Inhibition of prostaglandin E2 secretion. Failure to abolish autoregulation in the isolated dog kidney.

We studied the role of renal prostaglandins in the regulation of glomerular filtration rate (GFR) and renal blood flow (RBF) in the isolated dog kidney. Indomethacin or meclofenamate, 2 mg/kg of body weight, suppressed renal prostaglandin E2 (PGE2) secretion, measured by radioimmunoassay, to zero within 20 minutes; the effect persisted for the duration of the study. When renal arterial pressure (PRA) was maintained at 104 mm Hg both drugs caused a sharp decrease in sodium excretion and RBF with redistribution of flow from inner to outer cortes we examined autoregulation of GFR and RBF over the pressure ranges of 150-100 and 150-75 mm Hg, respectively, after inhibition of PGE2 secretion and under control conditions. deltaGFR/deltaPRA (ml/min per mm Hg) was 0.020 +/- 0.017 in the indomethacin group, 0.152 +/- 0.055 in the meclofenamate group, and 0.086 +/- 0.017 in the control group. The change in GFR for the indomethacin group was significantly less than that for meclofenamate (P less than 0.01) and control groups (P less than 0.025); the latter two groups were not statistically different from each other (P greater than 0.1). There was no significant difference (P greater than 0.1) between the three groups with respect to deltaRBF/deltaPRA, which measured 0.288 +/- 0.046, 0.370 +/- 0.112, and 0.438 +/- 0.123 ml/min per mm Hg in the indomethacin, meclofenamate and control groups, respectively. Renal was lowered from 150 to 75 mm Hg. The observation that inhibition of prostaglandin synthesis promotes a redistribution of RBF from inner to outer cortex suggests that renal prostaglandins may participate in the regulation of medullary blood flow. However, since autoregulation of GFR and RBF remained intact despite inhibition of prostaglandin secretion, these data argue against a role for renal prostaglandins in regulating whole kidney GFR and RBF.     

Renal cortical blood flow in glycerol-induced acute renal failure in the rat.

Renal hemodynamics and renal function were evaluated in rats at 3, 24, and 48 hours and at 7 days after the induction of acute renal failure (ARF) by glycerol injection. Three hours after induction of ARF, creatinine clearance was 0.04 ml/min/100 g; renal blood flow (RBF), 1.99 ml/min/100 g; and filtration fraction, 3.7%. All were abnormally low. Although the administration of isotonic saline (total dose, 3% of body weight) to rats 3 hours after glycerol injection significantly improved creatinine clearance (0.17 ml/min/100 g), RBF (2.54 ml/min/100 g), and filtration fraction (12.9%), these values still were significantly lower than those of controls (creatinine clearance = 0.50 ml. ml/min/100 g, RBF = 4.92 ml/min/100 g, filtration fraction = 20.0%, all P values less than 0.001). Serum creatinine concentrations were significantly elevated at 24 hours (3.72% gm/100 ml), 48 hours (4.69 mg/100 ml), and 7 days (0.66 mg/100 ml) after glycerol injection compared to control (0.46 mg/100 ml, all P less than 0.01). RBF during these phases was not different from normal (4.41 ml/min/100 g). RBF 3 hours after bilateral ureteral obstruction was measured to determine the effects of tubular obstruction on renal hemodynamics. The RBF of rats with ureteral obstruction (4.12 ml/min/100 g) was not significantly different from controls (4.41 ml/min/100 g), suggesting that tubular obstruction in this model of ARF is probably not the cause of decreased RBF. The depressed glomerular filtration, as reflected by the decreased creatinine clearance that occurs during glycerol-induced ARF, is probably related to altered intrarenal vascular resistance or to changes in glomerular capillary permeability, or both.     

Relationships among endotoxemia, arterial pressure, and renal function in dogs

This study evaluated the effects of increasing plasma endotoxin (Difco 055:B5) concentration by intravenous and intrarenal infusion on renal hemodynamics and renal function. Plasma endotoxin was increased to 130-150 ng/ml (infusion rate of 32 micrograms/min) in two groups of dogs and changes in plasma endotoxin concentration were correlated with arterial pressure (AP), glomerular filtration rate (GFR), renal blood flow (RBF), and urinary sodium excretion (UNaV) for 4 hr. In group 1, intrarenal endotoxin infusion decreased AP, GFR, RBF, and UNaV equally between infused and contralateral noninfused kidneys. In dogs with unilateral renal denervation (group 2), intravenous endotoxin maximally decreased AP, GFR, RBF, and UNaV in both kidneys by 90 min. Despite continued endotoxin infusion, RBF and GFR then spontaneously increased after 90 min, and by 240 min these values were significantly greater in the innervated kidneys compared with denervated kidneys (P less than 0.05). In both groups of dogs, the spontaneous increase in GFR and RBF was associated with a spontaneous increase in arterial pressure. These data suggest that renal dysfunction during moderate endotoxemia may be mediated by systemic hemodynamic changes rather than by direct intrarenal toxicity and that renal innervation may protect against endotoxin-induced reductions in RBF and GFR.     

Histamine H1 receptor antagonists inhibit autoregulation of renal blood flow in the dog

Histamine H1 and H2 receptors are present in the canine renal circulation. We have examined the effects of H1 and H2 receptor antagonists on autoregulation of renal blood flow in the dog. Renal arterial pressure was reduced in a step-wise fashion to 80 mm Hg by means of an adjustable aortic clamp positioned above the left renal artery. Infusion of H2 antagonists, cimetidine or ranitidine, into the left renal artery at 10(-5) mol/min had no effect on autoregulation of renal blood flow or on the reactive hyperemia that occurred when the aortic constriction was released. By contrast, intrarenal infusion of 10(-5) mol/min chlorpheniramine, an H1 receptor antagonist, reversibly attenuated reactive hyperemia and the ability of the kidney to autoregulate renal blood flow. Similar results were obtained with other, chemically dissimilar H1 antagonists (terfenadine, diphenhydramine, and pyrilamine). The effects of chlorpheniramine on autoregulation of glomerular filtration rate also were evaluated. Before chlorpheniramine was infused (at 10(-5) mol/min), the reduction of renal arterial pressure to 90 mm Hg had no effect on the glomerular filtration rate, whereas, during infusion of the H1 antagonist, the glomerular filtration rate fell significantly when renal arterial pressure was reduced to 90 mm Hg. Infusion of histamine (1 microgram/kg per min) with increasing amounts of cimetidine, chlorpheniramine, diphenhydramine, or pyrilamine resulted in virtually identical dose-dependent decreases in histamine-induced renal vasodilation. However, even with 10(-5) mol/min cimetidine or 10(-5) mol/min chlorpheniramine, diphenhydramine, or pyrilamine, a significant histamine-induced renal vasodilation was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary pressure-flow relations in hypertensive left ventricular hypertrophy. Comparison of intact autoregulation with physiological and pharmacological vasodilation in the dog

Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during perfusion of the circumflex artery by an extracorporeal circuit at controlled diastolic pressures of 20-200 mm Hg. Autoregulated pressure-flow relations were compared at three levels of myocardial oxygen demand: resting, high (dobutamine 10 micrograms/kg/min), and low (propranolol 2.5 micrograms/kg/min). Autoregulatory capacity was assessed by calculation of closed-loop flow gain. At each level of myocardial oxygen demand, the lower limit of autoregulation occurred at higher perfusion pressures in the hypertrophy group (rest 65 +/- 3, high 92 +/- 4, low 66 +/- 4 mm Hg) than in the normal group (rest 53 +/- 2, p less than 0.05; high 75 +/- 5, p less than 0.05; low 51 +/- 3 mm Hg) (p less than 0.05). Maximum autoregulatory gain was similar in the normal and hypertrophy groups during resting and low myocardial oxygen demand but was reduced in the hypertrophy group during dobutamine studies. When coronary flow decreased below the lower limit of autoregulation, systolic shortening was reduced in both normal and hypertrophy groups. However, as the autoregulatory limits were at higher pressures in the hypertrophy group, shortening in this group deteriorated at perfusion pressures that did not affect the normal heart. Coronary pressure-flow relations during physiological (peak hyperemia after 15-second flow occlusion) and pharmacologica (intracoronary adenosine 400 micrograms/min) vasodilation was curvilinear and fitted by quadratic regression. During hyperemic vasodilation, maximal conductance per unit mass of myocardium was less in the hypertrophy group over a wide range of perfusion pressures. At a diastolic perfusion pressure of 80 mm Hg, maximum conductance was 4.6 +/- 0.5 ml/min/100 g/mm Hg in the normal group and 3.4 +/- 0.4 ml/min/100 g/mm Hg (p less than 0.05) in the hypertrophy group. Intracoronary adenosine elicited further vasodilation in both groups, but maximum conductance remained less in the hypertrophy group (8.5 +/- 1.7 ml/min/100 g/mm Hg at a perfusion pressure of 80 mm Hg) than in the normal group (13.5 +/- 2.0 ml/min/100 g/mm Hg) (p less than 0.05). Maximal coronary flow reserve is reduced in left ventricular hypertrophy, with a consequent shift of the lower limit of autoregulation to higher perfusion pressures. Thus, as coronary perfusion pressure is decreased, coronary flow and myocardial shortening become impaired at higher     

Modest pressure natriuresis and autoregulation during water diuresis in dogs.

The effects of renal arterial pressure change on renal output of sodium and volume were measured during water diuresis in 25 chloralose-anesthetized dogs. Conditions included a minimal invasive stress, limited sodium administration, and mean renal arterial pressures varied suprarenally, by aortic balloon inflation to lowermost levels of 82-106 mm Hg. Group A dogs received no aldosterone; group B, C and D dogs were given aldosterone. Dogs of group C also received (1-Sar, 8-Ile)-angiotensin II. Group D dogs received phenylephrine which elevated arterial and right atrial pressures moderately without decrease in renal blood flow. In groups A, B and C, mean changes in sodium output, volume output, fractional excretions and free water clearances were not detectable with mean renal arterial pressure reductions, which averaged 29 +/- 2.9, 22 +/- 2.8 and 27 +/- 5.2 mm Hg, respectively. Right atrial pressures, effective renal blood flows and glomerular filtration rates did not change with the renal arterial pressure changes in these groups. In the group D dogs, during the larger pressure reductions of 54 +/- 6.6 mm Hg from higher values of 158 +/- 7.0 mm Hg, mean urine flow and effective renal blood flow remained constant while glomerular filtration rate and sodium output decreased only slightly. Output efficiency ratios related to perfusion pressure were calculated. With no more than modest pressure-induced excretory changes, it is concluded that excretory sodium and urinary volume autoregulation in concert with nearly perfect circulatory autoregulation were demonstrated with regionally varied mean renal arterial pressure. The same preglomerular myogenic responses to transvascular pressure, which restrict glomerular and transcapillary pressures, are viewed dominantly responsible for both circulatory and excretory autoregulation under normal conditions of minimal stress and low fractional sodium excretions. Homeostatic implications are discussed concerning likely relevance to the Guyton-Coleman theory for the long-term control of arterial blood pressure.     

Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of converting enzyme inhibition on renal hemodynamics and glomerular dynamics in sodium-restricted dogs

Clearance and micropuncture experiments were performed to evaluate the influence of converting enzyme inhibition (CEI) (SQ 14,225) on renal hemodynamics, glomerular filtration rate (GFR), segmental vascular resistances, and superficial nephron function in anesthetized sodium restricted dogs. In one series (n = 8), renal blood flow (RBF) and GFR exhibited a high degree of autoregulatory efficiency when renal arterial pressure (RAP) was reduced from 126 +/- 5 to 86 +/- 1 mm Hg. With RAP maintained at the reduced level, CEI elicited increases in RBF (3.9 +/- 0.3 to 5.8 +/- 0.5 ml/min per g kw) and GFR (0.81 +/- 0.03 to 0.94 +/- 0.04 ml/min per g kw). With return of RAP to spontaneous levels during continued CEI, RBF and GFR autoregulatory efficiency was maintained, and was similar to that observed in control dogs subjected to the same procedures (n = 5). In the micropuncture experiments (n = 12), RAP was maintained at the reduced level (87.5 +/- .9 mm Hg), and measurements were made before and during CEI. Proximal tubule pressure, peritubular capillary pressure, stop flow pressure, and single nephron GFR (SNGFR) increased significantly. Regression analysis suggested that the increases in SNGFR were associated with small increases in the filtration coefficient. CEI reduced preglomerular resistance by 29% to 35% and efferent arteriolar resistance by 24% to 32%. These results indicate that the increased activity of the renin-angiotensin system that occurs during salt restriction exerts approximately equivalent vasoconstrictor influences on both preglomerular and postglomerular vascular resistance elements.     

Acute intrarenal administration of cortisol has no effect on renal blood flow in hypertensive individuals

BACKGROUND: Cortisol is known to increase blood pressure. One possible mechanism is the reported increase in renal vascular resistance (RVR). It is unknown whether this is due to a direct effect of cortisol on the kidneys. OBJECTIVE: To study the effect of infusion of cortisol directly into the renal artery on renal blood flow (RBF) and on renal 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-mediated conversion of cortisol to cortisone in patients with primary hypertension. DESIGN AND METHODS: Twenty-seven patients with primary hypertension participated in this study. Fifteen received placebo and 12 received glycyrrhetinic acid (GRA; 500 mg) orally 2.5 h before the study. After a 10 min infusion of 5% glucose, cortisol was infused in stepwise increasing doses (0.625, 1.25 and 2.5 microg/kg per min), for 10 min each dose. At the end of each infusion step, RBF was measured using the xenon-133 washout technique. Plasma samples from the femoral artery and renal vein were taken for measurement of cortisol and cortisone. Urine was collected for measurement of steroid concentrations for 6 h on the day before the infusion and for 6 h after the infusion. RESULTS: After placebo or GRA, cortisol infusion did not change RVR, RBF or blood pressure. RVR values were 0.72 (0.45-0.89) mmHg/ml per min per 100 ml tissue [median (first and third quartiles)] and 0.71 (0.64-0.91) mmHg/ml per min per 100 ml tissue during infusion of 5% glucose and infusion of the highest dose of cortisol, respectively ( P= NS). Cortisol infusion increased the venous-arterial difference in plasma cortisone concentration across the kidney from 76 (40-115) nmol/l to 138 (100-186) nmol/l (P< 0.05) and increased the cortisol : cortisone ratios in the renal vein and in urine (both P< 0.05). As compared with placebo, administration of GRA increased the cortisol : cortisone ratios in peripheral and renal veins and in the urine. CONCLUSION: Acute infusion of cortisol in high doses directly into the renal artery in patients with primary hypertension did not affect RBF or RVR. Infusion of cortisol resulted in increased cortisol-cortisone conversion by renal 11beta-HSD2, but the concurrent increase in renal and urinary cortisol : cortisone ratio suggests a relative insufficiency of renal 11beta-HSD2 activity as a result of enzyme saturation. This may enhance mineralocorticoid receptor stimulation by cortisol.     

Coronary pressure-function and steady-state pressure-flow relations during autoregulation in the unanesthetized dog

The present study was intended to define the interrelation among endocardial flow, endocardial function, and coronary arterial pressure during spontaneous autoregulation in the left ventricle of chronically instrumented unanesthetized dogs. Steady-state sonomicrometric measurements of regional function and epicardial coronary artery pressure were used to determine the lower pressure limit of endocardial autoregulation while global indexes of myocardial demand remained constant. Transmural wall thickening in the circumflex bed remained unchanged (+/- 5% of control values) until coronary pressure fell below 39 +/- 5.6 (SD) mm Hg. Endocardial segment shortening was similarly constant until coronary pressure fell below 42 +/- 7.4 mm Hg. There was no significant change in endocardial flow as coronary pressure was reduced over the autoregulatory plateau from 84 to 49 mm Hg (1.05-0.99 ml/min/g, p = NS). Below the critical pressure limits, small additional reductions in pressure were associated with marked reductions in both endocardial flow and function. The coronary pressure-function relation was linear as well as steep in this range for both wall thickening (r = 0.94 +/- 0.05) and segment shortening (r = 0.96 +/- 0.03). Although the relation between endocardial flow and function showed more variability than pressure-function relations at low pressures, wall thickening reductions and endocardial flow reductions related on a nearly one-to-one basis. The present study establishes that the coronary pressure-function relation can be used to define the lower limit of endocardial autoregulation. It also indicates that the lower pressure limit of endocardial autoregulation is considerably less than in anesthetized animals (40 vs. 70 mm Hg) and that steady-state flow above this limit is controlled more tightly. Although these differences may relate to systemic hemodynamics, it seems likely that general anesthesia and/or acute surgical instrumentation alter coronary autoregulation under at least some experimental circumstances.     

Impaired myogenic responsiveness of renal microvessels in Dahl salt-sensitive rats.

The mechanisms mediating abnormal renal autoregulation in Dahl salt-sensitive (DS) rats have not been fully defined. In the present study, we assessed myogenic responsiveness of interlobular arteries (ILAs), afferent arterioles (AAs), and efferent arterioles in isolated perfused hydronephrotic Dahl rat kidneys. Dahl rats were divided into four groups according to strain (Dahl salt-resistant [DR] or DS rats) and dietary sodium manipulation (rats fed low or high salt diets). Systolic blood pressure was elevated only in DS rats fed the high salt diet (202 +/- 4 mm Hg, p less than 0.05). Myogenic responses were obtained by stepwise elevation of renal arterial pressure. Vessel diameters were determined by computer-assisted videomicroscopy. Preglomerular microvessels of DS and DR rats responded differently to changes in renal arterial pressure. AAs and ILAs manifested diminished myogenic responsiveness to increasing renal arterial pressure in DS rats compared with DR rats (p less than 0.05). Both AAs and ILAs in DS rats manifested a higher threshold pressure for eliciting myogenic responses and a decrease in maximal pressure-induced vasoconstriction. The sensitivity of the AA myogenic response to nifedipine was enhanced in DS rats compared with DR rats (p less than 0.05). For rats fed the high salt diet, preglomerular vessels exhibited reduced myogenic responsiveness in both strains. In contrast to preglomerular microvessels, efferent arterioles from all four groups of rats failed to exhibit pressure-induced vasoconstriction. Our data suggest that diminished myogenic responsiveness of AAs and ILAs in DS rats contributes to impaired renal autoregulation in this strain.     

Inhibition by diltiazem of pressure-induced afferent vasoconstriction in the isolated perfused rat kidney

The renal hemodynamic response to calcium entry blockade depends on the neural, hormonal and physiologic determinants influencing basal renal vascular tone. The effects of perfusion pressure per se on the renal vascular response of the rat kidney to diltiazem were evaluated using normal kidneys and hydronephrotic kidneys perfused extracorporally. In isolated perfused normal kidneys, diltiazem did not alter perfusate flow or glomerular filtration rate (GFR) when administered at a perfusion pressure of 100 mm Hg. In contrast, when diltiazem was administered at a perfusion pressure of 150 mm Hg, the calcium antagonists caused a striking increase in GFR, which was accompanied by an increase in renal perfusate flow. In the isolated perfused hydronephrotic rat kidney, elevation of perfusion pressure was associated with an increase in renal vascular resistance and a reduction in afferent arteriolar diameter. Diltiazem abolished the pressure-induced constriction of afferent arterioles and caused an increase in renal perfusate flow in hydronephrotic kidneys perfused at pressures above 100 mm Hg. These findings suggest that in the setting of increased renal perfusion pressure, diltiazem's effects on GFR are mediated in part by an inhibition of pressure-induced constriction of the afferent arteriole.     

Relation between renal interstitial ATP concentrations and autoregulation-mediated changes in renal vascular resistance

The present study was performed to examine the hypothesis that autoregulation-related changes in renal vascular resistance (RVR) are mediated by extracellular ATP. By use of a microdialysis method, renal interstitial concentrations of ATP and adenosine were measured at different renal arterial pressures (RAPs) within the autoregulatory range in anesthetized dogs (n=12). RAP was reduced in steps from the ambient pressure (131+/-4 mm Hg) to 105+/-3 mm Hg (step 1) and 80+/-2 mm Hg (step 2). Renal blood flow and glomerular filtration rate exhibited efficient autoregulation in response to these changes in RAP. RVR decreased by 22+/-2% in step 1 (P<0.01) and 38+/-3% in step 2 (P<0.01). The control renal interstitial concentration of ATP was 6.51+/-0.71 nmol/L and decreased to 4. 51+/-0.55 nmol/L in step 1 (P<0.01) and 2.77+/-0.47 nmol/L in step 2 (P<0.01). In contrast, the adenosine concentrations (117+/-6 nmol/L) were not altered significantly. Changes in ATP levels were highly correlated with changes in RVR (r=0.88, P<0.0001). Further studies demonstrated that stimulation of the tubuloglomerular feedback (TGF) mechanism by increasing distal volume delivery elicited with acetazolamide also led to increases in renal interstitial ATP concentrations, whereas furosemide, which is known to block TGF responses, reduced renal interstitial fluid ATP concentrations. The data demonstrate a positive relation between renal interstitial fluid ATP concentrations and both autoregulation- and TGF-dependent changes in RVR and thus support the hypothesis that changes in extracellular ATP contribute to the RVR adjustments responsible for the mechanism of renal autoregulation.     

Reduced regional myocardial perfusion in the presence of pharmacologic vasodilator reserve

To determine whether reductions in regional myocardial perfusion at reduced coronary arterial pressures reliably indicate maximal vasodilation of the distal vasculature, coronary autoregulation was studied in open-chest dogs at heart rates of approximately 60 beats/min, a level at which metabolic demand, time-averaged systolic compressive forces, and transmural vasodilator reserve approximate those found under usual resting conditions. Circumflex pressure was controlled with a programmable pressure source. Regional circumflex inflow was 0.56 +/- 0.04(SEM) ml . min-1 . g-1 when circumflex pressure equaled spontaneous aortic pressure and fell to 0.34 +/- 0.02 ml . min-1 . g-1 when circumflex pressure was reduced to 35 mm Hg. Reductions were similar in each myocardial layer, with endocardial flow falling from 0.68 +/- 0.04 to 0.39 +/- 0.03 ml . min-1 . g-1. During adenosine-induced vasodilation at 35 mm Hg, full-thickness and endocardial flows rose to 0.92 +/- 0.08 and 1.07 +/- 0.10 ml . min-1 . g-1, respectively. When coronary pressure was reduced to 25 mm Hg and autoregulation was again operative, full-thickness and endocardial flows fell to 0.28 +/- 0.03 and 0.28 +/- 0.04 ml . min-1 . g-1. During adenosine vasodilation at 25 mm Hg endocardial flow did not increase significantly but epicardial reserve remained present. These results indicate that significant reductions in regional myocardial perfusion can occur before pharmacologic vasodilator reserve is exhausted. In the absence of tachycardia, endocardial vasodilator reserve can persist to coronary pressures less than 35 mm Hg, but is ordinarily exhausted before epicardial vasodilator reserve.     

Effect of tachycardia on regional function and transmural myocardial perfusion during graded coronary pressure reduction in conscious dogs

The purpose of the present study was to examine subendocardial flow and function during graded coronary pressure reduction to determine the effect of tachycardia on the lower autoregulatory pressure limit (critical coronary pressure) in unanesthetized dogs. During atrial pacing at a rate of 200 beats/min, subendocardial flow measured by radioactive microspheres averaged 1.55 +/- 0.34 ml/min/g and remained unchanged as pressure was reduced over the autoregulatory plateau from 84 +/- 10 to 59 +/- 7 mm Hg. Further reductions in coronary pressure to below a critical coronary pressure of approximately 60 mm Hg were associated with concomitant reductions in subendocardial flow and the endocardial-epicardial flow ratio during tachycardia. Although regional function remained constant over the autoregulatory plateau, there was a rightward shift of the coronary pressure-function relation during ischemia in response to a steady-state increase in rate from 100 to 200 beats/min. Reductions in regional wall thickening began when coronary pressures reached 38 +/- 7 mm Hg at a heart rate of 100 beats/min and 61 +/- 6 mm Hg at a heart rate of 200 beats/min (p less than 0.005). Similar critical coronary pressure values were obtained for subendocardial segment shortening. Relations between subendocardial flow and myocardial function measured by both transmural wall thickening and subendocardial segment shortening were linear during pacing at a heart rate of 200 beats/min with relative reductions in wall thickening related to reductions in subendocardial flow on a nearly one-to-one basis. The results of this study demonstrate that there is a shift in the lower limit of subendocardial autoregulation during tachycardia as manifest by the onset of subendocardial ischemia at a higher distal coronary artery pressure. The shift in critical coronary pressure relates to an increase in resting flow requirements due to increased demand and diminished subendocardial vasodilator reserve at any given coronary pressure secondary to a reduction in the time available for diastolic subendocardial perfusion during tachycardia.     

Renal haemodynamic and tubular actions of urotensin II in the rat

Urotensin II (UTS) is a potent vasoactive peptide that was originally identified in teleost fish. Mammalian orthologues of UTS and its receptor (UTSR) have been described in several species, including humans and rats. We have shown previously that bolus injections of UTS caused a decrease in urine flow and sodium excretion rates in parallel with marked reductions in renal blood flow (RBF) and glomerular filtration rate (GFR). The aim of this study was to determine the effect of UTS infusion at a dose that has minimal impact upon renal haemodynamics in order to identify a potential direct tubular action of UTS. Infusion of rat UTS (rUTS) at 0.6 pmol/min per 100 g body weight in male Sprague-Dawley rats, which had no effect on RBF and caused a 30% reduction in GFR, resulted in a significant increase in the fractional excretion of sodium (vehicle 2.3+/-0.6 versus rUTS 0.6 pmol 4.5+/-0.6%, P<0.05) and potassium. At the higher dose of 6 pmol/min per 100 g body weight, haemodynamic effects dominated the response. rUTS induced a marked reduction in RBF and GFR (vehicle 1.03+/-0.06 versus rUTS 6 pmol 0.31+/-0.05 ml/min per 100 g body weight, P<0.05) resulting in an anti-diuresis and anti-natriuresis, but no change in fractional excretion of sodium or potassium. Uts2d and Uts2r mRNA expression were greater in the renal medulla compared with the cortex. Together, these data support an inhibitory action of Uts2d on renal tubule sodium and potassium reabsorption in the rat, in addition to its previously described renal haemodynamic effects.     

Renal effects of atrial natriuretic factor during control of the renin-angiotensin system in anesthetized dogs

The contribution of the renin-angiotensin system to the natriuretic responses to intrarenal infusions of 1, 5, 25, and 125 pmol/kg/min synthetic rat atrial natriuretic peptide 101-126 was determined in one-kidney anesthetized dogs. In vehicle-treated dogs, atrial natriuretic peptide 101-126 increased fractional sodium excretion from 1.8 +/- 0.6% to a peak response of 5.1 +/- 0.9% during infusion of 25 pmol/kg/min. The peptide progressively decreased mean arterial pressure from 110 +/- 5 to 94 +/- 4 mm Hg, renal vascular resistance from 0.40 +/- 0.02 to 0.30 +/- 0.02 mm Hg/ml/min, and arterial plasma renin activity from 4.3 +/- 1.6 to 3.1 +/- 0.8 ng/ml/hr. When the renin-angiotensin system was blocked by 3 mg/kg i.v. enalaprilat, baseline pressure fell to 86 +/- 4 mm Hg, and subsequent infusions of atrial natriuretic peptide 101-126 did not affect fractional sodium excretion. The decreases in blood pressure (from 86 +/- 4 to 76 +/- 4 mm Hg) and in renal vascular resistance (from 0.27 +/- 0.03 to 0.23 +/- 0.02 mm Hg/ml/min) were also ameliorated compared with the control responses. Intravenous infusion of 2.5 ng/kg/min angiotensin II restored mean arterial pressure and potentiated the natriuretic and renal vascular responses to atrial natriuretic peptide 101-126. In two additional groups of anesthetized dogs, enalaprilat did not produce the profound hypotension and did not affect the natriuretic responses to atrial natriuretic peptide 101-126. When renal vascular resistance was elevated by intrarenal infusion of angiotensin II in enalaprilat-treated dogs, the natriuretic response was improved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of acute and long-term treatment with felodipine in essential hypertension

Enhanced renal vasoconstriction and renal tubular sodium reabsorption mediated by noradrenaline and angiotensin II (Ang II) have been implicated in the pathogenesis of essential hypertension. Since these effects seem to be calcium-dependent, renal haemodynamic and tubular function were studied following acute and long-term treatment with the calcium antagonist felodipine in 10 patients with essential hypertension. After acute felodipine administration mean blood pressure (MBP) decreased (from 111 to 95 mmHg; P less than 0.01), renal blood flow (RBF), estimated from hippurate clearance, increased (from 1030 to 1175 ml/min; P less than 0.01) and glomerular filtration rate (GFR) was unchanged (109 versus 112 ml/min). Fractional excretion (FE) of sodium, potassium, calcium, magnesium, chloride, bicarbonate and urate increased for 12 h. Following long-term felodipine treatment, mean blood pressure was reduced (97 mmHg; P less than 0.01) and RBF and GFR were unchanged (1032 and 114 ml/min, respectively). Fractional excretion of urate and calcium was increased for 24 h (from 5.9 to 6.9%; P less than 0.05 and from 1.1 to 1.3%; P less than 0.05, respectively). Serum urate decreased (from 377 to 347 mumol/l; P less than 0.01) whereas serum calcium was unchanged. Fractional excretion of sodium, potassium and chloride was increased between 3 and 6 h after felodipine. The renal haemodynamic findings after acute felodipine administration are indicative of a direct renal vasodilator action of felodipine which augments the autoregulatory renal vasodilation to produce an overall increase in RBF. Since GFR was unchanged, the increased renal excretion of electrolytes and urate reflects an action at the tubular level. Following long-term felodipine administration autoregulatory adjustment of RBF predominated.     

Comparative effects of selective T- and L-type calcium channel blockers in the remnant kidney model

We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is approximately 10-fold more selective for T- than L-type channels, were compared with the L-type selective amlodipine. One week after 5/6 ablation, rats were left untreated or received mibefradil or amlodipine. Systolic BP was monitored by continuous radiotelemetry. At 7 weeks, proteinuria and percent GS were quantitated. Average BP was significantly and comparably reduced after mibefradil (141+/-3 mm Hg) and amlodipine (143+/-5 mm Hg) compared with untreated rats (188+/-5 mm Hg). Despite the reduction in BP, proteinuria and percent GS in the mibefradil- or amlodipine-treated groups were not significantly different from those in the untreated rats. Excellent correlations were observed between BP and GS in each group (r=0.74 to 0.85, P<0.02). However, the slope of the relationship between GS and BP (increase in percent GS/mm Hg increase in average BP) was made significantly steeper by both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with untreated rats (0.7+/-0.2; P<0.01). Thus, at any given BP elevation, greater GS was seen in mibefradil- and amlodipine-treated rats as compared with untreated rats. Additional studies performed at 3 weeks after renal ablation showed that the ability to autoregulate renal blood flow, already impaired in untreated rats, was essentially abolished by both mibefradil and amlodipine, thus providing an explanation for the shift in the slope of the relationship between BP and GS. These data indicate that CCBs with selectivity for either the T- or L-type calcium channel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.     

Mechanism of attenuated pressure-flow autoregulation in right coronary circulation of dogs

Right coronary autoregulation was assessed in 14 open-chest, anesthetized dogs. In Group 1 (n = 5), the left common and right coronary arteries were cannulated and perfused independently. As coronary perfusion pressures varied simultaneously between 70 and 120 mm Hg, right coronary blood flow changed by 48%, whereas left coronary flow changed by 13%. In this pressure range, the autoregulatory closed-loop gain of the right coronary circulation averaged 0.37 +/- 0.01, reflecting a modest autoregulatory capability but significantly less than that of the left coronary circulation, 0.78 +/- 0.08. In Group 2 (n = 9), only the right coronary artery was perfused, and right coronary venous blood was collected for determining arteriovenous oxygen extraction. Autoregulatory gain was similar to that of Group 1, indicating that collateral flow associated with intercoronary pressure gradients does not mask right coronary autoregulation. Right ventricular myocardial oxygen consumption varied directly with perfusion pressure, ranging from 7.1 +/- 1.0 to 2.9 +/- 0.8 ml O2/min/100 g as pressure was reduced from 160 to 40 mm Hg. Thus, right coronary autoregulation is masked by an opposing change in oxygen demand. When right ventricular oxygen consumption was altered by pacing, a linear flow-oxygen consumption relationship was observed (8.2 +/- 0.4 ml/min/100 g per ml O2/min/100 g). Subtraction of flows associated with pressure-induced changes in metabolism revealed a potential autoregulatory capability of the right coronary circulation similar to that manifested by the left coronary circulation.