5-Hydroxytryptamine의 항이뇨작용기전에 관한 연구

Abstract

[한글]

The Mechanism of antidiuretic Action of 5-hydroxytryptamine

Chun Sik Chu

Department of Physiology, Yonsei University, College of Medicine, Seoul, Korea

(Directed by Drs. P.H. Lee and S.K. Hong)

5-hydroxytryptamine(5-HT) has among many actions been known as a potent

antidiuretic agent. Erspamer and Asero(1952) indicated that 5-HT has a specific

action on the afferent arterioles of the glomerulas, resulting in the spasm.

Consistent with this view is the finding by Blackmore (1958) who demonstarated a

reduction in the glomerular filtration rate (GFR) by 5-HT. In addition to this

action on the renal hemodynamics, Blackmore also demonstrated an increase in the

tubular reabsorption of the filtered water and Na. Similar findings were also

reported by Hollander et al. (1957) who found in addition reductions in the renal

plasma flow(RPF) and in the excretion of K. In contrast to these findings, Corcoran

et al. (1954) observed that 5-HT has no appreciable effect on the excretion rate of

Na, K and Cl, while little et al. (1961) found a reduction in the excretion rate of

Na(but not K) in absence of any change in the renal hemodynamics.

In view of these apparent disagreements among various authors on the effect of

5-HT on the renal function, an attempt was made to reinvestigate the problem.

Having first established the effect of 5-HT on the renal hemodynamics as well as on

the electrolyte excretion, further attempts were made to localize the site of

action of 5-HT. In addition, a series of experiments were carried out in the frog

to further characterize the action of 5-HT on the Na and water permeability.

In the frist series of experiments with 12 dogs, anesthetized with Nembutal (27

mg/kg), various doses of 5-HT were intravenously administered, 5-10 ㎍/kg/min in 7

dogs and 15-20㎍/kg/min in 5 dogs; the clearances of inulin and PAH were determined

along with the excretion rate of Na, K, total osmotic substances and water, before

and after 5-HT. In the scond series of experiments with 4 anesthetized dogs, the

"stop-flow technique", originally developed by Malvin et al. (1958), was employed

in order to localize the tubular site of action of 5-HT on Na reabsorption. In the

third series of experiments with 84 frogs(R. nigromaculata), the whole frog (with

the cloaca ligated) was immersed in either distilled water or 0.024M NaCl solution

for a period of 3 hrs, and was weighed every hour. Varying doses of 5-HT (0.2 to

0.5㎍/gm) were injected into the dorsal lymph sac in the experimental group.

Moreover, oxytocin (0.1 units/gm) was also injected in two groups for comparison.

The results may be briefly summarized as follows:

(1) With a small dose of 5-HT (5-10 ㎍/kg/min), no alteration in the renal

hemodynamics was observed, although the fractional excretion of the filtered Na was

significantly reduced (p<0.025) while the fractional excretion of the filtered K

was significantly enhanced (p<0.05). These changes were accompanied by a

significant reduction in the urine flow (p<0.025).

(2) With a larger dose of 5-HT (15-20㎍/kg/min), the GFR was consistently lowered

(p<0.05) while the RPF was not significantly altered. Moreover, both the urine flow

and the fractional excretion of the filtered Na were significantly reduced

(p<0.05). However, there was no significant change in the excretion of K, although

the osmolar clearance was reduced (p<0.005).

(3) Regardless of the dose, the administration of 5-HT gave rise to a consistent

reduction in the urinary Na/K ratio.

(4) The "stop-flow" analyses of the renal function indicated that the u/p Na/u/p

creatinine ratio is greatly lowerd by 5-HT (5㎍/kg/min) in the proximal segment.

Although similar phenomena were seen in the distal segment, the difference was much

smaller than in the proximal segment, indicating that the main site of action of

5-HT on the Na reabsorption is the proximal tubule.

(5) When the whole frog was immersed in distilled water, the administration of

5-HT at a dose of 0.2-0.3 ㎍/gm resulted in a greater water uptake across the skin

than in the control (p<0.025 at 1 and 2 hrs). However, no enhancement in the water

uptake was observed with 5-HT at a dose of 0.4-0.5 ㎍/gm. Moreover, the observed

effect of 5-HT (0.2-0.3 ㎍/gm) was smaller than the effect of oxytocin at a dose of

0.1 units/gm.

(6) when the whole frog was immersed in 0.024M NaCl solution, 5-HT at a dose of

0.4-0.5 ㎍/gm enhanced the water uptake across the skin more than the control

(p<0.05 at 2 and 3 hrs). This enhancement of water uptake by 5-HT was again less

than that by oxytocin at a dose of 0.1 units/gm.

(7) 5-HT had an antidiuretic effect only in the NaCl solution but oxytocin had

antidiuretic effect regardless of the medium in which the frog was immersed.

The findings indicate that the effect of 5-HT on renal hemodynamics is dependent

upon the dose while the reduction in the fractional excretion of the filtered Na

can be demonstrated at any dose. In general, 5-HT enhances the tubular reabsorption

of Na as a result of which the tubular reabsorption of water is also enhanced.

Although there was a small increase in the fractional excretion of the filtered K,

it is not big enough to prevent the increases in water reabsorption and hence the

urine flow is reduced by 5-HT in all cases. This characteristic enhancement of

tubular Na reabsorption seems to be attributed mainly to the proximal tubule,

although there is no definite evidence for the distal participation. In other

words, 5-HT increases the Na reabsorption of the renal tubule, which is to some

extent linked to the K secretion. Experiments on the frog suggest that, while 5-HT

promotes Na transport across the skin, there seems to be another direct action of

5-HT on the water permeability per se.

[영문]

5-hydroxytryptamine(5-HT) has among many actions been known as a potent antidiuretic agent. Erspamer and Asero(1952) indicated that 5-HT has a specific action on the afferent arterioles of the glomerulas, resulting in the spasm.

Consistent with this view is the finding by Blackmore (1958) who demonstarated a reduction in the glomerular filtration rate (GFR) by 5-HT. In addition to this action on the renal hemodynamics, Blackmore also demonstrated an increase in the tubular reabsorption of the filtered water and Na. Similar findings were also reported by Hollander et al. (1957) who found in addition reductions in the renal plasma flow(RPF) and in the excretion of K. In contrast to these findings, Corcoran et al. (1954) observed that 5-HT has no appreciable effect on the excretion rate of

Na, K and Cl, while little et al. (1961) found a reduction in the excretion rate of Na(but not K) in absence of any change in the renal hemodynamics.

In view of these apparent disagreements among various authors on the effect of 5-HT on the renal function, an attempt was made to reinvestigate the problem.

Having first established the effect of 5-HT on the renal hemodynamics as well as on the electrolyte excretion, further attempts were made to localize the site of action of 5-HT. In addition, a series of experiments were carried out in the frog

to further characterize the action of 5-HT on the Na and water permeability.

In the frist series of experiments with 12 dogs, anesthetized with Nembutal (27mg/kg), various doses of 5-HT were intravenously administered, 5-10 ㎍/kg/min in 7 dogs and 15-20㎍/kg/min in 5 dogs; the clearances of inulin and PAH were determined

along with the excretion rate of Na, K, total osmotic substances and water, before and after 5-HT. In the scond series of experiments with 4 anesthetized dogs, the "stop-flow technique", originally developed by Malvin et al. (1958), was employed

in order to localize the tubular site of action of 5-HT on Na reabsorption. In the third series of experiments with 84 frogs(R. nigromaculata), the whole frog (with the cloaca ligated) was immersed in either distilled water or 0.024M NaCl solution

for a period of 3 hrs, and was weighed every hour. Varying doses of 5-HT (0.2 to 0.5㎍/gm) were injected into the dorsal lymph sac in the experimental group.

Moreover, oxytocin (0.1 units/gm) was also injected in two groups for comparison.

The results may be briefly summarized as follows:

(1) With a small dose of 5-HT (5-10 ㎍/kg/min), no alteration in the renal hemodynamics was observed, although the fractional excretion of the filtered Na was significantly reduced (p<0.025) while the fractional excretion of the filtered K was significantly enhanced (p<0.05). These changes were accompanied by a significant reduction in the urine flow (p<0.025).

(2) With a larger dose of 5-HT (15-20㎍/kg/min), the GFR was consistently lowered (p<0.05) while the RPF was not significantly altered. Moreover, both the urine flow and the fractional excretion of the filtered Na were significantly reduced

(p<0.05). However, there was no significant change in the excretion of K, although the osmolar clearance was reduced (p<0.005).

(3) Regardless of the dose, the administration of 5-HT gave rise to a consistent reduction in the urinary Na/K ratio.

(4) The "stop-flow" analyses of the renal function indicated that the u/p Na/u/p creatinine ratio is greatly lowerd by 5-HT (5㎍/kg/min) in the proximal segment.

Although similar phenomena were seen in the distal segment, the difference was much smaller than in the proximal segment, indicating that the main site of action of 5-HT on the Na reabsorption is the proximal tubule.

(5) When the whole frog was immersed in distilled water, the administration of 5-HT at a dose of 0.2-0.3 ㎍/gm resulted in a greater water uptake across the skin than in the control (p<0.025 at 1 and 2 hrs). However, no enhancement in the water

uptake was observed with 5-HT at a dose of 0.4-0.5 ㎍/gm. Moreover, the observed effect of 5-HT (0.2-0.3 ㎍/gm) was smaller than the effect of oxytocin at a dose of 0.1 units/gm.

(6) when the whole frog was immersed in 0.024M NaCl solution, 5-HT at a dose of 0.4-0.5 ㎍/gm enhanced the water uptake across the skin more than the control (p<0.05 at 2 and 3 hrs). This enhancement of water uptake by 5-HT was again less than that by oxytocin at a dose of 0.1 units/gm.

(7) 5-HT had an antidiuretic effect only in the NaCl solution but oxytocin had antidiuretic effect regardless of the medium in which the frog was immersed.

The findings indicate that the effect of 5-HT on renal hemodynamics is dependent upon the dose while the reduction in the fractional excretion of the filtered Na can be demonstrated at any dose. In general, 5-HT enhances the tubular reabsorption

of Na as a result of which the tubular reabsorption of water is also enhanced.

Although there was a small increase in the fractional excretion of the filtered K, it is not big enough to prevent the increases in water reabsorption and hence the urine flow is reduced by 5-HT in all cases. This characteristic enhancement of tubular Na reabsorption seems to be attributed mainly to the proximal tubule, although there is no definite evidence for the distal participation. In other words, 5-HT increases the Na reabsorption of the renal tubule, which is to some extent linked to the K secretion. Experiments on the frog suggest that, while 5-HT

promotes Na transport across the skin, there seems to be another direct action of 5-HT on the water permeability per se.