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. reduced blood pressure in SHR and in man. It also Similar defects in DA excretion and responses to caused an early tachycardia and enhanced noradren- DA infusion have been reported in Dahl salt-sensi- aline release, probably due to a direct neuronal tive rats. This strain also exhibits limited down- effect; it was eventually abandoned because of hepa- regulation of Na,K-ATPase activity in response to totoxicity. Other agents (A32390 A, BRL8242 and dietary salt loading compared with salt-insensitive bupicomide, a precursor of fusaric acid) also rats of the same strain. Activity of this enzyme in reduced BP, increased renal blood flow and sodium proximal tubular cells is normally regulated by DA1 excretion, but were hampered by unsatisfactory receptors. While urinary DA excretion is normal or side-effect profiles. The fact that recently described increased in the spontaneously hypertensive rat patients with total deficiency of DBH, suffer pro- (SHR), the natriuretic response to DA or fenoldopam found postural hypotension, has detracted further infusion may be impaired. Finally, mutant mice from this avenue of drug development.

Journal of Human Hypertension Dopamine and hypertension MB Murphy S49 DA1 receptor agonists in hypertension Fenoldopam in severe hypertension Mild to moderate hypertension Several large trials have been completed demon- strating substantial efficacy in severe hypertension. A 30-year search for a selective DA1 receptor agonist While hypotensive effects comparable to those seen proved fruitful eventually. Although several were with nitroprusside have been reported, fenoldopam synthesised, only the benzazepine derivative fenol- has shown contrasting effects on renal function. In dopam (SKF 82623) has been studied extensively. a randomised, controlled comparison of fenoldopam Its pharmacological characterisation was described 14 with nitroprusside in patients with accelerated originally by Hahn and colleagues in 1982; it was hypertension and average blood pressure 219/137 finally approved for the treatment of severe hyper- mm Hg. Elliott18 reported similar pressure tension in 1997. Early clinical trials used an oral for- reductions during titration with both agents. How- mulation but its hypotensive effects were erratic and ever, while there was little change in renal function short-lived. These findings resulted from its poor following nitroprusside administration, urinary out- oral bioavailability (less than 2%) and its short 15 put, sodium excretion and creatinine clearance were plasma half-life of about 10 min. enhanced by fenoldopam during the first 4 h of ther- In the first study of parenteral fenoldopam in 17 16 apy. To what extent these effects of fenoldopam mild hypertensives, Murphy et al demonstrated a resulted from renovascular effects or from direct hypotensive effect that was linearly dose-related at ␮ effects on renal tubular receptors could not be estab- infusion rates of 0.025–0.5 g/kg/min. Heart rate lished. Interestingly, Aronson et al19 have described increased by 13 beats per minute while plasma cat- contrasting effects of these two agents during a 60 echolamine concentrations doubled. The tachycar- mm Hg reduction in mean blood pressure in anaes- dia was later shown to be avoidable by prior beta- thetised mongrel dogs; while the reduction in press- adrenoceptor blockade. ure by nitroprusside was accompanied by a 15% In a second experiment, in 10 water-loaded mild reduction in renal blood flow, fenoldopam increased to moderate hypertensives (average blood pressure blood flow by 15%. 159/103 mm Hg), a 2-h infusion of fenoldopam In Elliott’s study, the addition of frusemide and decreased blood pressure to 144/90 mm Hg. Heart atenolol after 4 h allowed safe down-titration of fen- rate increased by 16 beats per min; there was no evi- oldopam. In some patients, fenoldopam was con- dence of tachyphylaxis. In spite of blood pressure tinued for up to 18 h without evidence of tachyphyl- reduction, urinary flow increased by 50%, urinary laxis. An unexpected observation was that sodium excretion trebled, but there was no fenoldopam caused a dose-dependent increase in increment in potassium excretion. Plasma renin intra-ocular pressure (IOP), from 16 prior to therapy activity increased by 50%. Renal blood flow, to 20 mm Hg after 4 h, in spite of a sharp reduction determined from clearance of para-amino-hippurate, in systemic BP. In contrast, patients randomised to rose by 42%, while glomerular filtration rate, meas- nitroprusside experienced no change in IOP. Sub- ured by inulin clearance, increased by 6%. Similar sequent experiments revealed that fenoldopam results were seen in a further experiment in the enhances cyclic adenosine monophosphate (AMP) same patient group, but without prior water load- 16 production in both canine and porcine ocular tra- ing. becular meshwork, an effect that can be blocked by There were few adverse reactions reported. Two prior treatment with the selective DA1 receptor of 17 patients described flushing. An unexpected antagonist SCH23390.20 While this suggests that DA finding was the observation that most patients exhi- receptor modulation might have therapeutic appli- bited flattening of T waves of the anterior and lateral cations in managing patients with glaucoma, the leads on electrocardiography, with T-wave inver- most practical implication is that fenoldopam might sion occurring in four of 17 patients studied. While best be avoided in patients with prior history of there had been earlier case reports of ECG changes raised IOP. The combination of a direct effect on following short-term administration of minoxidil, aqueous humor kinetics with simultaneous hydralazine or verapamil, the frequency of changes 17 reduction in ocular arterial perfusion pressure, as in fenoldopam-treated patients led Gretler et al to systemic blood pressure falls, might lead to retinal study the phenomenon formally in a later random- ischaemia. ised comparison of fenoldopam with nitroprusside. In summary, fenoldopam meets most of the cri- In 21 severely hypertensive patients, detailed analy- teria for a preferred drug in hypertensive emerg- sis of digitised ECG recordings revealed that both encies. It has a rapid, dose-dependent onset of fenoldopam and nitroprusside decreased T-wave action and a short plasma half-life, which permits amplitude in all leads, except AVR, while patients efficient down-titration in the event of over-shooting exhibited no other overt evidence of cardiac ischae- the hypotensive target. It has additional beneficial mia. The authors concluded that ECG changes are effects on renal function acutely; whether these common during acute blood pressure reduction and renal effects translate into better clinical outcome, remain undetected unless sought systematically. such as avoidance of dialysis in patients with severe They also speculated that acute changes in left ven- renal impairment, remains to be established. tricular geometry following acute blood pressure reduction might explain the observation since the height and duration of the T-wave depend on ven- References tricular wall thickness and trans-mural conduction 1 Barger G, Dale HH. Chemical structure and sympatho- velocity. mimetic effects of amines. J Physiol 1910; 41: 19–24.

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