nitroarginine and Hypertension--Renal

Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA; 20 mg/l water; SNX+L-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, L-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX+L-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose L-NNA (L-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX+L-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In L-NNA-High, LVSD was not as severe as in SNX+L-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in L-NNA-High after L-NNA was stopped, but both were persistently low in SNX+L-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX+L-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.

Topics: Animals; Blood Pressure; Body Weight; Echocardiography; Enzyme Inhibitors; Hematocrit; Hypertension, Renal; Male; Nephrectomy; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Poult Enteritis Mortality Syndrome; Proteinuria; Rats; Rats, Inbred Lew; Renal Insufficiency, Chronic; Systole; Urine; Ventricular Dysfunction, Left

Because nitric oxide (NO) regulates cardiac and vessel contraction, we compared the expression and activity of the endothelial NO synthase (eNOS) and caveolin, which tonically inhibits eNOS in normal and hypertrophic cardiomyopathic hearts. NOS activity (L-[(3)H]citrulline formation), eNOS immunostaining, and caveolin abundance were measured in heart tissue of 23 mongrel dogs before and at 3 and 7 wk of perinephritic hypertension (PHT). Hemodynamic parameters in vivo and endothelial NO-dependent relaxation of macro- and coronary microvessels in vitro were assessed in the same animals. eNOS immunostaining and total calcium-dependent NOS activity decreased at 7 wk in all four heart cavities (in left ventricle, from 17.0 +/- 1.3 to 0.2 +/- 0.2 fmol. min(-1). mg protein(-1), P < 0.001). Caveolin-1 and -3 also decreased in PHT dog hearts. Accordingly, basal vascular tone was preserved, but maximal endothelial NO-dependent relaxation was impaired in all vessels from 7-wk PHT dogs. The latter had preserved systolic function but impaired diastolic relaxation [relaxation time constant (T(1)), 25.1 +/- 0.9 vs. 22.0 +/- 1 ms in controls; P < 0.05]. Peripheral infusion of the NOS inhibitor N(G)-nitro-L-arginine methyl ester increased mean aortic pressure in both groups and reduced diastolic (T(1), 31.9 +/- 1.4 ms) and systolic function in PHT dogs (DP40, 47.5 +/- 2.5 vs. 59.4 +/- 3.8 s(-1) in control animals). In conclusion, both eNOS and caveolin proteins are decreased in the hypertrophic hearts of PHT dogs. This is associated with altered maximal (but not basal) vascular relaxation and impaired diastolic function. Further degradation of cardiac function after NOS inhibition suggests a critical role of residual NOS activity, probably supported by the concurrent downregulation of caveolin.

Topics: Animals; Cardiomyopathy, Hypertrophic; Caveolin 1; Caveolins; Coronary Circulation; Disease Models, Animal; Dogs; Echocardiography; Hemodynamics; Hypertension, Renal; Immunoblotting; Immunohistochemistry; Mesenteric Arteries; Microcirculation; Muscle Contraction; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Regression Analysis; Ventricular Function, Left

Renal hemodynamic and excretory responses to (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), a novel nitric oxide (NO) donor, were examined using anesthetized rats. When FK409 was infused into the renal artery of normal rats at 10 micrograms/kg per min, a moderate renal vasodilating effect was observed with a decrease in mean arterial blood pressure. Urine flow, urinary excretion of sodium and fractional excretion of sodium significantly increased by about 85%, 110% and 75%, respectively, compared with each control value. Simultaneously, urinary excretion of NO metabolites (UNOxV) was markedly increased with the administration of FK409. In hypertensive rats treated with NG-nitro-L-arginine (NOARG), the NO synthase inhibitor, FK409 produced a potent renal vasodilation, although the hypotensive effect of the agent was comparable to that seen in normal rats. In addition, glomerular filtration rate was significantly elevated by the agent. There were marked increases in the excretory responses, i.e., levels of urine flow, urinary excretion of sodium and fractional excretion of sodium were increased to about 3-, 6- and 5-fold of each control value, respectively. The extent of increment of UNOxV was similar to that seen in normal rats. These results clearly indicate that FK409 causes renal vasodilation and diuresis, via NO formation. Renal hemodynamic and excretory responses to the agent are sensitive in NO-depleted conditions. FK409 and related compounds may be useful for the treatment of renal diseases, in cases where the basal NO formation is impaired.

Topics: Anesthesia; Animals; Blood Pressure; Enzyme Inhibitors; Hemodynamics; Hypertension, Renal; Infusions, Intra-Arterial; Kidney; Male; Nitric Oxide; Nitro Compounds; Nitroarginine; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium; Vasodilator Agents