A Comparison of the Renal and Neuroendocrine Effects of Two 5-Hydroxytryptamine Renal Prodrugs in Normal Man

1993 ◽  
Vol 85 (5) ◽  
pp. 607-614 ◽  
Author(s):  
T. C. Li Kam Wa ◽  
S. Freestone ◽  
R. R. Samson ◽  
N. R. Johnson ◽  
M. R. Lee
Keyword(s):  
Renal Plasma Flow ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Serum Growth Hormone ◽  
Plasma Aldosterone Concentration ◽  
Urinary Dopamine ◽  
Normal Man ◽  
Male Subjects ◽  
Placebo Infusion ◽  
Observation Period

1. The effects of 1 h intravenous infusions of equimolar amounts (45 nmol min−1 kg−1) of two putative 5-hydroxytryptamine renal prodrugs, 5-hydroxy-L-tryptophan and γ-L-glutamyl-5-hydroxy-L-tryptophan, were investigated in a randomized, placebo-controlled, cross-over study in nine healthy male subjects. 2. Cumulative urinary 5-hydroxytryptamine excretion over the 3 h observation period rose by about 370-fold after 5-hydroxy-L-tryptophan and 390-fold after γ-L-glutamyl-5-hydroxy-L-tryptophan when compared with placebo infusion. Urinary 5-hydroxy-L-tryptophan excretion was three times higher after administration of γ-L-glutamyl-5-hydroxy-L-tryptophan than after 5-hydroxy-L-tryptophan infusion. Urinary 5-hydroxyindole-3-acetic acid excretion after 5-hydroxy-L-tryptophan infusion was significantly greater than that after γ-L-glutamyl-5-hydroxy-L-tryptophan administration. Urinary dopamine excretion was not affected by either compound when compared with placebo. 3. 5-Hydroxy-L-tryptophan significantly reduced urine flow rate and urinary sodium excretion. γ-L-Glutamyl-5-hydroxy-L-tryptophan was antinatriuretic but did not affect urine output. These changes occurred without significant alterations in effective renal plasma flow and glomerular filtration rate. 4. Both 5-hydroxy-L-tryptophan and γ-L-glutamyl-5-hydroxy-L-tryptophan significantly increased plasma aldosterone concentration without a concomitant rise in plasma renin activity. The increase after γ-L-glutamyl-5-hydroxy-L-tryptophan was smaller and delayed. 5-Hydroxy-L-tryptophan, but not γ-glutamyl-5-hydroxy-L-tryptophan, increased serum growth hormone concentration. 5. There was a significant increase in diastolic blood pressure after 5-hydroxy-L-tryptophan administration, but not after γ-L-glutamyl-5-hydroxy-L-rryptophan. 6. These results show that both prodrugs generate 5-hydroxytryptamine. The antinatriuresis after both compounds is presumably mediated by intrarenally generated 5-hydroxytryptamine and this appears to be predominantly a tubular effect. The urinary metabolite data and greater extrarenal effects produced by 5-hydroxy-L-tryptophan indicate that the glutamyl derivative is relatively more selective for the kidney than 5-hydroxy-L-tryptophan.

Acute and chronic actions of bradykinin on renal function and arterial pressure

1985 ◽  
Vol 248 (1) ◽  
pp. F87-F92 ◽  
Author(s):  
J. P. Granger ◽  
J. E. Hall
Keyword(s):  
Arterial Pressure ◽  
Renal Plasma Flow ◽  
Urine Volume ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Renal Perfusion ◽  
Acute Effects ◽  
Plasma Aldosterone Concentration ◽  
Control Value ◽  
Renal Vascular

The present study was designed to examine the acute and chronic effects of increased levels of circulating bradykinin (BK) on control of renal hemodynamics, electrolyte excretion, and arterial pressure. Intrarenal infusion of BK (50 ng X kg-1 X min-1) for 60 min in five anesthetized dogs with renal perfusion pressure maintained at a constant level of 108 +/- 1 mmHg had no significant effect on glomerular filtration rate (GFR), whereas it increased renal blood flow (RBF) from a control value of 230 +/- 14 to 282 +/- 18, 266 +/- 15, and 253 +/- 17 ml/min after 15, 30, and 60 min of infusion, respectively. Acute intrarenal infusion of BK also increased urine volume (UV) from 0.255 +/- 0.044 to 0.523 +/- 0.103 ml/min and urinary sodium excretion (UNaV) from 5.72 +/- 1.5 to 13.7 +/- 3.4 mueq/min. To determine whether the potent acute effects of BK on RBF, UV, and UNaV lead to a chronic reduction in arterial pressure, BK (50 ng X kg-1 X min-1) was infused intrarenally for 7 days in conscious dogs. Intrarenal infusion of BK for 7 days had no significant effect on GFR, UNaV, UV, or arterial pressure. However, BK elevated renal plasma flow and decreased renal vascular resistance throughout the 7 days of infusion. Chronic intrarenal BK infusion caused no significant changes in plasma renin activity or plasma aldosterone concentration. Results from these studies indicate that although increased levels of bradykinin in the renal circulation can have potent acute effects on RBF, UV, and UNaV, these effects on UV and UNaV are not sustained and therefore do not result in long-term changes in arterial pressure.

Lithium pretreatment affects renal and systemic responses to angiotensin II infusion in normal man

1992 ◽  
Vol 82 (5) ◽  
pp. 543-549 ◽  
Author(s):  
D. W. Eadington ◽  
S. Freestone ◽  
C. J. Waugh ◽  
C. P. Swainson ◽  
M. R. Lee
Keyword(s):  
Angiotensin Ii ◽  
Sodium Excretion ◽  
Plasma Renin ◽  
Lithium Carbonate ◽  
Urinary Sodium Excretion ◽  
Plasma Aldosterone Concentration ◽  
Normal Man ◽  
Normal Males ◽  
Renal Vascular ◽  
Systemic Responses

1. Renal and systemic responses to infusion of angiotensin II (1.25 and 2.5 ng min−1 kg−1 body weight) were examined in ten normal males 12 h after single doses of 750 mg of lithium carbonate, 250 mg of lithium carbonate (n = 6) or placebo. 2. Baseline mean arterial pressure [mean (sem)] was higher after 750 mg of lithium [93.1 (1.7) versus 89.5 (1.9) mmHg, P = 0.014], and the subsequent rise in blood pressure during angiotensin II infusion was lower [8.2 (1.8) versus 12.2 (2.4) mmHg, P < 0.02]. 3. Lithium at a dose of 750 mg increased overnight urinary sodium excretion before the study. The fall in fractional sodium excretion during angiotensin II infusion was reduced after pretreatment with 750 mg of lithium [750 mg of lithium, 2.73 (0.24) to 1.34 (0.08)%; placebo, 2.69 (0.26) to 1.01 (0.11)%; P=0.02]. The increases in effective filtration fraction [750 mg of lithium, 5.4 (1.0)%; placebo, 8.6 (0.7)%; P < 0.05] and total effective renal vascular resistance [750 mg of lithium, 3700 (390) dyn s cm−5; placebo 5100 (460) dyn s cm−5; P=0.03] during angiotensin II infusion were also attenuated after 750 mg of lithium. Responses after 250 mg of lithium did not differ from those after placebo. 4. The fall in plasma renin activity and the increase in plasma aldosterone concentration during angiotensin II infusion were similar on each study day. 5. Renal responses to exogenous angiotensin II are altered after pretreatment with a 750 mg dose of lithium in normal man. This dose of lithium is not an inert marker of sodium handling.

Evidence that intrarenal bradykinin plays a role in regulation of renal function

1993 ◽  
Vol 265 (4) ◽  
pp. E648-E654 ◽  
Author(s):  
H. M. Siragy
Keyword(s):  
Renal Function ◽  
Sodium Excretion ◽  
Sodium Intake ◽  
Renal Plasma Flow ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Sodium Balance ◽  
Kinin System ◽  
Plasma Aldosterone Concentration ◽  
Low Sodium

Bradykinin (BK) is produced by the kidney, but the role of the renal kallikrein-kinin system (KKS) in the control of renal function is not understood. We studied the effects of intrarenal infusion of the BK antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid (BKA, n = 5) and BK (n = 4) alone or combined with antagonist (BKA 0.025 ng.kg-1 x min-1 + BK 0.25 ng.kg-1 x min-1, n = 4) in uninephrectomized conscious dogs in sodium balance at 10 and 80 meq/day. During low sodium intake, administration of BKA (infusions from 0.025 to 2.5 ng.kg-1 x min-1) caused a significant antidiuresis (P < 0.0001) and antinatriuresis (P < 0.0001) and a decrease in fractional sodium excretion (P < 0.0001). There were no changes in estimated renal plasma flow (RPF) or glomerular filtration rate during intrarenal administration of BKA at 0.025 and 0.25 ng.kg-1 x min-1. A dose of 2.5 ng.kg-1 x min-1 BKA caused a significant decrease in RPF. There were no changes in plasma aldosterone concentration, plasma renin activity, or systemic arterial pressure during intrarenal BKA administration. At 80 meq/day sodium balance (n = 5), intrarenal administration of BKA did not cause any systemic or renal effects. Intrarenal administration of BK at 0.25 ng.kg-1 x min-1 during low sodium balance caused an increase in urine flow rate and urinary sodium excretion. Coinfusion of BK with BKA completely abrogated the renal excretory changes induced by BKA. These data suggest that intrarenal KKS plays a role in control of renal function largely by a tubular mechanism during low sodium intake.

Effects of hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume

1987 ◽  
Vol 252 (1) ◽  
pp. F91-F98
Author(s):  
R. D. Manning
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Sodium Excretion ◽  
Sodium Intake ◽  
Renal Plasma Flow ◽  
Urinary Sodium Excretion ◽  
Renal Hemodynamics ◽  
Fluid Volume ◽  
Urinary Sodium ◽  
Plasma Aldosterone Concentration

The effects of long-term hypoproteinemia on renal hemodynamics, arterial pressure, and fluid volume were studied in eight conscious dogs over a 34-day period. Plasma protein concentration (PPC) was decreased by daily plasmapheresis, and the effects of decreasing and increasing sodium intake were measured. By the 12th day of plasmapheresis, during which sodium intake was 30 meq/day, PPC had decreased to 2.5 g/dl from a control value of 7.2 g/dl, mean arterial pressure had decreased to 78% of control, glomerular filtration rate (GFR) was 75.2% of control, and urinary sodium excretion was decreased. By day 18 of plasmapheresis, estimated renal plasma flow (ERPF) was decreased to 60% of control due to the decreased arterial pressure and an increase in renal vascular resistance. Also, plasma renin activity and plasma aldosterone concentration were both increased, and the relationship between mean arterial pressure and urinary sodium excretion was distinctly shifted to the left along the arterial pressure axis. In contradistinction to acute experiments, chronic hypoproteinemia results in decreases in GFR, ERPF, and urinary sodium excretion and has marked effects on both fluid volume and arterial pressure regulation.

The renin-aldosterone system in pre-eclampsia, essential and transient hypertension during pregnancy, and normotensive pregnant and non-pregnant control subjects

1982 ◽  
Vol 101 (2) ◽  
pp. 273-280 ◽  
Author(s):  
E. B. Pedersen ◽  
A. B. Rasmussen ◽  
P. Johannesen ◽  
H. J. Kornerup ◽  
S. Kristensen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Urinary Sodium Excretion ◽  
Third Trimester ◽  
Plasma Aldosterone Concentration ◽  
The Third ◽  
Control Subjects ◽  
Hypertension In Pregnancy ◽  
Normotensive Pregnancy ◽  
In Pregnancy

Abstract. Plasma renin concentration (PRC), plasma aldosterone concentration (PAC), and blood pressure were determined in the third trimester in pregnancy, 5 days and 6 months after delivery in pre-eclampsia, essential and transient hypertension in pregnancy and in normotensive pregnant and non-pregnant control subjects. PRC and PAC were elevated several fold above non-pregnant level in all groups during pregnancy. In pre-eclampsia PRC and PAC were 220 and 160%, respectively, above the levels 6 months after delivery, and thus lower than the corresponding values, 360 and 402%, in normotensive pregnancy. In essential and transient hypertension PRC and PAC increased to the same degree as during normotensive pregnancy. Urinary sodium excretion, serum sodium and creatinine clearance were reduced in pre-eclampsia, but not in essential and transient hypertension when compared to normotensive pregnant controls. All the parameters determined were the same as in non-pregnant controls 6 months after delivery in all groups. There were no correlations between blood pressure and PRC or PAC in any of the groups neither in pregnancy nor after delivery. It is concluded that the renin-aldosterone system is stimulated in lesser degree in pre-eclampsia than in both essential hypertension, transient hypertension and normotensive pregnancy, and there was no evidence for a causal relationship between the renin-aldosterone system and blood pressure neither in normotensive nor hypertensive pregnancy.

Intrarenal renin inhibition increases renal function by an angiotensin II-dependent mechanism

1988 ◽  
Vol 255 (4) ◽  
pp. F749-F754 ◽  
Author(s):  
H. M. Siragy ◽  
N. E. Lamb ◽  
C. E. Rose ◽  
M. J. Peach ◽  
R. M. Carey
Keyword(s):  
Renal Function ◽  
Angiotensin Ii ◽  
Sodium Intake ◽  
Renal Plasma Flow ◽  
Plasma Renin ◽  
Competitive Inhibitor ◽  
Urinary Flow ◽  
Renin Substrate ◽  
Plasma Aldosterone Concentration ◽  
Renin Inhibition

ACRIP is a competitive inhibitor of renin in which an analogue of statine, (3R,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of porcine renin substrate. ACRIP inhibits the enzymatic activity of renin, thus blocking the initiation of the angiotensin cascade. We studied the intrarenal action of ACRIP in small quantities without measurable systemic effects on renal function. In the first experiment, ACRIP was administered intrarenally at 0.02, 0.2, and 2 micrograms.kg-1.min-1 to uninephrectomized conscious dogs (n = 6) in metabolic balance at sodium intake of 10 meq/day. ACRIP, in doses of 0.02 and 0.2 micrograms.kg-1.min-1, markedly increased urine sodium excretion (UNaV) from 5.8 +/- 1.4 to 15.1 +/- 5.1 and 19.9 +/- 3.2 mu eq/min, respectively. Urinary flow rate (UV) underwent a similar increase and glomerular filtration rate (GFR) increased from 25.7 +/- 2.5 to 35.6 +/- 2.5 at 0.02 micrograms.kg-1.min-1 of ACRIP. Renal plasma flow (RPF), plasma renin activity (PRA), and plasma aldosterone concentration (PAC) were not affected. At 2 micrograms.kg-1.min-1, ACRIP traversed the kidney in quantities large enough to produce a reduction in systemic PRA and mean arterial pressure and caused natriuresis, diuresis, and increased GFR. In a second experiment, ACRIP was administered intrarenally at 0.2 micrograms.kg-1.min-1 in a separate group (n = 4) under identical conditions. ACRIP-induced increases in UV and UNaV were completely blocked by concurrent intrarenal administration of angiotensin II. The results indicate that intrarenal angiotensin II acts as a physiological regulator of renal sodium and fluid homeostasis.

γ-l-Glutamyl-l-Dopa is a Dopamine Pro-Drug, Relatively Specific for the Kidney in Normal Subjects

1985 ◽  
Vol 69 (2) ◽  
pp. 207-214 ◽  
Author(s):  
D. P. Worth ◽  
J. N. Harvey ◽  
J. Brown ◽  
M. R. Lee
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Glomerular Filtration Rate ◽  
Plasma Renin Activity ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Plasma Renin ◽  
Normal Subjects ◽  
Urinary Sodium Excretion ◽  
Systemic Effects

1. γ-l-Glutamyl-l-dopa was given by intravenous infusion to eight normal subjects at doses of 12.5 and 100 μg min−1 kg−1. 2. Both doses of the dipeptide resulted in an increase in mean urinary sodium excretion. 3. Mean effective renal plasma flow rose at both doses, but mean glomerular filtration rate increased only at the lower dose. 4. There was a fall in mean plasma renin activity after the infusion of both 12.5 and 100 μg min−1kg−1. 5. Mean urine free dopamine excretion increased by 280- and 2500-fold at infusion rates of 12.5 and 100 μg min−1 kg−1 respectively. 6. Mean plasma free dopamine rose at both doses but the increase at 12.5 μg min−1 kg−1 was not to a level previously associated with systemic effects of the catecholamine. 7. On administration of the dipeptide at 12.5 μg min−1 kg−1 there were no changes in blood pressure or heart rate, but at the higher dose there was a fall in diastolic blood pressure. 8. At a dose of 12.5 μg min−1 kg−1 in man, there is kidney specific conversion of gludopa to dopamine.

Dissociation of Renin-Aldosterone and Renal Prostaglandin E during Volume Expansion Induced by Immersion in Normal Man

1980 ◽  
Vol 59 (1) ◽  
pp. 55-62 ◽  
Author(s):  
M. Epstein ◽  
M. D. Lifschitz ◽  
R. Re ◽  
E. Haber
Keyword(s):  
Plasma Renin Activity ◽  
Volume Expansion ◽  
Water Immersion ◽  
Plasma Renin ◽  
Normal Subjects ◽  
Plasma Aldosterone ◽  
Renin Activity ◽  
Prostaglandin E ◽  
Plasma Aldosterone Concentration ◽  
Normal Man

1. The relationship of the renin-angiotensin-aldosterone axis with renal prostaglandin E is complex. Although studies have suggested that these two hormonal systems respond to experimental manipulations in a parallel manner, their interdependence has not been assessed fully during volume expansion. Since studies have demonstrated that in normal man the central hypervolaemia induced by water immersion to the neck produces a prompt and profound suppression of plasma renin activity and plasma aldosterone concentration without concomitant alteration of plasma composition, immersion afforded a unique opportunity to assess simultaneously the effects of central hypervolaemia on plasma renin activity, plasma aldosterone concentration and prostaglandin E excretion. 2. Seven normal subjects were studied twice while in balance on a diet containing 10 mmol of sodium/day, 100 mmol of potassium/day: with indomethacin administration (50 mg given every 6 h for five doses) and without indomethacin. Urinary prostaglandin E excretion was measured hourly and plasma renin activity and plasma aldosterone concentration at 30 min intervals. 3. Immersion was associated with a marked suppression of plasma renin activity (59 ± 7%) and plasma aldosterone concentration (55 ± 3%) with a return to pre-study values during the recovery hour. Concomitantly, urinary prostaglandin E excretion increased from 4.7 to a peak of 10.9 ng/min. Although administration of indomethacin lowered the basal rate of urinary prostaglandin E excretion and plasma renin activity, it did not prevent the subsequent augmentation of urinary prostaglandin E or the suppression of plasma renin activity and plasma aldosterone during the subsequent 4 h of immersion. 4. These results demonstrate a dissociation of renin-aldosterone and prostaglandin E during hypervolaemia and suggest that whereas prostaglandin E may constitute one of the major determinants of renin release clinically and experimentally, these two hormonal systems can be dissociated from each other in response to central volume expansion in man.

Effect of prolonged exercise at altitude on the renin-aldosterone system

1983 ◽  
Vol 55 (2) ◽  
pp. 413-418 ◽  
Author(s):  
J. S. Milledge ◽  
D. M. Catley ◽  
E. S. Williams ◽  
W. R. Withey ◽  
B. D. Minty
Keyword(s):  
Prolonged Exercise ◽  
Marked Decrease ◽  
Recovery Period ◽  
Plasma Renin ◽  
Plasma Aldosterone ◽  
Plasma Aldosterone Concentration ◽  
Ace Activity ◽  
Low Altitude ◽  
Maximal Rise ◽  
Male Subjects

The combined effect of exercise and altitude on the renin-aldosterone system was studied in six male subjects on a fixed diet. After 4 control days at rest and at low altitude, subjects ascended to 3,100 m and took about 7 h exercise daily for 5 days. There followed a 4-day recovery period at low altitude. Daily blood samples were taken for estimation of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and angiotensin converting-enzyme (ACE) activity. Results showed a maximal rise in PRA and PAC with exercise at altitude maximal on the first 2 days. ACE activity fell by 23% at altitude. Compared with similar exercise at sea level, the rise in PAC was comparable but the rise in PRA was four times greater, indicating a marked decrease in PAC response to PRA. It is suggested that this loss of sensitivity of PAC to PRA is mediated by the measured reduction in ACE activity.

Evidence that intrarenal dopamine acts as a paracrine substance at the renal tubule

1989 ◽  
Vol 257 (3) ◽  
pp. F469-F477 ◽  
Author(s):  
H. M. Siragy ◽  
R. A. Felder ◽  
N. L. Howell ◽  
R. L. Chevalier ◽  
M. J. Peach ◽  
...  
Keyword(s):  
Sodium Excretion ◽  
Sodium Intake ◽  
Renal Plasma Flow ◽  
Sch 23390 ◽  
Plasma Renin ◽  
Systemic Arterial Pressure ◽  
Urinary Flow ◽  
Plasma Aldosterone Concentration ◽  
Renal Dopamine ◽  
Dose Dependent

Dopamine is synthesized within the kidney and dopamine 1 (DA1) receptors are associated with the proximal tubule. In pharmacological doses, dopamine increases renal blood flow and sodium excretion. It is possible that dopamine formed intrarenally acts locally via renal dopamine receptors to control renal function. We investigated the possible paracrine action of renal dopamine by intrarenal administration of a specific DA1 antagonist, Sch 23390, in doses confined to the kidney in conscious uninephrectomized dogs (n = 5) in metabolic balance at a sodium intake of 40 meq/day. Changes (mean +/- SE) in renal excretory and hemodynamic function in response to cumulative infusions of several doses of Sch 23390 (0.01, 0.1, 1.0, 5.0, and 10.0 pmol.kg-1.min-1) were studied. Sch 23390 at 0.01 pmol.kg-1.min-1 did not cause any changes in urinary flow rate or sodium excretion. Sch 23390 in doses from 0.1 to 10.0 mol.kg-1.min-1 caused a significant dose-dependent antidiuresis (F = 44.9, P less than 0.0001) and antinatriuresis (F = 42.1, P less than 0.0001) and a decrease in fractional sodium excretion (F = 44.2, P less than 0.0001). No changes in estimated renal plasma flow, glomerular filtration rate, plasma aldosterone concentration, plasma renin activity, or systemic arterial pressure occurred with any dose of intrarenal Sch 23390 infused into the renal artery. Rebound diuresis and natriuresis occurred after cessation of the DA1 blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

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