Role of nitric oxide in modulating the vasoconstrictor actions of angiotensin II in preglomerular and postglomerular vessels in dogs.

The purpose of this study was to determine the role of nitric oxide in modulating the vasoconstrictor effect of angiotensin II (Ang II) on renal segmental resistances in the dog. To achieve this objective we examined the effect of intrarenal infusions of Ang II on preglomerular and postglomerular resistances in the presence and absence of intrarenal nitric oxide synthesis inhibition established by an intrarenal infusion of NG-nitro-L-arginine-methyl ester at 5 micrograms/kg per minute in dogs. The whole-kidney stop-flow technique was used. Renal artery pressure was servo-controlled at 78 +/- 2 mm Hg throughout the study. Intrarenal infusion of Ang II alone at 0.5 and 2.0 ng/kg per minute increased renal vascular resistance (delta 0.064 +/- 0.011 and delta 0.171 +/- 0.030 mm Hg/mL per minute, respectively) and decreased renal blood flow (delta 21 +/- 4 and delta 45 +/- 9 mL/min). Associated with these changes, glomerular hydrostatic pressure and preglomerular resistance increased slightly (delta 1.1 +/- 0.9 and delta 1.6 +/- 1.8 mm Hg; delta 0.008 +/- 0.005 and delta 0.030 +/- 0.010 mm Hg/mL per minute, respectively), and postglomerular resistance increased markedly (delta 0.046 +/- 0.011 and delta 0.116 +/- 0.026 mm Hg/mL per minute). When dogs were pretreated with an intrarenal infusion of the nitric oxide synthesis blocker, Ang II at 0.5 and 2.0 ng/kg per minute increased renal vascular resistance (delta 0.271 +/- 0.058 and delta 1.088 +/- 0.242 mm Hg/mL per minute) and decreased renal blood flow (delta 28 +/- 5 and delta 62 +/- 9 mL/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelin antagonists improve renal function in spontaneously hypertensive rats.

Hypertension in the spontaneously hypertensive rat (SHR) is associated with reduced renal excretory function, low renal plasma flow, reduced glomerular filtration rate, and reduced renal interstitial hydrostatic pressure. The mechanisms responsible for these abnormalities in renal function are unknown. The purpose of this study was to determine the role of intrarenal endothelin in altering renal hemodynamic and excretory function in the SHR. Both PD 145065 (an endothelin A and B receptor antagonist) and FR 139317 (a selective endothelin A receptor antagonist) or saline was infused into the renal interstitium of 14- to 16-week-old SHR (n = 7) and age-matched Wistar-Kyoto rats (WKY) (n = 7). Renal perfusion pressure in some SHR was reduced to that of the WKY by a servocontrol system. At a renal perfusion pressure of 124 +/- 4 mm Hg, infusion of PD 145065. (0.03 mg.kg-1.min-1) and FR 139317 (0.02 mg.kg-1.min-1) significantly increased glomerular filtration rate (delta 22%), renal plasma flow (delta 37%), and renal interstitial hydrostatic pressure (from 3.2 +/- 0.5 to 5.4 +/- 0.6 mm Hg) in the SHR. These changes were associated with significant increases in urine flow, absolute sodium excretion, and fractional excretion of sodium. Similar improvements in renal plasma flow, renal interstitial hydrostatic pressure, and renal excretory function were obtained in the SHR whose renal perfusion pressure was not reduced (n = 7). Renal interstitial infusion of endothelin receptor antagonists had no effect on renal hemodynamic or excretory function in the WKY. These data demonstrate that endothelin receptor blockade within the kidney improves renal hemodynamic and excretory function in the SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal denervation attenuates the sodium retention and hypertension associated with obesity.

Recent studies have indicated that obesity is associated with hypertension, sodium retention, and increased sympathetic nervous system activity. The purpose of this study was to determine the role of renal nerves in mediating the sodium retention and hypertension associated with obesity. We determined the hemodynamic and renal excretory responses to a high-fat diet in control (n = 6) and bilaterally renal-denervated (n = 7) chronically instrumented dogs. After a control period of 8 days, dogs were placed on a high-fat diet for 5 weeks. In response to a high-fat diet, body weight increased from 19.9 +/- 2.2 to 29.9 +/- 2.4 kg in the control group and from 21.1 +/- 2.0 to 32.4 +/- 1.9 kg in the bilaterally renal-denervated group. Heart rate increased from 81 +/- 8 to 113 +/- 7 beats per minute in the control group and from 79 +/- 7 to 103 +/- 8 beats per minute in the bilaterally renal-denervated group. Arterial pressure increased significantly from 95 +/- 2 to 109 +/- 4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the bilaterally renal-denervated group did not significantly increase arterial pressure (which went from 87 +/- 3 to 90 +/- 4 mm Hg). Furthermore, the decrease in sodium excretion in response to the high-fat diet was significantly greater in the control group than in the bilaterally renal-denervated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased sensitivity to renal interstitial hydrostatic pressure in Dahl salt-sensitive rats.

The ability of Dahl salt-sensitive (DS) rats to excrete a sodium load is significantly lower than Dahl salt-resistant (DR) rats. Because renal interstitial hydrostatic pressure (RIHP) is a major mediator of natriuresis in response to a sodium load, we proposed that the renal tubules of DS rats are less responsive to increases in RIHP than those of DR rats. To test this hypothesis, we determined the effect of direct increases in RIHP on renal excretory function in prehypertensive DS and DR rats. RIHP was directly increased by renal interstitial volume expansion via injection of 50 microL of a 2% albumin and saline solution into the renal interstitium through a chronically implanted renal interstitial catheter. RIHP, mean arterial pressure, glomerular filtration rate, urine flow rate, urinary sodium excretion, and fractional excretions of sodium, potassium, and lithium (an indicator of proximal tubule sodium handling) were measured before and after direct increases in RIHP in DS (n = 8) and DR (n = 8) rats. Baseline urine flow rate; urinary sodium excretion; fractional excretions of sodium, potassium, and lithium; RIHP; mean arterial pressure; and glomerular filtration rate were not different between DS and DR rats. Renal interstitial volume expansion in DS rats significantly increased RIHP (delta 4.7 +/- 0.8 mm Hg), urine flow rate (delta 14.5 +/- 3.4 microL/min), urinary sodium excretion (delta 2.62 +/- 0.62 mumol/min), and fractional excretions of sodium (delta 1.54 +/- 0.37%), potassium (delta 17.84 +/- 2.90%), and lithium (delta 19.68 +/- 3.52%).(ABSTRACT TRUNCATED AT 250 WORDS)

Blunted natriuretic response to a high-sodium meal in obese dogs. Role of renal nerves.

Although the relation between body weight and arterial pressure is well established, the mechanisms involved in the pathogenesis of obesity-related hypertension are unclear. However, recent studies suggest that abnormalities in renal function may be involved. The purpose of this study was to test the hypothesis that obese animals have a reduced ability to excrete a sodium load as a result of abnormal renal nerve function. To quantify the role of renal nerves, we examined changes in renal hemodynamics and sodium excretion in response to a high-sodium meal (200 mmol Na) in separate innervated and denervated kidneys simultaneously within the same conscious dog. Two surgically designed hemibladders with indwelling catheters were used to collect urine from innervated and denervated kidneys of the same dog. Body weight averaged 19.9 +/- 1.0 kg in the control lean dogs and 25.1 +/- 1.1 kg in the obese dogs. Arterial pressure averaged 101 +/- 4 mm Hg in the obese dogs and 90 +/- 4 mm Hg in the lean dogs. In response to the high-sodium meal in lean dogs, urinary sodium excretion increased from 20.8 +/- 4.2 to 189.7 +/- 21.2 mumol/min in the innervated kidneys and from 25.3 +/- 5.9 to 194.8 +/- 26.9 mumol/min in the denervated kidneys. In contrast, urinary sodium excretion in obese dogs increased from 9.6 +/- 1.4 to 129.9 +/- 34.3 mumol/min in the innervated kidneys and from 18.4 +/- 3.7 to 125.2 +/- 30.5 mumol/min in the denervated kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of renal nerves in mediating the blunted natriuretic response to acute saline load in obese dogs.

We previously reported that the natriuretic response to an acute sodium load is markedly attenuated in obese dogs. Since obesity is associated with enhanced sympathetic nervous activity, the purpose of this study was to test the hypothesis that obese animals have a reduced ability to excrete a sodium load as a result of abnormal renal nerve function. To test this hypothesis, we determined the effects of an acute sodium load (100 mEq NaCl given as isotonic saline over 60 min) in lean (19.8 +/- 1.0 kg) and obese (25.8 +/- 1.1 kg) dogs. Two surgically designed hemibladders with indwelling catheters were used to collect urine from innervated (INN) and denervated (DNX) kidneys of the same dog. Arterial pressure averaged 99 +/- 3 mm Hg in the obese dogs and 90 +/- 3 mm Hg in the lean dogs. In response to the saline loading in lean dogs, sodium excretion (U(Na)V) increased from 31.0 +/- 7.8 to 145.6 +/- 25.9 microEq/min in the INN kidneys and from 43.1 +/- 10.6 to 151.1 +/- 28.4 microEq/min in the DNX kidneys. In contrast, U(Na)V in obese dogs increased from 10.3 +/- 3.0 to 110.1 +/- 25.5 microEq/min in the INN kidneys and from 24.4 +/- 2.7 to 106.1 +/- 20.6 microEq/min in the DNX kidneys. Cumulative sodium excretory response to sodium loading was significantly lower in the obese dogs. In addition, there was no difference in the cumulative U(Na)V response between the INN (8.4 +/- 2.2 mEq) and DNX kidneys (9.1 +/- 2.3 mEq) of obese dogs. These data indicate that the natriuretic response to an acute saline loading is markedly attenuated in obese dogs. Furthermore, factors other than renal nerves play a role in this abnormal response.

Systemic hemodynamics and renal function during long-term pathophysiological increases in circulating endothelin.

Although recent studies have reported endogenous plasma endothelin levels to be elevated two- to fivefold in chronic pathophysiological states, whether such an increase in circulating endothelin levels alone can lead to significant long-term alterations in cardiovascular and renal function is not known. The purpose of this study was to examine the long-term systemic hemodynamic and renal effects of a pathophysiological increase in plasma endothelin concentration in chronically instrumented, conscious dogs (n = 7). Infusion of endothelin-1 (2.5 ng.kg-1.min-1) for 8 days increased plasma concentration of immunoreactive endothelin approximately two- to threefold from 6.7 +/- 0.4 to 16.0 +/- 2.2 pg/ml. Mean arterial pressure increased 21% from a control value of 86.7 +/- 2.1 to 105.0 +/- 2.5 mmHg during the endothelin infusion period. Cardiac output averaged 2,200 +/- 205 ml/min during control and fell by 33% on day 4 of endothelin infusion (1,484 +/- 146 ml/min) and was still 14% below control after day 8 of endothelin infusion (1,885 +/- 154 ml/min). Endothelin increased total peripheral resistance from 42.0 +/- 3.1 to 80.3 +/- 9.1 mmHg.l-1.min. Increasing plasma endothelin two- to threefold was associated with an increase in renal vascular resistance and decreases in glomerular filtration rate and renal plasma flow. Endothelin-1 had no long-term effect on plasma renin activity or aldosterone concentration. These data indicate the importance of pathophysiological levels of endothelin in controlling renal and cardiovascular function in chronic conditions. Furthermore, the results indicate that endothelin may play a role as a mediator of chronic hypertension in pathophysiological states associated with endothelial dysfunction.

Chronic pathophysiologic circulating endothelin levels produce hypertension in conscious dogs.

Although recent studies have reported endogenous plasma endothelin (ET) levels to be elevated two- to fivefold in chronic pathophysiologic states, whether such an increase in circulating ET levels alone can lead to significant long-term alterations in cardiovascular function is not known. The purpose of this study was to examine the long-term systemic hemodynamic effects of a pathophysiologic increase in circulating ET concentration in chronically instrumented, conscious dogs (n = 4). Infusion of endothelin (2.5 ng/kg/min) for 8 days increased plasma concentration of endothelin two- to threefold. ET increased mean arterial pressure from 85 +/- 3 to 103 +/- 3 mm Hg, which was sustained throughout the period of infusion. Total peripheral resistance was increased by approximately 70%. Cardiac output decreased transiently by 25% and remained below control levels at the termination of ET infusion. These data indicate the importance of pathophysiologic levels of ET in controlling systemic hemodynamics in chronic conditions. Furthermore, ET may play a role as a mediator of chronic hypertension in pathophysiologic states associated with endothelial dysfunction.

Chronic endothelin-induced pressor and renal actions in conscious dogs do not require altered ANG II formation.

Plasma endothelin levels are elevated approximately two- to threefold in a number of chronic pathophysiological conditions associated with hypertension. Results from recent studies indicate an important interaction between endothelin and the renin-angiotensin system (RAS). The role of the RAS in mediating the increases in arterial pressure produced by long-term pathophysiological elevations in circulating levels of endothelin is unknown. Therefore, the purpose of this study was to chronically increase circulating levels of endothelin within the pathophysiological range and determine the long-term cardiovascular and renal actions of endothelin in control dogs (n = 6) and in dogs pretreated with a converting-enzyme inhibitor (CEI) (n = 6) or CEI + angiotensin II (ANG II) replacement (n = 6). Infusion of endothelin-1 for 8 days at a rate of 2.5 ng.kg-1.min-1 increased plasma endothelin from 7.1 +/- 0.9 to 19.8 +/- 3.3 pg/ml. In control dogs, endothelin increased mean arterial pressure (MAP) by 19% (90 +/- 2 to 107 +/- 3 mmHg) while decreasing renal blood flow (RBF) by 30% and glomerular filtration rate (GFR) by 15-20%. Long-term elevation of circulating endothelin produced similar elevations in MAP in dogs pretreated with CEI (+16%) or CEI + ANG II (+17%). Similar decreases in RBF and GFR also occurred in response to endothelin in all three groups. These results indicate that although long-term increases in circulating endothelin within the pathophysiological range produce significant increases in arterial pressure, this effect does not appear to be mediated by the RAS.