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The experiments, performed in pentobarbital sodium-anesthetized rats, consisted of a 1-h equilibration period followed by two 30-min control periods. Subsequently, synthetic rat pro atrial natriuretic peptide (ANP) [proANP-(1-30)] (n = 8) was given as a bolus of 10 microg in 1 ml of 0.9% saline followed by an infusion at 30 ng/min (20 microl/min) for six additional periods. Control rats (n = 6) received only 0.45% saline in the appropriate volumes. Mean arterial pressure, renal blood flow, and glomerular filtration rate did not change significantly in either group during the proANP-(1-30) infusion. Urine flow and potassium excretion increased approximately 50% in the proANP-(1-30)-infused group only (P < 0.05). Sodium excretion and fractional excretion of sodium, expressed as the change from their own baselines, were significantly increased by the proANP-(1-30) infusion (P < 0.05), whereas cGMP excretion was similar in both groups. These results suggest that the rat sequence of proANP-(1-30) produces a natriuresis in the rat independent of changes in hemodynamics and renal cGMP production. In a second study, rats (n = 8) were prepared as above and pretreated with 0.4 ml iv of rabbit serum containing an antibody directed against proANP-(1-30) (anti-proANP group). The rats were volume expanded with 3 ml of 6% albumin in Krebs and observed for 3 h to determine if the anti-proANP would attenuate the responses to volume expansion. Control rats (n = 7) received 0.4 ml of normal rabbit serum. The elevation in potassium excretion in response to volume expansion was significantly attenuated in the anti-proANP group (P < 0.05). Sodium excretion and urine flow responses also tended to be reduced but not significantly. These results suggest that in the rat, proANP-(1-30) plays a physiological role in regulating renal excretion.

Aging is associated with hypertension and electrolyte disturbances. The purpose of this study was to determine the effect of aging upon secretion and renal actions of atrial natriuretic peptide (ANP). Rats were anesthetized and received tracheal, jugular vein, carotid artery, and bilateral uretheral catheterization. One set of young (2-3 mo) rats (Group 2, n = 9) and one set of old (18-21 mo) rats (Group 4, n = 7) received bilateral atrial appendectomies. Control young (Group 1, n = 8) and old (Group 3, n = 8) rats received a sham appendectomy. All rats were infused (iv) with 6% albumin in Krebs buffer, sufficient to increase blood volume by 15%. Finally, each rat was injected with ANP (1 microgram/kg). Sodium excretion rate (U(Na+)V) in response to volume expansion was significantly decreased in all groups compared to Group 1 (young control, p < .05). All groups demonstrated a striking increase in U(Na+)V with the ANP injection, but the response was greatest in young control rats when factored by body weight (p < .05). There were no significant differences in MAP between the groups, suggesting that the differences in U(Na+)V observed were not the result of hemodynamic factors. Isolated perfused atria from young (n = 9) and old (n = 8) rats were subjected to stretch and endothelin stimulation (50 nM). Atria from young rats showed a dramatic increase in ANP secretion in response to atrial stretch and a further marked increase in secretion in response to endothelin, whereas both of these responses were markedly attenuated in old rats (p < .05). These results suggested that the secretion and renal effects of ANP are impaired in aging. Changes in secretion and actions of ANP in aging could contribute to the development of hypertension or heart failure.

ICAM-1 has been implicated in the pathophysiology of ischemic-reperfusion injury in a number of organs, but its role in mediating severe ischemic-reperfusion injury in the kidney has not been extensively studied. Uninephrectomized Sprague Dawley rats were pretreated with either control monoclonal antibody (mAb) or mAb to ICAM-1 and subjected to 60 min of renal artery occlusion. The serum creatinine, complete blood count and kidney histo-pathological damage scores (PDS) (Scale:0-4) were assessed prior to and 24 hours after ischemia. Mean serum creatinine (mg/dl) 24 hours after ischemia was significantly decreased in the anti-ICAM-1 group (1.38 +/- 0.23, p < 0.001) compared to control (2.87 +/- 0.34). PDS was also reduced in anti-ICAM-1 (2.55 +/- 0.20, p < 0.05) group compared to control (3.35 +/- 0.30). These data demonstrate that blocking ICAM-1 significantly mitigates severe ischemic acute renal failure, findings which may lead to improved therapy for this condition.

1. Atrial natriuretic factor (ANF) and pro ANF peptide appears to be secreted simultaneously from the atria in response to atrial stretch. 2. The major peptide forms secreted from rat atria appear to be ANF (pro ANF 99-126) as the primary C-terminal peptide and pro ANF 1-30 as the primary N-terminal peptide, as opposed to 1-67 or 1-98. 3. The plasma concentrations of ANF and pro ANF 1-30 are increased by acute stimulation with blood volume expansion and the plasma levels of ANF and N-terminal ANF prohormone peptides are chronically elevated by high salt diet. 4. Pro ANF 31-67 produces a natriuresis which is not dependent on an increase in renal cGMP excretion, decreases in plasma renin activity (PRA) or elevations in plasma ANF concentration.

Leukocytes, particularly neutrophils, have been implicated in ischemic-reperfusion organ injury (IRI). However, their role in kidney IRI is controversial. Leukocytes express the adhesion molecules CD11/CD18 on their surface, which mediate many functions that can lead to tissue damage. To determine the role of CD11a and CD11b in IRI in the kidney, uninephrectomized Sprague-Dawley rats were pretreated with monoclonal antibodies (MAbs) directed against CD11a and CD11b or control MAbs. The serum creatinine (SCr), complete blood count, and kidney histopathological damage scores (PDS) (scale: 0-4) were assessed prior to and 24 h after 60 min of ischemia. Mean SCr 24 h after ischemia was significantly decreased in the anti-CD11a- and -CD11b-treated group compared with the control MAb-treated group (2.5 +/- 0.3 mg/dl vs. 3.4 +/- 0.2 mg/dl, P < 0.05). PDS were also reduced in the CD11a and CD11b group compared with controls (2.7 +/- 0.2 vs. 3.5 +/- 0.1, P < 0.001). These data show that the CD11/CD18 leukocyte adhesion pathway plays a role in mediating ischemic acute renal failure in rats.

The clinical use of nonsteroidal anti-inflammatory drugs is gaining wide acceptance and acute oliguric renal failure in association with the administration of ibuprofen has been reported. This study was designed to evaluate the renal effects of intermittent versus continuous intravenous infusion of ibuprofen (Motrin) over a 24-h period in the anesthetized non-pregnant baboon. A total of 50 mg/kg of ibuprofen was either infused continuously or given as a bolus in four divided doses (intermittent). Control animals received only normal saline. Mean aortic pressure showed a tendency to decrease with time in all groups studied with a significant decrease occurring in the infusion group. There were no significant changes in the renal artery flow, renal resistance, central venous pressure and heart rate within the groups. Serum urea nitrogen decreased and was significantly different from the baseline value at 24 h in the infusion group. Serum creatinine, however, showed no such changes. Although, urinary output and creatinine clearance showed a tendency to decrease in the treated groups, it was not significantly different. Plasma renin activity decreased from 9.95 to 2.3 ng/ml/hr in the control group but showed no significant changes in others. Serum levels of angiotensin converting enzyme were well maintained. The circulating levels of ibuprofen reached a steady state after 2 h in the infusion group. The results of this study demonstrate that continuous infusion of ibuprofen does not possess an advantage over its intermittent administration. Despite the modifications we have observed in renal flow and function, this drug appears to be safe in the dose levels we have used in these experiments.

Recent work suggests that hypophysectomized (HYPOX) rats show low levels of atrial natriuretic factor (ANF) and an attenuated diuresis and natriuresis to blood volume expansion. The purpose of this was (i) to examine the effect of various hormone replacements on ANF and renal excretion in HYPOX rats and (ii) to compare the renal responses to exogenous ANF in intact and HYPOX rats. Groups of rats received subcutaneous pellet implant of either dexamethasone (DEX), thyroxine (T4), or a placebo. Approximately 1 week later, they were anesthetized and subjected to a 20% blood volume expansion. DEX rats had a higher mean arterial pressure than placebo-treated rats while both MAP and heart rate were higher in T4 rats. Only the DEX rat showed augmented renal responses to volume expansion while no group showed significant changes in plasma ANF concentration during volume expansion. In a second series, groups of HYPOX rats received renal capsular transplants of either six hemi-pituitaries or six pieces of muscle which markedly raised serum prolactin levels in the hemi-pituitary group. The hemi-pituitary rats showed a greater diuresis and natriuresis during volume expansion than the muscle group and also showed a transient increase in plasma ANF. In addition, groups of either intact or HYPOX rats were anesthetized and received intravenous bolus injections of ANF. Both intact and HYPOX rats showed a very similar diuresis and natriuresis to exogenous ANF. However, potassium excretion was markedly reduced in HYPOX rats. The results show that DEX augments the renal responses to volume expansion by some mechanism which does not involve changes in plasma ANF. Thyroxine increases mean arterial pressure and heart rate in HYPOX rats but does not augment the renal or ANF responses to volume expansion. Chronic elevations in prolactin increase the renal response to volume expansion. Finally, the kidneys of HYPOX rats are capable of increasing sodium and water output in response to large doses of exogenous ANF.

To investigate the role of endogenous prostaglandins in renin release stimulated via adrenergic pathways, isoproterenol, norepinephrine (NE) and NE in the presence of phentolamine (PTA) were infused into conscious sodium-replete rats and dogs. Isoproterenol (1 microgram.kg-1.min-1) infusion into intact rats increased plasma renin activity (PRA) eightfold. AFter pretreatment with the prostaglandin (PG) cyclooxygenase inhibitor indomethacin (5 mg/kg), isoproterenol increased PRA 16-fold. In dogs, isoproterenol (0.4 microgram.kg-1.min-1) increased PRA six-fold before indomethacin and 11-fold during PG inhibition. Infusion of NE into both rats (250 ng.kg-1.min-1) and dogs (1 microgram.kg-1.min-1) failed to increase PRA before indomethacin, but during inhibition of PG synthesis NE increased PRA in both species. During partial alpha-adrenergic blockade with PTA in dogs, PTA alone increased PRA by 38% and NE given during PTA infusion increased PRA further both before indomethacin by twofold and during PG inhibition by fivefold. In rats given NE during PTA infusion, PRA increased only after indomethacin injection. Additionally, in dogs the renin responses to these adrenergic agents were even greater after indomethacin administration than before the drug. These results in both conscious rats and dogs give no indication that renal prostaglandins mediate the renin response to adrenergic stimulation.

Renal function and renin release were studied in anesthetized, uninephrectomized dogs during intrarenal infusions of the calcium influx blockers, verapamil and nifedipine. Verapamil increased renal blood flow by 20% (p less than 0.05) but did not alter glomerular filtration rate. Verapamil produced five-to-seven fold increases in urine flow and the rates of excretion of sodium and chloride (p less than 0.01). Significant increases in the rates of excretion of potassium, calcium and magnesium were also observed. Despite its striking effects on renal function, verapamil, in nonhypotensive doses, failed to alter renin secretion. Intrarenal infusion of nifedipine had no consistent effect on renal blood flow or the rate of glomerular filtration but increased urine flow and the rates of excretion of sodium and chloride by more than three fold (p less than 0.01). Nonhypotensive doses of nifedipine had no significant effect on renin release. In dogs with a denervated nonfiltering kidney, an intrarenal verapamil or nifedipine infusion did not produce a significant change in renin release. This study demonstrates a striking effect of calcium entry blockers on the reabsorption of sodium, chloride, and water by the renal tubules in intact dogs but renin release did not increase unless hypotension occurred.

Verney's hypothesis of cerebral osmoreceptors controlling the renal excretion of water via vasopressin was reinvestigated in conscious trained dogs provided with bilateral skin loops containing the common carotid arteries. In multiple experiments in two dogs, bilateral intracarotid injections (0.25 ml. (kg b.wt.)-1 per artery in 10 s) of a hyperosmotic solution of sodium chloride (0.257 mol/l) during transient water diuresis failed to produce an antidiuretic response, although it is estimated that the injections elevated the osmolality of the carotid blood by 12-15%. In another 5 dogs, Bilateral intracarotid infusions of hyperosmotic saline (45 mumol.(kg b wt..min)-1 per artery for 10 min) during sustained water diuresis resulted in a 3% increase in jugular venous osmolality and an antidiuretic response without detectable changes in heart rate or mean arterial pressure. Equal intravenous hyperosmotic or intracarotid isosmotic infusions were not associated with antidiuretic response. Analysis of the concomitant concentrations of vasopressin in plasma fell short of supporting the hypothesis that the antidiuretic response to intracarotid hyperosmotic infusions was exclusively or mainly due to liberation of vasopressin, although the renal response could be mimicked by exogenous vasopressin. It is concluded that the present results-although discordant with several of Verney's results and assumptions-nevertheless support the concept of a cerebral solute receptor influencing the rate of renal water excretion.

The effects of a calcium channel agonist, BAY K-8644, on renin release and renal function were examined in perfused rat kidneys. BAY K-8644 increased renal vascular resistance and reduced glomerular filtration rate, sodium excretion and urine flow in a dose-dependent manner. These actions were prevented by the calcium channel blocker nifedipine. BAY K-8644 had no significant effect on basal renin secretion and failed to prevent renin stimulation by low-perfusion pressure or isoproterenol. The inhibitory effect of high-perfusion pressure on renin secretion was attenuated by the calcium entry blocker verapamil but not by nifedipine. Thus, if voltage-dependent calcium channels in the juxtaglomerular cell membrane participate in the regulation of renin release then these channels appear to be very insensitive to blockade or augmentation by 1,4-dihydropyridines.

Dose-response effects of prostaglandin D2 (0.125, 0.25, 0.5, and 0.75 micrograms/kg/min) infused intravenously in pentobarbital-anesthetized dogs were studied with particular reference to renal, pulmonary, and systemic effects. Another group receiving the vehicle alone served as controls. Prostaglandin D2 administration resulted in a significant dose-dependent increase in renal artery flow, urine output, creatinine clearance, plasma renin activity, sodium excretion, potassium excretion, and pulmonary artery pressure. A significant decrease occurred in renal resistance and arterial PO2. There were no appreciable changes in mean arterial pressure, heart rate, hematocrit, platelet count, arterial pH, and PCO2. In the vehicle control group, all other parameters remained relatively stable, except for some increase in the mean arterial pressure, plasma renin activity, and potassium excretion. The results of this study suggest that prostaglandin D2 administered intravenously at levels lower than those required to produce adverse pulmonary and systemic effects will improve the renal blood flow and function.

To examine the role of the renal vascular receptor in the control of renin secretion in the rat, a denervated, nonfiltering kidney model (DNFK) was developed. The left kidney was subjected to a 2-hr period of total renal ischemia followed by ureteral ligation and section Denervation was accomplished by stripping all visible nerves and painting the renal vessels with 5% phenol. Forty-eight hours later lissamine green dye was injected iv and failed to appear in either the cortical or medullary tubules, indicating that glomerular filtration had ceased. Histological study of these kidneys revealed diffuse tubular necrosis with extensive intratubular cast formation. Norepinephrine content of the DNFK was reduced 91% compared to the contralateral normal kidney (P less than 0.001). In another group of anesthetized rats with a single DNFK, 15 min of suprarenal aortic constriction (SAC) increased plasma renin activity (PRA) from 3.4 +/- 0.6 to 11.5 +/- 1.6 ng AI/ml/hr; in a time control series, PRA was unchanged. To exclude the influence of adrenal catecholamines in this response, bilateral adrenalectomy was performed in a separate group of animals with a DNFK. In this series, SAC also markedly increased PRA. The present data indicate that in the rat the macula densa, the renal nerves, and adrenal catecholamines were not essential for the hyperreninemia induced by a reduction in renal perfusion pressure.

This study examined renin release and renal function of the nonclipped kidney of 2K-1C rats (HYPER) with hypertension of 3 to 4 weeks duration. Kidneys from uninephrectomized rats (UN) served as controls. The kidneys were removed and perfused in vitro and renin release was compared under basal conditions and then under stimulated conditions using (a) a 50 mm Hg reduction in perfusion pressure (LP), (b) beta-receptor stimulation with isoproterenol (ISOP), or (c) perfusion with a low calcium solution (LCa). Basal perfusate flow, glomerular filtration rate, urine flow, sodium excretion, and basal renin release were all lower in HYPER kidneys than UN kidneys. UN kidneys showed striking increases in renin release with all three stimuli employed. HYPER kidneys showed a significant but attenuated response to ISOP and showed no detectable response to LP or LCa. Renin content of HYPER kidneys was found to be 28% of the renin content of UN kidneys. The results show that chronic hypertension leads to increased renal vascular resistance, reduced glomerular filtration, and reduced solute excretion in the nonclipped kidney. The results suggest that a reduction in renin content plays a major role in the reduced rates of basal renin release and the attenuated renin responses to a number of stimuli observed in this experimental model.

This study examines the hypothesis that the renal prostaglandins function as essential mediators in stimulus-secretion coupling for one or more of the basic receptor mechanisms in the control of renin release. Changes in plasma renin activity (PRA) were evaluated in response to suprarenal aortic constriction before and after indomethacin administration in conscious dogs with either a single denervated nonfiltering kidney or with intact filtering kidneys. Suprarenal aortic constriction was adjusted to reduce renal perfusion pressure below the autoregulatory range in both groups of dogs. Inhibition of cyclooxygenase with indomethacin significantly decreased urinary prostaglandin E2 (PGE2) excretion, but indomethacin failed to block or attenuate the increase in PRA in response to a decrease in renal perfusion pressure in either group of dogs. These results fail to support the hypothesis that the renal prostaglandins function as essential mediators of the intrarenal receptor mechanisms for renin release which are activated by a decrease in renal perfusion pressure below the autoregulatory range.

The role of renal prostaglandins and the adrenergic nervous system in the control of renin release was studied in conscious dogs with thoracic caval constriction. Indomethacin reduced plasma renin activity (PRA) in intact animals with thoracic caval constriction by 43% but failed to change PRA after surgical renal denervation and during chronic propranolol administration; adrenergic blockade reduced the initial control level of PRA before indomethacin from 15 to 4 ng angiotensin I/ml per hr. Renal hemodynamic function was markedly reduced by indomethacin both before and after adrenergic blockade. These observations indicate that prostaglandins are involved in the control of renin release, but they appear to have a more important role in the control of renal arterial resistance. The adrenergic nervous system also plays a role in the hyperreninemia of caval constriction and, possibly, a greater role than the renal prostaglandins. In the first experimental design, surgical renal denervation and daily oral propranolol administration in dogs with caval constriction reduced PRA to normal in two of seven dogs and a natriuresis occurred. In four of the five remaining animals, PRA fell, but not to normal, and renal sodium excretion failed to increase. In a second experimental design, the kidneys were denervated and propranolol was given before the dogs were subjected to caval constriction and propranolol was continued for 5 days; PRA increased markedly, sodium retention occurred, and ascites formed. Under these circumstances, compensatory mechanisms secondary to caval constriction led to increased PRA in spite of adrenergic blockade.