Impaired nitric oxide-independent dilation of renal afferent arterioles in spontaneously hypertensive rats.
(9/1299)
Sustained hypertension alters vasomotor regulation in various vascular beds. We studied whether nitric oxide (NO)-dependent and NO-independent vasodilator mechanisms are altered in renal microvessels in hypertension. To directly visualize the renal microcirculation, the isolated perfused hydronephrotic rat kidney model was used. After pretreatment with indomethacin (100 micromol/l), afferent arterioles were constricted by norepinephrine (NE) or by increasing renal arterial pressure (i.e., myogenic constriction; from 80 to 180 mmHg). Acetylcholine (ACH) was then added, and the renal microvascular response was assessed by computer-assisted video image analysis. A similar protocol was conducted in the presence of nitro-L-arginine methylester (L-NAME; 100 micromol/l). During NE constriction, ACH caused dose-dependent and sustained vasodilation of the afferent arteriole, similar in magnitude in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the presence of L-NAME, ACH (0.01-1 micromol/l) elicited only transient dilation, and the degree of vasodilation was very low in SHR. During myogenic constriction, afferent arterioles from WKY and SHR kidneys responded to ACH with only transient vasodilation, which was unaffected by NO inhibition; the transient vasodilative responses elicited by ACH (0.1-1 micromol/l) were smaller in SHR than in WKY. In conclusion, ACH has both sustained and transient vasodilative effects on the afferent arteriole. Sustained vasodilation is attributed to NO generation, which is similar in WKY and SHR. In contrast, transient vasodilation, mediated by NO-independent vasodilator factors, is impaired in SHR. Deranged vasodilatory mechanisms in hypertension may disturb the renal microcirculation, which may result in renal injury. (+info)
Endothelial dysfunction in acute renal failure: role of circulating and tissue endothelin-1.
(10/1299)
The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats (n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twenty-four hours after clamp release, contractions to angiotensin I (Angl) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET(A) and Et(B) receptor mRNA expression was determined. Sham-operated animals served as controls (n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased (P<0.01). Plasma half-life of radiolabeled 125I-ET-1 was markedly prolonged, whereas 125I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted (P<0.05) and those to KCl were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF (P<0.05 to 0.001). Correspondingly, ET(A) and Et(B) receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery (r = -0.827, P<0.001) and the aorta (r = -0.812, P<0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET(A) and Et(B) receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF. (+info)
Resonance in the renal vasculature evoked by activation of the sympathetic nerves.
(11/1299)
We examined the ability of different frequencies in sympathetic nerve activity (SNA) to induce oscillations in renal blood flow (RBF). In anesthetized rabbits the renal nerves were stimulated using modulated sine patterns (base frequency 5 Hz, 5-ms duration pulses) that varied in amplitude between 0 and 10 V at a frequency between 0.04 and 1.0 Hz. The strengths of the induced oscillations in RBF were calculated using spectral analysis. Although faster rhythms in simulated SNA >0.6 Hz contributed to the level of vascular tone, 95% of the power in the frequency response curve was below this frequency, indicating a low-pass filtering/integrating characteristic of the vasculature. Frequencies <0.6 Hz were associated with increasing ability to induce oscillations in RBF. The ability of an SNA rhythm at 0.6 Hz to induce a rhythm in RBF was 21 times less than that at 0.25 Hz. At 0.16 Hz there was a distinct peak in the frequency response curve, indicating the vasculature was more sensitive in this frequency band to sympathetic stimulation. Blockade of endogenous nitric oxide by NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg) did not alter resting RBF levels nor was the low-pass filtering/integrating characteristic of the vasculature to nerve stimulation changed (i.e., the curve was not shifted left or right); however, there was a selective increase in the sensitivity to stimulation at 0.16 Hz, i.e., larger oscillations in RBF were evoked. These results indicate an ability of SNA to induce resonant oscillations in the renal vasculature and that there may be active and passive modulators of these responses. Naturally occurring oscillations in SNA <0.6 Hz are likely to contribute to the dynamic control of RBF, ensuring it responds rapidly and with high gain to the stimuli of daily life, while filtering out the faster oscillations ensures stable glomerular filtration. (+info)
Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats.
(12/1299)
Profound vasodilation of the kidneys and other nonreproductive organs transpires during early pregnancy. Because nitric oxide (NO) was found to mediate renal vasodilation and hyperfiltration in conscious pregnant rats, and endogenous endothelin (ET) was suggested to be vasodilatory in the renal circulation of nonpregnant rats, we tested whether endothelin mediates the NO-dependent changes in the renal circulation during pregnancy. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured in conscious pregnant and virgin rats before and during infusion of 30 micrograms/min RES-701-1 (a selective ETB receptor subtype antagonist). Baseline GFR and ERPF were significantly increased by 35% in gravid rats relative to virgin controls. During infusion of RES-701-1, the pregnant rats responded more robustly, showing a greater decline in both GFR and ERPF such that renal function converged in the two groups of rats. ERPF also converged in pregnant and virgin rats during infusion of SB-209760, a nonselective ETA/B receptor subtype antagonist. Combined infusion of Nomega-nitro-L-arginine methyl ester [L-NAME, an NO synthase (NOS) inhibitor] and RES-701-1 reduced GFR and ERPF to levels comparable to those reached with either agent given alone, suggesting inhibition of a common vasodilatory pathway. RES-701-1 and SB-209670 significantly lowered the cGMP content of small renal arteries from gravid and virgin rats in vitro, strengthening the link between the renal endothelial ETB receptor subtype and NO. Importantly, we showed that RES-701-1 is not a direct inhibitor of NOS. We conclude that endothelin mediates the NO-dependent changes in the renal circulation of conscious rats during pregnancy. (+info)
Renal glucose production during insulin-induced hypoglycemia in humans.
(13/1299)
We investigated the effects of hypoglycemia on renal glucose production (RGP) and renal glucose uptake (RGU) using arteriovenous balance combined with tracer technique in humans. Our 14 healthy subjects had arterialized hand veins (artery) and renal veins (under fluoroscopy) catheterized after an overnight fast. Systemic and renal glucose kinetics were measured with infusion of [6-(2)H2]glucose, and renal plasma flow was measured by para-aminohippurate clearance. After a 150-min equilibration period, artery and renal vein samples were obtained between -30 and 0 min, and subjects received a 180-min peripheral insulin infusion (0.250 mU kg(-1) x min(-1)) with a variable infusion of [6-(2)H2]dextrose adjusted to maintain plasma glucose at either approximately 60 mg/dl (hypoglycemic clamp) or approximately 90 mg/dl (euglycemic clamp). Blood samples were obtained between 150 and 180 min during the study period. Insulin increased from 49 +/- 14 to 130 +/- 25 (hypoglycemia) and to 102 +/- 10 (euglycemia) pmol/l. Glucose decreased from 5.32 +/- 0.11 to 3.58 +/- 0.07 micromol/ml during hypoglycemia, but it did not change during euglycemia (5.20 +/- 0.19 vs. 5.05 +/- 0.15 micromol/ml). Endogenous glucose production decreased (9.30 +/- 0.70 vs. 5.65 +/- 0.50) during euglycemia but not during hypoglycemia (9.80 +/- 0.50 vs. 10.25 +/- 0.60 micromol x kg(-1) x min(-1)). During hypoglycemia, net renal glucose output increased from 0.54 +/- 0.30 to 2.31 +/- 0.40, RGP increased from 1.88 +/- 0.70 to 3.65 +/- 0.50 (P < 0.05), and RGU did not change (1.34 +/- 0.50 vs. 1.34 +/- 0.60 micromol x kg(-1) x min(-1)). During euglycemia, renal glucose balance switched from a net output of 0.72 +/- 0.20 to a net uptake of 1.70 +/- 0.92, RGP decreased from 2.31 +/- 0.50 to 1.20 +/- 0.58, and RGU increased from 1.59 +/- 0.50 to 2.90 +/- 0.70 micromol x kg(-1) x min(-1) (P < 0.05). During hypoglycemia, arterial glucagon increased from 105 +/- 6 to 129 +/- 8, epinephrine increased from 116 +/- 28 to 331 +/- 33, norepinephrine increased from 171 +/- 9 to 272 +/- 9 (all P < 0.05), and renal vein norepinephrine increased from 236 +/- 13 to 426 +/- 50 (P < 0.001). These data indicate that, in addition to counterregulatory hormones, activation of the autonomic nervous system during hypoglycemia stimulates glucose production by the kidney, which may represent an important additional component of the body's defense against hypoglycemia in humans. (+info)
Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist.
(14/1299)
J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist. (+info)
Surgical renal artery reconstruction without contrast arteriography: the role of clinical profiling and magnetic resonance angiography.
(15/1299)
PURPOSE: Contrast arteriography is the accepted gold standard for diagnosis and treatment planning in patients with atherosclerotic renovascular disease (RVD). In this study, the results of a selective policy of surgical renal artery reconstruction (RAR) with magnetic resonance angiography (MRA) as the sole preoperative imaging modality are reviewed. METHODS: From May 1993 to May 1998, 25 patients underwent RAR after clinical evaluation, and aortic/renal MRA performed with a gadolinium-enhanced and 3-dimensional phase contrast technique. Clinical presentations suggested severe RVD in all patients and included poorly controlled hypertension (16 patients), hospitalization for hypertensive crises and/or acute pulmonary edema (13), and deterioration of renal function within one year of operation (15). Thirteen patients had associated aortic pathologic conditions (12 aneurysms, 1 aortoiliac occlusive disease), and eight of these patients also underwent noncontrast computed tomography scans. Significant renal dysfunction (serum creatinine level, >/=2.0 mg/dL) was present in all but 4 patients with 14 of 25 patients having extreme (creatinine level, >/=3.0 mg/dL) dysfunction. RESULTS: Hemodynamically significant RVD in the main renal artery was verified at operation in 37 of 38 reconstructed main renal arteries (24/25 patients). A single accessory renal artery was missed by MRA. RAR was comprehensive (bilateral or unilateral to a single-functioning kidney) in 21 of 25 patients and consisted of hepatorenal bypass graft (3 patients), combined aortic and RAR (13 patients), isolated transaortic endarterectomy (8 patients), and aortorenal bypass graft (1 patient). Early improvement in both hypertension control and/or renal function was noted in 21 of 25 patients without operative deaths or postoperative renal failure. Sustained favorable functional results at follow-up, ranging from 5 months to 4 years, were noted in 19 of 25 patients. CONCLUSION: MRA is an adequate preoperative imaging modality in selected patients before RAR. This strategy is best applied in circumstances where the clinical presentation suggests hemodynamically significant bilateral RVD and/or in patients at substantial risk of complications from contrast angiography. (+info)
BACKGROUND: A recent study of human cadaveric renal arteries revealed that renal artery narrowing could be due not only to atherosclerotic plaque compensated for by adaptive remodeling, but also to hitherto undescribed focal narrowing of an otherwise normal renal arterial wall (ie, coarctation). The present study investigated whether vessel coarctation could be identified in patients with symptomatic renal artery stenosis (RAS). METHODS AND RESULTS: Consecutive symptomatic patients with angiographically proven atherosclerotic RAS who were referred for stent placement were studied by 30-MHz intravascular ultrasound before intervention (n=18) or after predilatation (n=18). Analysis included assessment of the media-bounded area and plaque area (PLA) at the most stenotic site and at a distal reference site (most distal cross-section in the main renal artery with normal appearance). Coarctation was considered present whenever the target/reference media-bounded area was +info)