Dopamine receptor agonists in cardiovascular therapy

Dopamine receptor agonists exert marked cardiovascular and renal actions that result from activation of specific dopamine receptors located at various sites within the cardiovascular system. The presence of at least two distinct subtypes of dopamine receptors is reported. (1) Neurotropic dopamine receptors, also referred to as δ₂ or DA₂ receptors, are located at various sites within the sympathetic nervous system, activation of which leads to inhibition of sympathetic nervous system activity. (2) Postsynaptic dopamine receptors, also referred to as δ₁ or DA₁ are located on vascular smooth muscles of blood vessels as well as at various sites in the kidney, and their activation causes, vasodilatation, inhibition of aldosterone release, and sodium and water reabsorption. The pharmacological responses to activation of neurotropic and postsynaptic dopamine receptors consist of hypotension, bradycardia, diuresis, and natriuresis. Since an elevated sympathetic nervous system activity and retention of salt and water appear to be responsible for several cardiovascular disorders, it is proposed that dopamine receptor agonists may represent a novel class of therapeutic agents for the treatment of certain cardiovascular diseases. Further research efforts in this area are required to understand better the role of endogenous dopamine and dopamine receptors in the maintenance of cardiovascular homeostasis and to develop more selective compounds for experimental and clinical studies in different disease states.     

Dopamine receptor agonists for treating prolactinomas

Prolactinomas are the most common hormone-secreting pituitary tumours and cause infertility and gonadal and sexual dysfunction in both sexes. The approach to prolactinomas has changed in the last 25 years thanks to the availability of dopaminergic drugs characterised by a potent prolactin-inhibitory effect, a tumour shrinking effect associated with a satisfactory tolerability. In more recent years, cabergoline 1-[(6-allelylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethyl-urea an ergoline derivative with potent, selective and long-lasting inhibitory activity on prolactin release, has been used to suppress prolactin secretion in women with hyperprolactinaemia. Cabergoline was shown to be significantly more effective than bromocriptine in inducing a complete biochemical response and clinical efficacy and was better tolerated than bromocriptine in the majority of patients. Notable tumour shrinkage until tumour disappearance was observed during cabergoline treatment in most patients with macroprolactinoma and it was also proven effective in patients resistant to or with a poor response to bromocriptine. In view of the limited data on cabergoline-associated pregnancies and the long half-life of the drug, it is currently recommended that women hoping to become pregnant, once ovulatory cycles have been established, should discontinue cabergoline therapy 1 month before they intend to conceive. However, no data concerning negative effects on pregnancy or offspring have been reported. The great efficacy of this compound together with its excellent tolerability makes this drug the current treatment of choice for the majority of patients with hyperprolactinaemic disorders.     

Dopamine receptor agonists for treating prolactinomas

Prolactinomas are the most common hormone-secreting pituitary tumours and cause infertility and gonadal and sexual dysfunction in both sexes. The approach to prolactinomas has changed in the last 25 years thanks to the availability of dopaminergic drugs characterised by a potent prolactin-inhibitory effect, a tumour shrinking effect associated with a satisfactory tolerability. In more recent years, cabergoline (1-[(6-allelylergolin-8β-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethyl-urea), an ergoline derivative with potent, selective and long-lasting inhibitory activity on prolactin release, has been used to suppress prolactin secretion in women with hyperprolactinaemia. Cabergoline was shown to be significantly more effective than bromocriptine in inducing a complete biochemical response and clinical efficacy and was better tolerated than bromocriptine in the majority of patients. Notable tumour shrinkage until tumour disappearance was observed during cabergoline treatment in most patients with macroprolactinoma and it was also proven effective in patients resistant to or with a poor response to bromocriptine. In view of the limited data on cabergoline-associated pregnancies and the long half-life of the drug, it is currently recommended that women hoping to become pregnant, once ovulatory cycles have been established, should discontinue cabergoline therapy 1 month before they intend to conceive. However, no data concerning negative effects on pregnancy or offspring have been reported. The great efficacy of this compound together with its excellent tolerability makes this drug the current treatment of choice for the majority of patients with hyperprolactinaemic disorders.     

Dopamine receptor agonists alter gap prestimulus modulation

An innocuous sensory event (a prestimulus) that briefly precedes a startle-eliciting stimulus (SES) will reduce the amplitude of the subsequently elicited reflex. In three experiments brief silent periods in otherwise continuous noise (gaps) were used as prestimuli to investigate the effects of the D₁ dopamine receptor agonist (±)-SKF-38393 (SKF) and the dopamine D₂ receptor group agonist (−)-quinpirole hydrochloride on gap inhibition of the rat’s acoustic startle reflex. Gap durations of 4 and 50 ms were analyzed. Quinpirole (0–1.6 mg/kg) had a biphasic effect on gap inhibition. Lower doses increased gap inhibition, an effect that peaked at the 0.4 mg/kg dose. For higher doses, inhibition returned to control levels for the 4-ms long gap, but remained elevated for the 50-ms long gap. SKF had no effect on gap inhibition, and haloperidol (0.2 mg/kg) reversed the quinpirole-induced increase of gap inhibition. These data implicate the D₂ dopamine receptor group in gap inhibition of startle modulation. The results are discussed in terms of the effects of catecholamine agonists on attention. Received: 25 July 1995/Final version: 28 April 1997     

Dopamine receptor sensitivity after chronic dopamine agonists

Several previous reports have demonstrated that chronic administration of both directly and indirectly acting dopamine agonists produces a supersensitive behavioral response to challenge doses of dopamine agonists when compared to the responses induced by acute administration of these drugs. That is, a given dose of a dopamine agonist will produce a greater response after chronic dopamine agonist treatment than is observed upon acute administration of that dose. A similar behavioral phenomenon resulting from chronic administration of dopamine antagonists has been suggested to be due to an increase in the number of dopamine receptors present in relevant brain areas. The same hypothesis has been put forward for the hypersensitivity induced by chronic dopamine agonist administration. The present study was designed to investigate the effect of chronic administration of high doses of both direct and indirect dopamine agonists on the dopamine receptors labeled by ³H-spiroperidol. Groups of animals (CD-1 mice) were sacrificed 1, 3 and 5 days following the last chronic injection. Striatal tissue from these mice was incubated with ³H-spiroperidol and dopamine receptor binding evaluated. Affinity of the receptors for the ligand was unaltered by treatments. The receptors labeled by ³H-spiroperidol showed no significant differences in number following the chronic administration of high doses of apomorphine (30 mg/kg). The B _max was significantly decreased at only one time period following chronic administration of dextroamphetamine (4 mg/kg); however, these was a dramatic 30% reduction in the B _max in striatal tissue from those mice treated with N-n-propylnorapomorphine. These results suggest that the hypersensitive behavioral response in mice following chronic administration of direct and indirect acting dopamine agonists is not due to an increase in the number of dopamine receptors in the striatum which are labeled by ³H-spiroperidol.     

Direct cardiac actions of the H2 receptor agonists, impromidine and dimaprit

Intracoronary administration of the H2 receptor agonists impromidine and dimaprit at doses that did not alter systemic hemodynamics increased coronary blood flow but had no regional positive inotropic effects. Dose-related increases in myocardial blood flow were observed with both drugs. These effects were attenuated by prior administration of cimetidine. The results of this study demonstrate that H2 coronary receptor stimulation results in vasodilation of both subepicardial and subendocardial regions.     

GABAC receptor ion channels

1. The present review gives an overview of studies conducted on GABAC receptors over the past 10 years since the author started at the University of Sydney. It concentrates on the structure-activity relationship profiles of the receptor and how these studies were used to: (i) develop selective GABAC receptor ligands; and (ii) understand the impact of amino acid changes on GABAC receptor pharmacology and function. 2. Structure-activity relationship studies involving variations of both ligands and their receptor targets are vital to the discovery of drugs that interact selectively with particular native and mutant receptor subtypes. Such agents may be useful for treating anxiety, depression, epilepsy and memory related disorders, such as Alzheimer's disease.     

Pharmacogenetics and cardiac ion channels

Ion channels control electrical excitability in living cells. In mammalian heart, the opposing actions of Na(+) and Ca(2+) ion influx, and K(+) ion efflux, through cardiac ion channels determine the morphology and duration of action potentials in cardiac myocytes, thus controlling the heartbeat. The last decade has seen a leap in our understanding of the molecular genetic origins of inherited cardiac arrhythmia, largely through identification of mutations in cardiac ion channels and the proteins that regulate them. Further, recent advances have shown that 'acquired arrhythmias', which occur more commonly than inherited arrhythmias, arise due to a variety of environmental factors including side effects of therapeutic drugs and often have a significant genetic component. Here, we review the pharmacogenetics of cardiac ion channels-the interplay between genetic and pharmacological factors that underlie human cardiac arrhythmias.     

Dopamine D1 receptor agonists induce penile erections in rats

The dopamine receptor agonist apomorphine has been recently introduced in the treatment of erectile dysfunction. While it is well established that dopamine D2-like receptors play a crucial role in this effect, conflicting result are reported in the literature as for the role of dopamine D1-like receptors. The aim of this study was to determine the effect of systemic administration of dopamine D1-like receptor agonists on penile erection in rats. Male Wistar rats were treated with three different, and not structurally related, dopamine D1-like receptor agonists: the partial agonists SKF38393 ((+) 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) and CY 208-243 ((-)-4,6,6a,7,8,12b-exahydro-7-methylindole [4,3-ab]fenantridine), and the full agonist A 77636 ((-)-(1R,3S)-3-Adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran hydrochloride). All three compounds dose-dependently increased the number of penile erections, with the full agonist A77636 showing a more pronounced effect with respect to the other two. Moreover, the dopamine D1-like receptor antagonist SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) dose-dependently antagonised A77636 effect. These results show that systemic administration of dopamine D1-like receptor agonists induce penile erection in rats. This observation suggests that dopamine D1-like receptor agonists might be considered as a possible alternative to apomorphine in the treatment of erectile dysfunction, thus avoiding the typical side effects related to the stimulation of dopamine D2-like receptors such as nausea.     

Dopamine receptor agonists for protection and repair in Parkinson's disease

Dopamine agonists have been usually used as adjunctive therapy for the cure of Parkinson's disease. It is generally believed that treatment with these drugs is symptomatic rather than curative and it does not stop or delay the progression of neuronal degeneration. However, several dopamine agonists of the D2-receptor family have recently been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson's disease models. Here we summarize some recent molecular evidences underlining the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson's disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These neuroprotective activities are molecule-specific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role.     

Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy

Dopamine receptor selectivity was investigated for a number of dopamine receptor agonists. In vitro, the benzazepine derivatives, e.g., SKF 38393 and SKF 75670 as well as the isoquinoline derivatives, SKF 89626 and SKF 89615, were D1 receptor-selective. All other compounds like apomorphine, CY 208-243, 6,7-ADTN and 3-PPP were either D2-selective or did not discriminate between subtypes. In general, the same receptor profile seen in vitro was observed in vivo. The exceptions to this pattern were: compounds which did not cross the blood-brain barrier, like 6,7-ADTN and SKF 89626, and compounds which appeared nonselective in vitro but demonstrated D2 selectivity in vivo like apomorphine, CI 201-678 and CY 208-243. A number of compounds were characterized in detail with respect to a GTP-induced affinity shift in inhibition of [3H]SCH 23390 binding, and potency and efficacy in stimulating adenylate cyclase from rat striatum. Inhibition of specific [3H]SCH 23390 binding by these agonists in the absence of GTP occurred with Hill slopes below unity and could best be explained by a two-site model with a high (KH)- and low-affinity (KL) component. Inhibition of [3H]SCH 23390 binding in the presence of 15 microM GTP occurred with Hill slopes of unity. The KI values obtained in the presence of 15 microM GTP were similar to the KL values, the low-affinity component observed in the absence of GTP. The capability of the agonists to stimulate the adenylate cyclase was analyzed in relation to dopamine (efficacy = 100%). The efficacy of the benzazepine derivatives varied from 24 (SKF 75670) to 100% (SKF 83189), dependent on the substituents on the benzazepine core. The isoquinolines, SKF 89626 and SKF 89615 had full efficacy, whereas most other agonists tested appeared to have only partial efficacy. In summary, the present paper presents data on dopamine receptor selectivity and efficacy in stimulating adenylate cyclase for a number of dopaminergic agonists. These data may create a basis for selection of agonists in future characterizations of dopaminergic-mediated events.     

Dopamine receptor agonists and antagonists enhance ATP-activated currents.

The effects of dopamine and related compounds on ATP-activated channels were investigated in pheochromocytoma PC12 cells. Dopamine (10 microM) enhanced an inward current activated by 100 microM ATP. A similar enhancement of the ATP-activated current was observed with apomorphine (10 microM), a non-selective dopamine receptor agonist, with (+)-SKF-38393 (10 microM), a selective dopamine D1 receptor agonist, and with (-)-quinpirole (10 microM), a selective dopamine D2 receptor agonist. Moreover, (+)-SCH-23390 (30 microM), a dopamine D1 receptor antagonist, and (-)-sulpiride (30 microM), a dopamine D2 receptor antagonist, also enhanced the ATP-activated current. The results suggest that ATP-activated channels are modulated by dopaminergic mechanisms, and that this modulation cannot be attributed to any single class of dopamine receptors.     

Dopamine receptor agonists: new angularly annulated tricyclic compounds

In order to study the influence on dopaminergic activity of the exchange of X in rigid dopamine congeners of structure 1, the synthesis of octahydrobenzo [f] trans-quinoxalines (VII c, d) and trans-hexahydro-4H-naphtho[1,2-b][1,4]thiazines (X c, d), is reported.     

Calcium ion channels in cardiac cell membranes

Understanding of the electrophysiological properties of the calcium channel in cardiac cell membranes has been hampered because of the difficulties in interpreting voltage-clamp data. Recently, new techniques for isolation of adult heart cells, internal dialyzation of the cell and analysis of the single ion channel current have been established. Some of the previous results and concepts obtained in intact cardiac tissues have been confirmed and new understanding of the nature of the calcium channels has been gained by the techniques. In this article, the author reviews the electrophysiological and electropharmacological properties of the calcium ion channels in cardiac cell membranes. Especially, emphasis is placed on new information gleaned from the new techniques.     

Muscarinic regulation of cardiac ion channels

The parasympathetic component of the autonomic nervous system plays an important role in the physiological regulation of cardiac function by exerting significant influence over the initiation as well as propagation of electrical impulses, in addition to being able to regulate contractile force. These effects are mediated in whole or in part through changes in ion channel activity that occur in response to activation of M(2) muscarinic cholinergic receptors following release of the neurotransmitter acetylcholine. The coupling of M(2) receptor activation to most changes in cardiac ion channel function can be explained by one of two general paradigms. The first involves direct G protein-dependent regulation of ion channel activity. The second involves indirect regulation of ion channel activity through modulation of cAMP-dependent responses. This review focuses on recent advances in our understanding of the mechanisms by which M(2) muscarinic receptor activation both inhibits and facilitates cAMP-dependent ion channel responses in the heart.     

Effects of duramycin on cardiac voltage-gated ion channels

The amphipathic peptide duramycin is in clinical development for the treatment of cystic fibrosis. It is deposited in cellular membranes where it binds to phosphatidylethanolamine. Duramycin may thereby change the biophysical membrane properties and perturb the function of ion channels. If so, in heart tissue, its application carries the risk to elicit cardiac arrhythmias. In fact, premature ventricular complexes were observed in the electrocardiogram during toxicological testing in dogs. To study the arrhythmogenic potential of duramycin, we investigated its effects on currents through voltage-gated hERG potassium, sodium, and calcium channels in native cells, and using a heterologous expression system, by means of the whole-cell patch clamp technique; duramycin bath concentrations between 1 nM and 0.1 μM did not generate any effects on these currents. Concentrations ≥0.3 μM, however, reduced the amplitudes of all investigated currents. Moreover, sodium current fast inactivation kinetics was slowed in the presence of duramycin. A further rise in duramycin bath concentration (≥3.3 μM) induced a leak current consistent with pore formation. The reported effects of duramycin on ion channel function are likely to arise from a change in the biophysical properties of the membrane rather than from a specific interaction of the peptide with ion channel proteins. Under therapeutic conditions (i.e., administration via inhalation), duramycin plasma concentrations are below 0.5 nM. Thus, upon inhalation, duramycin has a large safety margin and is highly unlikely to elicit arrhythmias. Eva Zebedin, and Xaver Koenig contributed equally.     

The opioid receptor independent actions of kappa receptor agonists in the cardiovascular system

It is not well known but the actions of opioid receptor agonist and antagonist drugs have not been well characterized in the heart and cardiovascular system. Under normal physiological conditions, opioid receptors have a limited role in the regulation of the cardiovascular system. Instead the primary focus of opioid receptor research, for many years, relates to the characterization of the actions as analgesics in the central nervous system (CNS). Recently, however a series of studies suggest that in particular the arylacetamide class of kappa (kappa) opioid receptor agonist drugs have significant opioid receptor independent actions on the heart and cardiovascular system. Some of the actions of these molecules may indeed be mediated by activation of peripheral opioid receptors; however, these new studies provide pharmacological evidence to the contrary and show using many different in vitro and in vivo animal models that these 'non-opioid' actions result from direct or opioid receptor-independent actions on cardiac tissue. This article will outline the molecular mechanism(s) that are responsible for the cardiovascular and cardiac actions these arylacetamide kappa opioid receptor agonists and characterize the role that these opioid receptors have in ischaemic arrhythmogenesis. In many instances it would appear that the effects of opioid agonists (and antagonists) in cardiovascular disease models of ischaemia may be mediated by opioid receptor-independent actions of these drugs.     

Dopamine agonists in Parkinson's disease

Levodopa (LD), the immediate precursor of dopamine, is the most effective agent in the treatment of Parkinson's disease (PD). While quite successful in treating the primary motor deficits of PD, most patients eventually develop LD-related motor fluctuation, dyskinesias and other adverse effects associated with chronic LD therapy. There is also concern that LD is neurotoxic, although this has not been demonstrated in any in vivo studies. Dopamine agonists (DAs) have been shown to be about as effective as LD in symptomatic treatment of mild-to-moderate PD. In addition, there is a lower tendency to develop motor fluctuations and dyskinesias with DA treatment than after initiation of therapy with LD. Furthermore, there is preclinical and clinical data to suggest a slowing of neurodegeneration with DAs. The adverse effects of DAs are similar to those experienced with LD, except that the ergot agents are associated with a small risk of tissue fibrosis not noted with the non-ergot DAs.     

Dopamine D3 receptor agonists for protection and repair in Parkinson's disease

Parkinson's disease is a severe, age-related neurodegenerative disorder in which a loss of substantia nigra-derived dopaminergic pathways to the striatum triggers profound motor perturbation, as well as cognitive, sensory and mood deficits. Although the dopamine precursor, L-dopa, is effective in the short-term in relieving motor dysfunction, it does not stop the progressive disappearance of dopaminergic neurons, encouraging interest in alternative therapeutic strategies. Dopaminergic agonists, such as pramipexole, appear to have neuroprotective and neurorestorative actions based on clinical and, most convincingly, experimental work. The role of specific dopaminergic receptor subtypes is an important issue, especially with respect to new drug development. Of particular interest, dopamine D3 receptors contribute to the beneficial influence of dopaminergic agonists for the protection and restoration of dopaminergic pathways in Parkinson's disease.