Alpha-methylDOPA dissociates hypertension, cardiovascular reactivity and emotional behavior in spontaneously hypertensive rats

doi:10.1016/0006-8993(83)91067-3

Brain Research

Volume 259, Issue 1, 17 January 1983, Pages 69-76

https://doi.org/10.1016/0006-8993(83)91067-3 Get rights and content

Abstract

The purpose of the present study was to determine whether the centrally-acting hypotensive agent, alpha-methylDOPA (MD), in addition to lowering tonic or resting blood pressure (BP), suppresses the phasic increases in BP which accompany emotional arousal. Spontaneously hypertensive rats (SHRs), chronically instrumented for computer-assisted recording of BP and heart rate (HR) from the aorta while awake and unrestrained, were subjected to classical fear conditioning. The next day, BP and HR were recorded before and 2 h following treatment (i.p.) with MD (3.75mg/kg,n= 7; 7.5mg/kg,n= 7; 15mg/kg,n= 10; 30mg/kg,n= 10;60mg/kg,n= 9; 120mg/kg,n= 9; 240mg/kg,n= 10) or saline (2ml,n= 10). Immediately thereafter, blood pressure and heart rate responses to the conditioned emotional stimulus were assessed. Additional SHRs were treated with MD (30mg/kg, n= 10; 60mg/kg, n= 10) or saline (2ml, n= 10) 2 hr prior to assessment of conditioned fear behavior (duration of immobilization or freezing behavior during a 300 s presentation of the conditioned emotional stimulus). Resting BP in saline controls was160 ± 5, and doses of MD of 7.5 mg/kg or more resulted in a dose-dependent suppression of resting BP, with the maximal hypotensive change (47 ± 5) produced by 60 mg/kg. The conditioned pressor response (averaged over the 10 s stimulus) was17 ± 3mm Hg in saline controls and was systemically reduced in groups treated with 15 mg/kg or more of MD, with the minimal response (maximal suppression) achieved by 60 mg/kg (4 ± 1mm Hg). Correlation analysis of the effects of MD on resting BP and on the conditioned BP response resulted in a low coefficient of correlation (4= −0.22). Freezing (in s) was not different in saline controls (160 ± 25) and animals treated with 30 mg/kg (170 ± 25) or 60 mg/kg (214 ± 11) of MD. MD thus suppresses the emotion-induced elevation of BP, independent of effects on resting BP and without altering emotional behavior. These findings suggest that MD is capable of regulating both basal BP and BP reactivity in hypertension, though through separate actions, and that central alpha-adrenergic mechanisms are involved in the autonomic, but not the behavioral, manifestation of emotional arousal.

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Citation Excerpt :
Methyldopa (MD) exerts its antihypertensive effect through a central mechanism that involves the biotransformation to methyl norepinephrine (Robertson et al., 1984; van Zwieten et al., 1984). This drug may inhibit the aromatic amino acid decarboxylase, an enzyme in the biosynthetic pathway of catecholamine’s (Ledoux et al., 1983). Sino aortic denervations (SAD) performed according to Krieger’s procedure induces a labile hypertension in rats, alteration in serotonergic and cholinergic pathways and an elevation of the peripheral sympathetic tone (Nakamura and Nakamura, 1981; Giarcovich-Mart́ınez et al., 1983; Alexander et al., 1976, 1980).
Methyldopa, which released in 1960, is one of the most popular blood pressure lowering drugs. Taking this medicine for high blood pressure, it seems that the effect drug in blood pressure duct ions convection to alpha-methyl is nor epinephrine. Alpha-methyl nor epinephrine from thus reducing central blood pressure is. This work reports an investigation of an antihypertensive drug methyldopa with the combined density functional theory (DFT) and its structure was optimized at B3LYP, BLYP and MP2(3–21G^∗,6–31G,6–31G^∗) levels and the molecular structure in different solvents (SCRF calculation), NMR parameters were calculated using DFT at B3LYP, BLYP and MP2(3–21G^∗,6–31G,6–31G^∗) basis set. And finally we calculated natural bond orbital (NBO) parameters for this structure.
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Pharmacokinetics of methyldopa (MD) and the effect on the dopaminergic metabolism was studied in anesthetized sham-operated (SO) and sinoaortic-denervated (SAD) rats by using the microdialysis technique. A concentric microdialysis probe was placed in the striatum or in the posterior hypothalamus. Levels of MD, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC).
Following the i.p. administration of MD (50 mg kg⁻¹, i.p.), striatal dialysates showed that this drug rapidly reaches the brain. However, in SAD rats the MD levels of dialysates were lower and decreased more rapidly compared to SO rats. On the other hand, dialysates of posterior hypothalamus showed that in SAD animals the accumulation of MD was significantly greater than in SO rats.
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In conclusion, this study by using a microdialysis technique shows that MD has different kinetic profiles in dialysates from posterior hypothalamus and striatum of SO and SAD rats at a dose that alters dopaminergic metabolism.
Pharmacokinetic and pharmacodynamic alterations of methyldopa in rats with aortic coarctation. A study using microdialysis
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A pharmacokinetic–pharmacodynamic study of methyldopa (MD) was made in anesthetized sham operated (SO) and aortic coarctated (ACo) rats by using a vascular shunt probe for arterial microdialysis and simultaneous blood pressure recording. Anesthetized Wistar rats were used 7 days after aortic coarctation or sham operation. A vascular shunt probe was inserted into the carotid artery and a concentric probe was placed into the striatum or posterior hypothalamus. MD and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysates by HPLC-EC. MD (50 mg kg⁻¹i.p.) induced an increase of heart rate in SO (Δ HR: 108 ± 22 bpm,n = 6) and in ACo rats (Δ HR: 55 ± 10 bpm, n= 6, P< 0.05, one way ANOVA). Moreover, MD also reduced the mean arterial pressure (MAP) of SO rats (Δ MAP: −10 ± 4 mmHg, n= 6) and ACo animals (Δ MAP: −51 ± 9 mmHg,n = 6, P< 0.05, one way ANOVA). Analysis of the arterial blood dialysates showed a lower half-life of MD in ACo rats (t_1/2: 1.5 ± 0.3 h, n= 6, P< 0.05, ‘t’ test) than in SO rats (t_1/2: 3.7 ± 1.0 h, n= 6). A low accumulation and a fast decay of striatal MD levels were seen in ACo rats. However, peak levels of drug were greater in the hypothalamic dialysates of ACo rats than in SO animals samples. On the other hand, MD also induced an increase of DOPAC levels in the hypothalamic dialysates of ACo rats. In conclusion, the aortic coarctation modifies the pharmacokinetic and cardiovascular effect of MD in the rat. The action of this drug on dopaminergic neurotransmission is also altered in the ACo animals.
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After a few pairings of a threatening stimulus with a formerly neutral cue, animals and humans will experience a state of conditioned fear when only the cue is present. Conditioned fear provides a critical survival-related function in the face of threat by activating a range of protective behaviors. The present review summarizes and compares the results of different laboratories investigating the neuroanatomical and neurochemical basis of conditioned fear, focusing primarily on the behavioral models of freezing and fear-potentiated startle in rats. On the basis of these studies, we describe the pathways mediating and modulating fear. We identify several key unanswered questions and discuss possible implications for the understanding of human anxiety disorders.
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Studies from this laboratory have shown that the first filial offspring of female spontaneouslyhypertensive rats and male Wistar-Kyoto (WKY) normotensive rats develop stress-induced hypertension. The present study sought to examine the effects of intracerebroventricular administration of clonidine (8 μg) on cardiovascular and sympathoadrenal responses to aversive classical conditioning in these borderline hypertensive rats (BHR) and in normotensive WKY control rats. Clonidine caused significant reductions in resting arterial pressure, vascular resistance, heart rate and concentrations of epinephrine (E) in plasma for both hypertensive and normotensive rats. Central administration of normal saline to control rats of each strain did not alter basal cardiovascular or sympathoadrenal function. The presentation of a conditioned stimulus (CS) elicited a significant increase in arterial pressure and total peripheral resistance in hypertensive rats treated with saline and clonidine and in normotensive rats treated with saline. In contrast, normotensive rats treated with clonidine showed no increases in arterial pressure or vascular resistance following the onset of the conditioned stimulus. The aversive conditioning session instigated significant increases in the concentrations of norepinephrine (NE) and E in plasma in saline-treated rats. Hypertensive and normotensive rats treated with clonidine-showed a blunted increase in plasma concentrations of NE and E during this period; however, concentrations of E in hypertensive rats increased significantly from the baseline period after injection. These data suggest that an abnormality in central alpha₂-adrenoceptor-mediated inhibition of sympathoadrenal discharge and sympathetic vasomotor tone may predispose the hypertensive rat to develop stress-induced hypertension.
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Alpha-methylDOPA dissociates hypertension, cardiovascular reactivity and emotional behavior in spontaneously hypertensive rats

Abstract

Brain Research

Europ. J. Pharmacol.

Baroreceptor function and changes in strain sensitivity in normotensive and spontaneously hypertensive rats

Circulat. Res.

Conditioned fear assessed by freezing and by the suppression of three different baselines

Animal Learning and Behavior

Brain amines and models of experimental hypertension

Circulat. Res.

Alpha-methylDOPA reduces locomotor activity in rats via the metabolite, alpha-methylnorepinephrine, acting on a2-adrenoceptors

Arch. int. Pharmacodyn

Some observations on the pharmacology of alpha-methylDOPA

Brit. J. Pharmacol.

The mechanism of the antihypertensive action of alpha-methylDOPA in hypertensive rats