Renal dopamine-1 defect in spontaneous hypertension.
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Biomedical subjects
R A Felder
Publications and source records attributed to R A Felder.
Diuresis and natriuresis during continuous dopamine-1 receptor stimulation.
Stimulation of renal dopamine-1 (DA1) receptors for 3 hours produces an increase in renal plasma flow and sustained natriuresis. The present study was designed to assess the response of renal hemodynamic and tubular function to long-term DA1 receptor stimulation. Fenoldopam, a selective DA1 receptor agonist, was infused intravenously for 24 hours in 10 normal male subjects in metabolic balance at 150 mEq sodium and 60 mEq potassium intake in a single-blind, vehicle-controlled protocol. During DA1 receptor activation, urine flow rate and fractional excretion of sodium increased for the first 5 hours, 16.9 +/- 0.9 ml/min compared with a vehicle control value of 12.4 +/- 0.5 ml/min (p less than 0.001) and 2.0 +/- 0.1% compared with a vehicle control value of 1.1 +/- 0.1% (p less than 0.005), respectively. Urinary sodium excretion rose at 5 hours, 0.27 +/- 0.02 mEq/min compared with a vehicle control value of 0.14 +/- 0.01 mEq/min (p less than 0.01). Renal plasma flow increased during fenoldopam at 5 hours, 505 +/- 47 ml/min compared with a vehicle control value of 397 +/- 25 ml/min (p less than 0.01), and was sustained for 24 hours, 523 +/- 40 ml/min compared with 432 +/- 31 ml/min (p less than 0.05). The distal sodium load increased and the percentage of distal sodium reabsorption decreased during fenoldopam. Glomerular filtration rate, blood pressure, heart rate, plasma aldosterone concentration, plasma renin activity, and fractional excretion of potassium were unchanged. Selective DA1 receptor activation produced sustained 5-hour diuresis and 11-hour natriuresis without kaliuresis or a systemic hemodynamic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Intrarenal dopamine-1 receptors control renal function.
Dopamine receptors are classified to DA-1 and DA-2 and are characterized in renal tissue by radioligand binding and by the response of renal adenylate cyclase to dopaminergic agonists and antagonists. DA-1 receptors are localized in the renal tubules, the medial layer of renal microvessels, and the juxtaglomerular apparatus. DA-1 receptor stimulation causes dilation of renal, mesenteric, coronary, and cerebral vessels. In the present study, we tested the hypothesis that dopamine is a paracrine substance in the control of renal function. We employed a potent specific DA-1 receptor antagonist, SCH, to evaluate the role of intrarenal DA-1 receptor in the maintenance of renal function. Intrarenal DA-1 receptor blockade with SCH caused a highly significant dose-dependent antidiuresis and antinatriuresis, and decreased FENa. A rebound diuresis and natriuresis above control values were observed after cessation of DA-1 receptor blockade. There were no changes in renal hemodynamic function during DA-1 receptor blockade. These results strongly suggest that the antinatriuresis and antidiuresis induced by DA-1 receptor blockade are mediated by an action at the renal tubule. The infusion rate of SCH administered intrarenally was sufficiently low to produce no measurable systemic effects including PRA, PAC, and MAP. Thus, these results can be interpreted as due to intrarenal DA-1 blockade. In summary, we have demonstrated that renal excretory function is highly sensitive to DA-1 receptor blockade within the kidney and appears to be mediated by renal tubular events. This study provides strong evidence that DA-1 receptors play a physiological role in the control of renal function.
Animals↗
Robotics in the clinical laboratory.
We are beginning to see the potential of robotics in the clinical laboratory through integration with automated analyzers and computer systems. However, there is a need for training programs that will prepare technologists to design and implement robotic systems for clinical laboratories. What will the robot laboratory of the future look like? We will see hospital laboratories begin to be located some distance away from the main facility because the labor component of staffing satellite laboratories will have been greatly reduced. Instrument manufacturers will see the need for analyzers that are robot-friendly and allow for simplified interfacing, both electronic and mechanical. Robots will become more versatile even to the point of performing complete instrument repair. Laboratories will be equipped with many task-oriented robotic stations, including, for example, accessioning and processing robots that prepare samples for transport by robotic carts. Analysis will be performed by a combination of robot and dedicated analyzer. Laboratory results will be reviewed by algorithms in the larger laboratory computer, which will alert the laboratory worker to unusual results. A large variety of analyses will be available to the patient with rapid turnaround. The end result will be more efficient health care delivery at reduced cost.
Computer Communication Networks↗
Effects of dopamine in the renal vascular bed of fetal, newborn, and adult sheep.
The renal hemodynamic response to renal arterial dopamine infusions was compared in unanesthetized fetal (129-137 days gestation, full term 145 days), newborn, and adult sheep. Mean arterial blood pressure and heart rate remained unchanged during intrarenal dopamine infusions. Dopamine produced dose-related decreases in mean renal blood flow velocity in all three groups. When compared with adult sheep fetal sheep were slightly more sensitive to the vasoconstrictive effects of dopamine ED50 (mean effective dose ratio: fetus/ED50 adult = 0.368 +/- 0.047, P less than 0.05). Increases in mean renal blood flow velocity were not seen at any dose given (1-16 micrograms/kg body wt in fetuses, 2-32 micrograms/kg body wt in newborns and adults) until dopamine was infused during alpha- and beta-adrenoceptor blockade. The largest mean increase in renal flow velocity was 13 +/- 3, 16 +/- 3, and 17 +/- 4% in fetal, newborn, and adult sheep, respectively. cis-Flupentixol inhibited the vasodilation. This study demonstrates the presence of renal vasodilation following renal arterial dopamine infusions in fetal, newborn, and adult sheep when renal alpha- and beta-adrenoceptors are blocked. Vasodilator responses are similar in all three groups, and increases in renal blood flow velocity are small compared with that of other experimental models.
Adrenergic beta-Antagonists↗
Two monoclonal-based assays for carcinoembryonic antigen compared.
Monoclonal antibody-based methods can provide clinically different impressions for some patients than does an earlier method involving a conventional antiserum. Therefore, performance of two commercial double-monoclonal-antibody methods for carcinoembryonic antigen (CEA) were studied further, those of Abbott Diagnostics and Roche Diagnostic Systems. The two methods showed similar precision. Total CVs over 20 days at three concentrations were 16, 6, and 6% in the Roche assay, and 15, 8, and 7% in the Abbott assay (n = 20). Within-run CVs for quality-control levels 1, 2, and 3, respectively, in the Roche assay were 14, 8, and 9%, and in the Abbott 15, 9, and 10% (n = 20). Mean CEA concentrations were consistently lower in the Roche assay than in the Abbott assay. Results of the two assays correlated significantly in patients with CEA-secreting carcinomas (r = 0.88), and in serial samples from cancer patients who had low, medium, or high CEA concentrations in their sera (r = 0.92 for all serial data). About 10% of values were false-positive (greater than 5.0 micrograms/L) by each of the two methods in 89 patients with various non-malignant conditions. The two methods appear to be more specific for tumor-associated CEA than are polyclonal antibody-based assays previously available from the two manufacturers.
Adolescent↗
Dopamine receptors modulate sodium excretion in denervated kidney.
Dopamine (DA) modulates sodium excretion by the innervated kidney. To examine the role of DA in the denervated (DNX) kidney the effects of the DA1/DA2 antagonist cis-flupenthixol (group 2, n = 7) (10 nmol X kg-1 X min-1), given intravenously in saline-loaded Wistar-Kyoto rats after acute unilateral left DNX, were compared with a placebo group (group 1, n = 7) and a group that received the DA1 antagonist SCH 23390 (group 3, n = 7) at 2.5 nmol X kg-1 X min-1. Pentobarbital sodium anesthesia was employed. Adequacy of DNX was assessed by a natriuresis and decrease in renal norepinephrine content in the DNX kidney and an antinatriuresis in the innervated right kidney. Mean arterial pressure slightly decreased in the placebo group (group 1, 106.7 +/- 2.2 vs. 99.3 +/- 2.4 mmHg) and after cis-flupenthixol (group 2, 108.8 +/- 2.7 vs. 92.8 +/- 1.8 mmHg) but not after SCH 23390 (group 3, 105.6 +/- 1.6 vs. 103 +/- 1.1 mmHg). Glomerular filtration rate was not affected by placebo or SCH 23390 in the DNX or innervated kidney but did slightly decrease after cis-flupenthixol in the DNX kidney. Sodium and water excretion after drug administration differed among the groups. In the DNX kidney urine flow decreased only in group 2, whereas fractional sodium excretion decreased modestly (P less than 0.05 paired t test) with SCH 23390 (3.53 +/- 0.34 vs. 2.89 +/- 0.20%) markedly with cis-flupenthixol (3.18 +/- 0.50 vs. 1.21 +/- 0.18%) and was unchanged in the placebo group (3.25 +/- 0.61 vs. 3.45 +/- 0.45%).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
An optimized method for measuring cyclosporin A with 125I-labeled cyclosporin.
We evaluated the use of the new iodinated ligand for the in vitro measurement of cyclosporin A by radioimmunoassay (RIA). Substitution of the iodinated cyclosporin (125I-CyA) for the corresponding tritium-labeled analog (3H-CyA) considerably simplifies and accelerates the currently available RIA, and improves its precision. Analysis of the respective dose-response curves showed that the 50% B0 value was lower for the 125I-CyA assay than for the 3H-CyA assay (37 vs 77 micrograms/L). Use of whole-blood specimens minimized interferences from temperature and hematocrit. We conclude that the use of 125I-CyA in a commercially available RIA for whole-blood specimens is accessible to most laboratories and provides rapid, reproducible data for management of transplant patients.
Computers↗
University of Virginia case conference. Macroamylase, macro creatine kinase, and other macroenzymes.
The importance of macroenzymes has become increasingly apparent in recent years (1,2). Macroamylase (EC 3.2.1.1) and macro CK (EC 2.7.3.2) are the macroenzymes most commonly noted in the clinical laboratory, and they are frequently responsible for diagnostic confusion. Several methods are available for the confirmation and analysis of macroenzymes, many of which require expensive equipment or complicated techniques. In this report we summarize two cases of macro creatine kinase and two cases of macroamylase that illustrate the clinical importance of recognizing these macroenzymes. We review the features of these macroenzymes, discuss their laboratory evaluation, and describe a simple method that we have used to detect the macroenzymes in these (and other) patients at our institution. Finally, we review the literature on other, less commonly observed macroenzymes in human blood. We stress (a) the impact of methodology on clinical impressions and (b) the importance of discussing laboratory observations with the patient's physician and communicating them to the patient's medical record in writing.
5'-Nucleotidase↗
Cortical tubular and glomerular dopamine receptors in the rat kidney.
Dopamine receptors in glomeruli and renal cortical tubules were characterized using radioligand binding and adenylate cyclase studies. The binding of [3H]haloperidol to glomeruli and tubules was rapid, saturable with time and ligand concentration, reversible, of high affinity, and demonstrated stereoselectivity and antagonist and agonist rank potency for binding to dopamine receptors. Analysis of kinetic data and Rosenthal plots in glomeruli revealed a single class of [3H]haloperidol binding sites with an apparent dissociation constant (Kd) of 6 nM and maximum receptor density (Bmax) of 0.42 pmol/mg protein. In tubules, at least two binding sites were noted, one with an apparent Kd of 38 nM and Bmax of 1.90 pmol/mg protein and another with an apparent Kd of 183 nM and Bmax of 3.50 pmol/mg protein. Dopamine and apomorphine increased adenylate cyclase in tubular membranes while no increases were noted in glomeruli. These studies suggest that glomeruli have D2 dopamine receptors, while renal cortical tubules contain the D1 dopamine receptor.
Adenylyl Cyclases↗
Dopamine receptors in the proximal tubule of the rabbit.
Our laboratory has characterized dopamine receptors in glomeruli and tubular homogenates. Since the heterogeneity of kidney homogenates limits the interpretation of these studies, the [3H]haloperidol binding site and adenylate cyclase sensitivity to dopamine were studied in the isolated proximal convoluted tubule and pars recta of the rabbit kidney. [3H]Haloperidol binding sites were saturable, stereoselective, and of high affinity. The apparent dissociation constant was 31.5 X 10(-9) M (+/- 8.5) and the maximum receptor density was 0.31 X 10(-15) M (+/- 0.08) per millimeter. In pars recta specific binding was 53% of total [3H]-haloperidol binding. Dopamine stimulated adenylate cyclase activity in a dose-related manner, which was inhibited by cis-flupenthixol but not by trans-flupenthixol or (-)-propranolol. Moreover, the stimulatory effect of the dopamine 1 (D1) agonist SKF 82526 on adenylate cyclase activity was blocked by the D1 antagonist SCH 23390. Dopamine receptors in the proximal convoluted tubule appear to be of the D1 subtype since they are linked to stimulation of adenylate cyclase. This is further substantiated by the stereoselectivity for (+)-sulpiride (a D1 antagonist), which had a greater affinity for the [3H]haloperidol binding site than (-)-sulpiride (a D2 antagonist).
Adenylyl Cyclases↗
Alpha-adrenoceptors in the developing kidney.
The maturation of renal alpha-adrenoceptors was investigated in dogs. Alpha-adrenoceptors were characterized by radioligand binding using the alpha-1-adrenergic antagonist, [3H]-WB-4101. In renal plasma membranes obtained from the outer cortex of neonates, the binding of the ligand was rapid, reversible, of high affinity, saturable, and stereoselective. The competition studies with adrenergic agonists and antagonists were indicative of alpha-receptors. In puppies less than 1-w-old, the binding affinity of [3H]-WB-4101 (Kd = 0.638 +/- 0.17 nM) was greater than 3-5 week-old puppies (Kd 1.573 +/- 0.315 nm); (P less than 0.05), but receptor number was similar (63.75 +/- 19.1 versus 79.10 +/- 5.99 fmole/mg protein). No consistent specific binding could be demonstrated in plasma membranes obtained from inner cortex of medulla. In the adult dog, no consistent specific binding could be demonstrated for plasma membranes obtained from any region of the kidney. These studies indicate that during maturation there is a decrease in alpha-adrenoceptor density and affinity in membranes from the outer cortex of the kidney.
Adrenergic alpha-Antagonists↗
Ontogeny of myocardial adrenoceptors II. Alpha adrenoceptors.
The maturation of myocardial alpha adrenoceptors was investigated in dogs. Alpha adrenoceptors were characterized by radioligand binding using [3H]-WB4101. In neonatal cardiac membranes, the binding of the ligand was rapid, reversible, of high affinity, saturable and stereoselective. The competition studies with adrenergic agonists and antagonists were indicative of alpha adrenoceptors. In adult dog cardiac membranes, consistent specific binding of the ligand could be demonstrated. These studies indicate that there is a decrease in alpha adrenergic receptor density of canine cardiac membranes during maturation.
Adrenergic alpha-Agonists↗
Transgenic mice to study the role of dopamine receptors in cardiovascular function.
Dopamine, an intrarenal regulator of sodium transport, is important in the pathogenesis of hypertension. The transduction of D1-like receptors in renal proximal tubules is defective in animal models of genetic hypertension. The defect is associated with an impaired regulation of proximal tubular sodium transport and cosegregates with hypertension in rats. Moreover, mice lacking one or both D1A receptor alleles develop hypertension. Extrasynaptic D3 receptors in renal tubules and juxtaglomerular cells may also regulate renal sodium transport and renin secretion while presynaptic D3 receptors may act as autoreceptors to inhibit neural norepinephrine release. Mice lacking one or both D3 alleles have elevated systolic blood pressure and developed diastolic hypertension. Although basal urine flow, sodium excretion, and glomerular filtration rate are similar, mice homozygous to the D3 receptor have an impaired ability to excrete an acute saline load compared to heterozygous and wild type mice. These studies suggest that abnormalities in dopamine receptor genes or their regulation may lead to the development of hypertension via different pathogenetic mechanisms.
Animals↗
Dopamine D3 receptors in rat juxtaglomerular cells.
D2-like receptors in the kidney have been suggested to be important in the regulation of renin release but the D2-like subtype(s) expressed in juxtaglomerular (JG) cells is not known. Therefore, we determined which of the D2-like family of dopamine receptors is located in primary cultures of rat juxtaglomerular (JG) cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) identified D3 and D4 but not D2Long mRNA in JG cells (n = 3). D3 receptor function was demonstrated by a concentration-dependent inhibition of forskolin-stimulated cAMP production by LY-171555 (a non-selective D2-like receptor agonist) and PD-128593 (a partially selective D3 agonist) (n = 3-7/group). The stimulatory action of LY-171555 and PD-128593 we blocked by the non-selective D2-like antagonist YM-09151. We conclude that D3 and D4 dopamine receptor subtypes are expressed in JG cells; the receptor subtype linked to the inhibition of cAMP in JG cells remains to be established.
Animals↗
Preferential release of renal dopamine into the tubule lumen: effect of chronic sodium loading.
Dopamine (DA), produced by the renal proximal tubule, has been demonstrated as an intrarenal paracrine hormone mediating diuresis and natriuresis. The precise mechanism by which DA exerts its cell-to-cell action is not fully understood. In the present study, renal interstitial (RIF) DA (by in vivo microdialysis) and urinary DA excretion (UDAV) were compared in anesthetized rats on either normal (0.28% NaCl, NS) or high (4.0% NaCl, HS) sodium balance (n = 9 in each group). Urine flow (UV) and sodium excretion (UNaV) in HS were greater than in NS rats (UV 7.2 +/- 0.6 vs 3.8 +/- 0.3 microliters/min, P < 0.01; UNaV 497 +/- 66 vs 265 +/- 27 nmol/min, P < 0.01). In rats on both NS and HS balance, UDAV was significantly higher than RIF DA (420 +/- 37 vs 3.68 +/- 0.49 pg/min in the NS rat; 601 +/- 68 vs 1.25 +/- 0.36 pg/min in the HS rat, both P < 0.01). UDAV was increased in HS compared with NS rats (601 +/- 68 vs 420 +/- 37 pg/min, P < 0.05). In contrast, RIF DA was significantly lower in HS than NS rats (1.25 +/- 0.36 vs 3.68 +/- 0.49 pg/min, P < 0.01). In conclusion, chronic sodium loading increased renal DA production and release predominantly into the tubular lumen rather than the peritubular interstitial space of the kidney. These results indicate that DA originating from proximal tubule cells has a direct tubule action in the control of sodium excretion.
Animals↗
Clinical laboratory robots: their impact on laboratory management.
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Laboratories, Hospital↗