Effect of chronic dietary treatment with L-tryptophan on the development of renal hypertension in rats.

Chronic dietary administration of L-tryptophan (2.5 and 5.0 g/100 g food) to rats provided significant protection against the development of hypertension induced by bilateral encapsulation of the kidneys with latex envelopes. Lower doses of tryptophan (0.5 and 1.0 g/100 g food) attenuated the rate of elevation of blood pressure, but failed to maintain systolic blood pressures at levels significantly below that of untreated renal hypertensive controls. The body weight of the rats was not affected significantly by treatment with any dose of tryptophan used. Chronic treatment with tryptophan also protected against the reduced urinary concentrating ability during a 24-hour dehydration that characteristically accompanies renal encapsulation. A modest (5-8%) effect of treatment to reduce cardiac hypertrophy was also observed. The mechanism of the antihypertensive effect of tryptophan is not revealed by these studies although they rule out the possibilities that reduction in sodium intake and/or reduction in body weight may be important factors.

Effect of chronic dietary treatment with nicotinic acid on the development and maintenance of deoxycorticosterone-acetate-salt-induced hypertension.

Chronic dietary administration of either l-tryptophan (5.0%) or nicotinic acid (5.0%) reduced the elevated blood pressure of rats with established, deoxycorticosterone-acetate (DOCA)-salt-induced hypertension without affecting either body weight or cardiac hypertrophy. In a second study, chronic dietary administration of nicotinic acid (2.5 and 5.0%) provided significant protection against the development of an elevated blood pressure in rats treated with DOCA salt. A modest (approximately 10%) reduction in cardiac hypertrophy was also observed in the two nicotinic-acid-treated groups. Treatment with either dose of nicotinic acid did not, however, prevent either the renal hypertrophy characteristic of DOCA-salt-induced hypertension in rats or their reduced renal concentrating ability during a 24-hour dehydration; nor did treatment with nicotinic acid reduce the excessive ingestion of saline characteristic of chronic treatment with DOCA. In contrast, treatment with the higher dose of nicotinic acid prevented the excessive loss of sodium into urine characteristic of DOCA-salt-induced hypertension when the rats were loaded (3% of body weight, i.p.) with a hypotonic (0.075 M) saline solution. These results suggest that increased production of nicotinic acid resulting from dietary administration of tryptophan may play a role in the protective effect of tryptophan against the development of DOCA-salt-induced hypertension. These studies do not, however, provide a mechanism by which nicotinic acid may manifest its beneficial effects.

Chronic treatment with L-5-hydroxytryptophan prevents the development of DOCA-salt-induced hypertension in rats.

Chronic subcutaneous (s.c.) infusion (osmotic minipump) of L-5-hydroxytryptophan (L-5-HTP, 4.2 to 12.6 mg/day) to uninephrectomized, deoxycorticosterone acetate-salt-treated (DOCA) rats (1.36 mg/kg per day via s.c. silastic implants) reduced their exaggerated intake of isotonic saline significantly (12.6 mg/day), prevented the elevation of blood pressure (4.2 to 12.6 mg/day), prevented cardiac hypertrophy (12.6 mg/day), and provided modest protection against reduction of urinary concentrating ability, characteristic of DOCA-treated rats during a 24-h dehydration. The exaggerated dipsogenic response of DOCA-treated rats to administration of angiotensin II (AII, 50 and 100 micrograms/kg, s.c.) was also reduced by treatment with L-5-HTP (4.2 and 8.4 mg/day). The specific binding of AII to its receptors in membranes from the diencephalon of the brain was increased significantly above control level by chronic treatment with DOCA, but was returned to control level by concomitant treatment with L-5-HTP. Daily urinary excretion of dopamine, increased by treatment with DOCA, was unaffected by treatment with L-5-HTP (6.3 mg/day). Daily urinary excretion of epinephrine was increased by treatment with L-5-HTP (6.3 and 12.6 mg/day). These results suggest that chronic administration of L-5-HTP provides significant protection against the development of DOCA-induced hypertension, polydipsia, polyuria, and cardiac hypertrophy in rats. The mechanism by which L-5-HTP protects is unclear and remains to be established.

Chronic dietary administration of tryptophan prevents the development of deoxycorticosterone acetate salt induced hypertension in rats.

Hypertension developed within 3 to 5 weeks in uninephrectomized rats administered deoxycorticosterone acetate (DOCA) at a dose of 850 micrograms X kg-1 X day-1 via Silastic tubes and given isotonic saline to drink. Chronic dietary administration of tryptophan (25 and 50 g/kg of food) to DOCA-treated rats reduced their exaggerated intake of NaCl solution and attenuated the elevation of blood pressure induced by treatment with DOCA alone. Treatment with tryptophan also protected against the reduction in urinary concentrating ability during a 24-h dehydration that is characteristic of DOCA-treated rats. Other tests assessed the responsiveness to the beta-adrenergic agonist, isoproterenol. These included measurement of drinking and heart rate following acute administration of isoproterenol. The characteristically depressed drinking and chronotropic responses of DOCA-treated rats to acute administration of isoproterenol were unaffected by tryptophan. Responsiveness to angiotensin II (AII) was also tested by assessment of dipsogenic and metabolic responses to acute administration of AII. The increased drinking and tail skin temperature responses to administration of AII, characteristic of DOCA-treated rats, were reduced in a graded fashion by treatment with graded doses of tryptophan. The specific binding of AII to its receptors in membranes form the diencephalon of the brain was increased by treatment with DOCA but was returned to control level by concomitant treatment with tryptophan. The content of serotonin in the mesencephalon of the brain was not changed significantly by treatment with tryptophan, but the content of 5-hydroxyindole acetic acid in the same region increased significantly, suggesting that turnover of serotonin was increased by chronic treatment with tryptophan. The cardiac hypertrophy characteristic of treatment with DOCA was attenuated significantly by chronic treatment with tryptophan, while the low, resting plasma renin activity of the DOCA-treated group was unchanged. These results suggest that tryptophan provides significant protection against the development of DOCA-induced hypertension, polydipsia, polyuria, and cardiac hypertrophy in rats. It also reduces the hyperresponsiveness to treatment with AII, possibly by decreasing the specific binding of AII to its receptors. It also appears to increase the turnover of serotonin in the brain. Whether either one or all of these is responsible for the antihypertensive effect of tryptophan remains for further study.

Water versus NaCl intake by rats administered certain dipsogens acutely.

Isotonic saline was ingested in a greater volume than water when any one of three dipsogenic agents [L-5-hydroxytryptophan (25 mg/kg, SC), isoproterenol (25 micrograms/kg, SC), and angiotensin II (100 micrograms/kg, SC)] was administered acutely to rats given either isotonic saline or water to drink. These results are consistent with, but not exclusive to, the hypothesis that feedback inhibition of ingested isotonic saline on further fluid intake is less than that of water. Additional studies showed that the dipsogenic response to angiotensin II (200 micrograms/kg, SC) decreased as the concentration of NaCl solution offered to drink increased beyond 0.15 M in rats given either water or NaCl solution to drink. This suggests the possibility that the intensity of taste of the NaCl solutions may be a factor in their intake under these conditions, although the intake of these salt solutions by untreated controls did not reflect this. When the rats were allowed to choose between either 0.15 or 0.25 M NaCl solution and water, administration of angiotensin II (either 100 or 200 micrograms/kg, SC) increased water intake in preference to the NaCl solution. These results suggest that the rat, under these conditions, has a preference for water over NaCl solution.

Effect of l-p-tyrosine on the development of renal hypertension in rats.

Dietary administration of tyrosine (0.25-2.50%) to rats whose kidneys were bilaterally encapsulated with latex envelopes provided modest protection against the development of hypertension. Elevation of blood pressure was slower (one experiment) and maximal level attained was reduced (two experiments) compared to untreated, renal encapsulated controls. In addition, the polydipsia, polyuria, and reduced renal concentrating ability characteristically accompanying hypertension were attenuated. The mechanism(s) accounting for the partial protection against hypertension reported here is unknown although administration of tyrosine was accompanied by a reduced cardiovascular responsiveness to graded doses of phenylephrine.

Effect of clonidine on the contractile responsiveness of aortic smooth muscle to norepinephrine.

A length-tension relationship was established for aortic smooth muscle of rats by means of membrane depolarization with KCl. Maximal tension was developed by aortic rings when the preload initial tension was 8--9 g. Two aortic rings (4 mm thick) were removed from segments of the aorta cut 1.5 (upper) and 2.4 cm (lower) below the aortic arch. Upper rings appeared to develop a greater tension than lower rings during depolarization with KCl. However, in spite of this quantitative difference between rings from upper and lower segments of the aorta, there were no qualitative differences observed. Clonidine, an antihypertensive agent, induced a contraction in aortic smooth muscle, apparently by way of alpha-adrenoreceptor stimulation. Clonidine also attenuated significantly the development of active tension by norepinephrine but did not inhibit significantly the development of active tension following membrane depolarization with KCl. This suggests that there is a partial antagonism between norepinephrine and clonidine, presumably at the site of the receptors on smooth muscle, and that clonidine does not interfere with the contractile mechanism, per se.