Journal of Human Hypertension (2000) 14, Suppl 1, S47–S50 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Dopamine: a role in the pathogenesis and treatment of hypertension MB Murphy Department of Pharmacology and Therapeutics, National University of Ireland, Cork, Ireland The catecholamine dopamine (DA), activates two dis- (largely nausea and orthostasis) have precluded wide tinct classes of DA-specific receptors in the cardio- use of D2 agonists. In contrast, the D1 selective agonist vascular system and kidney—each capable of influenc- fenoldopam has been licensed for the parenteral treat- ing systemic blood pressure. D1 receptors on vascular ment of severe hypertension. Apart from inducing sys- smooth muscle cells mediate vasodilation, while on temic vasodilation it induces a diuresis and natriuresis, renal tubular cells they modulate sodium excretion. D2 enhanced renal blood flow, and a small increment in receptors on pre-synaptic nerve terminals influence nor- glomerular filtration rate. Evidence is emerging that adrenaline release and, consequently, heart rate and abnormalities in DA production, or in signal transduc- vascular resistance. Activation of both, by low dose DA tion of the D1 receptor in renal proximal tubules, may lowers blood pressure. While DA also binds to alpha- result in salt retention and high blood pressure in some and beta-adrenoceptors, selective agonists at both DA humans and in several animal models of hypertension. receptor classes have been studied in the treatment of Journal of Human Hypertension (2000) 14, Suppl 1, S47– hypertension. An unfavourable side-effect profile S50. Keywords: dopamine; blood pressure; hypertension Historical context Having also shown that the pressor effects of high dose DA could be abolished by alpha-adrenoceptor Dopamine (DA) was synthesised for the first time in blockade, Goldberg speculated that there were likely 1910, simultaneously at the Wellcome Laboratories to be specific receptors for DA, which might modu- of Sir Henry Dale in Britain, and in Germany by late blood pressure reduction and might be 1,2 Mannich and Jacobsohn. Initially, its pharmaco- exploited in the treatment of hypertension. Proof of logical effects were thought to mimic those of the the concept followed when he infused DA, follow- previously identified sympathomimetic amines, ing alpha-adrenoceptor blockade with phenoxyben- noradrenaline and adrenaline, raising blood press- zamine, in a severely hypertensive patient at Grady ure dose dependently. In 1942, Holtz reported a Hospital in Atlanta. Blood pressure fell dramatically novel observation that administration of low dose during DA infusion.6 The hypotensive effect was not dopamine to the guinea pig resulted in lowering of seen during DA infusion alone. The search for selec- arterial pressure, but the significance of this finding tive dopamine receptor agonists commenced. remained unclear for another 20 years.3 The depressor capacity of dopamine was con- firmed in experiments in the anesthetised dog in Dopamine receptors 1959 by Goldberg and Sjoerdsma.4 They demon- strated that low dose infusions of DA initially low- Characterisation of specific DA receptors was ered diastolic pressure. As the infusion rate approached from several angles over the past 30 increased, cardiac output increased, while higher years. Using classic physiology and pharmacology, 7 infusion rates led to increases in both systolic and Goldberg and Kohli concluded that there were two diastolic pressures.4 This capacity of DA to increase distinct types of peripheral (that is outside the cen- cardiac output without increasing peripheral resist- tral nervous system (CNS)) receptors: DA1 receptors ance, a therapeutic ‘Holy Grail’ for the treatment of on vascular smooth muscle, mediating vasodilation, congestive heart failure, led to careful trials in man. and what they characterised as DA2 receptors on It was during the first study in heart failure patients pre-synaptic membranes of sympathetic nerve ter- that Goldberg made the critical observation that DA minals, minimising noradrenaline release and also promoted an impressive diuresis and natriuresis, promoting vasodilation.7 Using a biochemical 8 which he correctly ascribed following further approach, Kebabian and Calne described D1 recep- experiments, to direct effects on the kidney, inde- tors whose occupation activated adenylate cyclase pendent of changes in cardiac output (for review and D2 receptors either uncoupled from, or with 8 see Goldberg5). opposite effects on, this second messenger. More recent studies using molecular cloning techniques have identified at least seven structurally distinct Correspondence: Professor Michael Murphy, Department of Phar- DA receptors, but whose pharmacological effects are macology and Therapeutics, Clinical Sciences Building, Cork encompassed by the earlier two receptor model. In University Hospital, Wilton, Cork, Ireland the modern hierarchical classification the two main Dopamine and hypertension MB Murphy S48 groupings (D1A with D1B—known in the numerical deficient in D1 receptors develop systolic and dias- 11 system as D1 and D5, with the second group D2A, tolic hypertension. D2B and D2C—numerical system D2, D3 D4 respectively) correspond functionally to Goldberg’s 9 DA1 and DA2 receptors. All DA receptors belong to the G-protein linked Dopamine modulation in cardiovascular superfamily, are located within the plasma mem- therapy brane and possess seven transmembranous domains. The signal transduction pathways of DA receptors Following the elucidation of its pharmacology, sev- have not been fully characterised. D1 receptors are eral diverse methods have been used to exploit linked to the Gs protein which activates adenylate dopamine in treating heart failure, shock and hyper- cyclase with the resulting cAMP activating protein tension. Infusion of DA became the gold standard kinase A. D2 receptors, in contrast, interact with Gi treatment of acute heart failure and cardiogenic which inhibits adenylate cyclase, but may also acti- shock, and, in spite of a paucity of randomised clini- vate certain potassium channels, inactivate calcium cal trial data, to preserve renal function during all channels, or promote phosphoinosotide hydrolysis forms of shock and acute renal impairment from and arachadonic acid release. A D1 receptor capable diverse causes. However, the necessity for par- of activating phospholipase C, leading to the gener- enteral administration, and its simultaneous actions ation of inositol phosphates and diacylglycerol has on several receptors, limited its therapeutic useful- been described in the kidney. ness. Accordingly, much effort was expended on the Peripheral DA1 receptors have been found in a development of specific receptor agonists and antag- variety of vascular beds, in large numbers on renal onists, inhibitors of dopamine-beta-hydroxylase to and mesenteric arteries, and to a lesser degree in cor- enhance endogenous concentrations, and pro-drugs onary, cerebral, cutaneous and skeletal arteries. designed to be administered orally for post-absorp- They are also found in renal proximal and distal tion conversion to DA. All of these approaches have tubular cells, adrenal cortex and cardiac muscle been investigated in hypertension. Indeed, several cells. DA2 receptors are found on pre-synaptic nerve of the compounds have been used as probes to deter- terminals and in sympathetic ganglia. DA1 receptors mine whether abnormalities in DA genesis or bind the prototypic agonist, fenoldopam and antag- actions might contribute to the pathogenesis of onist SCH 23390 while the corresponding ligands hypertension. for DA2 receptors include quinpirole and domperi- done respectively. Dopamine and the pathogenesis of Pro-drugs and enzyme modulators hypertension Clinical exploitation of DA focused initially on Several abnormalities in dopamine excretion or DA methods to enhance the availability of DA at its receptor signal transduction have been reported in receptors either through the use of pro-drugs that hypertensive cohorts (for review, see Hussain and 10 might be administered orally or parenteral prep- Lokhandwala. Impaired urinary DA excretion has arations with longer duration of action, largely for been reported in salt-sensitive hypertensive patients the treatment of congestive heart failure. Levodopa, and in some low-renin hypertensives. Suppressed ibopamine—the precursor of epinine which is active dopaminergic activity has also been described in off- at DA , beta- and alpha-adrenoceptors, and ␥-gluta- spring of hypertensive patients and in the pre- 1 myl-dopa (gludopa) another DA precursor, were hypertensive phase in others. Infusion of DA in studied clinically. All had some beneficial effects on patients with essential hypertension has been cardiac output, but variable effects on vascular reported to result in enhanced urinary cAMP resistance, and all ultimately proved unreliable (for excretion compared with normal controls. These 12 data have been interpreted as suggesting distal renal review see Murphy et al ). tubular DA receptor up-regulation in response to An enzymatic approach to enhancement of tissue 1 DA levels, with associated blockade of noradrena- defective DA synthesis in hypertensive individuals. ␤ However, there are no experimental data available line synthesis, is inhibition of dopamine - on receptor numbers or receptor ligand affinity in hydroxylase (DBH). Fusaric acid, the first inhibitor, 13 kidneys of hypertensive subjects.