Pathophysiological effects of aldosterone in cardiovascular tissues.

The advent of antihypertensive therapy has resulted in a significant decrease in cardiovascular morbidity and mortality. Nevertheless, the incidence of heart failure, stroke and end-stage renal failure continues to increase. This trend suggests that a mechanism, independent of hypertension, is responsible for end-organ damage. Genetic and experimental models of hypertension have demonstrated that excess aldosterone induces severe injury in the heart, brain and kidneys, and that pharmacological antagonism of aldosterone or adrenalectomy markedly reduces myocardial injury, cerebral hemorrhage and renal vascular disease. In clinical studies, plasma aldosterone levels have been shown to correlate with left ventricular hypertrophy, stroke and renal dysfunction. Moreover, aldosterone antagonism has been shown to reduce morbidity and mortality in patients with heart failure. Thus, an increasing body of evidence now indicates that aldosterone is an independent risk factor for cardiovascular disease.

Prolactin and the rat kidney: a clearance and micropuncture study.

PRL is a pituitary hormone with important osmoregulatory properties in lower vertebrates and has been reported to decrease renal water and electrolyte excretion in mammals. Although several studies have suggested that the proximal tubule is the major site of action of PRL, no direct examination of such an effect has been made. In the present study we used micropuncture and clearance techniques to examine the effect of ovine PRL (oPRL) infusion on single nephron and whole kidney function in anesthetized volume-expanded rats pretreated with bromocriptine to suppress endogenous PRL release. oPRL infusion was associated with a significant reduction in urinary sodium, potassium, and water excretion compared to changes seen in the control group. There was no significant effect of oPRL on whole kidney glomerular filtration rate, renal plasma flow, filtration fraction, renal blood flow, renal vascular resistance, or arterial pressure compared to those in control rats. Single nephron studies failed to detect any significant effect of oPRL on single nephron glomerular filtration rate and absolute or fractional reabsorption by the proximal convoluted tubule. Although arginine vasopressin was detected in the oPRL preparation, the quantity infused was negligible compared to the plasma levels found in anesthetized rats prepared for kidney micropuncture. Our results suggest that oPRL exerts a renal tubular action separate from arginine vasopressin to decrease water and electrolyte excretion which occurs beyond the last superficial convolution of the proximal convoluted tubule.

Aldosterone: a mediator of myocardial necrosis and renal arteriopathy.

To determine the role of aldosterone in mediating cardiovascular damage, we performed ablation/replacement experiments with aldosterone in a rat model of cardiac injury. Administration of angiotensin II and Nomega-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthesis inhibitor) to male rats drinking 1% saline caused hypertension, severe biventricular myocardial necrosis, proteinuria, and fibrinoid necrosis of renal and cardiac vessels. Removal of aldosterone by adrenalectomy or through administration of the selective aldosterone antagonist eplerenone markedly reduced the cardiac and renal damage without significantly altering blood pressure. Aldosterone infusion in adrenalectomized, glucocorticoid-replaced L-NAME/angiotensin II-treated animals restored damage. Thus, we identified aldosterone as a critical mediator of L-NAME/angiotensin II induced vascular damage through mechanisms apparently independent of its effects on systolic blood pressure.

Role of prostanoids in renin-dependent and renin-independent hypertension.

We investigated the role of prostanoid-mediated pressor mechanisms in setting the level of blood pressure in renin-dependent and renin-independent models of hypertension in unanesthetized rats. Intravenous administration of a blocker of thromboxane A2/prostaglandin endoperoxide receptors, SQ29548 (2 mg/kg bolus injection plus 2 mg/kg/hr for 3 hours), reduced from 162 +/- 4 to 144 +/- 5 mm Hg (p less than 0.05) the blood pressure of rats with aortic coarctation-induced hypertension at 7-14 days after coarctation when plasma renin activity is greatly increased. In contrast, treatment with SQ29548 was without effect on the blood pressure of either normotensive or hypertensive rats (i.e., aortic coarctation-induced hypertension at 90-113 days after coarctation, deoxycorticosterone-salt-induced hypertension) having normal or depressed values of plasma renin activity. The blood pressure-lowering effect of SQ29548 in the early phase of aortic coarctation-induced hypertension was positively correlated with the prevailing plasma renin activity and could not be demonstrated in hypertensive rats pretreated with indomethacin. We attribute the hypotensive effect of SQ29548 to interference with pressor mechanisms that depend on activation of thromboxane A2/prostaglandin endoperoxide receptors and suggest that such prostanoid-mediated mechanisms are operational and contribute to an increase in blood pressure in angiotensin-dependent forms of hypertension. Also prostanoid-mediated vasodepressor mechanisms are operational in the early phase of aortic coarctation-induced hypertension since the blood pressure of rats pretreated with SQ29548 was increased by the subsequent administration of indomethacin. Accordingly, the blood pressure of rats with aortic coarctation-induced hypertension is influenced by the interplay of prostanoid-mediated pressor and vasodepressor mechanisms.

Regional renal nitric oxide release in stroke-prone spontaneously hypertensive rats.

Diminished nitric oxide (NO) production has been implicated in the pathogenesis of salt-sensitive hypertension. We questioned whether such a defect is responsible for the malignant hypertension and nephrosclerosis in stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-salt/stroke-prone diet (S) versus a regular diet (R). NO release from 30-minute incubates of cortex and outer and inner medulla were studied in SHRSP at 10, 12, and 16 weeks of age on the S diet versus R diet. SHRSP-S (n=16) exhibited a marked age-dependent increase in NO release, especially in the cortex. Increases were only modest in SHRSP-R (n=21). At 16 weeks, cortical NO was 93+/-25 versus 6+/-1 pmol/mg tissue in SHRSP-S versus SHRSP-R (P<.001). Immunohistochemical staining increased mostly for neuronal, slightly for endothelial, and negligibly for inducible isoforms of NO synthase and was predominantly in the cortex of SHRSP-S versus SHRSP-R. Despite similar hypertension in SHRSP-S versus SHRSP-R (mean arterial pressure, 174+/-7 versus 177+/-2 mm Hg), malignant nephrosclerosis was seen only in SHRSP-S, affecting 22+/-6% of glomeruli and 23+/-4 vessels per 100 glomeruli by 16 weeks. N omega-nitro-L-arginine (15 mg/kg per day) in SHRSP-S (n=6) abrogated the increase in cortical NO but further augmented the hypertension and accelerated lesion development. Wistar-Kyoto rats at 16 weeks on the R diet (n=8) had NO levels similar to those of SHRSP-R, showed increased cortical NO to only 28+/-10 pmol/mg on the S diet (n=9) (P<.05 versus SHRSP-S), but remained normotensive and lesion-free. We conclude that hypertension and lesion development in SHRSP are not due to deficient renal NO. Accelerated onset of malignant nephrosclerosis by NO synthase inhibition suggests that NO is protective in these animals, mitigating the effects of hypertension and S diet on renal pathology.

Role of aldosterone in renal vascular injury in stroke-prone hypertensive rats.

Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (n=8); captopril alone (50 mg. kg-1. d-1, orally) (n=10); aldosterone infusion alone (40 microg. kg-1. d-1, SC) (n=7); or captopril and aldosterone at 20 (n=6) or 40 (n=7) microg. kg-1. d-1. Systolic blood pressure was markedly elevated in all groups. Vehicle- and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21+/-3% and 29+/-3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 microg. kg-1. d-1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16+/-3% and 21+/-2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure.

Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats.

Chronic treatment of saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angiotensin II (Ang II) prevents the development of stroke and renal vascular damage. Ang II, in addition to its direct vascular effects, stimulates the synthesis and release of aldosterone. To assess the role of aldosterone in the development of pathologic changes in these rats, we implanted time-release pellets containing 200 mg of the mineralocorticoid receptor antagonist, spironolactone, into 14 SHRSP at 7.5 weeks of age. Eight SHRSP littermates received placebo pellets. Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) was not different between the groups. Spironolactone did not enhance water and electrolyte excretion. All placebo-treated SHRSP developed marked proteinuria (150+/-6 mg/d) whereas in spironolactone-treated SHRSP, urinary protein excretion (UPE) averaged 39+/-9 mg/d (P<.0001). In a second study to assess effects on survival, 6 SHRSP received spironolactone (10 mg/kg/d) and 6 received vehicle. All but one of the control rats displayed signs of stroke and died by 16 weeks of age, while the spironolactone-treated SHRSP remained asymptomatic through 19 weeks of age (P<.03). At 16 weeks of age, spironolactone-treated SHRSP were severely hypertensive (247+/-3 mm Hg), yet UPE remained at baseline levels. In contrast, preterminal UPE averaged 136+/-13 mg/d in control rats (P<.0001). In both studies, histopathologic examination revealed a marked protective effect of spironolactone against the development of malignant nephrosclerotic and cerebrovascular lesions. These observations indicate a vascular and end organ protective effect of spironolactone in the absence of lowered blood pressure in saline-drinking SHRSP and are consistent with a major role for mineralocorticoids as hormonal mediators of vascular injury.

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.

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.

[1-deaminopenicillamine,4-valine]-8-D-arginine-vasopressin, a highly potent inhibitor of the vasopressor response to arginine-vasopressin.

In attempting to design an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and oxytocic activities. dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). Like dVDAVP its antidiuretic effect in conscious diabetes insipidus rats is greatly prolonged when compared to AVP. dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to norepinephrine or angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the penicillamine substitution at position 1 in dVDAVP increased its antivasopressor activity sixfold (dVDAVP has a pA2 value of 7.03 +/- 0.11). dPVDAVP is thus the most potent vasopressor antagonist yet reported. dPVDAVP was also found to be a potent inhibitor of the in vitro oxytocic response to oxytocin (pA2 value = 7.23 +/- 0.04). dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.

The lipoxygenase inhibitor phenidone protects against proteinuria and stroke in stroke-prone spontaneously hypertensive rats.

The present study examined whether the dual cyclooxygenase/lipoxygenase inhibitor phenidone would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and hypertensive renal disease. Vehicle-treated SHRSP (N = 6), fed stroke-prone rodent diet and 1% saline, exhibited severe systolic blood pressure elevation (261 +/- 10 mm Hg, mean +/- SEM), marked proteinuria (90 +/- 12 mg/day), and stroke, with an average age at death of 14 +/- 1 weeks. In a second group of six saline-loaded SHRSP, treatment with phenidone (60 mg/kg/day) was started at 8.4 weeks of age. Despite establishment of severe hypertension in this group (274 +/- 10 mm Hg), proteinuria remained at basal levels (28 +/- 13 mg/day), and signs of stroke were absent (P less than .01 v vehicle) through at least 16 weeks of age. Phenidone treatment also prevented the declines in body weight and food intake observed in vehicle-treated SHRSP, and maintained urine volume and saline intake. Serum 12-hydroxy-eicosatetraenoic acid (12-HETE) generation was significantly inhibited greater than 50% in incubates of whole blood from phenidone-treated SHRSP. We have previously shown that agents which interfere with the renin-angiotensin system afford protection from renal and cerebrovascular injury in saline-loaded SHRSP; cyclooxygenase inhibition alone will hasten the onset of these pathologic changes. Whether phenidone, which has been reported to attenuate angiotensin II-mediated effects, affords vascular protection by interference with a lipoxygenase-mediated action of angiotensin II remains to be elucidated.

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)

Dietary arginine fails to protect against cerebrovascular damage in stroke-prone hypertensive rats.

Stroke-prone spontaneously hypertensive rats (SHRSP) develop severe hypertension and cerebrovascular lesions. We investigated the influence of dietary supplementation with L-arginine, an amino acid precursor of endothelium-derived nitric oxide, on blood pressure and stroke in these rats. L-Arginine, administered in the saline drinking solution at 2 or 6 g/l starting at 8.7 weeks of age, was without effect on blood pressure, cerebrovascular lesions, or longevity despite continuous treatment through 14 weeks of age. These findings do not support a beneficial influence of dietary arginine in the cerebrovascular pathology of SHRSP.

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.

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.

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.

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.

Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats.

BACKGROUND: Chronic angiotensin converting enzyme (ACE) inhibitor therapy with enalapril, captopril or ceranopril prevents the development of cerebrovascular lesions in stroke-prone spontaneously hypertensive rats (SHRSP) given a 1% NaCl solution to drink, with little or no effect on systolic blood pressure. OBJECTIVES: To determine the effect of the orally active angiotensin (Ang) II receptor antagonist losartan on blood pressure and stroke in SHRSP. METHODS: Losartan or vehicle was chronically administered to saline-drinking SHRSP, and systolic blood pressure was monitored. The effect of losartan on arterial blood pressure measured by radiotelemetry in enalapril-treated SHRSP was also examined. RESULTS: Oral losartan at 30 mg/kg per day delayed the development of severe hypertension and prevented stroke in saline-drinking SHRSP. Losartan therapy at a dose of 10 mg/kg per day did not affect the systolic blood pressure elevation but prevented the occurrence of cerebrovascular lesions at least until 28 weeks of age. Radiotelemetric monitoring of arterial blood pressure in enalapril-treated, saline-drinking SHRSP over a 3-month period verified the maintenance of severe hypertension without any strokes. Treatment with oral losartan at a dose of 30 mg/kg did not affect the blood pressure of SHRSP chronically treated with enalapril. CONCLUSIONS: These results are consistent with the theory that Ang II has an effect on the pathophysiology of cerebrovascular lesion development in saline-drinking SHRSP. These findings indicate that losartan has a protective action, similar to that previously observed with ACE inhibitors, against the development of cerebrovascular lesions in SHRSP in the absence of a blood pressure fall.

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 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.