α-sympathetic receptor stimulation in the brain and hypotensive activity of α-methyldopa

doi:10.1016/0014-2999(72)90180-X

European Journal of Pharmacology

Volume 17, Issue 2, February 1972, Pages 315-317

https://doi.org/10.1016/0014-2999(72)90180-X Get rights and content

Abstract

Part of the third and the entire fourth ventricle of cats were perfused with physiological saline containing α-methyldopa, α-methyldopamine or α-methylnoradrenaline. α-Methylnoradrenaline had the greatest depressor effect on blood pressure of these substances. The depressor effect was significantly inhibited by the α-blocking agents yohimbine and phentolamine. It was concluded that α-methyldopa exerts its blood pressure decreasing effect at least partly by the stimulation of central α-sympathetic receptors.

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  3. Dose-related changes seen, including bradycardia, hypotension and bradypnea, were opposite to those produced by i.v. doses.
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Alpha-adrenergic receptors and blood pressure control
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Alpha-adrenergic receptors play an important role in the regulation of blood pressure (BP). There are 2 principal types of α receptors, α₁ and α₂, and both participate in circulatory control. Alpha₁ receptors are the classic postsynaptic α receptors and are found on vascular smooth muscle. They determine both arteriolar resistance and venous capacitance, and thus BP. Alpha₂ receptors are found both in the brain and in the periphery. In the brain stem, they modulate sympathetic outflow. Their function in the periphery is not yet fully understood, but they may contribute both to control of sympathetic tone and to local and regional blood flow.
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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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Thirty patients with essential hypertension (supine diastolic blood pressure 100 to 115 mm Hg) were treated in a randomized, double-blind study with either pindolol (mean dose 28 ± 5 mg twice a day) or methyldopa (673 ± 158 mg three times a day) for 12 weeks after a 3-week, single-blind placebo period. In 17 pindolol-treated patients mean supine blood pressure was $163 ± 3 106 ± 1$ during the placebo period and $155 ± 3 99 ± 2 mm Hg$ (p < 0.01) during the high-dose period. In 13 patients treated with methyldopa mean supine blood pressure fell from $160 ± 4 104 ± 1$ to $156 ± 5 97 ± 2 mm Hg$ . Mean standing heart rate was reduced during pindolol therapy from 84 ± 2 to 79 ± 2 bpm (p < 0.05) but was unchanged during methyldopa treatment. Mean supine pretreatment plasma norepinephrine fell from 379 ± 40 to 337 ± 33 pg/ml in patients on pindolol therapy and from 448 ± 76 to 223 ± 39 pg/ml (p < 0.02) in the methyldopa-treated group. Although norepinephrine generally decreased in pindolol responders and not in nonresponders, changes in supine diastolic blood pressure and supine plasma norepinephrine did not correlate. In contrast, norepinephrine declined consistently in methyldopa-treated patients regardless of the blood pressure response; changes in diastolic blood pressure and norepinephrine correlated (r = 0.59; p < 0.05). The results suggest that suppression of sympathetic nervous system activity may play a role in the hypotensive effect of both pindolol and methyldopa.
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1981, Medical Hypotheses
Sodium restriction is not the only nutritional measure likely to prove valuable in the treatment and prevention of hypertension. The hypotensive effects of central adrenergic stimulation can be promoted by supplementary tyrosine, insulin potentiation (as with GTF), and (possibly) high-dose pyridoxine. Insulin potentiators (GTF) and prostaglandin precursors (essential fatty acids) should have direct relaxant effects on vascular muscle. A high potassium, low sodium diet, coenzyme O, and prevention of cadmium toxicity (as with dietary selenium) may act to offset renally-mediated pressor influences. Functional combinations of these measures might prove to be substantially effective, in which case they would offer considerable advantages over potentially toxic drug therapies.

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Short communicationα-sympathetic receptor stimulation in the brain and hypotensive activity of α-methyldopa

Abstract

European J. Pharmacol.

Deutsche Patentanmeldung der Farben Fabriken Bayer AG., vom 5. Juli 1962, Nr. 1173475

Periphere und zentrale Kreislaufwirkung des α-Sympathicomimeticums 2-(2,6-Xylidino)-5,6-dihydro-4H-1,3-thiazinhydrochlorid (BAY 1470)

Arch. Pharmacol.

α-sympathicomimetische Eigenschaften als Ursache der blutdrucksteigernden und blutdrucksenkenden Wirkung von Bay 1470 (2-(2,6-Xylidino)-5,6-dihydro- 4H-1,3-thiazinhydrochlorid)

Arch. Pharmacol.

Central hypotensive effect of α-methyldopa

J. Pharm. Pharmacol.

Untersuchungen zum Wirkungsmechanismus von α-Methyldopa

Short communication
α-sympathetic receptor stimulation in the brain and hypotensive activity of α-methyldopa