PROLONGED EFFECTS OF p‐CHLOROPHENYLALANINE ON THE BLOOD PRESSURE OF CONSCIOUS NORMOTENSIVE AND DOCA/SALINE HYPERTENSIVE RATS

Abstract

In deoxycorticosterone acetate (DOCA) saline hypertensive rats a single dose of p‐chlorophenylalanine methylester (PCPAME) (400 mg/kg i.p.) produced a significant fall in blood pressure (20–43 mmHg) which lasted for at least 8 days and was accompanied by a parallel depletion of brain stem 5‐hydroxytryptamine (5‐HT) but not of noradrenaline (NA). In normotensive rats single doses of PCPAME (200 and 400 mg/kg i.p.) produced a significant hypotension (15–20 mmHg) after a latent period of 5 days. An initial pressor response (12 mmHg) was observed at the higher dose level only on day 3. The hypotensive response to PCPAME (200 mg/kg i.p.) in normotensive rats was not modified by pretreatment with 5,6‐dihydroxytryptamine (5,6‐DHT; 50 μg i.c.v.) or 6‐hydroxydopamine (6‐OHDA; 3 × 250 μg intracerebroventricularly). It is concluded that the hypotensive response to PCPAME in normotensive rats is independent of brain stem depletion of 5‐HT and is probably not mediated by the formation of a false transmitter substance acting via central noradrenergic inhibitory pathways. The mechanism involved in the antihypertensive response to PCPAME in DOCA/saline hypertensive rats has yet to be defined.

5-HT in systemic hypertension: foe, friend or fantasy?

“…No measurements of 5-HT were made in plasma or arteries of the rats receiving PCPAME, and we propose that part of the fall in BP was because 5-HT was depleted in the periphery. This idea is supported by the findings that central 5-HT depletion by intracisternal injections of the serotonergic neurotoxin 5,6-DHT (5,6-dihydroxytryptamine) did not alter the course of development or magnitude of hypertension achieved in the deoxycorticosterone acetate (DOCA)-salt rat [143] or SHRs [144], nor did 5,6-DHT (i.c.v) alter the ability of PCPA to cause a reduction in BP [142]. Importantly, the study by Buckingham et al [142] has not been repeated.…”

“…In 1976, Buckingham et al [142] demonstrated that a single injection of 400 mg/kg of body weight (intraperitoneally) of the TPH inhibitor PCPAME (p-chlorophenylalanine methyl ester; Figure 2) produced a fall in BP in DOCA-treated rats ranging from 20-43 mmHg within the first day of injection, and kept BP depressed for 8 days. PCPAME competes directly with TPH and binds irreversibly to the enzyme, hence the long-lasting effects of PCPAME.…”

Vascular reactivity, 5-HT uptake, and blood pressure in the serotonin transporter knockout rat

“…However, we recognize that our experiments only indirectly address the issue of the importance of 5-HT to blood pressure regulation since 5-HT was not depleted from the KO animal. Pharmacological inhibition of tryptophan hydroxylase previously resulted in a ϳ40-mmHg fall in the blood pressure of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, suggesting that continued 5-HT synthesis supported the elevated blood pressure (2). However, there are multiple reports that suggest that inhibitors of 5-HT receptors do not lower blood pressure (20).…”