The cost of quality assurance

The relative importance of endothelial derived relaxing factor (EDRF)/nitric oxide (NO) in maintaining kidney function in normal condition and in acute renal failure (ARF) were evaluated in inactin anesthetized rats. ARF was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion, with the contralateral kidney serving as normal control. This protocol resulted in marked reductions in renal plasma flow (RPF), glomerular filtration rate (GFR) and increases in fractional sodium excretion (FENa) and urinary protein excretion in the post-ischemic kidney in comparison to the contralateral normal kidney. Administration of the nitric oxide (NO) synthase inhibitor NG--monomethyl-L-arginine (0.25 mg/kg per min, L-NMMA) exacerbated the ischemia-induced changes in renal functions as reflected by further reductions in urine flow (V), GFR, marked sodium wasting and renal edema. Pretreatment of the animals with NO precursor L-arginine (2.5 mg/kg per min, L-Arg) abolished the detrimental effects of L-NMMA in ARF. In contrast, D-Arginine (2.5 mg/kg per min, D-Arg) failed to reverse the detrimental effects of L-NMMA. Infusion of L-Arg alone also resulted in improvements in RPF and GFR in the ischemic kidney. The results of the present study suggest that the function of the ischemic kidney is sustained by EDRF/NO and is thus more sensitive to NO synthase inhibition.     

Differential effects of endotoxaemia on pressor and vasoconstrictor actions of angiotensin II and arginine vasopressin in conscious rats

1. Regional haemodynamic responses to arginine vasopressin (AVP; 0.5, 1.0, 5.0 pmol i.v.) and angiotensin II (AII; 5.0, 10.0, 50.0 pmol i.v.) were measured in conscious Long Evans rats at various times (0, 2, 6 and 24 h) during infusion of lipopolysaccharide (LPS, 150 microg kg(-1) h(-1), i.v., n=9) or saline (n=9). Additional experiments were performed in vasopressin-deficient (Brattleboro) rats infused with LPS (n=7) or saline (n=8) to determine whether or not, in the absence of circulating vasopressin, responses to the exogenous peptides differed from those in Long Evans rats. 2. In the Long Evans rats, during the 24 h infusion of LPS, there was a changing haemodynamic profile with renal vasodilatation from 2 h onwards, additional mesenteric vasodilatation at 6 h, and a modest hypotension (reduction in mean arterial blood pressure (MAP) from 103+/-1 to 98+/-2 mmHg) associated with renal and hindquarters vasodilatation at 24 h. 3. In the Brattleboro rats, the changes in regional haemodynamics during LPS infusion were more profound than in the Long Evans rats. At 2 h and 6 h, there was a marked fall in MAP (from 103+/-3 mmHg; to 65+/-3 mmHg at 2 h, and to 82+/-4 mmHg at 6 h) associated with vasodilatation in all three vascular beds. After 24 h infusion of LPS, the hypotension was less although still significant (from 103+/-3 mmHg; to 93+/-4 mmHg, a change of 10+/-4 mmHg), and there was renal and hindquarters vasodilatation, but mesenteric vasoconstriction. 4. During infusion of LPS, at each time point studied, and in both strains of rat, pressor responses to AII and AVP were reduced, but the changes were less marked at 6 h than at 2 h or 24 h. The reduced pressor responses were not accompanied by generalized reductions in the regional vasoconstrictor responses. Thus, in the Long Evans rats, the renal vasoconstrictor responses to both peptides were enhanced (at 6 h and 24 h for AVP; at all times for AII), whereas the mesenteric vasoconstrictor response to AVP was unchanged at 2 h, enhanced at 6 h and reduced at 24 h. The mesenteric vasoconstrictor response to AII was reduced at 2 h, normal at 6 h and reduced at 24 h. The small hindquarters vasoconstrictor responses to both peptides were reduced at 2 h and 6 h, but normal at 24 h. 5. In the Brattleboro rats, the renal vasoconstrictor responses to both peptides were reduced at 2 h and enhanced at 6 h and 24 h, whereas the mesenteric vasoconstrictor response to AVP was normal at 2 h and 6 h, and reduced at 24 h. The response to AII was reduced at 2 h, normal at 6 h and reduced again at 24 h. There were no reproducible hindquarters vasoconstrictions to AVP in the Brattleboro rats. The small hindquarters vasoconstrictor responses to AII were unchanged at 2 h and enhanced at 6 h and 24 h. 6. In isolated perfused mesenteric vascular beds, removed after 24 h of LPS infusion in vivo, there was an increase in the potency of AVP in both strains (Long Evans, ED50 saline: 56.9+/-15.0 pmol, ED50 LPS: 20.4+/-4.8 pmol, Brattleboro, ED50 saline: 38.6+/-4.2, ED50 LPS: 19.6+/-2.9 pmol), but no change in the responses to AII. 7. These findings indicate that a reduced pressor response to a vasoconstrictor challenge during LPS infusion is not necessarily associated with a reduced regional vasoconstriction. The data obtained in the Brattleboro rats indicate a potentially important role for vasopressin in maintaining haemodynamic status during LPS infusion in Long Evans rats. However, it is unlikely that the responses to exogenous AVP (or AII) are influenced by changes in the background level of endogenous vasopressin, since the patterns of change were similar in Long Evans and Brattleboro rats. 8. The results obtained in isolated perfused mesenteric vascular beds differed from those in vivo, possibly due to the conditions pertaining with in vitro perfusion.     

Haemodynamic and renal effects of felodipine in young and elderly subjects

OBJECTIVE: To study the influence of age on renal and haemodynamic effects of the calcium antagonist felodipine. METHODS: Eight young (mean age 27 years) and eight elderly (mean age 75 years) healthy normotensive subjects were given felodipine intravenously for 120 min aiming at close to therapeutic plasma level concentration. Renal blood flow (RBF) and renal vascular resistance (RVR) was estimated from para-aminohippuric acid (PAH) clearance 51CrEDTA clearance was used to measure glomerular filtration rate (GFR) and used in the calculations of fractional excretion (FE) of electrolytes. Impedance cardiography was performed to assess stroke volume and for the calculation of cardiac output and ejection fraction. RESULTS: At the end of felodipine infusion, the concentration of felodipine was on average 10.0 nmol x l(-1) in young and 12.0 nmol x l(-1) in elderly subjects (NS). During felodipine infusion blood pressure (BP) decreased from 138/76 to 120/68 in elderly subjects. The BP in young subjects was 126/74 at basal and 125/70 after infusion of felodipine. The systemic and renal vascular resistance decreased to a similar extent in young and elderly subjects after felodipine infusion. Felodipine caused a decrease in systemic vascular resistance from 25.6 to 23.3 in elderly and from 23.8 to 21.8 in the young subjects. Mean values for RVR at baseline and during infusion of felodipine were significantly higher in the elderly (10.1-15.1) than in the young subjects (5.4-6.7). Felodipine reduced RVR by 10% in the young and by 12% in the elderly at the end of infusion. The young subjects had 31% higher GFR than the elderly subjects at the start of infusion. Felodipine infusion did not affect GFR. There were no effects on stroke volume and ejection fraction. An initial natriuretic effect was found after infusion of felodipine in the young subjects. The fractional excretion of all electrolytes tended to increase after both felodipine and placebo, more in the elderly than in the young subjects. CONCLUSION: The effects of felodipine on central and renal haemodynamics previously observed in young and middle-aged subjects also seem to exist in the elderly. Volume expansion seems to increase the excretion of electrolytes more in elderly than in young people, and therefore the effect of felodipine on natriuresis is more evident in young subjects.     

Assessing renal effects and renal protection

ASSESSMENT OF RENAL FUNCTION: There are a number of methods of evaluating renal function, including measurements of glomerular filtration, renal plasma flow, tubular function, micro- and macroalbuminuria and urinary sediment. Of these, microalbuminuria, glomerular filtration and renal plasma flow are the most appropriate. RENAL EFFECTS OF CALCIUM ANTAGONISTS: Calcium antagonists have important effects on renal function, including a reduction in renal vasoconstriction, increased renal blood flow and, in some circumstances, reduced protein excretion. In particular, these agents can reverse the mild renal vasoconstriction that is seen in the offspring of hypertensive patients. The renal effects of calcium antagonists have been studied in animal models, where radioimaging techniques have shown a biphasic haemodynamic response. RENAL PROTECTION WITH CALCIUM ANTAGONISTS: Two important beneficial effects of calcium antagonists are prevention of acute renal failure and protection against cyclosporin nephrotoxicity. Calcium antagonists have thus been used therapeutically in renal transplant patients and in patients with acute renal failure secondary to the effects of nephrotoxic agents.     

ETA receptor-mediated role of endothelin in the kidney of DOCA-salt hypertensive rats

Renal effects of FR139317, an endothelin ETA receptor antagonist, were examined using anesthetized normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The intravenous bolus injection of FR139317 (10 mg/kg) produced a slight decrease in mean blood pressure (MAP; -13%) in the control rats and this hypotension was accompanied by a moderate renal vasodilation (renal vascular resistance: RVR; -12%). In the DOCA-salt hypertensive rat, FR139317 had a more pronounced hypotensive effect (MAP; -26%) accompanied by a potent renal vasodilation (RVR; -33%). FR139317 significantly increased renal blood flow only in the DOCA-salt rats. In contrast, FR139317 produced a significant decrease in urine flow and urinary sodium excretion only in control rats. Northern blot analysis revealed that the renal prepro endothelin-1 (ET-1) mRNA level was significantly increased in DOCA-salt hypertensive rats. Thus, it seems likely that endogenous ET-1 is responsible for the maintenance of DOCA-salt-induced hypertension. We also suggest that at least in part, ET-1 and ETA receptors are involved in renal hemodynamic abnormalities in DOCA-salt-induced hypertension. The augmentation of renal ET-1 production may possibly have a function in the development and maintenance of DOCA-salt-induced hypertension.     

Effect of KATP channel blocker U37883A on renal function in experimental diabetes mellitus in rats

An increase in glomerular filtration rate (GFR) in early diabetes mellitus is considered a risk factor for the development of diabetic nephropathy. Insulin deficiency may increase the activity of ATP-sensitive potassium channels (KATP), which could promote afferent arteriolar vasodilation und thus contribute to glomerular hyperfiltration in early diabetes mellitus. To further elucidate this hypothesis we performed renal clearance experiments in anesthetized rats at 2 and 6 weeks after onset of streptozotocin-induced insulin-treated diabetes mellitus and studied the acute effect of the putative KATP channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U37883A) on renal function. In control rats, application of U37883A (1.5 mg/kg i.v. bolus plus 1.5 mg/kg/hr) induced a significant reduction in heart rate, but did not affect or even slightly increased mean arterial blood pressure. Furthermore, U37883A did not significantly affect renal vascular resistance, renal blood flow or GFR, but caused an eukaliuretic diuresis and natriuresis and lowered plasma renin activity. Diabetic rats at both 2 or 6 weeks after streptozotocin exhibited essentially an identical response to U37883A; in particular, RVR and glomerular hyperfiltration remained unchanged. These results show that in both control and diabetic rats, the renal excretory function, renin secretion and pace setting in the heart were sensitiv to U37883A, implying a functional contribution of KATP channel activity. However, in both control and diabetic rats, renal vascular resistance, renal blood flow, or GFR were not altered by U37883A. These results argue against a substantial role for KATP channels in the basal control of renal hemodynamics in both nondiabetic and diabetic rats.     

Renal vascular responses to angiotensin II in conscious spontaneously hypertensive and normotensive rats

It has been postulated that exaggerated renal sensitivity to angiotensin II may be involved in the development and maintenance of hypertension in the spontaneously hypertensive rat (SHR). The purpose of this study was to compare the renal vascular responses to short-term angiotensin II infusions (50 ng/kg/min, i.v.) in conscious SHRs and Wistar-Kyoto (WKY) rats. Renal cortical blood flow was measured in conscious rats by using quantitative renal perfusion imaging by magnetic resonance, and blood pressure was measured by an indwelling carotid catheter attached to a digital blood pressure analyzer. Renal vascular responses to angiotensin II were similar in control SHRs and WKY rats. Pretreatment with captopril to block endogenous production of angiotensin II significantly augmented the renal vascular response to exogenous angiotensin II in the SHRs but not in the WKY rats. The renal vascular responses to angiotensin II were significantly greater in captopril-pretreated SHRs than in WKY rats (cortical blood flow decreased by 1.66 +/- 0.13 ml/min/g cortex in WKY rats compared with 2.15 +/- 0.14 ml/min/g cortex in SHR; cortical vascular resistance increased by 10.5 +/- 1.4 mm Hg/ml/min/g cortex in WKY rats compared with 15.6 +/- 1.7 mm Hg/ml/min/g cortex in SHRs). Responses to angiotensin II were completely blocked in both strains by pretreatment with the angiotensin II AT1-receptor antagonist losartan. Results from this study in conscious rats confirm previous findings in anesthetized rats that (a) the short-term pressor and renal vascular responses to angiotensin II are mediated by the AT1 receptor in both SHRs and WKY rats, and (b) the renal vascular responses to angiotensin II are enhanced in SHRs compared with WKY rats when endogenous production of angiotensin II is inhibited by captopril pretreatment.     

Involvement of nitric oxide in hyporeactivity of rat mesenteric vascular bed during endotoxic shock: effect of dexamethasone and endothelin-I

The present study was carried out on mesenteric vascular bed from LPS-injected rats in order to investigate the cause of hyporesponsiveness in resistance blood vessels, during septic shock syndrome. The involvement of L-Arg/NO pathway was evaluated by administration of L-Arg, which produced a decrease in perfusion pressure in LPS-treated rats, whereas it was ineffective in control rats. Furthermore, DEX-pretreatment in endotoxaemic rats significantly reduced the vasorelaxation by L-Arg, whereas it was ineffective to reverse vascular hyporeactivity occurring in septic shock. In order to evaluate whether hyporesponsiveness could be due to defects in contraction mechanisms, we tested the effect of ET-I. This peptide was able to markedly enhance the contractile response to NA in LPS-treated rats. Our findings suggest that vascular hyporesponsiveness during septic shock may depend on both activation of the L-Arg/NO pathway and alterations in post-receptor mechanisms involving calcium handling.     

An asymmetric deuterium labeling strategy to identify interprotomer and intraprotomer NOEs in oligomeric proteins

1. The aim of the study was to measure the regional haemodynamic responses to vasodilators, and the effects of nitric oxide (NO) synthase inhibition, in conscious, hypertensive, transgenic ((mRen-2)27) rats (TG rats) and normotensive, Hannover Sprague-Dawley (SD) rats. 2. The hypotensive response to acetylcholine was greater in TG than in SD rats, but the renal vasodilator responses were not different. 3. The responses to bradykinin were similar in the two strains, except that hindquarters vasodilatation occurred only in SD rats. 4. Salbutamol caused smaller renal and hindquarters vasodilatation in TG rats than in SD rats, and there was mesenteric vasodilatation only in the latter strain. 5. The hypotensive response to sodium nitroprusside was smaller, but the accompanying mesenteric vasodilatation was greater, in SD than in TG rats. 6. The contribution of NO to the vasodilator responses was taken as the difference between the responses in the presence of the NO synthase inhibitor, NG-nitro-L-arginine methylester (L-NAME), compared to those in the presence of a co-infusion of angiotensin II and vasopressin (to match the haemodynamic effects of L-NAME). 7. In TG rats, L-NAME caused a greater absolute pressor effect, but a smaller mesenteric vasoconstriction, than in SD rats. 8. L-NAME affected the vasodilator responses to all the challenges similarly in the two strains. 9. Collectively, the results provide no direct evidence for impaired NO-mediated vasodilator mechanisms in TG rats. It is feasible that the reduced hindquarters response to bradykinin and the reduced renal and hindquarters responses to salbutamol, in TG rats are due to abnormal beta2-adrenoceptor-mediated processes.     

Age-related changes in sympathetic modulation of sensory nerve activity in rat skin

OBJECTIVES: Sensory nerves play an important role in mediating neurogenic inflammation and subsequent tissue healing. A decrease in sensory nerve function with increasing age has been reported to correlate with poor tissue healing. Sympathetic nerves are known to modulate sensory nerve function, and changes in this modulation could also have important implications with ageing. The aims of this study were to examine the effect of different frequency electrical stimulation (ES) on the microvascular responses obtained to sensory nerve activation in young, aged and capsaicin-pretreated rats and modulation of these responses by sympathetic efferents. METHODS: Using laser Doppler flowmetry, vascular responses to antidromic ES of the sciatic nerve were monitored in the base of vacuum-induced blisters in the hind footpad. The non-selective alpha-adrenoceptor antagonist phentolamine (3 mg/kg, i.v.) was administered 20 min prior to ES. RESULTS: At high frequency ES (20V, 2ms, 15Hz for 1 min), the vascular response in old rats was significantly reduced (46 percent decrease, p < 0.05) compared to young control. At low frequency ES (20 V, 2 ms, 5 Hz for 1 min) however, older rats produced similar vascular responses to the young. Capsaicin-pretreated rats showed significantly reduced vascular responses to both high and low frequency ES, regardless of age. Pretreatment with phentolamine significantly increased the microvascular response in young rats at high (87 percent) and low (36 percent) frequency ES. In contrast, phentolamine significantly increased the ES-induced response in old rats at high frequency only (147 percent increase). CONCLUSIONS: The results suggest that the aged sensory nerve responds preferentially to low frequency ES and that sympathetic efferents exert an inhibitory modulatory effect on the vascular response evoked by sensory nerve stimulation. There are age-related changes in sympathetic modulation of sensory nerve-mediated responses which is dependent on stimulation frequency.     

Age-related changes in morphology and secretory responses of male rat lacrimal gland

This study investigates the differences in the outward appearance and morphology of lacrimal glands, the morphology within the lacrimal acinar cells and the secretion of protein from acinar cells of young (3-5 months) and aged (20 and 24 months) male rats. The appearance of the glands, as seen by the naked eye, differed between the three age-groups. The lacrimal gland of young animals was a smooth pink tissue, while the tissue from aged animals appeared lobular and white in colour, thought to result from infiltration of fatty/connective tissue. Glands from 24 month old animals had a more pronounced lobular appearance than the glands from 20 month old animals. Light microscopy studies revealed that as the animals aged there was evidence of progressive morphological changes. These changes included thickening of the connective tissue sheath, chronic inflammation with increased infiltration by mast cells, patchy destruction of ductal and vascular tissues, enlargement of lacrimal ducts, luminal swelling of the acini, and changes in acinar type. Electron microscopy (EM) studies revealed the presence of 3 types of acini in the rat lacrimal gland: acini which contained only protein secretory granules (serous acini), acini which contained protein and mucous secretory granules (seromucous acini), and acini which contained only mucous secretory granules (mucous acini). In young glands the majority of acini were serous with a few seromucous acini and even fewer mucous acini. In aged glands there were significant reductions in serous acini (ANOVA; P < 0.01) when compared to the young glands. In 20-month-old glands, there were marked increases in the percentage occurrence of seromucous acini, while in 24 month old glands, there were large increases in the relative number of mucous acini. Qualitative EM studies demonstrated that the typical acini from young glands contained numerous protein secretory granules. Ageing was associated with a progressive loss of protein (serous) secretory granules. Furthermore, marked changes and patchy destruction of the endoplasmic reticulum and Golgi apparatus were observed in acini of glands from aged rats when compared to acini of glands from young rats. Measurement of total protein output from acini revealed a significant (Student's t-test, P < 0.05) decrease in protein secretion from aged glands compared to glands from young animals. These results suggest that not only is there considerable structural damage, chronic inflammation and mast cell infiltration to the lacrimal gland with ageing, but also possible redifferentiation of acini from serous to seromucous and then to mucous acini. Furthermore, the results also suggest a reduction or an inability of the acini to synthesise and to secrete protein from glands of aged animals compared to glands of young rats. All of these changes appear to occur more rapidly as the rats mature between 20 and 24 months. These findings provide a morphological basis to explain the phenomenon of reduced tear/protein secretion with ageing.     

Investigations on the antihypertensive activity of timolol and bendroflumethiazide and the combination in dogs and rats

The effects of timolol and bendroflumethiazide, either alone or combined in a fixed ratio of 4:1, on blood pressure, plasma renin activity, and plasma potassium concentration, have been investigated in normotensive and renal hypertensive dogs, and in normotensive and spontaneously hypertensive rats. In addition, the urinary kallikrein excretion has been measured in normotensive and hypertensive rats. When administered to hypertensive dogs and rats, the drug combination significantly reduced the blood pressure. Marginal reductions were observed in normotensive animals or after the administration of the single drugs. The thiazide-induced hypokalaemia and hyperreninaemia were almost completely antagonised by the concomitant administration of timolol in both animal species. A highly significant elevation of urinary kallikrein excretion was also observed in rats treated with the drug combination. A less marked increase of kallikrein excretion was noted in the bendroflumethiazide treated rats. The possibility that renal haemodynamic changes, in addition to the inhibition of the increase in plasma renin, play a role in the observed antihypertensive effects is discussed.     

Factors influencing ketorolac-associated perioperative renal dysfunction

Nonsteroidal antiinflammatory drugs (NSAIDs) are useful for the treatment of postoperative pain, but there is continuing concern about adverse effects on renal function. We studied the renal effects of ketorolac in an animal model using Fischer 344 rats undergoing isoflurane anesthesia and laparotomy. Treatment groups--control (C), ketorolac (5 mg x kg(-1) x d(-1)) (K), large-dose ketorolac (15 mg x kg(-1) x d(-1)) (KH), dehydration-ketorolac (5 mg x kg(-1) x d(-1)) (DK), gentamicin (20 mg x kg(-1) x d(-1)) (G), and gentamicin (20 mg x kg(-1) x d(-1)) with ketorolac (5 mg x kg(-1) x d(-1)) (GK)--each comprised 10 animals. Renal function was assessed before laparotomy and after 3 treatment days using concurrent paraaminohippurate and iothalamate clearances, respectively, to estimate renal plasma flow and glomerular filtration rate, and by measuring serum and urine electrolytes, osmolality, urea, and creatinine. A significant increase in serum potassium was found in the GK and DK groups. There were no major changes in renal function in the C, K, KH, and DK groups. Mild renal dysfunction was found in the G group. We found severe and consistent changes in renal function, accompanied by severe, widespread histological changes of acute tubular necrosis, in the GK group. In this postoperative rat model, the combination of ketorolac and gentamicin was deleterious to renal function. Implications: We examined the renal effects of the nonsteroidal antiinflammatory drug ketorolac. Renal function was measured in rats before and after surgery and 3 days' drug administration; the kidneys studied by using microscopy. Only ketorolac plus the antibiotic gentamicin produced marked changes in kidney function and structure.     

Effects of BQ-123 on systemic and renal hemodynamic responses to endothelin-1 in the rat split hydronephrotic kidney

OBJECTIVE: To assess the site of action of endothelin-1 in vessels of different sizes in the kidney in vivo and investigate the function of endothelin A (ET(A)) receptors in mediating renal and systemic vasoconstriction. DESIGN: The luminal diameters of different vessels were measured and glomerular blood flow in cortical glomeruli was determined by intravital videomicroscopy in the split hydronephrotic kidney of anesthetized female Wistar rats. METHODS: The rats were infused with endothelin-1 (40 pmol/kg per min) with or without pretreatment with the selective ET(A)-receptor antagonist BQ-123 (0.5 mg/kg). Aortic clamping was used to control renal blood pressure during the endothelin-1 infusion. RESULTS: Exogenous endothelin-1 induced a significant rise (30+/-3%) in mean arterial pressure and a marked, long-lasting fall in glomerular blood flow (53+/-3%) related to reduction of the inner diameter of arcuate (-30%), interlobular arteries (-33%) and afferent arterioles (-17%). Aortic clamping to normalize renal blood pressure did not attenuate the vasoconstriction and reduction in glomerular blood flow. Pretreatment with BQ-123 significantly reduced both the endothelin-1-induced rise in mean arterial pressure (12+/-1%) and the fall in glomerular blood flow (-23+/-11%). BQ-123 blunted the response to endothelin-1 in arcuate (-12%), interlobular (-11%) and afferent vessels (-5%). Acetylcholine and nitroprusside completely reversed the vasoconstriction in BQ-123-pretreated animals. CONCLUSIONS: BQ-123 largely prevented the hemodynamic effects of exogenously administered endothelin-1. Our direct in-vivo techniques showed that ET(A) receptors are, at least in part, involved in endothelin-1 -mediated vasoconstriction in the rat kidney, and support the hypothesis that ET(A) receptors may help to control arterial pressure in anesthetized rats.     

Pioneer in public health education: Roscoe Conkling Brown

In order to study the influence of ageing on the hormonal function of the endothelium in man, plasma endothelin levels were measured in 11 normal young persons (mean aged 25.7 +/- 1.8 years) and in 16 apparently healthy elderly subjects (mean 87.5 +/- 5.4 years) without anamnestic or clinical signs of symptomatic atherosclerosis. The mean plasma level +/- SD of endothelin was 2.72 +/- 0.61 pg/ml in elderly subjects and 2.09 +/- 0.66 in young subjects. The difference was statistically significant (p < 0.05). Various humoral or local age-related environmental factors may be responsible for this result. In particular increased vascular production of endothelin may be the response to endothelial cell damage caused by an asymptomatic atherosclerotic process. Studies still need to define whether enhanced plasma endothelin levels in elderly subjects not suffering from symptomatic atherosclerosis are the consequence of ageing alone or an ongoing but clinically silent atherosclerotic process.     

Restoration and acceleration of the development of the capacity for antibody synthesis by the humoral factor of the thymus

A fraction stimulating the antibody synthesis to sheep erythrocytes in administration during the neonatal period to mice and partially restoring the antibodygenesis in neonatally thymectomized rats was isolated from a calf thymus extract. Morpho-histochemical studies demonstrated a marked plasmocytic reaction in the spleen of neonatally thymectomized rats under the effect of the thymus extract fraction in response to immunization with sheep erythrocytes; however, there occurred no normalization of morphotopographic peculiarities of the splenic tissue, including the thymus-dependent regions. Administration of the extract was also not accompanied by any weight gain of the lymphoid organs, or increase in lymphocyte count in the peripheral blood and the count of splenic cells transforming into blasts under the effect of phytohemagglutinin.     

Contrast media-induced nephrotoxicity--questions and answers

The intravascular administration of contrast media (CM) can produce acute haemodynamic changes in the kidney characterized by an increase in renal vascular resistance and a decrease in the glomerular filtration rate (GFR). These changes may lead to clinically significant reduction in renal function in patients with pre-existing risk factors such as diabetic nephropathy, congestive heart failure and dehydration. The pathophysiology of the renal haemodynamic effects of CM involves activation of the tubuloglomerular feedback (TGF) mechanism and the modulation of the intrarenal production of vasoactive mediators such as prostaglandins, nitric oxide, endothelin and adenosine. The TGF response is osmolality-dependent and accounts for about 50% of the acute functional effects of high osmolar CM on the kidney. Reduction in the synthesis of the endogenous vasodilators nitric oxide and prostaglandins increases the nephrotoxicity of CM. Endothelin and adenosine play a crucial role in mediating the acute functional effects of CM. Antagonists of these mediators attenuate the reduction in renal function induced by contrast agents. Vacuolization of the cells of the proximal tubules and necrosis of those of the medullary ascending limbs of loops of Henle are the main structural effects of CM in the kidney. The reduction in renal function induced by CM could be minimized by the use of low osmolar CM and adequate hydration. The prophylactic administration of calcium channel blockers and adenosine antagonists such as theophylline may also offer some protective effect.     

Prevalence of central autonomic neuropathy in elderly dialysis patients

BACKGROUND: Autonomic neuropathy is frequently present in dialysis patients. In addition, deterioration of autonomic function occurs with ageing. This study examines the true prevalence of autonomic neuropathy in elderly dialysis patients and questions whether the combination of age and uraemia further increases the chance of dysautonomia being present. METHODS: We compared the results of five different tests (30:15 ratio; Valsalva ratio; heart rate response to deep breathing and the blood pressure responses to sustained hand grip and standing) of parasympathetic and combined parasympathetic and sympathetic dysfunction in older haemodialysis patients (mean age 70.2 years), younger haemodialysis patients (mean age 48.1 years) and two groups of subjects with normal renal function (mean age 73.0 years and 42.5 years respectively). RESULTS: Parasympathetic dysfunction was most prevalent in older patients on dialysis (65.9% (95% confidence intervals 51.4-80.4%), compared with 33.3% (95% confidence intervals 19.0-47.5% in younger dialysis patients), and 11.8 and 0% in the old and young control groups respectively). Combined parasympathetic and sympathetic dysfunction was seen in 41.5% (95% confidence intervals 26.5-56.5%) and 11.9% (95% confidence intervals 2.1-56.5%) of the old and young dialysis patients respectively but not in any of the control subjects. No interaction was seen between age and subject type. CONCLUSIONS: We conclude that although older dialysis patients have severe impairment of cardiovascular autonomic innervation, the prevalence of dysfunction is not higher than would be expected in an ageing population with uraemia.     

Cloning, overexpression, purification, and spectroscopic characterization of human S100P

OBJECTIVES: We sought to study the renal circulatory effects of adenosine in patients with chronic congestive heart failure (CHF). BACKGROUND: Renal blood flow (RBF) is often reduced in patients with chronic CHF and may lead to decreased renal function. The cause of reduced RBF is multifactorial and involves systemic as well as local vasoregulatory mechanisms. Stimulation of renal adenosine A1 receptors in animal models has resulted in a significant vasoconstriction of afferent and efferent glomerular arterioles and deterioration of renal function. Although adenosine serum levels have been shown to be elevated in patients with CHF, their effect on the renal circulation in this patient population has not been studied. METHODS: Nine patients with CHF from left ventricular systolic dysfunction were studied. The effects of adenosine at a dose of 10(-5) mol/liter infused directly into the main renal artery on heart rate, renal artery blood pressure, renal artery cross-sectional area (measured by intravascular ultrasound), renal Doppler blood flow velocity (measured by a Doppler flow wire in the renal artery), RBF and renal vascular resistance (RVR) were evaluated. RESULTS: Infusion of adenosine resulted in no significant effect on heart rate or renal artery blood pressure but caused a substantial increase in RVR (11,204 +/- 1,469 to 31,494 +/- 3,911 dynes x s x cm(-5), p = 0.0005), which led to a marked fall in RBF in every patient (mean values 376 +/- 36 to 146 +/- 22 ml/m2, p = 0.0002). These changes in RVR and RBF were associated with no significant change in renal artery cross-sectional area (0.389 +/- 0.040 to 0.375 +/- 0.033 cm2, p = 0.3). CONCLUSIONS: Stimulation of renal adenosine receptors in patients with CHF results in marked renal vasoconstriction that leads to an important reduction in RBF. Lack of change in renal artery cross-sectional area suggests that adenosine affects intrarenal resistance blood vessels rather than large conductance vessels. These results may indicate a rationale for investigation of renal adenosine receptor blockade for enhancement of RBF and improvement of renal function in patients with chronic CHF.     

Augmented mesenteric and renal vasoconstriction during exercise in senescent Fischer 344 rats

The purpose of this study was to test the hypothesis that vasoconstriction in the mesenteric and renal circulations is greater at both submaximal and maximal exercise intensities with advancing age. Arterial blood pressure, heart rate, and mesenteric, renal, and iliac (hindlimb) artery blood flow velocities were measured before and during graded treadmill exercise in mature (12 mo) and senescent (24 mo) male Fischer 344 rats. During treadmill running at mild, moderate, and maximal exercise intensities (approximately 45, 70, and 100% of maximal oxygen uptake), the increases in arterial pressure were similar in the mature and senescent animals, whereas heart rate rose less in the older group (P < 0.05). Mesenteric and renal flow velocities declined and vascular resistances increased from resting levels in both groups in response to graded exercise; however, the magnitudes of the increases in both mesenteric and renal vascular resistance were significantly augmented in the older rats at the moderate and maximal workloads. Hindlimb blood flow velocity increased and resistance declined from resting levels at each exercise intensity in both groups. In contrast to the visceral and renal adjustments, the magnitudes of the changes in both hindlimb flow and resistance were similar for the two age groups at all exercise intensities. These findings support the hypothesis that mesenteric and renal vasoconstriction is augmented in senescent Fischer 344 rats during exercise at moderate and maximal intensities but not at mild workloads. Despite these regional differences, the maintenance of arterial pressure is not altered at either submaximal or maximal exercise intensities with advancing age.