Decrease In Renal Vascular Resistance Research Articles

The Effects of Epinine on Arterial Blood Pressure and Regional Vascular Resistances in Anesthetized Rats

1. We carried out experiments in anesthetized rats to study the hemodynamic effects of intravenous injections of epinine. 2. Epinine (1–320 μg/kg) produced a biphasic effect on mean arterial blood pressure n=30 . At doses lower than 40 μg/kg, arterial blood pressure decreased (by as much as 21.5±3.4%), though at higher doses it increased dose dependently (by as much as 73.2±14.5%). Epinine also produced bradicardia in a dose-dependent manner (by as much as 26.4±4.9%). Sulpiride (100 μg/kg) suppressed the hypotensive effect of epinine but did not change the hypertensive effect. In the presence of prazosin (1,000 μg/kg), arterial blood pressure remained significantly decreased at all doses of epinine. Neither sulpiride nor prazosin changed the bradycardic effect of epinine. 3. Prazosin produced a significant decrease in renal vascular resistance. Epinine (5 μg/kg) after prazosin reverted the effects of prazosin in renal vascular resistance, without any significant modification in the renal blood flows. However, 20 μg/kg epinine increased the renal vascular resistances and, moreover, produced a significant decrease in the blood flows of both kidneys. Neither prazosin nor epinine produced modifications in the intestinal vascular bed. 4. Although epinine possesses significant dopamine and α-adrenergic activities that are involved in the biphasic effect of the agent on mean arterial blood pressure in anesthetized rats, in the presence of prazosin, it is not possible to manifest dopaminergic activity involved in the increase in renal or mesenteric blood flow; this may be due to the low tone of the vascular wall induced by the α-adrenergic antagonist, though an α 2-activity cannot be discarded.

Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor.

Nepicastat (RS-25560-197) is a novel, selective, and potent inhibitor of dopamine beta-hydroxylase, which modulates catecholamine levels (reduces norepinephrine and elevates dopamine) in cardiovascular tissues. This study was designed to evaluate the cardiovascular effects of nepicastat. Acute oral administration of nepicastat (0.3, 1, 3, 10, and 30 mg/kg) produced attenuation of the pressor and positive chronotropic responses to preganglionic sympathetic nerve stimulation (about twofold to sixfold shift in the frequency-response curve) in pithed spontaneously hypertensive rats (SHRs). In inactin-anesthetized SHRs, the antihypertensive effects of nepicastat (3 mg/kg, i.v.) were accompanied by a significant decrease in renal vascular resistance (38%), a tendency toward an increase in renal blood flow (22%), and no adverse effects on urine output and Na/K excretion. In conscious, unrestrained, telemetry-implanted SHRs, nepicastat (30 and 100 mg/kg/day for 30 days) produced dose-dependent decreases in mean arterial blood pressure (peak decrease of 20 and 42 mm Hg, respectively) without evoking reflex tachycardia. Long-term, concurrent administration of nepicastat (30 mg/kg/day, p.o.) and a subthreshold dose of enalapril (1 mg/kg/day, p.o.) produced greater antihypertensive effects than those produced by nepicastat alone. In normal dogs, nepicastat (5.0 mg/kg, p.o., b.i.d., for 4.5 days) blunted the positive chronotropic and pressor response to tyramine. These findings suggest that nepicastat functionally modulates sympathetic drive to cardiovascular tissues and may be of value in the treatment of cardiovascular disorders associated with overactivation of the sympathetic nervous system such as hypertension and congestive heart failure.

Hemodilution mediates changes in renal hemodynamics after acute volume expansion in rats.

The present study examined the factors responsible for triggering renal hemodynamic adjustments during acute volume expansion. The renal hemodynamic effects of graded volume expansion with 0.9% saline (Sal; 1, 2, and 4% of body wt), 7% BSA solution (0.35, 0.70, and 1.4% body wt), or whole blood from a donor rat (WBL; 0.35, 0.70, and 1.4% body wt) were compared in rats anesthetized with pentobarbital sodium. Neural influences on the kidney were eliminated by vagus nerves, baro/chemoreceptor afferents, and renal nerves section, and renal perfusion pressure was controlled at constant level (approximately 120 mmHg) throughout the experiments. In Sal- and BSA-expanded rats, renal blood flow (RBF) increased (Sal: 15, 40, 71%; BSA 17, 49, 107%) and renal vascular resistance (RVR) decreased in parallel with the degree of volume expansion (RVR: Sal 17, 31, 44%; and BSA: 15, 35, 54%). Renal hemodynamics remained unaltered after expansion with WBL. In rats expanded with Sal or BSA, correction of the fall of hematocrit restored RBF and RVR to control levels. Interference with tubuloglomerular feedback by uretheral obstruction had no effect on the decrease in RVR with Sal or BSA. Inhibition of the vascular tone by intrarenal papaverine infusion also did not alter the renal hemodynamic response to volume expansion with Sal or BSA. These findings suggest that the changes in renal hemodynamics after acute expansion are likely mediated by changes in rheologic properties of the blood rather than by changes in active vascular tone.

Potential of dopamine A-1 agonists in the management of acute renal failure.

Many therapeutic approaches have been undertaken both to prevent acute ischemic or nephrotoxic renal injury and, once acute renal failure (ARF) has developed, to improve renal function and reduce mortality. To date, most therapeutic studies have investigated the effects of diuretics (eg, mannitol, furosemide), vasoactive agents (calcium channel blockers, atrial natriuretic peptide), or dopamine (a nonselective dopaminergic agent [DAA]) in one or more phases of ARF. Unfortunately, studies of the use of DAA in ARF are complicated by the existence of at least two different DAA receptors (DA-1 and DA-2), and by the stimulation of alpha- and/or beta-adrenergic receptors by high doses of DAA. The undesirable side effects of high doses of dopamine and the inconclusive results using low doses (ie, "renal doses") of dopamine (a nonselective DAA) have prompted consideration of the use of more selective dopaminergic agonists for the prophylaxis and treatment of ARF. Selective DA-1 agonists exhibit many desirable renal effects that theoretically support their use for the prophylaxis and/or treatment of ARF, including decreases in renal vascular resistance accompanied by increases in renal blood flow and glomerular filtration rate, and increases in sodium excretion and urine volume. Even at high doses, some selective DA-1 agonists, such as fenoldopam, do not stimulate DA-2 receptors, or adrenergic alpha- or beta-receptors, and thus are free of unwanted side effects (eg, arrhythmias). Results of several studies in normal and hypertensive humans, and a few studies in animal models, are consistent with the notion that DA-1 agonists may be useful in preventing or treating ARF. Careful randomized prospective clinical trials of DA-1 agonists in human ARF are needed to test this hypothesis.

Acute effects of bezafibrate on blood pressure and renal haemodynamics in SHR and WKY rats.

Bezafibrate, a fibric acid analogue, has well-established lipid- and fibrinogen-lowering properties. Some data exist pointing towards a blood-pressure-lowering effect of bezafibrate. Thus the aim of this study was to examine the acute effect of bezafibrate on blood pressure and renal haemodynamics in hypertensive and normotensive rats. 8 Wistar-Kyoto (WKY) and 12 spontaneously hypertensive rats (SHR) were treated with i.v. bolus injections of vehicle and 1-10 mg of bezafibrate in increasing doses every 15 min. Mean arterial pressure (MAP), renal blood flow (RBF), cortical blood flow (CBF), and medullary blood flow (MBF) were monitored continuously, together with plasma renin activity (PRA), urine volume and urinary Na+, K+, and protein concentration (15-min intervals). Bezafibrate reduced MAP in a dose-dependent manner (mean +/- SEM): in WKY, 1 mg bezafibrate, -1.13 +/- 0.61 mmHg and after 10 mg bezafibrate, -7.25 +/- 1.10 mmHg; in SHR, -0.60 +/- 0.43 and -5.83 +/- 0.90 mmHg respectively. In contrast to vehicle, bezafibrate induced a dose-dependent increase in RBF (WKY, 0.21 +/- 0.10 and 0.83 +/- 0.48 ml/min; SHR, 0.38 +/- 0.10 and 3.09 +/- 0.45 ml/min respectively) and a corresponding decrease in renal vascular resistance which was significantly greater in SHR than in WKY. The increase in RBF was paralleled by an increase in CBF. No effect of bezafibrate on MBF, PRA, urine flow, or urinary Na+, K+ or protein excretion was observed. The observed effects could not be attributed to one of the classic vasodilating mechanisms. We conclude that in rats bezafibrate is a potent hypotensive drug exhibiting additional effects on renal haemodynamics.

Impaired nitric oxide-mediated renal vasodilation in rats with experimental heart failure: role of angiotensin II.

Congestive heart failure (CHF) is associated with a decrease in renal perfusion. Because endothelium-derived NO is important in the regulation of renal blood flow (RBF), we tested the hypothesis that an impairment in the NO system may contribute to the decrease in RBF in rats with experimental CHF. Studies were performed in rats with experimental high-output CHF induced by aortocaval (AV) fistula and sham-operated controls. In controls, incremental doses of acetylcholine (ACh, 1 to 100 microg x kg(-1) x min(-1)) increased RBF and caused a dose-related decrease in renal vascular resistance (RVR). However, the increase in RBF and decrease in RVR were markedly attenuated in rats with CHF. Likewise, the effects of ACh on urinary sodium and cGMP excretion were also diminished in CHF rats, as was the renal vasodilatory effect of the NO donor S-nitroso-N-acetylpenicillamine (SNAP). These attenuated responses to endothelium-dependent and -independent renal vasodilators in CHF rats occurred despite a normal baseline and stimulated NO2+NO3 excretion and normal expression of renal endothelial NO synthase (eNOS), as determined by eNOS mRNA levels and immunoreactive protein. Infusion of the NO precursor L-arginine did not affect baseline RBF or the response to ACh in rats with CHF. However, administration of the nonpeptide angiotensin II receptor antagonist A81988 before ACh completely restored the renal vasodilatory response to ACh in CHF rats. This study demonstrates that despite a significant attenuation in the NO-related renal vasodilatory responses, the integrity of the renal NO system is preserved in rats with chronic AV fistula. This impairment in NO-mediated renal vasodilation in experimental CHF appears to be related to increased activity of the renin-angiotensin system and may contribute further to the decrease in renal perfusion seen in CHF.

Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs.

Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs. J. Appl. Physiol. 83(2): 414-419, 1997.-Cardiovascular and renal effects of either the angiotensin-converting enzyme inhibitor captopril or vehicle were measured in chronically instrumented lambs in the presence (intact; n = 6) and absence of renal sympathetic nerves (denervated; n = 5) to determine whether there was an interaction between the renin-angiotensin system and renal sympathetic nerves early in life. Captopril caused a similar decrease in mean arterial pressure (P < 0. 001) in intact and denervated lambs, predominantly through a decrease in diastolic pressure. Heart rate was increased from 177 +/- 34 to 213 +/- 22 (SD) beats/min during captopril compared with vehicle infusion in intact lambs. In denervated lambs, basal heart rates were elevated to 218 +/- 33 beats/min; there was no further increase in heart rate during captopril compared with vehicle infusion. Captopril infusion caused a decrease in renal vascular resistance but only in the absence of renal nerves. These findings provide evidence to suggest that early in life there is an interaction between renal sympathetic nerves and the renin-angiotensin system in regulating renal hemodynamics and the baroreflex control of the heart.

Exogenous Endothelin-1 Causes Renal Vasolidation in the Fetal Lamb

Endothelin-1 is known to be a potent vasoconstrictor. We investigated the effects and mechanisms of action of endothelin-1 and its receptors in regulating renal vascular tone in the fetal lamb. We observed the in vivo effects of endothelin-1, an endothelin-b receptor agonist (4-alanine-endothelin-1), endothelin-a receptor antagonists (BQ-610 and BQ-123), and the inhibition of prostaglandin and nitric oxide synthesis on the response of the renal circulation to endothelin-1 in a chronic preparation in third trimester fetal lambs. After injection of 250 ng./kg. endothelin-1 into the descending aorta proximal to the renal arteries in 8 fetal animals, renal blood flow increased (4.4 +/- 0.7 ml. per minute per kg., p < 0.001 versus vehicle), as did mean arterial blood pressure (3.0 +/- 0.3 mm. Hg,p < 0.001 versus vehicle). Calculated renal vascular resistance decreased (-1.1 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001 versus vehicle). After injection of 1,725 ng./kg. 4-alanine-endothelin-1 in 5 animals renal blood flow increased (3.8 +/- 0.4 ml. per minute per kg., p < 0.05 versus vehicle) and mean arterial blood pressure was unchanged (1.6 +/- 1.7 mm. Hg). Calculated renal vascular resistance decreased (-0.8 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.05 versus vehicle). After injection of 0.5 mg./kg. BQ-610 in 6 animals renal blood flow increased (2.3 +/- 0.7 ml. per minute per kg., p < 0.05) and mean arterial blood pressure decreased (-2.7 +/- 0.3 mm. Hg, p < 0.05 versus vehicle). Calculated renal vascular resistance decreased but this difference was not statistically significant (-0.7 +/- 0.3 mm. Hg per minute per kg./ml., p < 0.07). A dose of 1 mg./kg. BQ-123 in 2 animals decreased renal vascular resistance markedly. Infusion of a prostaglandin synthesis inhibitor (1 mg./kg. per minute meclofenamic acid) did not alter the decrease in renal vascular resistance after endothelin-1 (-0.7 +/- 0.4 mm. Hg per minute per kg./ml). In contrast, during infusion of a nitric oxide synthesis inhibitor (1.5 mg./kg. per minute N-omega-nitro-L-arginine) endothelin-1 increased renal vascular resistance (1.2 +/- 0.2 mm. Hg per minute per kg./ml., p < 0.001). Endothelin-1 is a vasodilator in the fetal renal circulation, which acts primarily via endothelin-b receptors. Ongoing activity of endothelin-a receptors contributes to renal vascular tone in fetal lambs. The vasodilatory effects of endothelin-1 in the fetal lamb renal circulation are mediated via the nitric oxide system and not via prostanoids.

Exogenous Endothelin-1 Causes Renal Vasolidation in the Fetal Lamb

Purpose Endothelin-1 is known to be a potent vasoconstrictor. We investigated the effects and mechanisms of action of endothelin-1 and its receptors in regulating renal vascular tone in the fetal lamb. Materials and Methods We observed the in vivo effects of endothelin-1, and endothelin-b receptor agonist (4-alanine-endothelin-1), endothelin-a receptor antagonists (BQ-610 and BQ-123), and the inhibition of prostaglandin and nitric oxide synthesis on the response of the renal circulation to endothelin-1 in a chronic preparation in third trimester fetal lambs. Results After injection of 250 ng./kg. endothelin-1 into the descending aorta proximal to the renal arteries in 8 fetal animals, renal blood flow increased (4.4 plus/minus 0.7 ml. per minute per kg., p less than 0.001 versus vehicle), as did mean arterial blood pressure (3.0 plus/minus 0.3 mm. Hg, p less than 0.001 versus vehicle). Calculated renal vascular resistance decreased (-1.1 plus/minus 0.2 mm. Hg per minute per kg./ml., p less than 0.001 versus vehicle). After injection of 1,725 ng./kg. 4-alanine-endothelin-1 in 5 animals renal blood flow increased (3.8 plus/minus 0.4 ml. per minute per kg., p less than 0.05 versus vehicle) and mean arterial blood pressure was unchanged (1.6 plus/minus 1.7 mm. Hg). Calculated renal vascular resistance decreased (-0.8 plus/minus 0.2 mm. Hg per minute per kg./ml., p less than 0.05 versus vehicle). After injection of 0.5 mg./kg. BQ-610 in 6 animals renal blood flow increased (2.3 plus/minus 0.7 ml. per minute per kg., p less than 0.05) and mean arterial blood pressure decreased (-2.7 plus/minus 0.3 mm. Hg, p less than 0.05 versus vehicle). Calculated renal vascular resistance decreased but this difference was not statistically significant (-0.7 plus/minus 0.3 mm. Hg per minute per kg./ml., p less than 0.07). A dose of 1 mg./kg. BQ-123 in 2 animals decreased renal vascular resistance markedly. Infusion of a prostaglandin synthesis inhibitor (1 mg./kg. per minute meclofenamic acid) did not alter the decrease in renal vascular resistance after endothelin-1 (-0.7 plus/minus 0.4 mm. Hg per minute per kg./ml.). In contrast, during infusion of a nitric oxide synthesis inhibitor (1.5 mg./kg. per minute N-omega-nitro-L-arginine) endothelin-1 increased renal vascular resistance (1.2 plus/minus 0.2 mm. Hg per minute per kg./ml., p less than 0.001). Conclusions Endothelin-1 is a vasodilator in the fetal renal circulation, which acts primarily via endothelin-b receptors. Ongoing activity of endothelin-a receptors contributes to renal vascular tone in fetal lambs. The vasodilatory effects of endothelin-1 in the fetal lamb renal circulation are mediated via the nitric oxide system and not via prostanoids.

Role of Nitric Oxide in Short-term and Prolonged Effects of Angiotensin II on Renal Hemodynamics

Short-term infusions of angiotensin II (Ang II) increase renal vascular resistance and thereby endothelial shear stress and nitric oxide (NO) release. Prolonged stimulation of Ang II can decrease the expression of NO synthase isoforms in the macula densa, but prolonged increases in shear stress can increase transcription of endothelial NO synthase. Therefore, we designed these studies to test the hypothesis that Ang II exerts time-dependent effects on renal NO generation as assessed from renal excretion of nitrate and nitrite, percent increases in renal vascular resistance during inhibition of NO synthase with intravenous NG -nitro-L-arginine methyl ester (L-NAME), or decreases in renal vascular resistance during stimulation of endothelial NO synthase with intravenous acetylcholine. Rats were tested during graded short-term (30 to 90 minutes intravenous) or prolonged (5 to 6 days subcutaneous) Ang II infusions that led to dose-dependent increases in blood pressure and renal vascular resistance and reductions in renal blood flow. Captopril was administered for 3 to 4 days to suppress Ang II generation. The renal excretion of nitrate and nitrite was increased during short-term Ang II infusions (from 205 +/- 22 to 331 +/- 58 pmol.min-1, P < .05) but was unchanged during prolonged Ang II infusion (control group, 197 +/- 33 versus Ang II, 245 +/- 42 pmol.min-1, P=NS). The percent increase in renal vascular resistance with L-NAME was potentiated dose dependently by short-term but not long-term Ang II infusions. The increase in renal vascular resistance with L-NAME in control rats without Ang II infusions was +150 +/- 13%. At an Ang II infusion of 200 ng.kg-1.min-1, the L-NAME-induced percent increase in renal vascular resistance was significantly (P < .01) increased compared with controls in short-term Ang II-infused rats (+369 +/- 70%) but was not significantly different in prolonged infused rats (+190 +/- 33%). Intravenous acetylcholine caused dose-dependent renal vasodilation that was not significantly changed in rats receiving short-term intravenous Ang II but was significantly (P < .005) potentiated in those receiving prolonged Ang II infusions (change in renal vascular resistance with acetylcholine at 10 micrograms.kg-1.min-1 versus control, -21.5 +/- 5.0%; with short-term Ang II, -24.9 +/- 4.5%; with long-term Ang II, -52.1 +/- 7.2%). In conclusion, short- and long-term Ang II infusions caused equivalent changes in blood pressure and renal blood flow and hence presumably equivalent increases in endothelial shear stress. However, only short-term Ang II infusions increased NO generation and the dependence of the renal circulation on NO, whereas acetylcholine-induced NO release was enhanced selectively during long-term Ang II infusions. This suggests that during long-term Ang II, renal NO release may become uncoupled from shear stress yet remains highly responsive to receptor-mediated stimulation.

Blockade of radiocontrast-induced nephrotoxicity by the endothelin receptor antagonist, SB 209670.

The effect of the novel nonpeptide endothelin (ET) receptor antagonist, (+/-)-SB 209670, on the renal effects of the high osmolar tri-iodinated ionic contrast media, Hypaque, was evaluated in anesthetized dogs in the presence or absence of the cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.v.). Hypaque alone (5 ml/kg, i.v.) resulted in a marked diuresis and natriuresis but little change in either renal blood flow or renal vascular resistance. When the ET receptor antagonist, (+/-)-SB 209670, was infused into the renal artery at a dose that inhibited ET-induced renal vasoconstriction, Hypaque resulted in a significant increase in renal blood flow and decrease in renal vascular resistance. In the presence of indomethacin, Hypaque caused a significant increase in renal vascular resistance which was abolished by (+/-)-SB 209670. The data indicate that the radiocontrast media, Hypaque, can cause renal vasoconstriction which may be mediated by ET.

Renal responses to intra-arterial administration of adrenomedullin in dogs.

The present study was undertaken to evaluate the renal responses to intra-arterial infusion (12.5 pmol.kg-1.min-1) for 30 min of adrenomedullin (ADM) in denervated kidneys of anesthetized dogs (n = 8). Total renal blood flow (RBF) was measured with an electromagnetic flow probe, and two single-fiber laser-Doppler needle flow probes were used to measure relative changes in cortical (CBF) and medullary blood flow (MBF). ADM administration resulted in decreases in renal vascular resistance (32.3 +/- 4.9 to 22.3 +/- 3.0 mmHg.ml-1.min.g) and increases in RBF (4.5 +/- 0.5 to 6.0 +/- 0.6 ml.min-1.g-1), CBF (33 +/- 1.3%, n = 41, and MBF (32 +/- 5.7%, n = 5) without changes in glomerular filtration rate. There were also substantial increases in urine flow (11.3 +/- 1.9 to 28 +/- 4.8 microliters.min-1.g-1), as well as in sodium excretion (1.8 +/- 0.2 to 4.2 +/- 0.6 microliter.min-1.g-1). After cessation of ADM infusion, partial recovery of these responses was observed within a 30-min period. Responses to ADM were attenuated during inhibition of nitric oxide (NO) synthesis by nitro-L-arginine (50 micrograms.kg-1.min-1). These findings indicate that renal vasodilator, diuretic, and natriuretic responses to ADM may be mediated by the release of endogenous NO and suggest that ADM could play a role in regulating water and electrolyte excretion by the kidney.

Renal Vascular Responses to High and Low Ionized Calcium

The aim of this study was to examine the influence of norepinephrine (NE) on renal vascular responses to high (1.88 mmol/L) and low (0.56 mmol/L) perfusate-ionized calcium ([Ca2+]) in the isolated perfused kidney of the rat. High and low [Ca2+] encompassed the clinical concentration range in this multiexperiment, randomized trial. Rats (n = 25), ranging in age from 3 to 4 months, were anesthetized and the ureter and renal artery were cannulated. The right kidney was perfused with oxygenated, warmed albumin (67 g/L) containing Krebs-Henseleit buffer and placed in a thermostated chamber without interruption of flow. In protocol A (n = 7), steady-state high [Ca2+] (1.88 mmol/L) and low [Ca2+] (0.56 mmol/L) were instituted in randomized order in each experiment under basal conditions. In protocol B (n = 9), the same interventions were instituted during constant rate NE infusion. Changes in renal flow were measured at constant perfusion pressure (110 mm Hg), and renal vascular resistance (RVR) was calculated. Renal function was assessed by clearance of [14C]inulin and by fractional excretion of sodium. With NE-induced preconstriction, the increase in RVR observed during high [Ca2+] was +17.8 +/- 1.8% of control, and the decrease in RVR observed during low [Ca2+] was -35.9 +/- 8.2% of control. Both values were greater by a factor of 2 than corresponding results obtained under basal conditions (7 +/- 2.1% vs. -13.5 +/- 4.1% of control, respectively, p < 0.05). Whereas the decrease in glomerular filtration rate with high [Ca2+] was not significantly influenced by NE pretreatment (-9 +/- 1.8% of control with high [Ca2+] in combination with NE vs. 4.1 +/- 0.7% of control under basal conditions), the increase in glomerular filtration rate with low [Ca2+] was significantly greater in the presence of NE (12 +/- 0.7 vs. 102 +/- 8.5% of control, p < 0.01). Whereas under basal conditions renal vascular effects of high and low [Ca2+] (varied within the clinical concentration range) are small, the changes recorded with the same interventions after NE pretreatment are increased by a factor of > 2. Hypercalcemia-induced renovascular constriction and decreased function are unfavorable, especially in patients who are at risk for renal dysfunction from other causes.

Postnatal maturation of tissue kallikrein-producing cells (connecting tubule cells) in the rat kidney: a morphometric and immunohistochemical study

The mature, fully differentiated connecting tubule (CNT) cell plays an important role in the regulation of serum potassium levels and synthesizes the enzyme tissue kallikrein, a main component of a renal vasoactive system, the kallikrein-kinin system. To characterize the growth of CNT cells (tissue kallikrein-producing cells), we studied the rat kidney at three different time points of postnatal development: at day 5, day 15, and day 30. The CNT cells were identified on tissue sections by a standardized immunohistochemical procedure. The tissue kallikrein content was determined by radioimmunoassay and the activity of the enzyme in kidney homogenates was measured using a selective synthetic substrate. The number of immunolabeled CNT and CNT cells per cortex area gradually increased from day 5 to day 30. A similar rise in the content and activity of tissue kallikrein was observed when the enzyme levels were determined by radioimmunoassay or by the enzymatic method. In addition, the morphometric analysis showed that the distal end of CNT had larger cells that displayed a more intense tissue kallikrein staining than those present in the proximal end, suggesting that the postnatal development of CNT is induced from its juxtamedullary portion. Our results show that tissue kallikrein expression is very low in the newborn rat, increasing gradually with age to reach adult levels at day 30. This finding, together with the morphometric data, suggests immaturity of CNT cells in newborn rats, a fact that could contribute to explaining the high serum potassium levels reported at this stage. In addition, the contrasting behavior of kallikrein and renin in the postnatal development (kallikrein increasing and renin decreasing) could explain the gradual decrease in renal vascular resistance and increase in renal blood flow observed after birth.

Developmental renal hemodynamics

Renal blood flow, which is lower in the immature than in the mature animal, achieves adult values in human subjects by 1-2 years of age. The age-related increase in renal blood flow cannot be completely explained by increases in kidney size, since nephrogenesis is complete by 36 weeks' gestation in humans. Thus, other factors, especially changes in renal hemodynamics, are likely to be responsible for the increase in renal blood flow. The increase in renal blood flow appears to be directly related to the decrease in renal vascular resistance during the postnatal period. Decreases in the effect of renal vasoconstrictors, increases in the effect of renal vasodilators, or a combination of the two, may be responsible. Many mediators of vasoconstriction have been studied, including adenosine, catecholamines, endothelin, endogenous digitalis-like peptide, and the renin-angiotensin system. Mediators of vasodilation include endothelium-derived relaxing factor (e.g., nitric oxide), prostaglandins, atrial natriuretic peptide, dopamine, and kinins. However, the decrease in renal vascular resistance with age is most likely related to decreases in activity of the renin-angiotensin system and responsiveness to catecholamines; these effects are modulated by nitric oxide. Other mediators may also be important in determining the age-related decrease in renal vascular resistance, but their exact roles remain to be defined.

Renal hemodynamic response to the creation of vascular access in patients with end-stage renal disease.

To evaluate the possibility that the placement of arteriovenous anastomosis (a/v a) may lead to the attenuation of glomerular hyperfiltration, we studied 5 nondiabetic patients before and after creation of vascular access for hemodialysis. Patients received no EPO and antihypertensive therapy was discontinued 24 h before each study. Cardiac output (CO) and a/v a flow rates were measured by Doppler echo, and GFR and ERPF by plasma decay curves of Tc99m DTPA and 131I-hippuran, respectively. Other parameters were calculated by standard formulas. Augmentation of CO and decrease in systemic vascular resistance occurred in all patients (p = 0.05), yet renal findings were less predictable since only three patients showed a decrease in renal vascular resistance and filtration fraction post a/v a. Thus, there is a discordant pattern of renal hemodynamic response to the creation of a/v a in end-stage renal disease and further studies are needed to better define the subset of patients who are prone to renal vasodilation after the placement of a/v a.

The effect of misoprostol on indomethacin-induced renal dysfunction in well-compensated cirrhosis

Background/Aims: Indomethacin has been shown to have adverse effects on renal function in patients with well-compensated alcoholic cirrhosis. The aim of this study was to determine whether an oral prostaglandin E 1 analogue, misoprostol, could prevent this indomethacin-induced renal dysfunction. Methods: Six patients with well-compensated alcoholic cirrhosis were studied. Renal hemodynamics and tubular function were assessed by clerance techniques before and after an oral dose of (i) 50 mg of indomethacin alone (I 50), and (ii) a combination of I 50 and 200 μg of misoprostol. Results: I 50 produced a significant reduction in glomerular filtration rate, a fall in effective renal plasma flow and an increase in renal vascular resistance. Two hundred micrograms of misoprostol was able to abolish the deleterious renal effects of indomethacin totally, yielding an increase in glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance as well as an increase in urinary volume and urinary sodium excretion. These beneficial effects were maximal in the hour immediately following medication, but were only transient, and this may be a limiting factor in its clinical use. Conclusions: If the beneficial renal effects of misoprostol could be confirmed after chronic administration, then the vasodilatory, natriuretic and diuretic potential of 200 μg of misoprostol could be of potential therapeutic value in patients with well-compensated alcoholic cirrhosis who require non-steroidal anti-inflammatory drug therapy.

Stereoselective renal effects of the loop diuretic ozolinone in the anesthetized dog

The renal effects of i.v. injections of (+/-)-ozolinone, its enantiomers (-)-ozolinone and (+)-ozolinone and its prodrug (+/-)-etozoline, were compared with those of furosemide, in pentobarbital anesthetized dogs. Renal blood flow (electromagnetic flow-meter) and glomerular filtration rate (polyfructosan clearance) were assessed on the left denervated kidney together with renin secretion and urinary electrolyte excretion. (-)-Ozolinone (15.5 mg/kg i.v.) behaves as a stereoselective loop diuretic equipotent to 20 mg/kg of furosemide and 45 mg/kg of (+/-)-ozolinone; (+)-ozolinone induced only minor salidiuretic effects. Both ozolinone enantiomers markedly increased the renal blood flow and decreased the filtration fraction, suggesting that the vosodilating effect predominates on the efferent glomerular arterioles. (-)-Ozolinone also induced an acute rise in renin secretion. The inhibition of prostaglandin synthesis (indomethacin or meclofenamate) prevented renin hypersecretion in response to (-)-ozolinone and modified its salidiuretic effects but had no effect on the vascular response. The inhibition of the kallikrein-kinin system by aprotinin had no effect on the overall renal response to (-)-ozolinone. The inhibition of the renin-angiotensin system by captopril decreased blood pressure, prolonged the (-)-ozolinone-induced decrease in renal vascular resistance and increased renin secretion. Our results demonstrate that the loop diuretic, ozolinone, induces stereoselective and prostaglandin-dependent renin secretion, which is involved in the regulation of intra-renal hemodynamics.

Mechanisms of adrenomedullin-induced vasodilation in the rat kidney.

To explore the mechanisms of adrenomedullin-induced vasorelaxation, we tested the effects of adrenomedullin on renal function in rats in vivo and measured the release of endothelium-derived nitric oxide from isolated perfused rat kidney (using a chemiluminescence assay) and the diameters of the glomerular arterioles in the hydronephrotic kidney. Adrenomedullin decreased blood pressure in a dose-dependent manner (3 nmol/kg: -29 +/- 2% [SEM]; P < .01) and slightly increased the glomerular filtration rate and urinary sodium excretion (+108%; P < .05). These changes were associated with significant increases in urinary excretion of cyclic AMP (+54%; P < .05). Adrenomedullin decreased renal vascular resistance (10(-7) mol/L adrenomedullin: -41 +/- 2%; P < .001) and increased release of nitric oxide (+5.1 +/- 0.7 fmol/min per gram kidney weight; P < .001) in the isolated kidney. This increase in nitric oxide release was abolished by the inhibitor NG-monomethyl-L-arginine, and it also reversed the decrease in renal vascular resistance seen with adrenomedullin. Renal responses of deoxycorticosterone acetate-salt hypertensive rats to adrenomedullin were significantly smaller than those of control rats for both release of nitric oxide (10(-7) mol/L adrenomedullin: +0.8 +/- 0.2 fmol/min per gram kidney weight; P < .01 versus control) and renal vasodilation (-28 +/- 6%; P < .05). Videomicroscopic analysis revealed that adrenomedullin increased the diameters of both afferent and efferent arterioles (3 nmol/kg: +11%; P < .05). Thus, adrenomedullin-induced renal vasodilation is partially endothelium dependent and is attenuated in deoxycorticosterone acetate-salt hypertension, probably due to endothelial damage.

Hypertension After Renal Transplantation

We compared the effects of 4 weeks of calcium channel blockade (amlodipine) or converting enzyme inhibition (lisinopril) on blood pressure and renal hemodynamics in a double-blind crossover trial in a group of 20 hypertensive cyclosporine-treated renal transplant patients. Amlodipine (10 mg) was more effective than the same dose of lisinopril in controlling hypertension (mean 24-hour arterial pressure, 111 +/- 9 and 115 +/- 9 mm Hg, respectively; P < .05). Blood pressure during both treatments was lower than during placebo (124 +/- 12 mm Hg, P < .05). Compared with placebo, amlodipine treatment was associated with a significant increase in glomerular filtration rate (10 +/- 20%, P < .05) and effective renal plasma flow (27 +/- 20%, P < .01) and a decrease in renal vascular resistance (23 +/- 18%, P < .01). Renal hemodynamics did not change during lisinopril. Neither drug had an effect on proteinuria. The data indicate that amlodipine is more effective than lisinopril in controlling hypertension in cyclosporine-treated patients and that treatment with amlodipine but not with lisinopril is accompanied by an increase in glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance. The data suggest that the renin-angiotensin system does not play a main role in determining cyclosporine-associated changes in renal hemodynamics and has a limited role in determining cyclosporine-associated hypertension.