Summary
Dopamine is an endogenous catecholamine with an important role in the regulation of renal function, sodium homeostasis and blood pressure. D1 receptors on vascular smooth muscle mediate vasodilatation, while stimulation of D1 receptors in the renal proximal tubules leads to natriuresis and diuresis. D2 receptors on presynaptic sympathetic nerve endings inhibit noradrenaline release. Dopamine infusions are used widely for the management of cardiovascular disorders and renal dysfunction in intensive care units. The ability of dopamine to `protect' the kidney against ischaemic or toxic insults requires proper evaluation in controlled trials. A number of dopaminergic prodrugs, selective dopamine agonists and dopamine congeners with additional actions on other adrenoceptors have been developed. These drugs are undergoing clinical trials in the management of cardiovascular disorders such as hypertension, heart failure and shock.

Endogenous dopamine and dopamine receptors
Dopamine is an endogenous catecholamine which modulates many physiological functions. These include peripheral cardiovascular control and central nervous system actions. Central dopamine receptors and pathways are likely to be involved in the control of cardiovascular function, but this has been a rather neglected area of research. Most studies have focused on the peripheral actions of dopamine.

Activation of D1 receptors* on vascular smooth muscle is associated with vasodilatation, primarily in the renal, mesenteric, cerebral and coronary circulations. In the kidney, D1 receptors have also been localised at both the luminal and basolateral membranes of proximal tubules. Stimulation of these receptors leads to natriuresis and diuresis via activation of enzymes involved in second messenger systems i.e. adenylate cyclase and phospholipase C.

Renal D2 receptors are found in intra-renal arteries and arterioles, in the adventitia-media (corresponding to sympathetic terminals), in the intima and in the tubules. Presynaptic D2 receptors on sympathetic nerve terminals decrease the release of noradrenaline.

In addition to its effects on renal blood flow, glomerular filtration rate, sodium and water excretion, dopamine also promotes phosphate excretion, antagonises the hydro-osmotic effect of vasopressin (? via D2 receptors) and may interact with other renal hormonal systems such as prostaglandins and atrial natriuretic peptide.

Urinary dopamine arises largely from proximal tubular decarboxylation of levodopa, taken up from the tubular lumen. This locally produced dopamine has a paracrine action and is significantly influenced by sodium intake, dietary protein and renal impairment. A defect in this endogenous renal dopamine system may be one of the pathogenic factors in essential hypertension as some patients have a defect in their ability to mobilise renal dopamine.

Pharmacological and haemodynamic responses to dopamine
Intravenous dopamine infusion is one of the most commonly employed drugs in intensive care units. The cardiovascular and renal effects of dopamine result from its direct action on alpha and beta adrenoceptors as well as dopamine receptors. Appreciation of the dose-dependent effects of dopamine is essential for its optimum and safe therapeutic use. There is some overlap in receptor activation as well as inter-patient variability in binding affinities at different doses.

In general, at low doses (0.5-2.0 micrograms/kg per minute), specific dopamine receptors are preferentially activated, leading to a reduction in peripheral vascular resistance and left ventricular after load, and increases in renal blood flow and sodium excretion. As the dose is increased further (2-4 micrograms/kg per minute), beta1 adrenoceptor activation becomes evident and cardiac output is increased. Finally, beginning at about 5 micrograms/kg per minute, the alpha adrenoceptors are stimulated, mediating vasoconstriction and elevation of peripheral vascular resistance. Dopamine infusion at 5 micrograms/kg per minute and higher may be employed short term for treatment of circulatory shock, where an increase in perfusion pressure is desirable.

Renal failure
Low dose (`renal dose') dopamine is used commonly in patients with inadequate urine output or deteriorating renal function secondary to ischaemia or toxic insult. However, there are no adequately controlled trials to support the practice and its efficacy has been challenged. In animals, dopamine appears to be no better than saline in preserving renal function. In oliguric acute renal failure, studies showing that dopamine infusion, usually combined with a loop diuretic, increases urine output have been generally small and poorly controlled. Low dose dopamine should be restricted to patients with an adequate intravascular volume and those who, despite receiving diuretics, continue to have an inadequate urine output.

Heart failure
Dopamine infusions in the range of 0.5-4 micrograms/kg per minute are beneficial in the acute treatment of congestive heart failure because of the renal effects and the positive inotropic effects of direct beta1 adrenoceptor stimulation. The concurrent administration of dopamine and dobutamine or vasodilating agents such as nitroprusside and glyceryl trinitrate can be an effective regimen. It provides a greater increase in cardiac output and avoids the alpha adrenergic effects (vasoconstriction) of high doses of dopamine.

Dopamine prodrugs
The poor oral bioavailability of dopamine and its complex actions at various receptors makes it inappropriate in the therapy of chronic cardiovascular disorders. Dopamine agonists which are effective orally and/or exhibit specific receptor activity have recently been developed. Levodopa, ibopamine and docarpamine are dopamine prodrugs which are converted into active forms after absorption and produce beneficial effects in congestive heart failure.

Levodopa is converted to dopamine by aromatic amino acid decarboxylase. Doses of 1.5-2.0 g per day over at least 3 months produce sustained beneficial haemodynamic effects in heart failure. However, levodopa cannot be recommended for general use because of its frequent adverse effects.

Ibopamine, hydrolysed to the active drug epinine by plasma esterases, produces natriuresis, increases cardiac output and reduces left ventricular filling pressure in heart failure. It acts by combined stimulation of D1 and D2 receptors and beta2 adrenoceptors. Ibopamine reduces the activity of the sympathetic and renin-angiotensin-aldosterone systems in heart failure; it is reportedly free of pro-arrhythmic effects and not subject to the development of tolerance during sustained treatment. Only preliminary clinical results are available with docarpamine and gludopa (g-glutamyl-L-Dopa) indicating beneficial cardiac and renal effects in heart failure patients. None of these drugs are currently available in Australia.

Dopamine agonists
Dopexamine, a structural analogue of dopamine, is a potent agonist at beta2 adrenoceptors and dopamine receptors. It has minimal activity at beta1 adrenoceptors and none at alpha adrenoceptors. However, like dopamine, dopexamine is inactivated in the gastrointestinal system and must be given as a continuous infusion. Improvements in cardiac performance result from increased stroke volume and falls in total peripheral vascular resistance and left and right ventricular filling pressures. Responses to dopexamine may be attenuated when the infusion is prolonged for 6 hours or more. Dopexamine may be useful in shock and acute renal failure. It may also preserve renal function during anaesthesia in patients with heart failure.

Fenoldopam is a potent D1 agonist with a short plasma half-life of 7-9 minutes when given intravenously. It has poor oral bioavailability. Fenoldopam produces acute increases in cardiac output and cardiac index and decreases systemic vascular resistance in congestive heart failure. Unfortunately, clinical trials in the chronic treatment of congestive heart failure have been disappointing. It is not currently available in Australia.

Theoretically, stimulation of sympathetic postganglionic and ganglionic D2 receptors leads to inhibition of sympathetic activity with vasodilatation and decreased blood pressure. A limited number of studies with D2 agonists, including bromocriptine and propylbutyldopamine, have been conducted in patients with cardiovascular disease.

Further clinical trials with D2 agonists in heart failure and hypertension are needed.

Conclusion
The peripheral dopamine system is an important regulator of renal function, sodium excretion and blood pressure. Dopamine infusions are widely used in critical care areas, although the ability of this therapy to protect the kidney against ischaemic or toxic results requires more rigorous evaluation. The cloning of dopamine receptors, studies of their molecular biology and transduction pathways and drug developments offer exciting prospects for new therapies of cardiovascular and renal disorders.

Further reading

Szerlip HM. Renal-dose dopamine: fact and fiction [editorial]. Ann Intern Med 1991;115:153-4.

Horn PT, Murphy MB. New dopamine receptor agonists in heart failure and hypertension: implications for future therapy. Drugs 1990;40:487-92.

Lopez-Sendon J. Ibopamine in chronic congestive heart failure: hemodynamic and neurohumoral effects. Am J Med 1991;90(5B Suppl):43S-49S.

Fitton A, Benfield P. Dopexamine hydrochloride: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in acute cardiac insufficiency [published erratum appears in Drugs 1990;40: following Table of Contents]. Drugs 1990;39:308-30.

* In this article, the terms D1 and D2 receptors refer to the D1 and D2 subfamilies described in Professor Crocker's article (`Dopamine - mechanisms of action' Aust Prescr 1994;17:17-21).

Self-test questions

The following statements are either true or false.

1. Dopamine infusions can reduce peripheral vascular resistance.

2. Dopamine infusions can cause vasoconstriction by stimulating alpha adrenoceptors.

Answers to self-test questions

1. True

2. True