L De Nicola

Nitric oxide and angiotensin II. Glomerular and tubular interaction in the rat.

Nitric oxide (NO) has been proposed to modulate the renal response to protein as well as basal renal hemodynamics. We investigated whether NO and angiotensin II (AII) interact to control glomerular hemodynamics and absolute proximal tubular reabsorption (APR) during glycine infusion and in unstimulated conditions. In control rats, glycine increased single nephron GFR and plasma flow with no change in APR. The NO synthase blocker, NG-monomethyl L-arginine (LNMMA), abolished the vasodilatory response to glycine, possibly through activation of tubuloglomerular feedback due to a decrease in APR produced by LNMMA + glycine. Pretreatment with an AII receptor antagonist, DuP 753, normalized the response to glycine at both glomerular and tubular levels. In unstimulated conditions, LNMMA produced glomerular arteriolar vasoconstriction, decreased the glomerular ultrafiltration coefficient, and reduced single nephron GFR. These changes were associated with a striking decrease in APR. DuP 753 prevented both glomerular and tubular changes induced by LNMMA. In conclusion, NO represents a physiological antagonist of AII at both the glomerulus and tubule in both the basal state and during glycine infusion; and inhibition of NO apparently enhances or uncovers the inhibitory effect of AII on proximal reabsorption.

Arginine Feeding Modifies Cyclosporine Nephrotoxicity in Rats

Glycine (G) infusion causes renal vasodilation mediated by nitric oxide (NO). Cyclosporine A (CsA) nephrotoxicity is characterized by preglomerular vasoconstriction and decreased efferent arteriolar tone probably related to reduced NO and angiotensin II, respectively. L-Arginine (ARG) is a precursor to NO. To test the hypothesis that chronic CsA decreases renal NO activity, we compared the glomerular hemodynamic response to glycine infusion in rats after 8 d of CsA (30 mg/kg per d s.c.), CsA and ARG (1.6 g/kg per d p.o.) (A/CsA), and in two groups of pair-fed controls (CON, A/CON). Single nephron GFR (SNGFR), single nephron plasma flow (SNPF), glomerular capillary hydrostatic pressure gradient (delta P), proximal tubular reabsorption (APR), and kidney tissue angiotensin II (AIIk) were measured before and during G. CsA was associated with baseline decrements in SNGFR, SNPF, delta P, and AIIk, and with a blunted hemodynamic response to G. In CON, ARG did not affect baseline hemodynamics or modify the response to G. In CsA, ARG decreased baseline preglomerular resistance and restored the glomerular hemodynamic response to G. G was associated with a significant increase in AIIk in both CON and CsA. These findings suggest that (a) CsA is associated with decreased AIIk, and (b) CsA may diminish NO activity within the kidney, and that this capacity may be partially restored by arginine feeding.

Renal Functional Reserve in the Early Stage of Experimental Diabetes

The role of renal functional reserve (RFR; increase in plasma flow and glomerular filtration rate in response to protein loading) as an indicator of increased glomerular hydrostatic pressure and flow was evaluated in recent-onset poorly controlled diabetic rats. Streptozocin-induced diabetic (STZ-D) rats were studied with micropuncture (MP) technique after 10–15 days of diabetes (daily blood glucose level 15.3–18 mmol). We also studied STZ-D rats treated with the converting-enzyme inhibitor (CEI) enalapril or the angiotensin II (ANG II) receptor antagonist DuP 753 (DuP) for 3 days before MP. Nondiabetic rats (NOR) served as controls. Glomerular hemodynamics and proximal tubular reabsorption were measured in the control period and during intravenous glycine infusion. In NOR rats, glycine increased single-nephron plasma flow (SNPF) and single-nephron glomerular filtration rate (SNGFR). Although STZ-D rats did not exhibit hyperfiltration, SNGFR and SNPF were not modified by glycine, defining loss of RFR. CEI rats responded to glycine with an increase in SNGFR due to a rise in SNPF and a rise in the ultrafiltration coefficient. Interestingly, loss of RFR in STZ-D rats was associated with a decrease in absolute proximal reabsorption. The decrease in absolute proximal reabsorption was corrected by both CEI and DuP, although glomerular vasodilation was restored only in the CEI group. In conclusion, at the early stage of diabetes mellitus, loss of RFR does not detect hyperfiltration, but rather the presence of a tubular alteration probably dependent on ANG II. The CEI enalapril but not DuP restored RFR in diabetic rats, suggesting that other ANG II-independent effects of CEI are important in restoring a normal response to glycine.

Catecholamine secretory vesicles. Augmented chromogranins and amines in secondary hypertension.

Chromogranins A and B are major soluble proteins in chromaffin granules. Their adrenomedullary content is increased in the spontaneously (genetic) hypertensive rat. Is augmented catecholamine vesicular storage of the chromogranins a specific feature of genetic hypertension? To explore this question, we measured chromogranin A immunoreactivity, using a novel, synthetic peptide radioimmunoassay, in rat adrenal medullas 4-6 weeks after induction of the two-kidney, one clip Goldblatt model of renovascular hypertension and in unmanipulated control animals. We also measured messenger RNAs of chromogranins A and B and dopamine beta-hydroxylase by Northern blot. Immunoreactive adrenal chromogranin A was 3.3-fold higher (p < 0.01) in clipped rat adrenals. Adrenal catecholamine concentrations and phenylethanolamine-N-methyltransferase activity were also higher in clipped rats. Adrenal dopamine beta-hydroxylase activity (both membrane-bound and soluble forms) and corticosterone (glucocorticoid) concentration did not significantly differ between the groups. Adrenal medullary chromogranin A messenger RNA levels in clipped rats were 3.2-fold higher (p = 0.029) than those in the control group, and chromogranin B messenger RNA levels were 4.6-fold higher (p = 0.05). Dopamine beta-hydroxylase messenger RNA levels were 2.9-fold higher (p = 0.038). Thus, augmented synthesis and storage of adrenomedullary chromogranins A and B, catecholamines, and their biosynthetic enzymes appear to be characteristic of both acquired and genetic hypertension.

Angiotensin II and renal functional reserve in rats with Goldblatt hypertension.

We have previously demonstrated that loss of renal functional reserve (renal response to protein loading) in two-kidney, one clip Goldblatt hypertension is characterized by no change in glomerular filtration rate or single nephron glomerular filtration rate and decreased absolute proximal tubular reabsorption during glycine administration. Captopril restores proximal reabsorption and renal functional reserve in this condition. Because captopril suppresses angiotensin II generation and increases bradykinin, prostaglandins, and potentially nitric oxide, we have investigated the role of angiotensin II blockade in restoring proximal reabsorption and renal functional reserve by comparing captopril with DuP 753, an angiotensin II receptor antagonist, in Goldblatt rats. One month after clipping, two period micropuncture studies (control and glycine) were performed on the undipped kidney. Normal rats and three groups of clipped rats were studied: an untreated group (HYP), a group treated with captopril (CEI), and a group treated with DuP 753 (DuP) 5 days before micropuncture. Glycine increased glomerular filtration rate, nephron plasma flow, and single nephron glomerular filtration rate in normal rats. Systemic and glomerular hypertension in HYP rats was associated with loss of renal functional reserve and a decrease in absolute proximal reabsorption during glycine. Captopril and DuP 753 normalized systemic and glomerular capillary pressure and prevented the decrease in proximal reabsorption during glycine; however, only CEI rats increased single nephron glomerular filtration rate and glomerular filtration rate after glycine. In conclusion, abnormal responses of both glomerular and tubular function are responsible for the loss of renal functional reserve in Goldblatt rats. Inhibitory angiotensin II activity is responsible for decreasing proximal reabsorption during glycine; however, factors other than angiotensin II limit the glomerular response to glycine. Other, angiotensin II–independent, effects of captopril (i.e., bradykinin and nitric oxide) are important in restoring a normal glomerular response to glycine.

Reversibility of Acute Cyclosporine Renal Impairment by Dopamine in Healthy Subjects

Up to now, no studies were designed to investigate the role of renal hemodynamic abnormalities in relation to acute Cyclosporine A (CsA) nephrotoxicity and to verify whether dopamine infusion could cuonteract this acute renal disfunction in healthy subjects.