Praveen N. Chander

Aldosterone as a mediator in cardiovascular injury.

The renin-angiotensin-aldosterone system plays a central role in the development of hypertension and the progression of end-organ damage. Although angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists can initially suppress plasma aldosterone, it is now well established that aldosterone escape may occur, whereby aldosterone levels return to or exceed baseline levels. The classic effects of aldosterone relate mainly to its action on epithelial cells to regulate water and electrolyte balance. However, blood pressure reduction or fluid loss could not account for the results of the Randomized Aldactone Evaluation Study, which showed that a low dose of spironolactone in addition to conventional therapy could decrease the overall risk of mortality by 30% among patients with severe congestive heart failure. The action of aldosterone at nonepithelial sites in the brain, heart, and vasculature is consistent with the presence of mineralocorticoid receptors in these tissues. Aldosterone has a number of deleterious effects on the cardiovascular system, including myocardial necrosis and fibrosis, vascular stiffening and injury, reduced fibrinolysis, endothelial dysfunction, catecholamine release, and production of cardiac arrhythmias. Several studies have now shown vascular and target-organ protective effects of aldosterone receptor antagonism in the absence of significant blood pressure lowering, consistent with a major role for endogenous mineralocorticoids as mediators of cardiovascular injury. The advent of selective aldosterone receptor antagonists such as eplerenone should prove of great therapeutic value in the prevention of cardiovascular disease and associated end-organ damage.

Renal Lesions in Plasma Cell Dyscrasias: Ultrastructural Observations

The renal biopsies from 47 patients with plasma cell dyscrasias were studied by light and electronmicroscopy, and by immunohistochemical methods. This report is primarily concerned with the ultrastructural features of 24 cases of Bence Jones cast nephropathy and of ten cases of light chain deposit disease. In Bence Jones cast nephropathy, crystals derived from light chain proteins were detected in the majority of cases within the casts or in tubular cells and appeared to be related to the hard and fractured appearance of the casts as well as to the presence of foreign body type giant cells, the latter probably being of monocyte-macrophage origin. In light chain deposit disease, linear deposits of light chain proteins (eight kappa and two lambda) were present in a subendothelial position along the glomerular basement membrane and along the outer aspect of the tubular basement membranes in all cases, quite often in the mesangial matrix, but much less commonly in the interstitium and in the wall of small arteries. The light and electronmicroscopic features of both Bence Jones cast nephropathy and light chain deposit disease can be considered diagnostic for plasma cell dyscrasia. The possible pathogenetic mechanisms of these two different forms of renal involvement are discussed briefly.

Idiopathic Microscopic Polyarteritis Nodosa: Ultrastructural Observations on the Renal Vascular and Glomerular Lesions

Although the glomerulonephritis (GN) and renal vasculitis in polyarteritis nodosa (PAN) are generally considered to be immune-mediated, the pathogenesis of the renal injury and the role of immune complex (IC) deposition are unclear. To better define the nature of the glomerular and vascular injury in PAN, we performed a detailed ultrastructural study of 27 renal biopsies from 20 patients with histologically confirmed PAN of the microscopic or overlap (microscopic/macroscopic) type. A total of 48 arteries and arterioles were studied ultrastructurally, including 20 vessels with recognizable vasculitis in 1 micron-thick survey sections. By immunofluorescence, glomerular and vascular immunoglobulin deposits were generally scanty, primarily located in areas of necrosis or sclerosis. Fibrinogen, C3 and C1 were more commonly detected, often in the absence of demonstrable immunoglobulin. By electron microscopy, discrete electron-dense deposits of probable immune-type were found in the glomeruli of five initial biopsies. No electron-dense deposits were identified in any of the arteries or arterioles studied. In both glomeruli and vessels, endothelial injury and subendothelial fibrin deposition were the earliest detectable ultrastructural changes. The pathogenetic implications of these findings are discussed.

Beneficial action of beraprost sodium, a prostacyclin analog, in stroke-prone rats.

Beraprost sodium is a stable analog of the vasodilator, platelet antiaggregatory eicosanoid, prostacyclin. Experiments were performed to determine whether long-term therapy with beraprost produces vascular protective effects in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSPs). Oral beraprost at 30, 100, or 300 micrograms/kg/day starting at 8.4 weeks of age did not affect the progressive increase of systolic blood pressure (measured by tail-cuff plethysmography) in these rats. Additional experiments in SHRSPs, prepared for continuous monitoring of blood pressure by radiotelemetry, revealed that oral beraprost administration reduced mean arterial pressure but that these hypotensive responses were not sustained (< 4 h). In all SHRSPs receiving oral beraprost, proteinuria and cerebrovascular lesions developed. In contrast, continuous subcutaneous infusion of beraprost at 2.8 mg/kg/day from age 8.3-12.3 weeks reduced systolic blood pressure and markedly diminished the development of renal lesions and the occurrence of stroke in saline-drinking SHRSPs. Beraprost at 0.9 mg/kg/day reduced blood pressure less than did 2.8 mg/kg/day and provided partial protection against cerebral and renal lesions after a 4-week infusion period. These results indicate that long-term subcutaneous infusion of beraprost can protect saline-drinking SHRSPs against stroke and renal damage. This effect is not readily dissociated from the ability of beraprost to reduce blood pressure in SHRSPs.

1116 NIACIN PROTECTS AGAINST RENAL BUT AGGRAVATES CARDIAC DAMAGE IN RATS WITH THE METABOLIC SYNDROME

Objectives: Studies were conducted to examine the end-organ protective effects of niacin in obese spontaneously hypertensive rats (SHROB/cp); a model of the metabolic syndrome. Design and Methods: Animals were chronically treated with either a low dose (1% in chow; n = 5) or a high dose (5% in chow; n = 5) starting at 7.14 weeks of age. SHROB/cp (n = 9) and lean hypertensive control animals (SHROB/Kol) received Purina 5008 chow to which no niacin was added. Urinary protein excretion and pretermial systolic blood pressure (SBP) were measured and the animals sacrificed at 15 weeks of age. Hearts and kidneys were harvested for histology. Results: SBP was slightly but significantly lower in SHROB/cp vs SHROB/Kol and was not affected by niacin treatment (Table). Consistent with the metabolic syndrome, SHROB/cp showed hyperinsulinemia which was lowered by high dose but not low dose niacin. However, both dose levels of niacin significantly decreased urinary protein excretion and the degree of focal segmental glomerular sclerosis (FSGS) in SHROB/cp. Despite lower SBP in SHROB/cp, these animals had significantly more myocardial microinfarcts frequently undergoing organization. Additionally, there were hypereosinophillic myocardial fibers suggesting ongoing acute necrosis in a few animals. Unlike kidney damage, cardiac injury was not reduced by niacin treatment and, with low dose niacin, was significantly increased. Table. No title available. Conclusions: These results suggests that 1) cardiac and renal damage in SHROB/cp are independent of hypertension; the latter considered secondary to hyperperfusion injury of the metabolic syndrome and 2) niacin causes a target-organ protection in the kidney, but may further aggravate cardiac injury.

DO SILICONE TESTICULAR IMPLANTS INCREASE THE RISK OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IN CHILDREN?(2) MICRO-VASCULAR IMMUNE COMPLEXES MAY BE DEMONSTRATED IN THE FIBRO-MUSCULAR TISSUE AROUND SILICONE IMPLANTS.

We have previously reported the occurrence of severe SLE with nephritis in two children, a 15 year old boy in 1992, 12 years after a silicone testicular prosthesis was implanted in the scrotum for cosmetic reasons (unilateral cryptochordism) and a 10 year old girl in 1981, two years after a silicone scleral sponge was implanted in her eye (retinal detachment) (Lancet, 1994.343:354-5). 2/50 children who have had renal biopsies for lupus nephritis at our hospital between 1977-1993 have had silicone implants prior to their developing SLE.

INHIBITION OF NITRIC OXIDE (NO) SYNTHESIS: A PRIMARY DEFECT IN PULMONARY HYPERTENSION (PH). † 178

INHIBITION OF NITRIC OXIDE (NO) SYNTHESIS: A PRIMARY DEFECT IN PULMONARY HYPERTENSION (PH). † 178