Gross, Jennifer M.

The purpose of the present investigation was to study the effects of inhibition of monoamine oxidase (MAO) and/or catechol- O-methyltransferase (COMT), enzymes involved in the degradation of dopamine (DA) and serotonin (5-HT), on intrarenal DA and 5-HT, as reflected in the renal interstitial fluid (RIF) microdialysate and urine, and on renal function. Inhibition of MAO selectively increased RIF 5-HT from 3.16 ± 0.38 to 8.03 ± 1.83 pg/min ( n = 7, P < 0.05), concomitant with decreases in mean arterial blood pressure and glomerular filtration rate (2.09 ± 0.18 to 1.57 ± 0.22 ml/min, n = 7, P < 0.05). Inhibition of COMT significantly increased RIF DA (3.47 ± 0.70 to 8.68 ± 1.96 pg/min, n = 9, P < 0.05), urinary DA (2.00 ± 0.16 to 2.76 ± 0.26 ng/min, n = 9, P < 0.05), and absolute excretion of sodium (6.42 ± 2.00 to 9.82 ± 1.62 μmol/min, n = 10, P < 0.05). Combined inhibition of MAO and COMT significantly increased RIF DA, urinary DA, and urinary 5-HT, which was accompanied with increases in urine flow rate, and absolute (3.03 ± 0.59 to 8.40 ± 1.61 μmol/min, n = 9, P < 0.01) and fractional excretion of sodium. We conclude that inhibition of MAO selectively increases RIF 5-HT. COMT appears to be more important than MAO in the metabolism of intrarenal DA. Physiological increases in intrarenal DA/5-HT induced by inhibition of their degrading enzymes are accompanied with significant alterations of renal function.

We investigated the role of prostaglandins in the renal vascular response to exogenous and endogenous adenosine in control and streptozotocin (STZ) diabetic rats. Exogenous adenosine (0.01–100 nmol) injected into the abdominal aorta decreased renal blood flow (RBF) in a dose-dependent manner to a much greater extent in STZ rats than in control rats ( P < 0.001). Inhibition of prostaglandin synthesis with indomethacin (Indo; 10 mg/kg iv) potentiated the adenosine-induced renal vasoconstriction in control rats but not in STZ rats. In control rats, Indo shifted the dose response curve of exogenous adenosine-induced RBF reductions to the left by a factor of 10 (ED50: from 5.5 ± 0.51 to 0.55 ± 0.07 nmol adenosine, n = 6, P < 0.001) and in STZ rats only by a factor of two (ED50: from 0.32 ± 0.03 to 0.16 ± 0.02 nmol adenosine, n = 6, P > 0.05). The renal response to endogenous adenosine was assessed by the magnitude of the postocclusive reduction of RBF (POR), an adenosine-mediated phenomenon. POR was greater in STZ rats (−65.3 ± 5.2%, P < 0.001) compared with control rats (−36.2 ± 3.5%). Indo markedly enhanced POR in control rats (−20.3 ± 3.7%) but not in STZ rats (−4.5 ± 2.7%). Renal cortical and medullary PGE2microdialysate concentrations and urinary PGE2excretions were clearly not lower in STZ (cortex: 169 ± 61 pg/ml; medulla: 640 ± 88 pg/ml, urine: 138 ± 25 pg/min) compared with control rats (cortex: 99 ± 12 pg/ml; medulla: 489 ± 107 pg/ml; urine: 82 ± 28 pg/min). Indo significantly decreased renal cortical, medullary, and urinary excretion of PGE2in STZ and control rats. These findings demonstrate that the adenosine-induced renal vasoconstriction is increased in the presence of Indo in control rats but not in STZ rats. The observations suggest that the diabetic renal vasculature may have a diminished vasodilatory capacity in response to prostaglandins to counteract adenosine-induced renal vasoconstriction.

Abstract —Elevation of renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion increases sodium excretion. This natriuretic response is blunted by the nonspecific inhibition of the cyclooxygenase (COX) enzymes. The present study tested the hypothesis that the natriuretic response to increased RIHP during direct renal interstitial volume expansion is dependent on COX-1 but not COX-2. RIHP and fractional excretion of sodium (FE Na ) were measured before and after direct renal interstitial volume expansion in control rats (n=7), rats infused with the COX-1 inhibitor piroxicam (n=6, 1.5 mg/kg), and rats infused with the COX-2 inhibitors NS-398 (n=5, 1.5 mg/kg) and meloxicam (n=6, 0.3 mg/kg). In control animals, direct renal interstitial volume expansion significantly increased RIHP (Δ2.3±0.5 mm Hg, P <0.05) and FE Na (Δ1.1±0.3%, P <0.05). Likewise, in animals infused with NS-398 or meloxicam, direct renal interstitial volume expansion significantly increased RIHP (Δ1.8±0.6 mm Hg, P <0.05, and Δ1.7±0.3 mm Hg, P <0.05) and FE Na (Δ1.5±0.4%, P <0.05, and Δ1.1±0.3%, P <0.05), respectively. In contrast, infusion of piroxicam significantly blunted the natriuretic response to direct renal interstitial volume expansion (ΔFE Na 0.3±0.2%), even though RIHP was increased (Δ1.9±0.6 mm Hg, P <0.05). Infusion of piroxicam but not NS-398 or meloxicam blunted the natriuretic response to increased renal interstitial hydrostatic pressure, suggesting that the natriuretic response to increased blood pressure may be preserved during inhibition of COX-2.