Introduction

One Minute Weight Loss

Best Weight Loss Programs That Work

Get Instant Access

Renal NaCl excretion varies directly with renal perfusion pressure (defining the phenomenon of pressure natriuresis; see Fig. 1), renal blood flow, and extracellular fluid (ECF) volume. Thus, it is not surprising that alterations in mean arterial pressure and systemic hemodynamics affect the response to diuretic drugs. Many vasoactive drugs have pronounced effects on renal function and renal Na excretion, both because they affect systemic hemodynamics and because they have direct effects on renal Na and CI handling along the nephron. In this chapter, the actions of a unique endogenous catecholamine, dopamine, on renal function will be summarized (see also Chapter IIIB), the effects of systemic hemodynamics on renal function will be reviewed, and the use of dopamine and dobutamine to improve systemic hemodynamics in patients with severe congestive heart failure will be discussed. Dopamine in low doses is frequently employed to "protect" the kidney from hemodynamic insults and to improve renal function in acute renal failure. The use of "renal dose" dopamine in these settings will be discussed in the third section of this chapter. Finally, oral drugs that activate dopamine receptors have been developed during the past several years for use in hypertension and in treating chronic congestive heart failure. Some of these drugs are currently available outside the United States. These drugs will be discussed in the last section of this chapter.

Diuretic Agents: Clinical Physiology and Pharmacology o n 1

Copyright © 1997 by Academic Press. All rights of reproduction in any form reserved. -3U X

FIGURE 1. (A) Effects of renal perfusion pressure on urinary Na excretion, renal plasma flow (RPF) and glomerular filtration rate (GFR). From Guyton A. C. Science 252; 1813-1816, 1991, with permission. (B) Effects of dietary NaCl intake on extracellular fluid volume at steady state in normal (filled circles and solid line), mildly (squares and dashed line), and severely (triangles and dotted line) edematous individuals. At steady state, dietary intake will equal urinary excretion. A typical Western salt intake is given by the dashed line. From Ellison, D. H. Am. J. Kidney Dis. 23: 623-624, 1994, with permission.

Renal Perfusion Pressure (mm Hg)

FIGURE 1. (A) Effects of renal perfusion pressure on urinary Na excretion, renal plasma flow (RPF) and glomerular filtration rate (GFR). From Guyton A. C. Science 252; 1813-1816, 1991, with permission. (B) Effects of dietary NaCl intake on extracellular fluid volume at steady state in normal (filled circles and solid line), mildly (squares and dashed line), and severely (triangles and dotted line) edematous individuals. At steady state, dietary intake will equal urinary excretion. A typical Western salt intake is given by the dashed line. From Ellison, D. H. Am. J. Kidney Dis. 23: 623-624, 1994, with permission.

5 200

uj ca

25 30 35 40 ECF Volume, Liters

Normal level

I GFR

Normal level

I GFR

DOPAMINE AND RENAL FUNCTION

Based on the intimate relation between systemic hemodynamics and renal function, it is not surprising that vasoactive drugs affect renal function. Many vasoactive agents have both direct effects on glomerular filtration and salt reabsorption and indirect effects on renal function mediated by changes in systemic hemodynamics. Renin, angiotensin, aldosterone, atrial natriuretic peptide, prostaglandins, adenosine, and other hormones and paracrine factors alter both renal blood flow and ion transport. The effects of these vasoactive substances are reviewed elsewhere in this volume. Catecholamines also affect renal blood flow and ion transport, both directly and indirectly, by interacting with a and ¡3 adrenergic receptors. Dopamine (3,4-dihydroxyphenylethylamine) is a unique catecholamine that interacts with a and ¡3 adrenergic receptors as well as with specific dopaminergic receptors. Dopamine is produced by the kidney and by dopaminergic neurons by the actions of tyrosine hydroxylase and aromatic L-amino-acid decarboxylase (see Fig. 4, Chapter IIIB). Dopaminergic neurons lack dopamine /3-hydroxylase or phenylethanolamine N-methyltransferase; therefore catecholamine synthesis halts at dopamine and does not proceed to norepinephrine or epinephrine [25]. In the renal cortex, dopamine is produced primarily from circulating L-dopa, by cells of the proximal convoluted tubule.

Renal dopamine receptors have been classified physiologically as DA, and DA2 (see Fig. 2 [23]). DA! receptors, defined functionally, include D1A and D1B receptors. DA2 receptors include D2, D3, and D4 receptors. DA! receptors are expressed by renal arteries, mesenteric, coronary, and cerebral arteries, by proximal convoluted and straight tubules (at both the apical and the basolateral

Receptor_2nd Messengers_Sites_Actions_Effects

DA, ft Adenylyl Cyclase ftPhospholipase C (DARP-32)

Adenylyl Cyclase

Kidney Tubules

(PT, TAL, CD) Blood Vessels

(Coronary, Cerebral, & -Mesenteric)

Autonomic Ganglia Sympathetic

Nerves Adrenal Cortex

Vasodilation (Direct) JJNa/H Exchange r J Na/K ATPase-

tRBF

tUNaV

Vasodilation (Indirect) RBF ^Aldosterone

FIGURE 2. Functional classification of dopamine receptors, predominant second messengers, sites of action, and renal effects. Some data suggest that activation of both DAt and DA2 receptors is needed to fully inhibit Na/K ATPase.

brush border membrane basolateral membrane

FIGURE 3. Mechanisms of dopamine actions on Na transport pathways of the proximal tubule. AT brush border membrane, stimulatory effect of dopamine on adenylyl cyclase activity predominates, resulting in an inhibition of Na/H antiport activity. At basolateral membrane stimulatory effect of dopamine on phospholipase C predominates, resulting in activation of protein kinase C and inhibition of Na/K ATPase activity. Calcium may also influence transport activities. AC, adenylyl cyclase; PIP2, phophatidyl inositol 4,5-bisphosphate; IP,, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; ATP, adenosine trisphosphate. From Felder et al. Am. J. Physiol. 257; F315-F327,1989, with permission.

brush border membrane basolateral membrane

FIGURE 3. Mechanisms of dopamine actions on Na transport pathways of the proximal tubule. AT brush border membrane, stimulatory effect of dopamine on adenylyl cyclase activity predominates, resulting in an inhibition of Na/H antiport activity. At basolateral membrane stimulatory effect of dopamine on phospholipase C predominates, resulting in activation of protein kinase C and inhibition of Na/K ATPase activity. Calcium may also influence transport activities. AC, adenylyl cyclase; PIP2, phophatidyl inositol 4,5-bisphosphate; IP,, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C; ATP, adenosine trisphosphate. From Felder et al. Am. J. Physiol. 257; F315-F327,1989, with permission.

cell membranes (see Fig. 3)), by thick ascending limb cells, and along the cortical collecting duct. They do not appear to be expressed by glomeruli. DA2 receptors are expressed in the adventitia and intima of renal blood vessels and the glomerulus, as well as in renal cortical and medullary tissue. Molecular cloning has identified several classes of dopamine receptors. Dopamine receptors that correspond to DA2 receptors have been shown to be expressed by glomeruli and proximal tubules [12]. Data for expression of DA2 receptors along tubules has been contradictory.

Infusions of dopamine into normal animals or humans lead to dose-dependent increases in renal blood flow, glomerular filtration rate, natriuresis, and diuresis. Both the renal vasodilatory effects of dopamine and the direct effects on tubule epithelial cells appear to be mediated predominantly by DAi receptors (see Fig. 3), which stimulate adenylyl cyclase. These receptors appear to be associated with a 32-kDa protein (dopamine-regulated phosphorprotein, DARP-32) that has been postulated to act as a third messenger for dopamine actions in kidney and brain. DA2 receptors appear to inhibit the activity of adenylyl cyclase and inhibit angiotensin-induced aldosterone secretion from the adrenal gland [25]. Recent data suggest that DA2 receptors of that D4 subclass inhibit Na transport and water permeability in rat cortical collecting tubule [43]. Dopamine increases urinary Na excretion both because it increases renal blood flow and, less predictably, glomerular filtration rate, and because it inhibits renal Na/K ATPase, proximal Na/H exchange, and adrenal aldosterone secretion. At low dopamine infusion rates (threshold=0.5 /tg/kg/min, maxi-mum=3 /¿g/kg/min) dopamine activates only the specific dopamine receptors (both DAi and DA2). As doses are increased, ¡3 adrenergic receptors (thresh-old=5 /xg/kg/min, maximum = 10/xg/kg/min) and then a adrenergic receptors (threshold=5/Ag/kg/min, maximum=20 /xg/kg/min) are stimulated. Although dopamine infusion rates <3 /ig/kg/min are frequently referred to as "renal dose" it has been noted that these doses can have significant systemic effects as well [45],

Endogenous dopamine is released in response to increases in dietary or exogenous NaCl load and in response to increases in dietary protein intake. Dopamine may play a physiological role in controlling the natriuretic responses to these maneuvers (see Fig. 3). Blocking dopamine synthesis, either systemically or via intrarenal infusion of a DA2 receptor antagonist, reduces salt excretion in response to dietary salt loading. Intravenous furosemide stimulates urinary dopamine production [24], but evidence for a contributory role of dopamine in the natriuretic response to loop diuretics has been controversial. In isolated perfused rat kidneys and in anesthesized rats, blockade of dopamine synthesis or DAi receptors attenuates the natriuretic response to furosemide [36]. In contrast, Jeffrey et al. [22] found that complete inhibition of dopamine synthesis did not affect the furosemide response in normal humans.

SYSTEMIC HEMODYNAMICS AND RENAL FUNCTION

In normal individuals, renal blood flow and glomerular filtration rate remain relatively constant until the mean arterial pressure declines to below 80 mm Hg. This is the phenomenon of renal autoregulation. Renal Na excretion, however, is directly related to extracellular fluid volume, in a linear manner across the entire range of dietary NaCl intake and ECF volume (see Fig. 4 [47]). Hypotension may result from hypovolemia, vasodilation, impaired cardiac func-

FIGURE 4. Effects of dopamine on extracellular fluid volume homeostasis. RIHP, renal interstitial hydrostatic pressure; ECFV, extracellular fluid volume. From Gonzalez-Compoy, J. M. & Knox, F. G. Chapter 56 in The Kidney: Physiology and Pathophysiology, Eds. Seldin & Giebisch, with permission.

FIGURE 4. Effects of dopamine on extracellular fluid volume homeostasis. RIHP, renal interstitial hydrostatic pressure; ECFV, extracellular fluid volume. From Gonzalez-Compoy, J. M. & Knox, F. G. Chapter 56 in The Kidney: Physiology and Pathophysiology, Eds. Seldin & Giebisch, with permission.

tion, neuropathy, or drugs and may impair diuresis and natriuresis. In the acute setting, hypotensive shock impairs renal function and urinary Na and CI excretion. The best method of increasing urinary volume and solute excretion in this setting is to improve the systemic hemodynamics; volume losses are replaced, impaired cardiac function is corrected, sepsis is treated. In some patients, however, while attempts to achieve definitive control of the underlying disorder are ongoing, pressor support must be employed to prevent serious organ compromise. The appropriate use of pressor support in these situations is beyond the scope of this chapter, but the importance of maintaining renal perfusion pressure should be emphasized; in general, a systolic pressure of 90 mm Hg (or a mean arterial pressure of 65 mm Hg) should be targets in the initial treatment of shock. Fluid is usually administered as the primary mode of resuscitation from shock, but in many cases, pressor agents are also employed. It has been suggested that the use of systemic vasoconstrictors in these settings will uniformly compromise renal perfusion, but this view has been challenged recently. In septic shock, in which systemic vasodilation plays a key role, a adrenergic agonists, including norepinephrine and phenylephrine, have been observed to improve parameters of renal function, at least in some studies [16]. Some experimental data support adding low dose dopamine in this setting. In a study of dogs, low dose dopamine improved renal blood flow even when added to a high dose of norepinephrine [42].

In the foregoing, the renal perfusion pressure was assumed to be reflected by the mean arterial or systemic pressure. In fact, many patients who receive diuretic drugs are older, have renal arterial atherosclerosis, or take drugs that affect renal perfusion. Renal artery stenosis affects the renal response to diuretics not only by reducing renal perfusion pressure, but also by enhancing the effects of diuretics to activate the renin/angiotensin/aldosterone pathway; diuretic-induced renin/angiotensin system activation predisposes to Na retention and may contribute to sudden ("flash") pulmonary edema, now recognized as a presenting manifestation of renal artery stenosis [6]. Drugs such as agioten-sin converting enzyme inhibitors and nonsteroidal anti-inflammatory agents limit the range of blood pressures over which autoregulation of glomerular filtration rate (and renal blood flow) can be maintained. An illustration of the complex interactions between mean arterial pressure, cardiac output, and renal function is the effects of afterload reduction on renal salt excretion in the setting of congestive heart failure. Angiotensin I converting enzyme inhibitors reduce afterload and increase cardiac output in patients with systolic dysfunction. Angiotensin I converting enzyme inhibitors can increase renal Na excretion in these situations by increasing renal perfusion, when combined with a diuretic [8], On the other hand, excessive doses of angiotensin I converting enzyme inhibitors can be anti-natriuretic. In one study [38], captopril, a short acting angiotensin I converting enzyme inhibitor (50 mg three times daily), and enala-pril, a long acting angiotensin I converting enzyme inhibitor (20 mg/day), had similar effects in improving cardiac hemodynamics and symptoms of congestive heart failure. Only treatment with captopril, which led to less sustained reduction in mean arterial pressure, was associated with significant weight loss and natriuresis. Enalapril did not affect either parameter significantly. This difference in renal responses was attributed to the prolonged reductions in mean arterial pressure which tended to counteract the effects of afterload reduction to improve renal NaCl excretion; although both drugs are useful for treating congestive heart failure, this study highlights the central role of renal perfusion pressure in natriuresis and diuresis. It suggests that each patient has an optimal mean arterial pressure during treatment with afterload reducing agents. Above this pressure, cardiac output is compromised and renal NaCl excretion declines; below this pressure, cardiac output is high, but renal NaCl excretion declines because of inadequate perfusion pressure.

Was this article helpful?

0 0
Lose Weight Today With Yoga

Lose Weight Today With Yoga

Want to lose weight but don't know where to start? Transform Your Life With The Knowledge Of The Yogi's And Begin Losing Weight Today. This guide is one of the most valuable resources you can have when learning about yoga to lose weight.

Get My Free Ebook


Post a comment