Dopamine DA1 Receptor Agonist Research Articles

Pharmacological and Pharmacokinetic Characteristics of YM435, a Novel Dopamine DA1-Receptor Agonist, in Anaesthetized Dogs

Time-course of plasma concentration of unchanged drug of the dopamine DA1-receptor agonist (-)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4- tetrahydroisoquinoline hydrochloride hydrate (YM435), and its effects on blood pressure and renal blood flow were investigated in anaesthetized dogs. Continuous intravenous infusion of YM435 (0.1-3 micrograms kg-1 min-1) rapidly increased renal blood flow and lowered blood pressure in a dose-dependent manner. These effects remained generally stable throughout the infusion period. Following the start of infusion, plasma concentration of unchanged drug also rose rapidly and dose-dependently and remained virtually constant throughout the infusion period. A significant correlation was observed between log YM435 plasma concentration and the increase in renal blood flow (r = 0.93, P < 0.0001) and between the former and the reduction in blood pressure (r = 0.93, P < 0.0001). The present results indicate that YM435 produces renal vasodilatation and lowering of blood pressure in a dose-dependent manner and with rapid onset following continuous intravenous infusion, and that these effects are generally stable throughout the period of infusion. These haemodynamic effects of YM435 were in good agreement with the time-course of plasma concentration of unchanged drug.

Effect of Fenoldopam Mesylate in Critically Ill Patients at Risk for Acute Renal Failure is Dose Dependent

Background: Acute renal failure (ARF) is common and difficult to prevent, especially in intensive care unit (ICU) patients with cancer. Therapeutic trials with various agents have generally been ineffective in preventing ARF. We describe the effects of two different doses of the dopamine DA-1 receptor agonist fenoldopam mesylate on renal function in a series of critically ill cancer patients at risk of developing ARF. Methods: We performed a retrospective chart review of 100 consecutive patients who received fenoldopam mesylate for at least 72 h in the medical and surgical ICUs of The University of Texas M. D. Anderson Cancer Center who were at risk of developing ARF. Eighteen patients received low-dose fenoldopam mesylate (≤ 0.05 µg/kg/min). The remaining 82 patients received high-dose fenoldopam mesylate (0.07–0.1 µg/kg/min). Data were collected relating to drug dosage, patient demographics, severity of illness, and indices of renal function. Results: Patients were moderately ill, with a mean APACHE II score of 18 ± 6 at initiation of fenoldopam infusion. Eighty-five percent of patients had at least two risk factors for the development of ARF, and 20% had four. For the group overall, the incidence of ARF was 13%, and the hospital mortality rate was 37%. When compared with the low-dose group, patients who received high-dose fenoldopam had a significantly shorter ICU length of stay despite a significantly higher APACHE II score (p = 0.01). The high-dose group also had a highly significant decrease in serum creatinine levels at 72 h (p = 0.005). Conclusions: These data support the hypothesis that fenoldopam mesylate may provide a degree of dose-dependent renal protection in cancer patients with early acute renal failure.

Effect of YM435, a Dopamine DA 1 Receptor Agonist, in a Canine Model of Ischemic Acute Renal Failure

1. The effects of (-)-( S)-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7,8-diol monohydrochloride monohydrate (YM435), a dopamine DA1 receptor agonist, were evaluated in a canine model of ischemic acute renal failure (ARF). 2. ARF was induced by clamping the left renal artery for 1 hr and subsequent reperfusion of the left kidney in anesthetized uninephrectomized dogs. 3. After 1-hr complete renal artery occlusion, an intravenous infusion of either YM435 (0.3 μg/kg/min) or 0.9% saline (vehicle) was begun and continued for 1 hr. 4. In the vehicle group, renal ischemia markedly decreased glomerular filtration rate, urine flow and urinary sodium excretion. The YM435 group was characterized by significant recoveries in glomerular filtration rate, urine flow, and urinary sodium excretion as compared with the vehicle group. 5. These results indicate that YM435 can facilitate recovery in glomerular filtration rate, urine flow, and urinary sodium excretion in a canine model of ARF induced by ischemia. YM435 may be useful in the preservation of renal function in ischemia-induced ARF.

Effects of Fenoldopam on Intracranial Pressure and Hemodynamic Variables at Normal and Elevated Intracranial Pressure in Anesthetized Pigs

Fenoldopam (FE), a dopamine DA1-receptor agonist, has been introduced for treatment of arterial hypertension and heart failure and for preservation of renal function. Vasodilators are generally assumed to affect all vascular beds including the cerebral circulation. We have evaluated effects of FE-induced (4 micrograms.kg-1.min-1) arterial hypotension on intracranial pressure (ICP) and intraocular pressure (IOP) under conditions of normal and increased intracranial elastance. ICP and IOP responses to hypertension were tested by infusion of angiotensin II (15 micrograms.kg-1.min-1), and the response to hypercapnia was tested by elimination and reintegration of soda lime canisters in the breathing circuit. Intracranial elastance was increased by infusing mock cerebrospinal fluid (CSF) into the lateral ventricle (20 +/- 3 ml.h-1). Arterial hypotension induced with FE did not increase ICP. With increased intracranial elastance, the infusion rate of mock CSF had to be reduced while administering FE to avoid a rise in ICP (p < 0.05 compared with preinfusion value); this indicates a shift on the volume-pressure curve to the right. There were no indicators that cerebral autoregulation or CO2 reactivity of the cerebral vasculature were affected by FE in this anesthetized porcine model, as speculated from analysis of the time course of delta ICP. There are, however, indicators of increased intracranial elastance, most likely caused by vasodilation. Caution should hence be exercised when FE is administered to patients with increased intracranial elastance.

The dopamine DA-1 receptor agonist fenoldopam enhances amino-acid-induced hyperemia in dogs.

The effect of the dopamine DA-1 receptor agonist fenoldopam on amino-acid-induced glomerular hyperemia and hyperfiltration was evaluated in conscious chronically instrumented dogs. Infusion of either amino acids (L-alanine, 4.1 mg/kg.min; L-proline, 3.2 mg/kg.min; L-serine, 2.9 mg/kg.min) or fenoldopam (0.05 micrograms/kg.min) alone resulted in significant (p < 0.05) increases in renal plasma flow of 85 +/- 41 and 53 +/- 24%, respectively. In dogs infused with both amino acids and fenoldopam, there was a dramatic (143 +/- 27%) increase in renal plasma flow (p < 0.01). This response was significantly greater than either treatment alone. The glomerular filtration rate did not change significantly when fenoldopam was infused; however, it increased to a similar degree when dogs were infused with either amino acids or a combination of fenoldopam and amino acids. The data suggest that fenoldopam either acts synergistically with amino acids to increase renal blood flow or perhaps magnifies the renal functional reserve.

Dopamine DA1 receptor agonist, fenoldopam, reverses glycine-induced hyperfiltration in rats.

Stimulation of dopamine DA1 receptors can prevent glomerular hyperfiltration in streptozotocin-induced diabetic rats. In the present study we have therefore investigated whether the DA1 agonist, fenoldopam, can prevent glycine-induced hyperfiltration. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate clearances in conscious chronically instrumented rats. Glycine (3.7 mg/min iv; n = 8) significantly increased GFR by 37% (from 1.09 +/- 0.53 to 1.49 +/- 0.11 ml.100 g-1.min-1, P less than 0.01), ERPF by 23% (from 2.96 +/- 0.30 to 3.64 +/- 0.43 ml.100 g-1.min-1, P less than 0.05), and filtration fraction (FF) by 13% (from 0.39 +/- 0.04 to 0.44 +/- 0.05, P less than 0.05). Fenoldopam, at a dose (1 microgram.kg-1.min-1 iv; n = 8) that increased ERPF by 26%, decreased FF by 13%, but did not change GFR, significantly attenuated the glycine-induced hyperfiltration. In the presence of fenoldopam, glycine resulted in only an 8% increase in GFR (from 1.08 +/- 0.07 to 1.17 +/- 0.09 ml.100 g-1.min-1; n = 8). ERPF increased by 20% (from 3.34 +/- 0.24 to 4.00 +/- 0.21 ml.100 g-1.min-1, P less than 0.05), and FF decreased by 13% (from 0.34 +/- 0.03 to 0.29 +/- 0.02, P less than 0.05). Infusion of the DA1-selective antagonist, Sch 23390, abolished the effects of fenoldopam. Thus DA1 receptor activation can prevent glomerular hyperfiltration induced by glycine.

Dietary salt and blood pressure

We have previously shown that the association between salt intake and blood pressure is large and of substantial public health importance. Analysis of the average blood pressure and average sodium intake in different communities yielded estimates of the decrease in blood pressure for a given reduction in dietary sodium according to age and blood pressure centile that successfully predicted both the association between sodium and blood pressure in observational studies and the reduction in blood pressure obtained in trials of dietary salt reduction. Here we consider the validity of criticisms of the appraisal. The fact that the observed blood pressure reductions in individual trials closely mirrored predicted values for individuals trials that varied widely (from 2.6 to 25.2 mmHg systolic according to age, existing blood pressure and the extent of salt restriction) renders bias implausible since it would be too great a coincidence for a source of error to reproduce such close matching. If the analysis is restricted to trials that avoided possible bias because (1) the high- and low-salt diets were otherwise identical, (2) the order of the diet avoided regression to the mean or (3) the trials were double-blind with diets that were otherwise identical and the order was random, the matching between observed and predicted blood pressure reductions is equally close. Our results are consistent with the Intersalt study. A reduction in dietary salt could be a simple change, yet the reduction in mortality would be large.

Do Renal Tubular Dopamine Receptors Mediate Dopamine-Induced Diuresis in the Anesthetized Cat?

The aim of this study was to investigate whether the pentobarbitone anesthetized cat is a suitable preparation in which to characterize renal tubular dopamine receptors. Intravenous infusion of dopamine (10-100 micrograms/kg/min) resulted in a dose-related increase in mean blood pressure (MBP), urine output, sodium excretion (UNaV), and fractional sodium excretion (FENa). This diuretic effect occurred despite little change in glomerular filtration rate, suggesting that it is a consequence of decreased tubular reabsorption. Dopamine (10-100 micrograms/kg/min, i.v.) also induced marked dose-related falls in renal vascular conductance; however, renal blood flow was not significantly reduced. The increases in MBP, urine output, UNaV, and FENa induced by dopamine (10-100 micrograms/kg/min, i.v.), were unaffected by pretreatment of cats with either the selective dopamine DA1 or DA2 receptor antagonists, SCH 23390 (30 micrograms/kg, i.v.), or domperidone (100 micrograms/kg, i.v.) respectively. In contrast, pretreatment of cats with the nonselective alpha-adrenoceptor antagonist, phentolamine (1 mg/kg, i.v.) prevented dopamine-induced increases in urine output and MBP. Infusion of the selective dopamine DA1 receptor agonist fenoldopam (0.01-10 micrograms/kg/min) into the left renal artery failed to increase left renal vascular conductance, or left kidney urine output, UNaV, or FENa. In conclusion, this study provides no evidence for the involvement of renal tubular dopamine receptors in dopamine-induced diuresis in anesthetized cats. Rather, the diuretic effect appears to be linked to stimulation of alpha-adrenoceptors.

P-423 - Renal effects of YM435, a novel dopamine DA1 receptor agonist, in anesthetized dogs.

P-423 - Renal effects of YM435, a novel dopamine DA1 receptor agonist, in anesthetized dogs.

Tubuloglomerular feedback and blood flow autoregulation during DA1-induced renal vasodilation

The effect of renal vasodilation produced by the dopamine DA1-receptor agonist, fenoldopam (SKF-82526), on tubuloglomerular feedback (TGF) activity and the autoregulation of renal blood flow (RBF) was determined in euvolemic rats. Fenoldopam (2.5 micrograms.kg-1.min-1 iv) increased RBF by 17% (electromagnetic flow probe) while glomerular filtration rate (GFR) was unchanged; mean arterial pressure was decreased by 6%. Superficial cortical blood flow was increased by 12% (laser-Doppler flowmetry) while single-nephron GFR (SNGFR) and estimated glomerular capillary pressure (stop-flow pressure, Psf) were stable. SNGFR measured at proximal and distal sites along the same nephron was not affected by fenoldopam. Partial inhibition of TGF was indicated by the constancy of distal SNGFR and the proximal-distal SNGFR difference in the presence of increased distal delivery of native fluid. However, fenoldopam did not affect feedback control of Psf evaluated by perfusing artificial fluid through Henle's loop at 0-62 nl/min. Despite the decrease in renal vascular resistance over an arterial pressure range of 130 to 70 mmHg, RBF was autoregulated efficiently during fenoldopam infusion. These results indicate that DA1-receptor activation dilates the preglomerular and efferent arterioles without affecting GFR or glomerular pressure. However, this vasodilatory mechanism operates independent of autoregulation and TGF-induced changes in glomerular pressure such that preglomerular vessels remain responsive to the appropriate signals from these intrinsic control systems. The ability of fenoldopam to blunt feedback control of SNGFR may depend on changes in the filtration coefficient independent of glomerular pressure and/or a constituent of natural tubular fluid.

Involvement of cyclic‐AMP in the hypotensive response to fenoldopam but not to quinpirole in the anaesthetized rat

1. The objective of the present investigation was to ascertain whether cyclic-AMP acts as a mediator in the hypotensive responses to fenoldopam, a selective dopamine DA-1 receptor agonist and quinpirole, a selective DA-2 receptor agonist, in the anaesthetized rat. 2. The hypotensive response to two doses of fenoldopam (10 and 40 micrograms kg-1, i.v.), when administered in separate groups of animals was reproducible following the administration of saline. 3. Following the i.v. bolus administration of theophylline, IBMX or forskolin, the hypotensive response to fenoldopam (10 micrograms kg-1, i.v.) was significantly potentiated. In addition, the hypotensive response to the higher dose (40 micrograms kg-1, i.v.) was augmented by IBMX. 4. Neither theophylline nor forskolin influenced the hypotensive response to quinpirole. 5. Prior administration of theophylline or forskolin did not alter the hypotensive response to acetylcholine. On the other hand, the hypotensive response to histamine which is reportedly mediated through cyclic-AMP accumulation was significantly potentiated after theophylline administration. 6. These results suggest that cyclic-AMP may be acting as a mediator in the vasodilation and the resultant hypotension following DA-1 receptor activation by fenoldopam. However, the hypotensive response seen with DA-2 receptor activation does not appear to involve cyclic-AMP.