Homocysteine effects classical pathway of GPCR down regulation: Galpha(q/11), Galpha(12/13), G(i/o).

G protein-coupled receptors (GPCRs) are known to modulate intracellular effectors involved in cardiac function. We recently reported homocysteine (Hcy)-induced ERK-phosphorylation was suppressed by pertussis toxin (PTX), which suggested the involvement of GPCRs in initiating signal transduction. An activated GPCR undergoes down regulation via a known mechanism involving ERK, GRK2, beta-arrestin1: ERK activity increases; GRK2 activity increases; beta-arrestin1 is degraded. We hypothesized that Hcy treatment leads to GPCR activation and down regulation. Microvascular endothelial cells were treated with Hcy. Expression of phospho-ERK1 and phospho-GRK2 was determined using Western blot, standardized to ERK1, GRK2, and beta-actin. Hcy was shown to dephosphorylate GRK2, thereby enhancing the activity. The results provided further evidence that Hcy acts as an agonist to activate GPCRs, followed by their down regulation. Hcy was also shown to decrease the content of the following G proteins and other proteins: beta-arrestin1, Galpha(q/11), Galpha(12/13), G(i/o).

Endogenous norepinephrine regulates blood flow to the intact rat tibia.

The goal of our study was to determine if endogenous norepinephrine (NE) has a role in the regulation of basal blood flow to intact bone. The experimental plan was to measure bone blood flow before and after pharmacological blockade of alpha-adrenergic receptors. A significant increase in blood flow after receptor blockade would suggest that endogenous norepinephrine exerts a tonic constrictor effect on the vessels supplying blood to the bone. Mature, male rats were anesthetized with Inactin. Arterial blood pressure and left tibia blood flow (laser Doppler flowmetry) were measured. A cannula was inserted into the right iliac artery and advanced to the aortic bifurcation to deliver drugs into the left hindlimb circulation, including the left tibia vasculature. Bolus injection of norepinephrine caused a dose-dependent decrease in bone blood flow (30-40%). Blockade of alpha-adrenergic receptors with phentolamine or phenoxybenzamine attenuated by more than 50% the norepinephrine-induced decrease in bone blood flow. In separate rats that had not received exogenous norepinephrine, injection of phentolamine alone decreased bone vascular resistance by 34+/-3%. Similarly, phenoxybenzamine decreased resistance by 25+/-4%. These results are consistent with the conclusion that alpha-adrenergic receptors mediate a significant constriction of blood vessels which participate in the partial control of basal blood flow to the intact rat tibia.

Dietary chloride does not correlate with urinary thromboxane in deoxycorticosterone acetate-treated rats.

Renal vascular resistance in deoxycorticosterone acetate (DOCA) salt-treated uninephrectomized rats is increased by high dietary chloride. Because DOCA salt-hypertensive rats exhibit an increased urinary excretion of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), the increased TXB2 excretion by DOCA salt-treated rats could relate to elevated dietary chloride, increased blood pressure, and/or the presence of intact renal tubules. We hypothesized that high NaCl intake, resulting in an elevated tubular chloride excretion, stimulates TXA2 production. A result of that production could be renal vasoconstriction. Baseline blood pressures were measured for 10 days, and then the rats were treated with DOCA (30 mg/kg) and fed (1) normal NaCl, (2) normal sodium with high chloride, or (3) high sodium chloride (NaCl) for 4.5 weeks. Next, the rats were uninephrectomized (1K) or unihydronephrectomized (1KHK) to yield one kidney without an intact tubular system and therefore no macula densa. Two and a half weeks later, urinary excretion of TXB2 was determined. DOCA-high NaCl-fed 1KHK or 1K rats had significant increases in systemic blood pressure to 172 +/- 12 and 190 +/- 5 mm Hg, respectively, compared with no significant increase in blood pressure among the other groups. Urinary TXB2 excretion was increased to 29 +/- 4 pg per 24 hours per gram of body weight in all DOCA-treated 1KHK and 1K animals regardless of diet compared with DOCA-treated animals with two intact kidneys (13 +/- 2 pg per 24 hours per gram of body weight). DOCA treatment in rats with one functional kidney results in the excretion of high levels of urinary TXB2 unrelated to dietary chloride load, blood pressure, or intact renal tubules.

Altered expression and activity of G-proteins, mitogen activated protein kinases, and tyrosine kinases in aging kidney cortex.

BACKGROUND: Renal function declines with age and this may be related to changes in the expression or activity of various signal transduction proteins in the kidney. METHODS: The present study compared the expression and activity of G alpha i(1-3) and G alpha s phosphorylation of mitogen activated protein kinases (MAP-K) (44 and 42 kd) and the activity of tyrosine kinase in renal cortical homogenates of young (4-month-old) and aging (14-month-old) rats. RESULTS: The GTP/(GTP + GDP) binding ratio of G alpha s was significantly decreased in the kidney cortex of aging rats compared to young rats, while the GTP/(GTP + GDP) binding ratio of G alpha i(1-3) increased significantly in kidney cortex of aging rats. Tyrosine kinase activity and phosphorylation of MAP-K (44 and 42 kd) were also reduced in the kidney cortex of aging rats compared to young rats. CONCLUSIONS: These results suggest that diminished phosphorylation of MAP-K and tyrosine kinase activity as well as changes in the binding of GTP/(GTP + GDP) to G alpha i(1-3) and G alpha s may contribute to the age-related decline in renal tubular and vascular function seen in aging animals.

Neutrophils and renal failure.

In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils' ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This review summarizes the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. Nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase is a membrane-associated enzyme that generates a family of reactive oxygen intermediates (ROI). There is increasing evidence that ROIs are implicated in glomerular pathophysiology: ROIs contribute to the development of proteinuria, alter glomerular filtration rate, and induce morphological changes in glomerular cells. Specific neutrophil granules contain microbicidal peptides, proteins, and proteolytic enzymes, which mediate the dissolution of extracellular matrix, harm cell structures or cell function, and induce acute and potentially irreparable damage. Although both ROI and neutrophil-derived proteases alone have the potential for tissue destruction, it is their synergism that circumvents the intrinsic barriers designed to protect the host. Even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of neutrophil-derived myeloperoxidase (MPO) and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage if not properly controlled. In addition, neutrophil-derived phospholipase products such as leukotrienes and platelet-activating factor contribute to vascular changes in acute inflammation and amplify tissue damage. Increasing evidence suggests that mesangial cells and neutrophils release chemotactic substances (eg, interleukin 8), which further promote neutrophil migration to the kidney, activate neutrophils, and increase glomerular injury. Also, the expression of adhesion molecules (eg, intercellular adhesion molecule 1 on kidney-specific cells and beta-2-integrins on leukocytes) has been correlated with the degree of injury in various forms of glomerulonephritis or after ischemia and reperfusion. Together, these results suggest that neutrophils and adhesion molecules play an important role in mediating tissue injury with subsequent renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase susceptibility to infection and sepsis.

Dietary calcium decreases blood pressure without decreasing renal vascular resistance or altering the response to NO blockade.

Many vasoactive elements are involved in the elevation of blood pressure in spontaneously hypertensive rats (SHR). Elevated dietary calcium has been observed to reduce blood pressure in SHR. This study investigates interactions among dietary calcium, renal vascular resistance (RVR), elevation of blood pressure and effects of norepinephrine and nitric oxide synthesis. We completed a series of experiments on two groups each (fed low, 0.1% and high, 2.0% dietary calcium, respectively) of 9-week-old Wistar Kyoto (WKY), 9-week-old and 6-week-old SHR. Although 9-week-old SHR had elevated baseline blood pressure compared to 9-week-old WKY and also compared to 6 week-old SHR, there was no corresponding elevation in baseline RVR. All SHR fed high calcium diets had lower blood pressure compared to low calcium diets, and there was no corresponding reduction in RVR. WKY controls' blood pressure and RVR were unaffected by dietary calcium levels. In all hypertensive rats the blood pressure and renal vascular resistance were elevated by N(G)-nitro-L-arginine methylester (L-NAME), but the dietary differences were sustained. Blood pressure of WKY was unaffected by the low dose of L-NAME. The increase in RVR to L-NAME was greater in SHR than in controls. The renal vascular response to norepinephrine was related to diet in older SHR, but smaller and unrelated to diet in younger SHR. Following L-NAME, WKY had greater responses to norepinephrine than 9-week-old SHR. We conclude that noradrenergic vasoconstriction is enhanced in the adult SHR, especially in the absence of high calcium diet. Alterations in NO synthesis may effect the norepinephrine response.

Effect of human chorionic gonadotropin on reproductive organ blood flow in cycling rats.

Recent characterization of luteinizing hormone++ (LH)/human chorionic gonadotropin (hCG) receptors in uterine vascular tissue, evidence that expression of these receptors is cyclic in nature, and demonstration of a correlation between hCG level and uterine vascular resistance lead us to investigate the effect of hCG administration on blood flow in reproductive organs of cycling and ovariectomized Sprague-Dawley rats. Blood flow (ml/min/g dry wt/cardiac output +/- SEM) was determined by microsphere spectroscopy (57Co, 113Sn, 95Nb, 141Ce). Baseline uterine (0.5842 +/- 0.1037) and cervical (0.7785 +/- 0.1199) blood flows were greater in diestrus-2 rats than in every other group. Diestrus-2 (0.4530 +/- 0.0584) and estrus (0.4692 +/- 0.0848) rats had greater baseline ovarian blood flow than proestrus rats (0.2521 +/- 0.0279). A single intraperitoneal injection of 50 IU hCG on each day of the 4-day estrus cycle decreased uterine flow by more than 30% within 20 min (P<0.05), but did not alter uterine flow in ovariectomized rats. This dose of hCG also decreased ovarian flow in diestrus-2 rats (0.5219 +/- 0.0857 to 0.4207 +/- 0.0753), decreased liver flow in diestrus-2 (0.0282 +/- 0.0060 to 0.0231 +/- 0.0051) and estrus (0.0301 +/- 0.0029 to 0.0203 +/- 0.0038 rats, and increased liver flow in ovariectomized rats (0.0279 +/- 0.0054 to 0.0325 +/- 0.0050). Injection of 0.10 IU hCG did not alter blood flow to reproductive organs in any group, but decreased liver flow in estrus rats (0.0469 +/- 0.0121 to 0.0326 +/- 0.0088). Neither dose of hCG altered cervical, kidney, or skeletal muscle flow in any group. Our results indicate an organ specific, dose-dependent blood flow response to hCG in cycling rats, which appears, in the case of uterine flow, to be attenuated by removal of the ovaries. The present findings suggest high doses of hCG given clinically may decrease uterine flow and potentially lead to implantation failure.

Chloride alters renal blood flow autoregulation in deoxycorticosterone-treated rats.

Renal blood flow autoregulation was studied in deoxycorticosterone acetate (DOCA)-treated rats. DOCA pellets (75 mg) were implanted in uninephrectomized rats, and the animals were then fed one of four diets: (1) normal sodium chloride level, (2) high in NaCl, (3) high in chloride, or (4) high in sodium. After 40 to 45 days of the DOCA-diet treatment, animals were subjected to renal blood flow autoregulation experiments; an inflatable aortic occluder was placed proximal to the renal artery, and renal blood flow (electromagnetic flow probe) was measured while renal perfusion pressure was reduced from normal (in that animal) to 20 mm Hg, in 10 mm Hg decrements to determine the lower threshold of autoregulation. Directly measured arterial blood pressure was higher in the DOCA-high NaCl group compared with the DOCA-normal NaCl group (127 +/- 3 mm Hg vs 103 +/- 4 mm Hg) during anesthesia. Significant elevation of lower autoregulatory thresholds were demonstrated in both the DOCA-high NaCl (98 +/- 7 mm Hg) and high chloride groups (94 +/- 3 mm Hg) compared with the DOCA-normal NaCl (77 +/- 4 mm Hg) and the DOCA-high sodium (76 +/- 5 mm Hg). Pressure-flow curves of the DOCA-high chloride groups were shifted significantly downward (reduced renal blood flow at all pressures) and rightward (elevated lower threshold) compared with the DOCA-normal NaCl and -high sodium groups. These data indicate that DOCA-treated rats consuming a diet high in chloride have altered renal blood flow autoregulatory mechanisms.

Effect of leukotrienes of renal water excretion.

To investigate the renal actions of leukotrienes (LT), we infused arachidonic acid into the renal artery of anesthetized dogs during systemic cyclooxygenase inhibition (with ibuprofen) alone or in combination with lipoxygenase inhibition or LTD4/LTE4 receptor antagonism. Renal arachidonic acid infusion following ibuprofen alone decreased urine osmolality (945 +/- 143 to 698 +/- 144 mosm/kg; p < 0.01) and increased urine flow rate (0.34 +/- 0.11 to 0.56 +/- 0.16; p < 0.05) without altering renal blood flow, glomerular filtration rate or sodium excretion. In separate groups, prior inhibition of lipoxygenase (propylgallate) or blockade of LTD4/LTE4 receptors (LY171883) prevented the changes in urine osmolality and urine flow rate. Intrarenal oleic acid infusion following ibuprofen had no effect on renal function. Analysis of the renal papillae at the end of the experiment indicated that interstitial osmolality and sodium, potassium and urea contents were the same in all groups, ruling out a decrease in papillary interstitial osmolality as the cause of the decrease in urine osmolality in the arachidonic acid-infused group. Our experiments suggest that renal LT can decrease urine osmolality and increase urine flow rate and may play a role in renal water excretion.

Renal vasodilation with acetylcholine but not secretin increases nonnutrient blood flow.

To investigate the fact that, despite its renal vasodilator properties, acetylcholine (ACh) provides no protection against acute renal failure, we measured nutrient (NBF) and nonnutrient renal blood flow (NNBF) during ACh infusion. The effect of ACh and secretin on NBF in the outer and inner cortex and outer medulla using 133Xenon (133Xe) washout with freeze dissection analysis was determined. We then calculated NNBF as the difference between NBF in the entire cortex and outer medulla (133Xe washout) and total renal blood flow (TRBF) measured by electromagnetic flow probe. NNBF was also assessed from the 86Rubidium (86Rb) recovery after administration into the renal artery. ACh increased TRBF without increasing NBF, resulting in an increased calculated NNBF. ACh, but not secretin, increased NNBF in the kidney as measured with 86Rb. Thus we conclude that ACh selectively induces a large increase in NNBF in the kidney.

Effectiveness of dual cyclooxygense and leukotriene blockade with ibuprofen and LY203647 during canine endotoxic shock.

Ibuprofen and the leukotriene antagonist, LY203647, were used to evaluate the effectiveness of LY203647 in the dual blockade of cyclooxygenase and leukotriene to maintain hemodynamic parameters in endotoxemia. Ibuprofen pretreatment alone or dual blockade (ibuprofen plus LY203647) protected blood pressure and renal blood flow at 1 and 3 hr after endotoxin infusion. Cardiac output at 1 hr after endotoxin in dogs treated with ibuprofen was slightly but significantly decreased. Dual pretreatment prevented this decrease at 1 hr; however, cardiac output was similar in both groups by 3 hr. Dual blockade administered after endotoxin induced increases in blood pressure and cardiac output at 3 hr. LY203647 pretreatment alone did not prevent the postendotoxemic declines in any measured parameters. The increased plasma SGOT and lactate of endotoxemia were exacerbated by LY203647 and blunted by ibuprofen treatment. We conclude that the addition of LY203647 to ibuprofen treatment offers no additional significant protection of hemodynamic parameters.

Effect of chloride on renal blood flow in angiotensin II induced hypertension.

The effect of selective dietary sodium and (or) chloride loading on blood pressure and renal blood flow (RBF) in the rat angiotensin II (AII) model of hypertension was determined. AII (200 ng/min) or saline was infused intraperitoneally. Diets were provided with either high or low concentrations of sodium, chloride or both ions for 22 days. The blood pressure of saline-treated animals was not increased by the high sodium chloride diet. Animals on a high sodium, high chloride diet had a significantly greater increase of blood pressure at 8, 15, 18, and 22 days of AII infusion compared with AII-treated animals on a low sodium, low chloride diet (p less than 0.05). Selective dietary loading of either high sodium or chloride in AII-treated rats produced no greater elevation of blood pressure than AII with the low sodium, low chloride diet. Selective high dietary chloride was associated with a lower RBF in AII- and vehicle-treated rats compared with low dietary chloride. The chloride effect on RBF was greater in AII-treated animals. In conclusion, both sodium chloride are necessary to produce the maximum increase of blood pressure in AII animals. AII enhances the decreased RBF induced by dietary chloride.

Nicotine impairs reflex renal nerve and respiratory activity in deoxycorticosterone acetate-salt rats.

Smoking exacerbates the increase in arterial pressure in hypertension. The effect of nicotine on the baroreceptor-mediated reflex responses of renal nerve activity (RNA), heart rate, and respiratory activity (minute diaphragmatic activity [MDA]) after bolus injections of phenylephrine was compared in deoxycorticosterone acetate (DOCA)-salt sensitive and normotensive rats. Osmotic minipumps that dispensed either nicotine (2.4 mg/kg/day) or saline were implanted in DOCA and normotensive rats for 18 days. Anesthetized DOCA-nicotine, DOCA-saline, control-nicotine, and control-saline rats had mean arterial pressures (MAP) of 117 +/- 3, 110 +/- 9, 90 +/- 3, and 89 +/- 5 mm Hg, respectively. Nicotine decreased the sensitivity (p less than 0.05) of baroreceptor reflex control of RNA (% delta RNA/delta MAP) in the DOCA-nicotine rats (-0.92 +/- 0.08) compared with the DOCA-saline (-1.44 +/- 0.16), control-nicotine (-1.45 +/- 0.08), or control-saline (-1.45 +/- 0.21) rats. The reflex decrease in respiratory activity (% delta MDA/delta MAP x 100) was impaired (p less than 0.01) in both control-nicotine (-24.5 +/- 3.3) and DOCA-nicotine (-18.2 +/- 4.6) rats compared with control-saline (-59.2 +/- 9.1) and DOCA-saline (-52.5 +/- 9.9) rats. The reflex decrease in heart rate (absolute delta HR/delta MAP) in both DOCA-nicotine (1.56 +/- 0.17) and control-nicotine (1.54 +/- 0.24) rats was augmented compared with DOCA-saline and control-saline rats (0.91 +/- 0.12 and 0.97 +/- 0.14).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac output and the blood pressure increase in deoxycorticosterone acetate-salt hypertension after nicotine infusion.

We wished to determine if nicotine exaggerates the blood pressure increase in deoxycorticosterone (DOCA)-salt hypertension. Uninephrectomized, male Sprague-Dawley rats were implanted with DOCA pellets (75 mg) and placed on a 5.2% salt diet for sixteen days and then infused with nicotine (DOCA-Nicotine; 2.4 mg/kg/day) or vehicle (DOCA-Sham). Control animals were treated with vehicle (Control) or nicotine (Control-Nicotine). The DOCA-Nicotine group had significantly greater tail-cuff blood pressures than the DOCA-Sham group by one week of nicotine infusion. At 2.5 weeks of nicotine infusion the DOCA-Nicotine rats had significantly greater tail-cuff blood pressures, direct arterial blood pressures, and cardiac outputs compared to the DOCA-Sham animals. Renal blood flows were similar in the two groups. Control-Nicotine animals demonstrated no response to nicotine during 2.5 weeks of infusion. We conclude that in the DOCA-salt rat nicotine induces an exaggerated rise in blood pressure and that the mechanism involves an increase in cardiac output.

Hemodynamic and renal advantages of dual cyclooxygenase and leukotriene blockade during canine endotoxic shock.

The decline in mean arterial pressure (MAP), cardiac output (CQ), and renal blood flow (RBF) that accompany endotoxic shock is partly ameliorated by cyclooxygenase or leukotriene blockade. This study determined whether dual cyclooxygenase and leukotriene blockade provided greater hemodynamic protection than either single blockade alone. Mongrel dogs were pretreated with either ibuprofen or LY171883 alone or dual blockade consisting of ibuprofen combined with LY171883 or propylgallate, then given Escherichia coli endotoxin, and monitored for 10 hr. Postendotoxemic MAP was equally maintained with dual blockade and with ibuprofen. For the first 5 hr postendotoxin, CQ was best maintained by dual blockade. However, by 9 hr postendotoxin, CQ in LY171883-treated animals was 88 +/- 8% of control. LY171883 provided the greatest protection of RBF, while dual blockade provided the least protection for both RBF and urine flow rates (V). Ibuprofen-treated dogs required less NaHCO3 for acid-base maintenance than did dual-blocked animals. In summary, dual cyclooxygenase and leukotriene blockade was advantageous in protecting MAP and CQ during the early phases of shock but provided no greater protection of RBF, GFR, V or acid-base balance than did single blockade. Overall, LY171883 provided the best protection from circulatory dysfunction.

Separate hemodynamic roles for chloride and sodium in deoxycorticosterone acetate-salt hypertension.

It has been reported that both sodium and chloride ions must be ingested to induce the elevated blood pressure of deoxycorticosterone acetate (DOCA)-salt-sensitive hypertension. This study was designed to determine the separate roles of the sodium and chloride ions in the altered hemodynamics underlying the high blood pressure. DOCA pellets (75 mg) were implanted in uninephrectomized rats and the animals were then fed one of four diets: (i) high sodium chloride, (ii) high sodium-low chloride, (iii) high chloride-low sodium, or (iv) low sodium chloride. Blood pressures were measured weekly by tail-cuff plethysmography for 5 weeks and the animals were then subjected to a terminal experiment to measure cardiac output by thermodilution technique, renal blood flow by electromagnetic flow probe, and direct arterial pressure. Blood pressure in the DOCA-high NaCl group was significantly greater (P less than 0.05) compared with that of the DOCA-low NaCl group (160 +/- 3 mm Hg vs 124 +/- 2 mm Hg, respectively) at 5 weeks after treatment; all other groups were not significantly different from the DOCA-low NaCl group. Cardiac output was significantly greater in DOCA-treated rats consuming diets high in sodium (44 +/- 2 ml/min/100 g) or sodium chloride (40 +/- 2 ml/min/100 g) compared with animals consuming low sodium chloride (31 +/- 2 ml/min/100 g; P less than 0.01 for each comparison). Direct intraarterial blood pressure and renal blood flow were used to calculate renal vascular resistance. Renal vascular resistance was increased in those DOCA-treated rats consuming diets high in chloride (42 +/- 3 mm Hg/ml/min/100 g) and high sodium chloride (54 +/- 3 mm Hg/ml/min/100 g) compared with rats consuming low sodium chloride (30 +/- 3 mm Hg/ml/min/100 g; P less than 0.01 for each). It appears that elevations in cardiac output are associated with increased dietary sodium and act in synergy with the elevations in renal vascular resistance associated with increased dietary chloride. Increases in both cardiac output and renal vascular resistance are involved in the maintenance of elevated blood pressure in the DOCA-salt-sensitive model of hypertension.

Nutrient and nonnutrient renal blood flow.

The role of prostaglandins in the distribution of total renal blood flow (TRBF) between nutrient and nonnutrient compartments was investigated in anesthetized mongrel dogs. Renal blood flow distribution was assessed by the xenon 133 freeze-dissection technique and by rubidium 86 extraction after ibuprofen treatment. Ibuprofen (13 mg/kg) significantly decreased TRBF by 16.3% +/- 1.2% (mean +/- SEM electromagnetic flow probe; p less than 0.005), but did not alter blood flows to the outer cortex (3.7 vs 4.3 ml/min per gram), the inner cortex (2.6 vs 2.7 ml/min per gram), and the other medulla (1.5 vs 1.5 ml/min per gram), which suggests a decrease in nonnutrient flow. In a separate group of animals the effect of reduced blood flow on the nutrient and nonnutrient components was determined by mechanically reducing renal arterial blood flow by 48%. Unlike the ibuprofen group, nutrient blood flows were proportionally reduced with the mechanical decrease in TRBF in the outer cortex (1.9 ml/min per gram, p less than 0.05), the inner cortex (1.4 ml/min per gram, p less than 0.05), and the outer medulla (0.8 ml/min per gram, p less than 0.01). These results indicate no shift between nutrient and nonnutrient compartments. Nutrient and nonnutrient renal blood flows of the left kidney were also determined by 86Rb extraction. After ibuprofen treatment, nonextracted 86Rb decreased to 12.1% from the control value of 15.6% (p less than 0.05). Mechanical reduction of TRBF did not significantly decrease the proportion of unextracted 86Rb (18.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular correlates of predisposition to hypertension in pups of one kidney: one clip renal hypertensive dams.

We reported that the pups of one kidney:one-clip Goldblatt hypertensive (HT) rats have a predisposition to the induction of experimental hypertension. To investigate the nature of the predisposition, pups of HT dams were challenged with vasopressor agents at 28-days-of-age or treated with DOCA and 6.5% salt diet between 35 and 81 days-of-age. Pups of HT dams had a significantly greater blood pressure between 28 and 81 days-of-age and also showed a greater change in blood pressure when provided a 6.5% salt diet than did pups of normotensive dams. Pups of HT dams demonstrated a decreased bradycardic response after injection of angiotensin II (p less than .05) and a lesser change in mean arterial blood pressure after injection of angiotensin II or norepinephrine than did the pups from normotensive dams. These results suggest an effect of maternal hypertension on the development of cardiovascular control mechanisms in her offspring. The decreased pressor response suggests the predisposition is not due to an increased vascular sensitivity to vasopressors.

Urinary and renal papillary solutes during cyclooxygenase inhibition with ibuprofen.

We investigated the mechanisms by which prostaglandin synthetase (cyclooxygenase) inhibitors cause antidiuresis and antinatriuresis in anesthetized dogs. Cyclooxygenase inhibition with ibuprofen caused an increased total solute (Na+, K+, and urea) concentration in the renal papilla. Xenon 133 washout studies revealed no change in medullary blood flow. Ibuprofen induced a 147% increase in papillary Na+ concentration, while increasing urea and K+ only 98% and 35%, respectively, suggesting that a Na+ reabsorption mechanism rather than decreased papillary blood flow was responsible for a majority of the increased papillary solute concentration. A decrease in the excretion of Na+, but not of K+ or urea, in treated dogs further implies increased Na+ reabsorption. Thus, it appears that cyclooxygenase inhibition increases papillary solute concentration primarily by increasing Na+ transport into the papilla.

Effect of hemorrhagic shock on oxidative phosphorylation and blood flow in rabbit gastrointestinal mucosa.

The pathophysiologic mechanism responsible for ulceration of gastric fundus and corpus mucosa following hemorrhagic shock is not well defined. We examined the effect of hemorrhagic shock (25 ml blood/kg) and resuscitation (reinfusion of shed blood) on oxidative phosphorylation in different tissues of the rabbit to determine if differences in mitochondrial response to hemorrhagic shock and resuscitation contribute to the propensity of gastric fundus and corpus to necrose before other tissues. Blood flow was measured by using radioisotope-labeled microspheres to determine if changes in regional blood flow could be correlated with this propensity to ulcerate. The respiratory control index (RCI), an index of the integrity of mitochondrial function, was significantly increased in gastric antrum, liver, and kidney from the animals subjected to hemorrhagic shock and successful resuscitation when compared to control animals. In liver and kidney, these differences were largely due to increases in state 3 respirations. Duodenal and gastric corpus and fundus mitochondria showed no differences in RCI between bled and control groups. Blood flow data did not implicate ischemia as the mechanism responsible for the differential rate of ulceration after hemorrhage. The inability of fundus, corpus, and small-bowel mucosal mitochondria to respond to the stress of hemorrhagic shock and resuscitation in a manner similar to liver, kidney, and gastric antral mitochondria may place these tissues at greater risk to ulcerate. Further work is necessary to define whether this difference in mitochondrial response patterns represents a real increase in the maximal respiratory capacity of liver, kidney, and antrum after shock and resuscitation.