Inducible Nitric Oxide Synthase and Blood Pressure

Abstract

Abstract-In the present studies, the influence of inducible nitric oxide synthase (NOS) inhibition with aminoguanidine on renal function and blood pressure was examined in rats. Intravenous aminoguanidine infusion (60 mg ⅐ kg Ϫ1 ⅐ hr Ϫ1) for 40 minutes to anesthetized Sprague-Dawley rats (nϭ7) resulted in no significant changes in mean arterial pressure or renal cortical blood flow, while medullary blood flow was slightly increased. Despite minimal effects on renal blood flow, urine flow was significantly decreased from 14.2Ϯ2.7 to 10.4Ϯ2.3 L ⅐ min Ϫ1 ⅐ g kidney wt Ϫ1 during aminoguanidine infusion. To examine the possible effects of inducible NOS on blood pressure, aminoguanidine (10 mg ⅐ kg Ϫ1 ⅐ h Ϫ1 IV) was infused chronically into uninephrectomized rats maintained on a high salt (4.0% NaCl) diet. Mean arterial pressure significantly increased from 104Ϯ2 to 118Ϯ3 mm Hg after 6 days of aminoguanidine infusion (nϭ7) and returned to levels not different from those in the control group after 2 days of postcontrol infusion. Calcium-independent NOS activity in the renal medulla, a tissue that expresses inducible NOS in normal rats, was significantly decreased by 49% in the aminoguanidine-infused group (nϭ6) compared with that activity in the vehicle-infused control animals (nϭ6). In contrast, calcium-dependent NOS activity in the renal medulla was not significantly altered by aminoguanidine infusion, indicating specificity of aminoguanidine for inducible NOS in these experiments. In a final group of rats (nϭ5), oral L-arginine administration in drinking water (2% wt/vol) increased plasma arginine levels from 118Ϯ5 to 232Ϯ16 mol/L and blocked the increase in arterial pressure after 6 days of aminoguanidine infusion. The present experiments provide evidence supporting a role for inducible NOS in the control of arterial pressure, possibly by renal tubular effects. 6-7 Because nNOS, iNOS, and eNOS are all present in the normal rat kidney, 8 -14 it is not clear which NOS isoform(s) is/are responsible for these functional effects. Of interest is the presence of iNOS in the normal rat kidney. In situ hybridization and reverse transcription-polymerase chain reaction of microdissected vascular and tubular segments have identified iNOS mRNA in arcuate and interlobular arteries, glomeruli, proximal tubules, thick ascending limbs, and collecting ducts. 8,11 The greatest amount of iNOS message was observed in the medullary thick ascending limbs and the inner medullary collecting ducts 11 ; this observation is consistent with protein blotting experiments that demonstrate greater amounts of iNOS immunoreactive protein in renal medullary than in renal cortical tissue homogenates.10 Despite the morphological localization of iNOS in the kidney, the role of this isoform in the control of normal renal function is unclear.Several indirect studies suggest that iNOS may participate in the regulation of renal function and arterial pressure. The genetic locus containing the gene for iNOS cosegregated with the high blood pressure phenotype...

Role of renal NO production in the regulation of medullary blood flow

“…Chronic intravenous infusions of aminoguanidine in Sprague-Dawley rats that resulted in a 49% reduction of Ca 2ϩ -independent NOS (inducible NOS) in the renal medulla, produced a salt-dependent form of hypertension with mean arterial pressure rising nearly 15 mmHg when these rats were fed a high-salt (4%) diet. The results also suggested that these events occurred independently of renal vascular changes, because intravenous infusion of this inhibitor at the same dose in anesthetized rats resulted in no significant changes in mean arterial pressure, CBF, or MBF, whereas urine flow and sodium excretion were significantly decreased (60).…”

“…Tan et al (120) observed hypertensive responses in the absence of any measurable changes in renal plasma flow or GFR with chronic intravenous administration of aminoguanidine in salt-resistant Dahl R rats exposed to a high-salt diet, consistent with predominant tubular effects. Recent work by Kakoki et al (42) and Mattson et al (60) using a variety of NOS isoform-specific inhibitors indicated that NO derived from NOS I and/or NOS II has minimal effect on blood flow in the renal medulla (42,60). The results also suggest that the enhanced salt sensitivity with NOS inhibition may be largely a consequence of a reduction of NOS I and NOS II activity within the deep nephrons of the renal medulla.…”

“…In another study, the effects of chronically inhibiting the inducible NOS II isoforms were examined (60). Chronic intravenous infusions of aminoguanidine in Sprague-Dawley rats that resulted in a 49% reduction of Ca 2ϩ -independent NOS (inducible NOS) in the renal medulla, produced a salt-dependent form of hypertension with mean arterial pressure rising nearly 15 mmHg when these rats were fed a high-salt (4%) diet.…”

Physiology of the renal medullary microcirculation

“…Inhibition of NOS in the renal medulla has isoform-specific effects. NOS1 inhibition reduces NO levels in the medulla and induces salt-sensitive hypertension but fails to alter medullary perfusion (50,74,77). Global inhibition of NOS1, NOS2, and NOS3 isoforms with nonselective blockers decreases medullary NO levels and induces salt retention and hypertension.…”

Prevention of Rat Cerebral Aneurysm Formation by Inhibition of Nitric Oxide Synthase

“…The NOS inhibitor aminoguanidine (AG) was used to confirm whether NOS inhibition prevents both the early aneurysmal changes and the formation of aneurysms in rats. 6 We also examined the mechanism of iNOS induction in the development of aneurysms. Clinical and epidemiological evidence suggests that the heightened hemodynamic stress due to an increase in blood flow may be an important factor underlying aneurysm development.…”