Effects of SK&F 85174, a DA-1/DA-2 receptor agonist, on pre- and postganglionic sympathetic neurotransmission to the heart

We have performed experiments to determine the effects of SK&F 85174, a mixed DA-1/DA-2 receptor agonist, on the tachycardia elicited during pre- and postganglionic stellate stimulation in anesthetized dogs in order to identify a possible action of this compound on the stellate ganglia. SK&F 85174 produced hypotension and caused significant impairment of positive chronotropic responses elicited during pre- and postganglionic stellate stimulation. Pharmacological analysis of SK&F 85174-induced inhibition of cardiac sympathetic function with selective DA-1 and DA-2 receptor antagonists revealed that prior treatment with either S-sulpiride or domperidone (DA-2 receptor antagonists) significantly attenuated the inhibitory effects of SK&F 85174 on responses to pre- and postganglionic stellate stimulation. R-sulpiride (DA-1 receptor antagonist) failed to antagonize SK&F 85174-induced inhibition of tachycardia elicited during preganglionic stellate stimulation. Pretreatment with SCH 23390 (DA-1 receptor antagonist) did not modify the inhibitory effect of SK&F 85174 on responses to postganglionic nerve stimulation. However, SCH 23390 was most effective in antagonizing the hypotensive effect of SK&F 85174. These results show that SK&F 85174 inhibits sympathetic neurotransmission to the heart by activating presynaptic and possibly ganglionic DA-2 receptors, whereas the hypotension produced by SK&F 85174 results predominantly from the activation of the vascular DA-1 receptors. SK&F 85174 does not seem to exert any effect on the ganglionic DA receptors which are reported to be activated by the selective DA-1 receptor agonist, fenoldopam.     

Renal,cardiac, and systemic hemodynamic effects of the dopamine receptor agonist SK&F 85174 in anesthetized dogs

SK&F 85174 is a mixed DA-1/DA-2 receptor agonist which is shown to inhibit sympathetic neurotransmission and cause hypotension in anesthetized animals. In this study, we have determined the regional and systemic hemodynamic effects of an intravenous infusion of SK&F 85174 (5 μg/kg/min for 5 min) in pentobarbital-anesthetized dogs and attempted to identify the dopamine receptor subtype(s) involved in the cardiac as well as vascular effects of this compound. SK&F 85174 produced significant decreases in mean blood pressure (MBP), left ventricular pressure (LVP), left ventricular dp/dt, total peripheral resistance (TPR) and renal vascular resistance (RVR), and a significant increase in renal blood flow (RBF). There were no significant changes in heart rate, cardiac output, coronary blood flow, or coronary vascular resistance. Prior treatment with SCH 23390 (DA-1 receptor antagonist) significantly attenuated the effects of SK&F 85174 on MBP, LVP, TPR, RBF, and RVR. In a second group of dogs S-sulpiride (DA-2 receptor antagonist) significantly antagonized the effects of SK&F 85174 on MBP, LVP, and dp/dt, but did not influence its effects on RBF, TPR, and RVR. These results show that (a) a decrease in total peripheral resistance and not the cardiac output accounts for the hypotensive action of SK&F 85174, (b) the renal hemodynamic effects of SK&F 85174 are mediated primarily via the activation of DA-1 receptors, and (c) whereas DA-1 receptors are involved primarily with the hypotensive action of this compound, it appears that activation of DA-2 receptors also contributes to the hypotension.     

Dose-response analysis of the effects of fenoldopam,dopamine-1 receptor agonist,on renal function

The present study was carried out to perform a dose-response analysis of the effect of fenoldopam, a DA-1 receptor agonist, on renal sodium excretion. Infusions of fenoldopam for 30 min at doses of 0.125, 0.25, 0.5, and 1.0 μ/kg/min in four separate groups of pentobarbital-anesthetized dogs cused dose-dependent hypotension and renal vasodilation. The reflex tachycardic response was not dose-dependent and seen only with the three higher doses. There was no change in glomerular filtration with any of the four doses of fenoldopam. At the doses of 0.25 and 0.5 μ/kg/min fenoldopam caused significant increases in urine volume, urinary sodium excretion, and fractional excretion of sodium during the infusion as well as during the first recovery period of 30 min. At the highest dose of 1 μ/kg/min no diuresis or natriuresis was seen during the infusion; however, significant increases in urine volume and sodium excretion were seen during the two recovery periods. At the lowest dose (0.125 μ/kg/min) fenoldopam caused minimal hemodynamic changes but produced maximum increases in urine volume and urinary sodium excretion. These effects of fenoldopam were antagonized by the DA-1 receptor antagonist, SCH 23390. The results of our study show that the tublar effects of fenoldopam leading to increased renal sodium excretion are evident at doses lower than those required to cause changes in systemic and renal hemodynamics. In addition, at higher doses when the magnitude of hypotension is very pronounced, this effect may limit the increase in sodium excretion produced by fenoldopam.     

Hypotensive and bradycardic effects elicited by spinal dopamine receptor stimulation: effects of D1 and D2 receptor agonists and antagonists.

In anesthetized rats, intrathecal (i.t.) administration, at the upper thoracic level of the spinal cord of fenoldopam (a selective dopamine D1-receptor agonist) or quinpirole (a selective D2-receptor agonist) decreased blood pressure (BP) and heart rate (HR) in a dose-dependent manner. Apomorphine, a nonselective DA receptor agonist, produced similar effects. Apomorphine-induced hypotension was competitively antagonized by either SCH 23390 or remoxipride, selective D1- and D2-receptor antagonists, respectively, but only remoxipride antagonized the bradycardia. Furthermore, SCH 23390 antagonized the hypotensive effect of fenoldopam but did not change that induced by quinpirole. Remoxipride antagonized the hypotensive effect of quinpirole but did not alter the hypotensive effect of fenoldopam. Quinpirole-induced bradycardia was antagonized only by remoxipride. Bradycardia elicited by fenoldopam did not appear to be generated by dopamine receptor stimulation, as suggested by the lack of blocking effects of SCH 23390 and remoxipride. Data obtained with fenoldopam were corroborated with use of SK&F 38393, another dopamine D1-receptor agonist. We conclude that hypotensive effects of i.t.-administered DA receptor agonists appear to result from activation of spinal D1- and D2-receptors whereas bradycardia is related only to activation of spinal D2-receptors.     

Preclinical and clinical studies on the cardiovascular and renal effects of fenoldopam: A DA-1 receptor agonist

Recent research in the area of peripheral dopamine (DA) receptors has led to the identification of two distinct subtypes of DA receptors, activation of which results in marked changes in the cardiovascular and renal function consisting of hypotension, bradycardia, diuresis, and natriluresis. Peripheral DA receptors mediating these effects are subdivided into DA-1 and DA-2 subtypes. The development of selective DA-1 and DA-2 receptor agonists and antagonists has made it possible to furhter characterize DA receptors located at various sites within the cardiovascular system. It is now established that activation of DA-1 receptors located on blood vessel produces vasodilation, whereas stimulation of DA-2 receptors on postganglionic sympathetic nerves results in the inhibition of norepinephrine release. The renal effects of DA receptor agonists either involve activation of specific DA receptors at various sites in the kidney and/or result from renal hemodynamic changes produced by these compounds. The concept of developing selective DA receptor agonists as therapeutic agents in the treatment of cardiovascular disorders has been proposed by several investigators. Fenoldopam (SK&F 82526) represents one of these new orally active DA receptor agonists developed for potential use in the treatment of hypertension and ischemic renal disease. In animal experiments fenoldopam was shown to produce hypotension and increase renal blood flow. It produced natriuresis and diuresis, and these effects were due to the activation of DA-1 receptors. Recent clinical studies show that fenoldopam decreases blood pressure and renal vascular resistance and causes diuresis and natriuresis in hypertensive patients. The antihypertensive action of fenoldopam is mediated by a decrease in total peripheral resistance. There are increases in heart rate and plasma renin activity in hypertensive patients. Fenoldopam also improves left ventricular performance in patients suffering from congestive heart failure. These initial studies with fenoldopam show that peripheral DA-1 receptor stimulation may represent an effective approach in the treatment of cardiovascular diseases. Future research in this area should be aimed toward developing DA-1 receptor agonists that have longer duration of action and do not evoke renin release, while maintaining the beneficial effects on the kidney.     

Dopamine agonists related to 3-allyl-6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzaz epi ne-7, 8-diol. 6-Position modifications

The N-allyl derivative (SK&F 85174) of 6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-diol (SK&F 82526) retains the DA-1 agonist potency of the latter compound but unlike the parent also shows substantial DA-2 agonist activity. In a previous study of N-substituted benzazepines these combined agonist effects were shown to be uniquely associated with the N-allyl group. A continuation of this research has examined dependency of combined DA-2/DA-1 agonist activities on 6-position modification with the specific objective of developing an agonist with maximum effectiveness and potency at the DA-2 receptor subtype. DA-2 agonist activity was measured in a rabbit ear artery assay, and DA-1 agonist activity was determined in an adenylate cyclase assay. Replacing chloro with bromo retains the activity pattern and the potency of the chloro compound; replacement with a hydrogen causes a decrease of both DA-1 and DA-2 receptor activating potency. Introduction of a 6-methyl group causes loss of DA-2 agonist activity and reduction in DA-1 agonist potency. Substitution with a 6-fluoro provides the best balance of DA-2 and DA-1 agonist activities; this compound was moderately potent in both assays.     

Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed.

The effect of local administration of the dopamine 2 (DA2)-receptor agonist quinpirole and of the DA1-receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. Local infusion of quinpirole (30 micrograms kg-1 min-1 for 5 min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 +/- 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. The inhibitory effect of quinpirole was antagonized by the selective DA2-receptor antagonist domperidone (10 micrograms kg-1) but not by the selective DA1-receptor antagonist SCH 23390 (50 micrograms kg-1). Local infusion of fenoldopam (30 micrograms kg-1 min-1 for 5 min) reduced baseline perfusion pressure to 89.9 +/- 1.9%, increased the pressor response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 +/- 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 +/- 8.2%. Similar pressor responses induced by the selective alpha 1-adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 +/- 6.4%), but responses to locally administered angiotensin II were not modified. Pretreatment with SCH 23390 (50 micrograms kg-1) antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. Pretreatment with the selective alpha 2-adrenoceptor antagonist rauwolscine (100 micrograms kg-1) had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

A68930 is a potent, full agonist at dopamine1 (D1) receptors in renal epithelial LLC-PK1 cells.

The selective dopamine1 (D1) receptor agonists SK&F 82526 (fenoldopam) and A68930 and the mixed D1/D2 agonist SK&F 85174 were tested for their ability to stimulate adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation in the porcine renal epithelial cell line, LLC-PK1. SK&F 82526 and SK&F 85174 were potent stimulators of cyclic AMP accumulation (EC50s 21.4 and 14.5 nM, respectively), but only partial agonists (intrinsic activities 31% and 46% of dopamine respectively). In contrast, A68930 was a potent, full agonist (EC50 12.7 nM, intrinsic activity 102% of dopamine). The stimulatory effects of A68930 and dopamine on cyclic AMP accumulation were not additive, and the stimulation of cyclic AMP accumulation by A68930 was blocked by the D1-selective antagonist, SCH 23390. These properties of A68930 suggest that it may be a useful D1-selective agonist to study renal D1 receptor mechanisms in vitro and in vivo.     

Relative dopamine D1 and D2 receptor affinity and efficacy determine whether dopamine agonists induce hyperactivity or oral stereotypy in rats

The effects of a range of dopamine (DA) agonists on stereotyped behaviour in rats were analysed and compared both with the affinity of the compounds for D1 and D2 receptor binding sites in vitro and their ability to stimulate the adenylate cyclase activity in rat striatal homogenates. Full and partial agonists at the D1 receptor coupled to adenylate cyclase do not induce sterotypies when given alone, whereas full D2 agonists (e.g. quinpirole) induce hyperactivity but not oral sterotypies. Partial D2 agonists (e.g. (-)-3-PPP) only induce sedation. Mixed D1/D2 agonists (e.g. apomorphine) induce both hyperactivity and oral stereotypies. Maximum stereotypies were induced by combination of SK & F 38393 and a series of D2 agonists, including full agonists and the partial D2 agonist B-HT 920, whereas partial agonists with low intrinsic activity (e.g. (-)-3-PPP, EMD 23448) did not induce stereotypies when given together with SK & F 38393. However, these partial agonists reduced the maximum effect of apomorphine, whereas the full agonists (e.g. quinpirole, (-)-NPA) and B-HT 920 had no apomorphine antagonistic activity. The mixed D1/D2 agonists apomorphine and N,N-dipropyl-5,6-ADTN were only weakly influenced by SK & F 38393, or not at all. D1 agonists with central effects, including SK & F 38393, SK & F 81297 (with relatively high efficacies), and the partial agonist SK & F 75670 with low efficacy, changed the hyperactivity induced by quinpirole into maximum oral stereotypy, whereas the peripheral D1 agonist fenoldopam had no such effect. Inhibition of DA and NA synthesis with alpha-methyl-p-tyrosine depleted striatal DA levels by 72 per cent and antagonized the hyperactivity induced by the D2 agonists quinpirole and (-)-NPA, but not that of apomorphine. Combination of SK & F 38393 and quinpirole induced maximum stereotypy in DA-depleted animals. These results suggest that D1 receptor tonus is a necessary prerequisite for the expression of a DA agonist's effect. The hyperactivity induced by full D2 agonists appears to be mediated by D1 tonus provided by endogenous DA activity, but stronger D1 stimulation is necessary to induce oral stereotypy. A high degree of D1 receptor activation increases the ability of partial D2 agonists to induce hyperactivity or oral stereotypies since treatment with both SK & F 38393 and B-HT 920 had marked effects while B-HT 920 was ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhibition of Na+, K+-ATPase in rat renal proximal tubules by dopamine involved DA-1 receptor activation

Summary Endogenous kidney dopamine (DA) causes natriuresis and diuresis, at least partly, via inhibition of proximal tubular Na⁺,K⁺-ATPase. The present study was done to identify the dopamine receptor subtype(s) involved in dopamine-induced inhibition of Na⁺,K⁺-ATPase activity. Suspensions of renal proximal tubules from Sprague-Dawley rats were incubated with dopamine, the DA-1 receptor agonist fenoldopam or the DA-2 receptor agonist SK&F 89124 in the presence or absence of either the DA-1 receptor antagonist SCH 23390 or the DA-2 receptor antagonist domperidone. Dopamine and fenoldopam (10^–5 to 10^–8 mol/1) produced a concentration-dependent inhibition of Na⁺,K⁺-ATPase activity. However, SK&F 89124 failed to produce any significant effect over the same concentration range. Incubation with fenoldopam (10^–5 to 10^–8 mol/1) in the presence of SK&F 89124 (10^–6 mol/l) inhibited Na+,K+-ATPase activity to a degree similar to that with fenoldopam alone. Furthermore, DA-induced inhibition of Na⁺,K⁺-ATPase activity was attenuated by SCH 23390, but not by domperidone. Since -adrenoceptor activation is reported to stimulate Na⁺,K⁺-ATPase activity and, at higher concentrations, dopamine also acts as an a-adrenoceptor agonist, the potential opposing effect from -adrenoceptor activation on DA-induced inhibition of Na⁺,K⁺-ATPase activity was investigated by using the -adrenoceptor blocker phentolamine. We found that, in the lower concentration range (10^–5 to 10^–7 mol/1), dopamine-induced inhibition of Na⁺,K⁺-ATPase activity in the presence of phentolamine was similar in magnitude to that observed with dopamine alone. However, at the highest concentration used (10^–4 mol/1), dopamine produced a significantly larger degree of inhibition of Na⁺,K⁺-ATPase activity in the presence of phentolamine. These results indicate that the DA-1 dopamine receptor subtype, but not the DA-2 receptor subtype, is involved in dopamine-mediated inhibition of Na⁺,K⁺-ATPase. At higher concentrations of dopamine, the DA-1 receptor-mediated inhibitory effect on Na⁺,K⁺-ATPase activity may be partly opposed by a simultaneous -adrenoceptor-mediated stimulation of the activity of this enzyme.     

Studies on the mechanisms of the development of tolerance to the hypotensive effects of fenoldopam in rats

In pentobarbital-anesthetized rats prepared for hemodynamic measurements with Doppler flow probes, intravenous (i.v.) infusions of fenoldopam (2.5 - 160.0 micrograms/kg/min during 15 min) decreased mean carotid artery blood pressure, total peripheral, hindquarter, renal, and mesenteric vascular resistances and increased renal blood flow strongly. The hypotensive effects attained a maximum within the first 3 min of infusion but waned by greater than 30% at the end of fenoldopam administration. This tolerance was observed for calculated total peripheral and hindquarter vascular resistances and to a lesser extent for mesenteric resistance. However, it was absent on the renal vascular bed. Pretreatment with either enalapril, pepstatine, or bilateral nephrectomy significantly increased the hypotensive response to fenoldopam and attenuated the development of tolerance. In conscious spontaneously hypertensive rats (SHR), enalapril potentiated strongly the small blood pressure-lowering activity of fenoldopam. The fall in blood pressure produced by fenoldopam was specifically blocked by SCH 23390, an antagonist of DA-1 dopamine receptors. In normotensive vasopressin-supported pithed rats given phenoxybenzamine plus propranolol, fenoldopam, like SCH 23390, blocked the vasodepressor effects of i.v. bolus injection of dopamine and fenoldopam. In pithed rats, fenoldopam evoked a pressor response that was significantly reduced by enalapril, SCH 23390, or bilateral nephrectomy. In conclusion, fenoldopam exerts DA-1 agonist and antagonist effects. The latter property, together with the activation of the renin-angiotensin system, appears to be responsible for the development of tolerance to the fenoldopam evoked-hypotension. The lack of a tolerance at the level of the renal vascular bed is possibly due to the existence of a large population of DA-1 receptors in this region.     

Cardiac and peripheral vascular effects of decaborane

Decaborane (4–10 mg/kg, iv) produced bradycardia and an initial transient hypertensive effect in the anesthetized dog. The compound produced an increase in perfusion pressure in the isolated denervated canine hind limb, which was antagonized by phentolamine and reserpine but not by P-286 (N,N-diisopropyl-N-isoamyl-N′-diethylamino urea HCl). Decaborane produced an immediate decrease in cardiac output without affecting stroke volume, whereas right ventricular contractile force gradually decreased to below basal levels in approximately 60 min in anesthetized dogs. The bradycardia produced by decaborane was partially antagonized in the initial stages by atropine and chlorisondamine. Subsequently, these agents had no effect on this response of decaborane. Carotid sinus denervation and bilateral vagotomy did not alter the bradycardiac response of decaborane. It was concluded that the initial hypertensive effect and increase in perfusion pressure to the denervated hind limb was due to the acute release of norepinephrine from peripheral adrenergic neurons and the myocardial depression was induced by cholinergic stimulation as well as by a direct, nonspecific depression of myocardial contraction produced by decaborane.     

Studies on renal dopamine receptors with a new agonist.

SK & F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) is a new dopamine receptor agonist which selectively increased renal blood flow when administered i.v. to dogs at cumulative doses of 3.3-1333 microgram/kg. Consistent changes in arterial blood pressure heart rate and cardiac output were not observed. The renal response, which was mediated locally in the kidney, was not antagonized by adequate blocking doses of atropine, propranolol, metiamide and/or mepyramine nor by reserpinization or treatment with indomethacin. It was inhibited, however, by the selective peripheral dopamine receptor antagonist, bulbocapnine. Perhaps as a result of its action on renal blood flow, SK & F 38393 produced a diuresis in normally hydrated rats which was characterized by an increased excretion of sodium, potassium and chloride and a increased urinary pH. Compounds of this type may be useful in better defining dopaminergic receptors and in the treatment of disease states where renal ischemia is present.     

Impaired renal vascular response to a D1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats.

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D1-like receptor agonist fenoldopam (2 microg/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p < 0.01), whereas this response was absent in SHRs (+7 +/- 3%; NS). Mean arterial pressure (MAP) was significantly reduced in SHRs (-11 +/- 2%; p < 0.001), demonstrating a systemic vasodilator response to fenoldopam in SHRs. The reduction in renal vascular resistance (RVR) was more pronounced in WKY rats (-24 +/- 2%) than in SHRs (-13 +/- 4%; p < 0.05). Captopril significantly increased ERPF in SHRs (+16 +/- 3%; p < 0.001), demonstrating a preserved renal vasodilatory capacity in SHRs. The blunting of the renal vasodilatory response to fenoldopam in SHRs is present during a high as well as a low sodium intake. In conscious SHRs, the renal vasodilatory response to a D1-like receptor agonist is impaired, whereas the blood pressure response is more pronounced. The preserved renal vasodilatory response to captopril indicates that the defective vasodilatory response in SHRs is functional rather than due to altered structural properties of the renal vascular bed.     

Synergistic interaction between dopamine D-1 and D-2 receptor agonists: circling behaviour of rats with hemitransection

Circling behaviour induced by dopamine (DA) agonists with different D-1/D-2 receptor selectivity was studied in rats with hemitransection at a level caudal to the striatum. The mixed D-1/D-2 agonist apomorphine induced ipsilateral circling behaviour after administration of doses similar to those that induced stereotyped behaviour in unlesioned rats. The effect of apomorphine was not influenced by co-treatment with SK & F 38393 or quinpirole, indicating that apomorphine induces a comparable D-1 and D-2 receptor stimulation in vivo also. Three selective D-1 agonists, SK & F 38393, SK & F 75670 and Lu 24-040 had no effects alone, while the preferential D-2 agonists quinpirole, pergolide and (-)-N-propylnorapomorphine induced ipsilateral circling of weaker intensity than did apomorphine. After co-treatment with SK & F 38393 the effects of these compounds were markedly increased. Combination of SK & F 38393, SK & F 75670 or Lu 24-040 with quinpirole induced circling with intensities similar to those seen after apomorphine. Pretreatment with the D-1 antagonist SCH 23390 or the D-2 antagonist YM 09151-2 completely antagonized the ipsilateral circling induced by either apomorphine or quinpirole + SK & F 38393. A range of partial (autoreceptor) D-2 agonists, i.e. (-)-3-PPP, (+)-3-phenethyl-PP, terguride, EMD 23448 and B-HT 920 were all ineffective as was the alpha 2-adrenoceptor agonist clonidine. However, B-HT 920 induced strong ipsilateral circling after combination with SK & F 38393, whereas (-)-3-PPP was ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of dopamine D1 and dopamine D2 receptor agonists on coronary and peripheral hemodynamics

This study evaluated the coronary dopamine receptors by using the dopamine D1 receptor agonist fenoldopam, dopamine D2 receptor agonist propylbutyldopamine, and their selective antagonists SCH23390 and domperidone. Left circumflex coronary flow (CF), coronary perfusion pressure at constant flow, left ventricular hemodynamics, and total peripheral vascular resistance (TPR) were measured in pentobarbital-anesthetized dogs at constant arterial pressures. At doses of 200, 500 and 5000 nM, both fenoldopam and propylbutyldopamine induced dose-related inotropic effects, as evidenced by maximal dp/dt and cardiac output, an increase in CF, decrease in coronary vascular resistance and a decrease in TPR. Fenoldopam was more potent in its cardiac and coronary effects while propylbutyldopamine was more potent peripherally. On the basis of dosage used, the positive inotropic effects of fenoldopam and propylbutyldopamine were much weaker than dopamine. After beta-receptor blockade, the inotropic and coronary effects of fenoldopam and propylbutyldopamine were extremely attenuated. Domperidone could largely antagonize the propylbutyldopamine-induced inotropic and coronary effects while SCH23390 showed no significant effect. In addition, under our experimental conditions, the fenoldopam- and propylbutyldopamine-induced decreases in TPR were markedly reduced by SCH23390 and domperidone, respectively. The results indicate that the coronary effects of fenoldopam and propylbutyldopamine result not from a primary coronary vasodilating action, but from vasodilation secondary to positive inotropic effects. Both dopamine D1 and dopamine D2 receptors are involved in the peripheral vascular hemodynamics.     

Covalent binding of a selective agonist irreversibly activates guinea pig coronary artery A2 adenosine receptors

Summary Experiments employing guinea pig heart Langendorff preparations compared the coronary vasoactivity of a functionalized congener of adenosine, 2-[(2-aminoethyl-aminocarbonylethyl)phenylethylamino]-5-N-ethylcarboxamidoadenosine, APEC, with the vasoactivity of the product of the reaction of APEC with 1,4-phenylenediisothiocyanate, 4-isothiocyanatophenylaminothiocarbonyl-APEC (DITC-APEC). Previous experiments showed that whereas APEC binds reversibly to the A_2A adenosine receptor of brain striatum, DITC-APEC binds irreversibly. APEC caused concentration-dependent coronary vasodilation that persisted unchanged when agonist administration continued for up to 165 min, but promptly faded when the agent was withdrawn. The unselective adenosine receptor antagonist 8-(4-sulfophenyl)theophyline (8-SPT) antagonized the vasoactivity of APEC. By contrast, DITC-APEC1 (0.125 -1.0 nM) caused progressive, concentration-independent vasodilation that persisted unchanged for as long as 120 min after the agent was stopped and that was insensitive to antagonism by subsequently applied 8-SPT. However, perfusion of the heart with buffer containing 0.1 mM 8-SPT strongly antagonized the coronary vasodilatory action of DITC-APEC1 given subsequently. Such observations indicate that the covalent binding of DITC-APEC1 causes irreversible activation of the guinea pig coronary artery A_2A adenosine receptor. Neither APEC nor DITC-APEC appeared to desensitize the coronary adenosine receptor during two or more hours of exposure to either agonist. Correspondence to R. A. Olsson at the above address     

Neuroinhibitory effects of SK&F 85174, a novel dopamine receptor agonist

SK&F 85174 (3-allyl-6-chloro-2,3,4,5-tetra-hydro-1-(4-hydroxy-phenyl)-1-H-3-benzaze pine-7, 8-diol methanesulfonate) the N-allyl derivative of SK&F 82526, a selective postjunctional dopaminergic agonist, retains the potent agonist activity of the parent molecule at the postjunctional dopamine receptor, as evidenced by activation of the dopamine-sensitive adenylate cyclase in rat caudate homogenates (EC50 = 11 nM). However, unlike SK&F 82526, SK&F 85174 is a potent inhibitor of adrenergic neurotransmission. This neuroinhibitory effect can be demonstrated both in isolated vascular preparations, and in in situ preparations in the anesthetized dog measuring both cardiac and vascular neurotransmission. In each of these preparations, the effect of SK&F 85174 can be blocked by the dopamine receptor antagonists, metoclopramide, or 1-sulpiride, showing that its action occurs via activation of prejunctional dopamine receptors. Inhibition of the responses to sympathetic nervous system activation, when combined with the ability to increase renal blood flow by stimulation of postjunctional dopamine receptors, could make SK&F 85174 an effective therapeutic agent for a variety of cardiovascular disorders, including angina pectoris, hypertension, and congestive heart failure.     

Rat juxtaglomerular cells are endowed with DA-1 dopamine receptors mediating renin release

Under control conditions a primary culture containing about 80-90% of granular juxtaglomerular (JG) cells prepared from rat kidneys continuously released renin into the culture medium at a rate of 17.9 +/- 1.4 ng angiotensin I/h per mg of cell proteins per 30 min (n = 14). Dopamine (1.0 microM), the DA-1 dopamine receptor agonist fenoldopam (0.5 microM), and isoproterenol (1.0 microM) increased renin secretion markedly (130-200%). Propranolol (0.1 microM) reduced the effects of isoproterenol significantly (80%), but not those of dopamine or fenoldopam. In contrast, SCH 23390 (0.01 microM), a DA-1 dopamine receptor antagonist, inhibited markedly only the renin release evoked by the latter two agonists, whereas S-sulpiride (10 microM), a DA-2 dopamine receptor antagonist, and phentolamine (10 microM), a nonselective alpha-adrenoceptor antagonist, did not modify the effects of either dopamine or fenoldopam. In rats, pithed to eliminate reflexogenic mechanisms regulating renin release, at the end of a 15 min i.v. infusion of fenoldopam (20 micrograms/kg per min) there was a significant increase in plasma renin activity. This effect was completely prevented by SCH 23390 (0.1 mg/kg i.v.) but not significantly changed by S-sulpiride (0.3 mg/kg i.v.) or phentolamine (3.0 mg/kg i.v.) plus propranolol (0.75 mg/kg i.v.). In conclusion, these results indicate that DA-1 dopamine receptors are present in rat kidney JG cells and that pharmacological stimulation of these receptors with dopamine or fenoldopam leads to renin secretion.     

A novel transduction mechanism mediating dopamine-induced vascular relaxation: opening of BKCa channels by cyclic AMP-induced stimulation of the cyclic GMP-dependent protein kinase.

Dopamine dilates the coronary, renal and other vascular beds; however, the signaling pathway underlying this effect is unclear. In this study the signal-transduction process mediating dopamine-induced relaxation of porcine coronary arteries was investigated in isolated vessels and single arterial myocytes. Dopamine-induced relaxation of arteries was mediated through the DA- receptor and involved K+ efflux, and subsequent patch-clamp studies demonstrated that either dopamine or fenoldopam, a selective DA-1 agonist, increased the opening probability of the large-conductance, calcium- and voltage-activated K+ (BKCa) channel in coronary myocytes. Moreover, blockade of this channel by iberiotoxin prevented dopamine-induced coronary relaxation. Dopamine stimulation of BKCa channels was completely prevented by a DA-1-receptor antagonist, but was unaffected by propranolol. Furthermore, inhibiting adenylyl cyclase activity prevented stimulation of BKCa channel activity, whereas chlorophenylthio (CPT)-cyclic adenosine monophosphate (AMP), a membrane-permeable analog of cyclic AMP, mimicked the effects of dopamine. Interestingly, inhibiting the cyclic AMP-dependent protein kinase (PKA) did not affect the response to dopamine, whereas dopamine-induced channel activity was completely blocked by inhibiting the activity of the cyclic guanosine monophosphate (GMP)-dependent protein kinase (PKG). These findings demonstrate that activation of DA-1 receptors causes stimulation of BKCa channel activity by a mechanism involving cyclic AMP-dependent stimulation of PKG, but not PKA, and further suggest that this cross-reactivity mediates dopamine-induced coronary vasodilation.