Antihypertensive therapy targeted to the needs of the patient: focus on the renin-angiotensin system; older and newer agents.

Antihypertensive drug therapy can lower blood pressure and prolong life, but many hypertensive patients continue to develop further risk factors and to die prematurely of heart disease. Antihypertensive drugs can also interfere with the patient's quality of life, and many are not compatible with the concomitant medical conditions of the patient and the medications taken to treat them. For these reasons, the antihypertensive therapy selected should meet the specific and complete needs of each patient, not just treat the high blood pressure. An analysis of the drugs that inhibit the renin-angiotensin system suggests that several of these drugs have a more favorable therapeutic profile than other classes of hypotensive agents. The newly developed receptor-site-specific blockers are expected to be tolerated better by hypertensive patients and, consequently, to enhance their quality of life. The first of the new class of nonpeptide blockers of the AT1 receptor, losartan--which has no partial agonist activity--is likely to have the advantages of the angiotensin-converting enzyme inhibitors without their adverse effects, notably cough. In selected patients, the AT1-receptor blockers could become the drugs of first choice for the management of hypertension.

Alpha 1-blockade for the treatment of hypertension: a megastudy of terazosin in 2214 clinical practice settings.

The purpose of this study was to evaluate the effects of the alpha 1-blocking agent terazosin on blood pressure (BP) and blood lipids in a large, variant population of patients with hypertension. A total of 16,917 patients with hypertension were evaluated at 2214 primary and community care facilities; 7808 of these patients had not been treated previously for hypertension; 3928 were switched to terazosin from another antihypertensive agent; and 5181 received terazosin in addition to an agent that had not controlled their hypertension. Terazosin produced highly significant reductions in systolic (-18.2 +/- 0.2 mm Hg) and diastolic (-13.2 +/- 0.1 mm Hg) BP when used as monotherapy (mean dose, 3.1 mg; range, 2 to 10 mg) without causing a significant increase in heart rate. Equal antihypertensive efficacy was demonstrated in men, women, blacks, and whites of all ages, with particular benefit to elderly patients (> or = 65 years of age) with systolic hypertension. Comparative studies indicated that terazosin had equal antihypertensive efficacy in combination with diuretics, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. Patients who had not responded to monotherapy with one of these classes of antihypertensive drugs showed significant reductions of BP after terazosin, in the following average doses, was added to diuretics, 3.1 mg; beta-blockers, 3.4 mg; calcium channel blockers, 3.3 mg; and ACE inhibitors, 3.4 mg. Terazosin produced highly significant reductions in blood levels of total cholesterol (-5.0%), triglycerides (-6.1%), and low-density lipoprotein cholesterol (-7.6%) without change in high-density lipoprotein cholesterol when used as monotherapy. Similar favorable effects on blood lipid levels were demonstrated when terazosin was used in combination with all other classes of antihypertensive drugs. The greatest reductions in blood cholesterol (-9.2%) were observed among patients with hyperlipidemia (total cholesterol > or = 240 mg/dL). Terazosin maintained its antihypertensive efficacy and was well tolerated by patients with a variety of concomitant diseases, including congestive heart failure, peripheral vascular disease, chronic obstructive pulmonary disease, benign prostatic hyperplasia, diabetes, and obesity. Adverse effects occurred in 17.9% of patients and caused 2.2% to drop out of the study. The most frequent adverse effects were dizziness (4.8%), headache (2.5%), and asthenia (2.4%). Only 0.4% suffered syncope and 0.2% impotence. These data demonstrate the usefulness of terazosin as monotherapy or add-on therapy for treatment of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary dopamine and sodium excretion in spontaneously hypertensive rats.

We measured urinary dopamine in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) before (days 0-6) and during high-salt diet, in the absence (days 6-10) and presence (days 10-14) of added L-dopa (2 mg/kg/day by gavage). Urinary excretion of sodium (UNaV) increased 20-fold during intake of chow containing 8% NaCl in both strains. Systolic blood pressure (SBP) of SHR increased slightly (9 +/- 4 mmHg; p < 0.05) on the high-salt diet, whereas SBP did not change in WKY. Urinary dopamine excretion was not different between strains in the basal state, and was as great or greater in SHR than WKY during high-salt intake with and without added L-dopa. SBP was unaffected by L-dopa administration and UNaV did not increase or differ between strains despite higher urinary dopamine excretion in SHR. We conclude that renal dopamine formation in vivo is not diminished in SHR, compared with WKY, on normal or high-salt diets, and that elevation of renal dopamine formation secondary to L-dopa administration is not associated with reductions in SBP or altered UNaV in these rats.

Enhanced thromboxane formation by blood but not whole platelets from spontaneously hypertensive rats.

Increased serum levels of immunoreactive thromboxane B2 (iTXB2) were observed in spontaneously hypertensive rats of the Okamoto-Aoki strain (SHR) compared with normotensive Wistar-Kyoto rats (WKY). Serum iTXB2 levels in whole blood allowed to clot at 37 degrees C for 1 hour were significantly greater in SHR than WKY at 8, 16-20, and 38 weeks of age, whereas formation of iTXB2 by thrombin-stimulated whole platelets from 6 16-week-old SHR and 6 age-matched WKY was 399 +/- 44 and 377 +/- 38 ng/10(9) platelets/30 min, respectively. No significant difference in radioconversion of exogenous arachidonic acid to TXB2 was observed in whole platelets from SHR (18.2 +/- 2.5%, n = 4) and WKY (20.1 +/- 3.0%, n = 4) at 16 weeks of age. These results support the proposal that enhanced ability of blood from SHR to generate iTXB2 is independent of the stage of hypertension development. This enhancement probably depended on factors or blood elements other than platelets since no difference in formation was observed on stimulation of whole platelets.

Enhanced vasodilatory responses to bradykinin in stroke-prone spontaneously hypertensive rats.

Vasodilatory responses to bradykinin (BK) and acetylcholine (ACh) were compared in phenylephrine preconstricted perfused kidneys from 30-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Responses to ACh did not differ between kidneys from SHRSP and WHY. BK-induced dilatation was greater in kidneys from SHRSP relative to WHY and was not affected by indomethacin or captopril. These results indicate that renal vasodilatory responsiveness to bradykinin is enhanced in SHRSP with established hypertension.

Therapeutic benefit of captopril in salt-loaded stroke-prone spontaneously hypertensive rats is independent of hypotensive effect.

In the present study we examined whether the angiotensin I converting enzyme inhibitor, captopril, would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and renal pathology over a 26-week period. In the control group of six untreated SHRSP fed Stroke-Prone Rodent Diet and 1% NaCl drinking solution, all animals developed severe hypertension and stroke by 16.1 weeks of age. In eight salt-loaded SHRSP treated with oral captopril (50 mg/kg/day) beginning at 8.4 weeks of age, systolic blood pressure was slightly but temporarily suppressed and then continued to rise; by 12 weeks of age systolic blood pressure reached levels of severe hypertension, 240 +/- 8 mm Hg, and did not differ from that of untreated SHRSP. No deaths or brain lesions were noted in captopril-treated SHRSP despite severe hypertension maintained through 26 weeks of age when the study ended. Captopril treatment prevented increases in urinary protein excretion (14 +/- 2 v 63 +/- 16 mg/day at 11.7 weeks of age, P less than .01) and the severe brain, renal, and cardiac vascular lesions observed in untreated SHRSP. When maintained on Stroke-Prone Rodent Diet and saline, plasma renin activity of untreated SHRSP surviving until 14.5 weeks of age was markedly increased (29.1 +/- 9.4 ng Ang I/mL/h) compared with either untreated SHRSP (9.2 +/- 2.5 ng Ang I/mL/h, P less than .01) or Wistar-Kyoto rats (3.5 +/- 1.0 ng Ang I/mL/h, P less than .01) maintained on standard diet and water.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha 1 blockers. Safe, effective treatment for hypertension.

Alpha 1-adrenergic blocking agents, used alone or in combination with other medications, are efficacious in the management of hypertension. They are safe and well tolerated, and they offer unique advantages. Their mechanism of action in lowering blood pressure targets elevated peripheral vascular resistance, which is the principal hemodynamic abnormality of essential hypertension. The alpha 1 blockers maintain cardiac output and blood flow to vital organs, and they do not affect renin release. These agents have beneficial lipid and metabolic effects and can improve left ventricular hypertrophy, theoretically having a positive impact on cardiovascular morbidity and mortality. The only drug interaction identified with the alpha 1 blockers is an increased hypotensive effect when they are combined with other antihypertensive agents. A further advantage of the alpha 1 blockers is that, because of the widespread location of alpha 1 receptors, the agents offer potential benefit for a number of disease states, including benign prostatic hyperplasia. They also provide an especially useful antihypertensive choice for middle-aged and elderly patients.

The role of adrenergic drugs in antihypertensive therapy.

Abnormalities in the adrenergic system are believed by some to be a major contributing factor to primary hypertension, which may explain the increasing clinical usefulness of drugs that affect the adrenergic system. The clinical effects of drugs in this class can be predicted by the location of the alpha or beta receptors that are activated or inhibited by the drug. With the wide range of antihypertensive drugs now available, including diuretics and vasodilators as well as adrenergic agents, it is possible to individualize treatment in ways more appropriate than the traditional stepped-care approach.

Effect of lovastatin on serum lipids in patients with nonfamilial primary hypercholesterolemia.

The effect of lovastatin on serum lipids and its tolerability in patients with non-familial primary hypercholesterolemia (type II-A and type II-B) during a six-month period were evaluated in this open-label study. Thirty-eight patients were enrolled in the study; tolerability was assessed in all 38 patients. Thirty patients completed the study, and the effect of lovastatin on serum lipids in these patients was assessed. Some patients had been treated for hypercholesterolemia with long-term dietary and other non-pharmacologic means before entry into the study. All patients were unresponsive to a six-week program of intensive dietary therapy and other nonpharmacologic treatment to lower their blood cholesterol levels before receiving lovastatin. While maintaining intensive dietary therapy, administration of lovastatin was instituted at a dosage of 20 mg/day, which was increased by 20-mg increments monthly, as necessary, to a maximum of 80 mg/day. In an effort to achieve goal levels of low-density lipoprotein cholesterol (LDL-C), ten patients received a daily dosage of 20 mg, 12 patients received 40 mg, seven patients 60 mg, and one patient 80 mg. Twenty-nine of the 30 patients achieved significant lowering of serum levels of total cholesterol (TC), LDL-C, and apolipoprotein (apo) B-I; this was demonstrated after the first month of therapy with lovastatin and was maintained throughout the six-month treatment period. One patient failed to demonstrate lowering of these serum lipids, despite receiving the maximum recommended dosage of lovastatin of 80 mg/day. Comparative measurements of serum lipids during dietary therapy alone and after six months of diet plus lovastatin therapy were as follows: TC, 289 +/- 5 versus 216 +/- 9 mg/dl (P less than 0.0005); LDL-C, 206 +/- 4 versus 141 +/- 5 mg/dl (P less than 0.0005); and apo B-I, 112 +/- 3 versus 89 +/- 2 mg/dl (P less than 0.0005). Serum levels of very-low-density lipoprotein cholesterol (VLDL-C) and triglycerides decreased slightly during lovastatin therapy, but the changes were not statistically significant. There were slight but statistically insignificant increases in serum levels of high-density lipoprotein cholesterol (HDL-C), apo A-I, and apo A-II.(ABSTRACT TRUNCATED AT 400 WORDS)

Serotonin and 5-hydroxytryptophan on blood pressure and renal blood flow in anesthetized rats.

The effects of exogenous (injected) serotonin on mean blood pressure and renal blood flow in male Sprague-Dawley rats were compared with the effects of enhanced endogenous serotonin, accomplished by injections of 5-hydroxytryptophan (5-HTP). Responses were evaluated with and without carbidopa, which blocks peripheral conversion of 5-HTP to serotonin, and with and without indomethacin to assess the contribution of prostanoids. Both serotonin (0.25-1.0 micrograms) and 5-HTP (50-200 micrograms) decreased blood pressure and renal blood flow and increased renal vascular resistance in dose-dependent fashion. Hypotensive responses with both agents were greater after arterial injections into the aortic arch than after intravenous injections (into the jugular vein). Carbidopa had no significant effects on responses to serotonin but ablated the ability of 5-HTP to increase renal vascular resistance and decrease renal blood flow. Carbidopa did not alter the hypotensive action of 5-HTP. Indomethacin had no significant effect on responses to serotonin or 5-HTP. These results support a direct renal vasoconstrictor effect for exogenous and endogenously formed serotonin and a hypotensive effect probably arising in the central nervous system.

5-Hydroxytryptophan and carbidopa in spontaneously hypertensive rats.

Serial measurements of blood pressure, body weight, food and water intake, and salt and water excretion were compared in two groups of spontaneously hypertensive rats (SHR) over a 12-day period: control SHR (n = 11) and a group (n = 9) which received supplementary 5-hydroxytryptophan (5-HTP; 2 mg/ml) in its drinking water. During the final 4 days of study, both groups received additional oral carbidopa (50 mg/kg twice a day) to inhibit peripheral, but not brain aromatic L-amino-acid decarboxylase (LAAD), an enzyme necessary to the formation of 5-hydroxytryptamine (5-HT, serotonin) from 5-HTP. 5-Hydroxytryptophan increased urinary 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) markedly; following carbidopa, urinary 5-HT, and to a lesser degree urinary 5-HIAA, decreased, whereas brain 5-HT and 5-HIAA increased. Spontaneously hypertensive rats treated with 5-HTP plus carbidopa had significantly lower blood pressure levels, lower pulse rates, reductions in food and water intake, salt and water excretion, and a loss of body weight, when compared with the control SHR. These data indicate that enhanced brain formation of 5-HT can give rise to metabolic and circulatory responses with a resultant lowering of blood pressure.

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

The influence of chronic treatment with the angiotensin I converting enzyme (ACE) inhibitor enalapril on blood pressure, kidney function, and survival was examined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed a Japanese rat chow plus a 1% NaCl drinking solution beginning at 7-8 weeks of age developed severe hypertension and stroke; 14 of 18 untreated control SHRSP died by 14 weeks of age and exhibited evidence of cerebrovascular lesions. When enalapril (15 mg/kg/day) was included in the drinking solution of 15 SHRSP, blood pressure was initially reduced by only a slight degree, whereas survival improved markedly; only one of 10 SHRSP died before the rest were killed at 18 to 21 weeks. The remaining five enalapril-treated SHRSP lived beyond 36 weeks and on histological examination exhibited no evidence of cerebrovascular lesions. Chronic enalapril treatment also prevented the greater urinary excretion of protein and severe renal lesions observed in untreated SHRSP but did not affect urinary salt and water excretion. In anesthetized rats, glomerular filtration rate and tubular reabsorption of water were lower in untreated control SHRSP when compared with enalapril-treated SHRSP. Mean arterial pressure was comparable in both groups. These data support a possible role for ACE inhibition in the prevention of stroke and maintenance of kidney function independent of any marked change in blood pressure of SHRSP. Whether the protective effects of ACE inhibition relate to reduced angiotensin II formation, increased tissue kinins, or another mechanism remains to be determined.

The long-term antihypertensive effects of prazosin and atenolol.

The efficacy and tolerability of the alpha-blocker prazosin was compared with that of atenolol, a beta-blocker, in the long-term treatment of uncomplicated, essential hypertension. Twelve patients were randomly assigned to prazosin treatment and 15 to treatment with atenolol. Drug therapy was titrated to reduce diastolic blood pressure by 10 mm Hg or to below 89 mm Hg, whichever was lower. If monotherapy with either study drug failed to do this, hydrochlorothiazide was added to the regimen. Once blood pressure control was established, patients received maintenance therapy at that dosage and were followed for up to 12 months. Blood pressure, side effects, and plasma lipid levels were monitored during this period. Seventy-five percent of patients receiving prazosin monotherapy attained blood pressure goals, compared with 60 percent of patients given atenolol monotherapy. With the addition of low-dose hydrochlorothiazide, those patients not having an adequate response to monotherapy attained blood pressure control. Blood pressure reductions were maintained without dosage adjustment throughout the maintenance period; patient acceptance was good, and there was no evidence of tolerance. Treatment with atenolol produced slight increases in plasma triglyceride levels and little change in total or low-density lipoprotein cholesterol. In contrast, patients treated with prazosin demonstrated no adverse effects with regard to lipid levels. Although a higher percentage of patients reached goal blood pressure with prazosin monotherapy than with atenolol, the response rates were comparable when hydrochlorothiazide was added to the regimens.

Reciprocal renal effects of dopamine and 5-hydroxytryptamine formed within the rat kidney.

1. Clearance of inulin and p-aminohippurate and excretion of water and sodium were measured for eight to 11 clearance periods of 20 min duration in anaesthetized, 3% volume-expanded rats, before and after intravenous infusions of the amino acids L-dopa (L-3,4-dihydroxyphenylalanine) and 5-hydroxytryptophan. During the final two clearance periods, the peripheral decarboxylase inhibitor, carbidopa (S-alpha-hydrazino-3,4-dihydroxy-alpha-methylbenzenepropanoic acid monohydrate), was infused additionally. 2. Renal formation of dopamine (3,4-dihydroxyphenethylamine) and 5-hydroxytryptamine was demonstrated during infusions of L-dopa and 5-hydroxytryptophan, respectively; carbidopa blocked the renal formation of these biogenic amines. 3. During infusion of dopa, a diuresis and a natriuresis were observed; during the infusion of 5-hydroxytryptophan, slight reductions in clearances of inulin and p-aminohippurate, but significant reductions in sodium and water excretion, were measured. 4. The addition of carbidopa diminished diuretic and natriuretic responses to dopa as renal dopamine excretion decreased; the infusion of carbidopa also ameliorated the antinatriuretic and antidiuretic effects of 5-hydroxytryptophan, as 5-hydroxytryptamine excretion decreased. 5. Although dopa and 5-hydroxytryptophan are substrates for the same enzyme, aromatic L-amino-acid decarboxylase, simultaneous infusions of both amino acids at comparable rates gave no evidence of competitive inhibition of amine synthesis. However, the infusion of dopa, after 5-hydroxytryptophan, decreased its antinatriuretic and antidiuretic effects. 6. These data raise the possibility that dopamine and 5-hydroxytryptamine are formed as reciprocal intrarenal hormones by the identical enzyme, aromatic L-amino-acid decarboxylase, which is located within cells of the renal tubule.

Thromboxane A2 and the development of hypertension in spontaneously hypertensive rats.

Osmotic minipumps containing OKY-046 (15-20 mg/kg per day), to inhibit thromboxane (TX) A2 synthase, were implanted into 43-day-old SHR and age-matched Wistar-Kyoto rats (WKY) to study the role of TXA2 in the development of hypertension in SHR. Inhibition of TXA2 synthase with OKY-046 did not affect urine volume, sodium excretion, potassium excretion, food and water intake or body weight in either WKY or SHR during the two weeks of study. In the first week systolic blood pressure (SBP) was significantly lower in SHR receiving OKY-046 in comparison to SHR which received no OKY-046 (127 +/- 3 vs. 110 +/- 4 mm Hg, P less than 0.01). OKY-046 did not affect SBP in WKY. By the second week SBP in SHR and WKY receiving OKY-046 did not differ from their respective controls despite an 85% reduction in serum immunoreactive TXB2 (iTXB2; the stable hydrolysis product of TXA2) and a 45% reduction in urinary iTXB2 excretion. These results support a possible role for TXA2 in the developmental stage of hypertension in SHR and other factors in the sustained elevation of blood pressure.

Dopamine and L-dopa potentiation of pressor responses to norepinephrine in isolated perfused rat kidneys.

The ability of l-dopa and dopamine to modulate renal vascular responses to norepinephrine (NE, 50-150 ng) was examined in isolated Tyrode-perfused kidneys from male Sprague-Dawley rats. Renal pressor responses to bolus injections of NE were constant during saline infusion. In contrast, l-dopa (15 micrograms/min and 75 micrograms/min) and dopamine (15 micrograms/min) infusions that did not alter baseline perfusion pressure increased pressor responses to NE significantly. Concomitant infusion of the aromatic l-amino-acid decarboxylase inhibitor carbidopa (20 micrograms/min) suppressed the ability of l-dopa (75 micrograms/min) but not dopamine to enhance renal pressor responses to NE. The pressor potentiation of NE did not appear to be the result of a general musculotropic effect or altered alpha-1 adrenoreceptor activity since increased vasoconstrictor responses to phenylephrine (PE) and serotonin (5-HT) were not observed. Infusions of cocaine (15 micrograms/min) enhanced the renal pressor effects of NE but not PE in similar fashion to l-dopa and dopamine. In the presence of cocaine, l-dopa did not potentiate NE constriction further. These results suggest that endogenous or exogenous dopamine in the kidney may affect neuronal NE uptake to enhance its renal vascular effects.

Renal calcium metabolism and diuretics.

Diuretic agents have variable effects on calcium excretion as studied in vivo and in isolated kidneys and nephron segments. Generally, by increasing sodium and water excretion, diuretics will cause a concomitant increase in calcium excretion. As they diminish blood volume and alter renal hemodynamics, diuretics enhance calcium reabsorption in the proximal tubule, modulating their usual effects on calcium excretion. These general effects can be further modulated by additional metabolic actions. For instance, chronic administration of thiazide diuretics may diminish calcium excretion on the basis of altered levels of or responsiveness to PTH. Agents such as acetazolamide, which diminish bicarbonate reabsorption in the proximal tubule, will cause a modest calciuria, if any, because of reabsorption of the increased delivery of calcium, but not sodium, at the distal nephron. Agents acting in the loop of Henle that increase chloride excretion relative to sodium tend to cause greater calcium excretion. Finally, agents that act beyond the loop of Henle, which have their primary effects on cation excretion, tend to cause lesser degrees of calcium excretion, especially relative to sodium. These principles indicate that it may be appropriate to select a specific diuretic agent for different patients, depending upon the state of their calcium balance. It also may be possible to predict alterations in calcium balance, so that these may be anticipated and compensated for with patients on long-term therapy with various diuretic agents.

Formation of biogenic amines by isolated kidneys of spontaneously hypertensive rats.

Kidneys form dopamine (DA) from L-dopa and serotonin from L-5-hydroxytryptophan (L-5-HTP) via aromatic L-amino acid decarboxylase. We compared the ability of isolated perfused kidneys from adult (20-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) to form these biogenic amines. Renal vascular resistance (RVR) was greater in perfused kidneys from SHR (n = 10) than WKY (n = 8) (p less than 0.01). Slight decreases in RVR were observed during L-dopa infusion but these were unrelated to DA formation. L-Dopa infusion was associated with greater DA output in SHR than WKY in both the renal venous and urinary effluents although the latter did not achieve statistical significance. L-5-HTP increased RVR to a greater degree in SHR than WKY kidneys. This was associated with larger quantities of serotonin in the urinary and venous effluents and greater pressor responses to exogenous serotonin in SHR than WKY kidneys; however, either parameter alone was not significantly increased. Our findings do not support a deficiency of intrarenal DA formation as a pathogenic factor for hypertension in SHR. Biogenic amine formation is as great if not greater in SHR than WKY kidneys and appears to contribute largely to the greater increases in renal resistance seen in SHR kidneys on infusion of L-5-HTP. Enhanced renal serotonin formation may elevate blood pressure, whereas enhanced renal DA formation would favor blood pressure lowering, perhaps as a compensatory mechanism.

Formation of serotonin by rat kidneys in vivo.

Renal formation of serotonin by decarboxylation of its amino acid precursor L-5-hydroxytryptophan (L-5-HTP) has been demonstrated with renal tissue homogenates and isolated perfused rat kidneys. Our objective in the present study was to determine whether the conversion of L-5-HTP to serotonin was associated with functional changes by kidneys in vivo. Renal clearance studies were conducted in anesthetized, volume-expanded male Sprague-Dawley rats receiving either saline (n = 9) or L-5-HTP (15 and 75 micrograms/min iv, n = 9). No change in mean arterial pressure was measured during infusions of L-5-HTP at either dose, whereas glomerular filtration rate (GFR), as measured by the clearance of inulin, and effective renal plasma flow (CPAH) decreased by 34 +/- 5% (mean +/- SE, P less than 0.001) and 26 +/- 7% (P greater than 0.07), respectively. Urine flow and sodium excretion decreased by 41 +/- 9% (P less than 0.01). Serotonin and 5-HTP were determined in urine and plasma using HPLC. High levels of 5-HTP were present in plasma, but not urine. Urinary serotonin increased in the rats receiving L-5-HTP without concomitant increases in plasma serotonin. More than 20% of the infused L-5-HTP was recovered in the urine as serotonin. The decarboxylase inhibitor carbidopa (20 micrograms/min) markedly reduced urinary serotonin excretion in the rats which received L-5-HTP and reversed the changes in GFR, CPAH, urine flow, and sodium excretion. Infusions of the amino acid precursor of L-5-HTP, L-tryptophan (n = 7), did not alter kidney function or increase plasma or urinary 5-HTP or serotonin levels. These results are consistent with the intrarenal formation of serotonin by renal decarboxylase with attendant alterations in renal hemodynamics and salt and water excretion.

Renal functional status and patterns of catecholamine excretion.

Twenty-four hour urinary catecholamine measurements were obtained in seven normal individuals and 23 patients with essential hypertension or renal disease. As renal function decreased, large reductions in the excretion of free catecholamines and total dopamine were measured. Since urinary catecholamine measurements are used for diagnostic and physiologic studies, our data indicate a need to assess renal function for accurate interpretation of these measurements. Our results are also consistent with a renal origin for a major portion of the urinary dopamine content.