulted in a dose-dependent reduction of blood pressure, independent of the initial blood pressure, even to zero if the dosage was sufficient. The effect persisted for several hours. In conclusion, both hormones are extremely potent vasodilators, and are expected to lead to paradigmatic changes in the treatment of hypertension. With regard to potency, only sodium nitroprusside is comparable, but the effects of medullipin and angiolysin persist for hours after a single injection.     

Orthostatic hypotension and incident chronic kidney disease: the atherosclerosis risk in communities study

Orthostatic hypotension is associated with cardiovascular disease and mortality, but little is known of its association with incident chronic kidney disease. We evaluated this association in the Atherosclerosis Risk in Communities study. Orthostatic hypotension was defined as a decrease in systolic blood pressure ≥ 20 mm Hg or a decrease in diastolic blood pressure ≥ 10 mm Hg within 2 minutes of standing. Incident chronic kidney disease was defined using an estimated glomerular filtration rate < 60 mL/min/1.73 m2, or a coded hospitalization (discharge) or death for chronic kidney disease through 2005, after exclusion of chronic kidney disease at baseline. The associations between orthostatic hypotension and chronic kidney disease were modeled using Cox proportional hazard while adjusting for confounders including resting blood pressure and medications. Among 12 593 participants, 1326 developed chronic kidney disease (6.3 cases per 1000 person-years; median follow-up of 16 years), with higher rates in blacks than whites. An increased risk of chronic kidney disease was observed among persons with orthostatic hypotension compared with those without it (blacks hazard ratio 2.0, 95% CI, 1.5 to 2.8; whites hazard ratio 1.2, 95% CI, 1.0 to 1.6; P for race interaction = 0.02). An alternative chronic kidney disease classification, based on an increase in serum creatinine at the 3- or 9-year follow-up visits, showed significant associations with orthostatic hypotension in both whites and blacks. These findings suggest that orthostatic hypotension increases the risk of chronic kidney disease in middle-aged persons, but race effects vary by choice of chronic kidney disease definition.     

Biologic differences between vasodilator prostaglandins and medullipin I.

Vasodepressor prostaglandins (PGs), PGE2, PGI2, and medullipin I (Med I) are synthesized in the kidney. These vasodilator substances are thought to be involved in the antihypertensive function of the kidney. At issue is whether there are biologic differences between the vasodilator PGs and Med I. Two separate studies have shown that Med I's vasodepressor action is inhibited by four procedures: mixing with Tween 20; treatment with n-butyl boronic acid; treatment of the assay animal with SKF 525A, an inhibitor of cytochrome P-450; and removing the liver from the circulation. These same procedures were applied to the vasodilator PGs. All four failed to inhibit the vasodepressor action of the PG's. It is concluded that Med I and vasodilator PGs of the kidney are separate and distinct biologic entities.     

Morphometric studies of the renomedullary interstitial cells

The renomedullary interstitial cell (RIC) is a unique cell found in the renal medullary interstitium among the collecting ducts, Henle's loop, and the vasa recta. A combination of morphologic and physiologic studies has defined some of the properties of this cell, which is the apparent source of the mediators of the antihypertensive function of the kidney. These may include prostaglandins (PGE2), APRL or platelet activating factor, and the incompletely defined neutral lipid, ANRL (or medullipin), the most likely candidate for this function. The lipid droplets in the RIC apparently are the precursors of the mediator(s). Degranulation of the RIC by an experimental maneuver usually indicates increased activity of these cells. The presence of abundant well-granulated RIC in a kidney indicates a resistance of that animal to the induction of salt-sensitive forms of experimental hypertension. There is definite evidence for an extrarenal antihypertensive function of the RIC mediators, but an intrarenal effect also is considered.     

Hypertension, orthostatic hypotension and the microvascular complications of diabetes

Prevalences of hypertension and orthostatic hypotension and their relationship to the microvascular complications of diabetes were assessed in 702 individuals aged 18-74 years, who had been selected as a representative sample of surviving patients with diabetes diagnosed at the Joslin Clinic between 1939 and 1965. In diabetes of short, long and very long duration, hypertension was 1.7, 1.9 and 2.1 times more frequent, respectively, than in the white U.S. population, regardless of gender. The excess frequency of hypertension in short duration diabetes suggests that some etiologic factor is shared by both conditions, while the magnification of the excess with increasing duration could be explained by an effect of diabetes on the kidney. Hypertension without accompanying proteinuria was not associated with retinopathy. Orthostatic hypotension was observed in 12% of the males and 13% of the females. The magnitude of the fall in systolic blood pressure was correlated with age, postprandial blood glucose, supine diastolic blood pressure, and the presence of retinopathy. Patients with proliferative retinopathy had the largest fall in systolic blood pressure.     

The association between orthostatic hypotension and recurrent falls in nursing home residents

PURPOSE: Orthostatic hypotension is common among the elderly, but its relation to falls is not certain. We determined whether orthostatic hypotension, including its timing and frequency, was associated with falls in elderly nursing home residents. SUBJECTS AND METHODS: We conducted a prospective study of 844 elderly (60 years of age and older), long-stay residents at 40 facilities that were part of a multistate nursing home chain. All subjects were able to maintain weight-bearing for at least 1 minute. Orthostatic hypotension was defined as a 20 mm Hg or greater decrease in systolic blood pressure from supine to standing, as measured after 1 or 3 minutes of standing on four occasions (before or after breakfast, or before or after lunch). The outcome was any subsequent fall during a mean of 1.2 years of follow-up. RESULTS: Orthostatic hypotension was present (at least on one measurement) in 50% of the subjects but was not associated with subsequent falls. However, among subjects with a history of previous falls in the past 6 months, those with orthostatic hypotension had an increased risk of recurrent falls [adjusted relative risk (RR) = 2.1; 95% confidence interval (CI), 1.4 to 3.1 ]. The risk of subsequent falls was greatest in previous fallers who had orthostatic hypotension at two or more measurements (RR = 2.6; 95% CI, 1.7 to 4.6). The association between orthostatic hypotension and recurrent falls was independent of measured demographic or clinical risk factors for falls. The timing of orthostatic hypotension (before or after meals) did not affect the risk of falls. CONCLUSIONS: Orthostatic hypotension is an independent risk factor for recurrent falls among elderly nursing home residents. Although the benefit of treating orthostatic hypotension will require further study, it may be prudent to identify high-risk residents and institute precautionary measures.     

Orthostatic hypotension in an octogenarian--an unusual presentation

Orthostatic hypotension is a common problem in older adults and can be associated with falls, dizziness and syncope and their associated consequences. Therefore, it is important to recognise the condition and institute appropriate management. We report an elderly woman who presented with orthostatic hypotension and was found to have a rare, benign yet potentially fatal condition.     

Features of renal dynamics among patients with vasorenal hypertension according to rheographic findings

Preoperative and late postoperative rheonephrographic findings in 23 patients with vasorenal hypertension are reported. Renal rheography was supplemented with a controlled hypotension test. Diagnostic and predictive value of renal rheography and the controlled hypotension test is explained. Indirect evidence of the irreversible nature of renal angiosclerotic changes on the side of occlusive lesion was demonstrated in patients with poor surgical results and a relatively intact contralateral kidney.     

Isolated diastolic hypotension and incident heart failure in older adults

Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively, who were balanced on 58 baseline characteristics. During >12 years of median follow-up, centrally adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension, respectively (hazard ratio associated with isolated diastolic hypotension: 1.33 [95% CI: 1.10-1.61]; P=0.004). Among the 5376 prematch individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% CI: 1.09-1.53; P=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.     

Postural hypotension and postural dizziness in patients with non-insulin-dependent diabetes.

BACKGROUND: Postural hypotension with a decline of 20 mm Hg or more in systolic blood pressure on standing is considered a potentially dangerous hypotensive response. Postural dizziness is often strongly associated with postural hypotension. However, there is conflicting evidence, and previous studies have been confined to the elderly, not specifically to patients with diabetes. Thus, we evaluated the association between postural hypotension and postural dizziness, and determined the factors most likely related to postural hypotension in patients with diabetes. METHODS: The subjects were 204 consecutive noninsulin-dependent patients with diabetes and 408 age- and sex-matched control subjects. Postural hypotension was defined as a decline of 20 mm Hg or more in systolic blood pressure 1 minute after standing. Postural dizziness was any feelings of dizziness, lightheadedness, or faintness that occurred while standing during the examination. RESULTS: The prevalence of postural hypotension and postural dizziness in patients with diabetes was higher than in control subjects. Those patients with both diabetes and postural hypotension were older and had higher supine systolic blood pressures and higher plasma glycosylated hemoglobin and fasting glucose levels. They had higher prevalence of postural dizziness, hypertension, and cerebrovascular disease, and lower standing systolic blood pressures than those without postural hypotension. They also were more often being treated with antihypertensive agents. Only 32.8% of patients with diabetes with postural hypotension suffered from postural dizziness. Postural dizziness, hypertension, cerebrovascular disease, and plasma glycosylated hemoglobin levels were independently associated with postural hypotension in patients with diabetes. CONCLUSIONS: Postural dizziness, glycemic control, hypertension, and cerebrovascular disease were important determinants of postural hypotension in patients with diabetes. Postural hypotension was associated with postural dizziness, but it cannot be determined clinically just from the presence of postural dizziness because the sensitivity for diagnosis of postural hypotension is low.     

Differentiation syndrome in acute myeloid leukemia after treatment with azacitidine

We report a case report of hyperleukocytosis, fever, hypotension, pulmonary and pericardial effusions, and acute kidney injury during initial treatment with azacitidine in a patient with AML‐MRC. Collectively, the symptomatology resembled differentiation syndrome. Azacitidine has been previously associated with fever, peripheral edema, and hyperleukocytosis, but its side effect profile has never been described as similar to differentiation syndrome. The patient's deteriorating course quickly turned around after treatment with dexamethasone. This potential reaction, and potential treatment, is important for clinicians to be aware of.     

Orthostatic hypotension-related hospitalizations in the United States

Background

Orthostatic hypotension has been commonly described in elderly persons and is associated with an increased risk of falls, syncope, and cerebrovascular events. Nevertheless, the precise burden of this condition in the US is currently unknown.

Methods

We analyzed discharge data from the Nationwide Inpatient Sample to identify orthostatic hypotension-related hospitalizations and associated comorbidities after excluding acute causes of this condition. National hospitalization rates were estimated using US census population estimates, and the medical conditions most frequently associated with orthostatic hypotension were assessed.

Results

In 2004, there were an estimated 80,095 orthostatic hypotension-related hospitalizations, yielding an overall rate of 36 (95% confidence interval, 34 to 38) hospitalizations per 100,000 US adults. Orthostatic hypotension was the primary diagnosis in 35% of these hospitalizations. The number of orthostatic hypotension-related hospitalizations increased steadily with age, and patients aged 75 years or older had the highest annual hospitalization rate, 233 per 100,000 (95% confidence interval, 217 to 249). The median length of hospital stay was 3 days (IQR 2-6) and the overall in-hospital mortality was 0.9%. Caucasian males were most likely to be hospitalized with orthostatic hypotension. Syncope was the most common comorbid condition reported among orthostatic hypotension patients.

Conclusions

Orthostatic hypotension is a relatively common condition among hospitalized US elderly patients. In light of the progressive aging of the US population, the contribution of orthostatic hypotension to morbidity and mortality is likely to increase, and deserves further scrutiny.     

Changes in regional vascular resistance after myocardial infarction in the dog.

The possibility that failure of vascular resistance to increase during hypotension in cardiogenic shock is a generalized phenomenon affecting many vascular beds was investigated in anesthetized dogs subjected to coronary arterial embolization. Blood flow in the carotid, mesenteric and renal vascular beds was monitored. Efferent vagus nerve stimulation, which, through bradycardia, produces hypotension of cardiac origin without myocardial damage, was associated with reflex vasoconstrictor responses in the carotid and mesenteric vascular beds; no change in resistance occurred in the renal vascular bed. In marked contrast, vasoconstriction failed to occur in any of the vascular beds in response to the hypotension produced by coronay embolization. These responses to cardiogenic shock mimicked those seen after ganglionic blockade, in which hypotension of partly cardiac origin was produced and reflex vasoconstriction blocked. The data support the previous hypothesis that myocardial infarction is associated with reflex inhibition of the reflex vasoconstrictor response to hypotension.     

Systemic microvascular leak in an in vivo rat model of ventilator-induced lung injury

Positive pressure mechanical ventilation has significant systemic effects, but the systemic effects associated with ventilator-induced lung injury (VILI) are unexplored. We hypothesized that VILI would cause systemic microvascular leak that is dependent on nitric oxide synthase (NOS) expression. Rats were ventilated with room air at 85 breaths/minute for 2 hours with either VT 7 or 20 ml/kg. Kidney microvascular leak, which was assessed by measuring 24-hour urine protein and Evans blue dye, was used as a marker of systemic microvascular leak. A significant microvascular leak occurred in both lung and kidney with large VT (20 ml/kg) ventilation. Injection of 0.9% NaCl corrected the hypotension and the decreased cardiac output related to large VT, but it did not attenuate microvascular leak of lung and kidney. Serum vascular endothelial growth factor was significantly elevated in large VT groups. Endothelial NOS expression significantly increased in the lung and kidney tissue with large VT ventilation but not inducible NOS. The NOS inhibitor, N-nitro-L-arginine methyl ester, attenuated the microvascular leak of lung and kidney and the proteinuria with large VT ventilation. Endothelial NOS may mediate the systemic microvascular leak of the present model of VILI.     

Levocarnitine Decreases Intradialytic Hypotension Episodes: A Randomized Controlled Trial

Intradialytic hypotension is common complication in stage 5 chronic kidney disease patients on hemodialysis. Incidence ranges from 15 to 30%. These patients have levocarnitine deficiency. A randomized, placebo‐controlled quadruple‐blinded trial was designed to demonstrate the levocarnitine efficiency on intradialytic hypotension prevention. Patients were randomized into four groups, to receive levocarnitine or placebo. During the intervention period, levocarnitine and placebo was administered 0 and 30 min before each hemodialysis session, respectively. During the trial, 33 patients received 1188 hemodialysis sessions. We identified 239 (21.3%) intradialytic hypotension episodes. The intradialytic hypotension episodes were less frequent in the levocarnitine group (9.3%, 60 IH events) (P < 0.001). Hemodialysis is frequently perplexed by intradialytic hypotension episodes. Levocarnitine supplementation before each hemodialysis session efficiently diminishes the intradialytic hypotension episodes. This is a new application method that must be considered and explored.     

Glomerular tubular reflux--a morphologic renal lesion associated with the hepatorenal syndrome

The hepatorenal syndrome, a primary cause of death from acute and chronic liver disease, consists of a functional renal failure whereby examination of the kidney has previously shown no distinct or specific morphologic change. We describe an unusual renal lesion consisting of the reflux of proximal convoluted tubular epithelium into Bowman's space. An autopsy series shows this glomerular change to be present in 71.4% of cases with the hepatorenal syndrome, while only present in 0 to 27.3% in other autopsy categories (p less than 0.001). Since this lesion has been previously described with experimental renal ischemic change and terminal hypotension, it is possible that it is caused in part by the decreased or altered renal blood flow known to be associated with the hepatorenal syndrome.     

Exertional hypotension after myocardial infarction

A retrospective study was conducted on 488 patients admitted in our rehabilitation center after a recent acute myocardial infarction. Purpose of the study was to assess the incidence and prognostic value of exertional hypotension in these patients. Of 488 patients admitted to the study 33 (6%) were found to have exertional hypotension; 14 patients had an inferior myocardial infarction, 18 patients had an anterior myocardial infarction, 3 patients had a history of previous myocardial infarction. In the follow-up period (28.3 +/- 13.2 months) the worse prognosis (death or pulmonary oedema) was associated with the presence during exercise of hypotension, ST segment elevation in leads were Q waves were present and no ST depression in other leads. In conclusion, recent anterior myocardial infarctions associated with hypotension and ST segment elevation during exercise appear to be at risk for future cardiac events.