Keywords models; cardiovascular diseases; nitric oxide synthase; nitric oxide; blood pressure; reninangiotensin system; vasodilationThe discovery in 1987 that endothelium-derived nitric oxide (NO) mediates the vasodilatory effect of certain endothelium-dependent agonists 1,2 inaugurated the current huge field of NO biology. It is now recognized that NO plays essential roles in many diverse physiological processes and in some pathophysiologic events. Development of these concepts has been based largely on evidence obtained by limiting NO biosynthesis. This review is centered on the cardiovascular and particularly the renal functional and structural consequences of chronic pharmacologic NO inhibition by L-arginine analogues. We devoted special attention to the mechanisms of hypertension and organ injury that occur under these circumstances, while appreciating the inherent limitations surrounding interpretation of this data. Ubiquity and Heterogeneity of NO BiosynthesisNO is made by the enzymatic action of several widely distributed NO synthases (NOS). In the presence of the substrates L-arginine and oxygen, as well as a number of essential cofactors, NO is produced in response to appropriate stimuli. The constitutively expressed NOS play a major role in the physiological control of vascular tone and kidney function. 3,4 Vascular endothelial NOS (eNOS) and brain-type NOS (bNOS) are widely distributed throughout the kidney 5 as well as the cardiovascular system and in strategic locations in the peripheral and central nervous system (CNS). 6,7 Both eNOS and particularly bNOS are abundant in the kidney, glomeruli, and vasculature as well as in most segments of the tubule, 3,5 and NOS activity in medulla is considerably greater than in cortex. 8 NO generated within the kidney controls the glomerular filtration rate (GFR), total renal and medullary blood flow, pressure natriuresis, epithelial sodium transport, and production of various vasoactive factors including renin. 3-5 eNOS is distributed throughout most parts of the arterial and venous circulation, although there is considerable heterogeneity in the extent to which NO controls tone in regional circulations. 9 Although there is some basal NO release from eNOS, shear stress is the physiologically important regulator of vascular NO production. 3 In the CNS, NO is made in the nucleus tractus solitarius, the paraventricular nucleus, and the ventral medulla and can control sympathetic outflow. 6,10 In addition to central regulation of efferent renal sympathetic nerve activity, there is direct nitrergic innervation to several locations including the renal vasculature. 7

The glomerulus develops progressive injury with advancing age which is particularly pronounced in males and is not the result of any specific disease process. In the present studies conducted in rats, glomerular function and structure were examined in adult (8 mo), elderly (12 mo), and old (19 mo) Munich Wistar rats. Intact males and females and castrated rats of both sexes were studied to determine the role of the sex hormones in mediating age-dependent glomerular damage. Intact males developed glomerular injury and proteinuria whereas females, both intact and ovariectomized, and castrated males were protected from injury. Glomerular blood pressure did not increase with advancing age in any group and did not correlate with glomerular damage. Glomerular volume did increase with advancing age in all groups but did not correlate with glomerular damage. We found that the presence of the androgens rather than the absence of the estrogens provide the risk factor for development of age-dependent glomerular damage. Neither glomerular hypertension nor glomerular hypertrophy provide the primary mechanism by which age-dependent glomerular injury occurs in the intact male. (J. Clin. Invest. 1994.

Twelve weeks of DDR-use improved FMD, aerobic fitness, and MAP in overweight children. Improvements occurred without changes in inflammatory markers or nitric oxide production. The results document the need to explore relationships between obesity, endothelial function, inflammation, lipids, exercise intensity, and gender in a larger sample of overweight children.

In 23 Munich-Wistar rats with surface glomeruli, the determinants of glomerular ultrafiltration and peritubular capillary uptake of proximal reabsorbate were studied before and during intra-arterial infusions of mildly vasodepressor doses of prostaglandin E1,acetylcholine, and bradykinin. For each drug single-nephron glomerular filtration rate remained unchanged from normal hydropenic values while glomerular plasma flow rate increased, resulting in declines in single-nephron filtration fraction (SNFF). Mean glomerular transcapillary hydraulic pressure difference (delta P) increased or remained unchanged on average. Declines in SNFF were accompanied by reductions in efferent arteriolar oncotic pressure (piE). Filtration pressure equilibrium, equality between pi E and delta P, obtained before but not during drug infusions. In the latter situation values for the glomerular capillary ultrafiltration coefficient were calculated and found to be significantly reduced from published control values. Despite marked falls in pi E during drug infusion, absolute proximal reabsorption was not reduced significantly, due, it is suggested, to the opposing effects of increases in efferent arteriolar plasma flow and interstitial hydraulic pressure.

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The inbred obese Zucker (ZDF/Gmi, fa/fa) rat develops severe hyperglycemia and also exhibits severe renal disease. In this study, we compared the relative benefits of long-term treatment with angiotensin-converting enzyme inhibition (ACEI) to a peroxisome proliferator-activated receptor ␥ (PPAR␥) agonist. Four groups of obese inbred Zucker rats were studied over a 6-month observation period; untreated animals, rats treated with ACEI alone, rats treated with PPAR␥ agonist alone, and rats treated with a combination of ACEI and PPAR␥ agonist. PPAR␥ agonist treatment normalized plasma glucose and led to massive increases in body weight. Both ACEI and PPAR␥ agonist were effective in reducing the proteinuria and glomerular and tubular kidney damage. However, the PPAR␥ agonist exerted superior renal protection compared with ACEI, in this model of spontaneously occurring chronic renal disease in the diabetic, obese inbred Zucker rat. Of note, although ACEI lowered blood pressure, there was no difference in glomerular blood pressure in any group at the end of the study. The glomerular filtration rate (GFR) was improved by ACEI with a borderline effect of PPAR␥ agonist alone. A mild additive protection on GFR and tubulointerstitial damage was seen with the combination. Based on the literature it is likely that the superior protection by PPAR␥ agonist versus glomerular and tubular damage as well as proteinuria extends beyond glycemic and lipidmic control and also reflects direct, protective intrarenal actions of the PPAR␥ agonists.

SUMMARY1. Whole kidney and micropuncture techniques were employed to investigate the determinants of glomerular ultrafiltration in virgin and 12-day pregnant rats.2. A significant increase in whole kidney glomerular filtration rate (g.f.r.) and superficial cortical single nephron g.f.r. was noted in pregnant rats compared to virgins.3. Increases in whole kidney and glomerular plasma flow rate also occurred in pregnancy which were in proportion to the increase in rate of filtration. No differences were noted in the hydrostatic and oncotic pressures which influence formation of glomerular ultrafiltrate in the superficial nephron population.4. Reduction in arterial haematocrit and no change in mean red cell volume indicate that a plasma volume expansion has occurred by day 12 of pregnancy in the rat.5. It is concluded that the increased g.f.r. seen in 12-day pregnant rats is exclusively the result of an increase in renal plasma flow rate (r.p.f.) since the other determinants of glomerular ultrafiltration are unaffected by pregnancy. The plasma volume expansion which also occurs must be, at least in part, responsible for the increase in r.p.f.

A B S T R A C T To investigate the mechanism(s) of increased filtration of serum proteins after glomerular injury, polydisperse samples of uncharged [ 42A were determined in these rats, together with direct measurements of the forces governing the glomerular filtration rate of water. Whole kidney and single nephron glomerular filtration rates were -40% lower in PAN-treated rats, relative to controls, due mainly to a marked reduction in the glomerular capillary ultrafiltration coefficient and, to a lesser extent, to a small reduction in glomerular plasma flow rate as well. In PAN-treated rats, as in normal controls, inulin was found to permeate the glomerular capillary wall without measurable restriction, and both D and DS were shown to be neither secreted nor reabsorbed. Fractional clearances of uncharged D were reduced after PAN administration, falling significantly for effective D radii from 22 to 38A. Utilizing a theory based on macromolecular transport through pores, these results indicate that in PAN-treated rats, effective pore radius is the same as in controls, -44A. In PAN nephrosis, however, the ratio of total pore surface area/pore length, a measure of pore density, is reduced to approximately one-third that of control, due very likely to a reduction in filtration surface area. In contrast to the results with uncharged D, fractional clearances of DS were found to increase after PAN