[Specific aspects of the action of serotonin and ketanserin in the regulation of arterial pressure].
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Biomedical subjects
Publications and source records attributed to D Wellens.
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Two double-blind multicenter trials were performed to compare the antihypertensive action of ketanserin, at an oral dosage of 20 mg three times daily, with that of placebo over a period of four to six weeks. A subset of patients was treated in a crossover fashion for either four weeks (36 patients) or six weeks (24 patients). The patients had essential hypertension, with a diastolic blood pressure greater than or equal to 95 mmHg measured in sitting position at the end of a placebo run-in period of at least one week. In a first trial, 78 of 82 patients completed the four-week study period, where the mean drop of the systolic/diastolic blood pressure was -14/-12 mmHg in the ketanserin group (n = 32) versus -8/-5 mmHg in the placebo group (n = 46). This difference is statistically significant (p = 0.05/p less than 0.01). In 13 patients who after the initial ketanserin treatment were further treated with placebo in crossover for four weeks, the blood pressure rose slightly (+1/+3 mmHg). In the alternative group (n = 23), the blood pressure fell by -10/-7 mmHg after placebo and decreased further by -10/-8 mmHg after ketanserin. In a second trial, 24 patients completed a two by six week crossover treatment. In 12 patients assigned to the sequence placebo-ketanserin, there was a drop of the systolic/diastolic blood pressure by -7/-4 mmHg after placebo and an additional drop by -26/-10 mmHg after ketanserin.(ABSTRACT TRUNCATED AT 250 WORDS)
In vitro exposure of depolarized caudal artery preparations of the rat to a high calcium concentration resulted in a strong contraction of the smooth muscle cells. This muscle contraction was suppressed by flunarizine. It was shown cytochemically, using the combined oxalate-pyroantimonate method for the localization of calcium, that a considerable amount of electron-dense precipitate was seen over the depolarized muscle cells after incubation in a calcium containing medium. On the other hand this precipitate was not present on the smooth muscle cells when flunarizine was added to this incubation medium. The reaction product was only present in the extracellular space. These results were controlled by Laser Microprobe Mass Analysis. By evaporating and ionizing small parts of the smooth muscle cells (+/- 1 micron), it was confirmed that the cytochemical method indeed demonstrated calcium, with negligible interference of other cations.
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Intermittent claudication is a non-pathognomic symptom elicited by an inbalance between the metabolic demands of the exercising skeletal muscle and its blood supply. In normal conditions hyperemia to the working muscles will be impaired during the exercise by mechanical compression of the microvessels. The resulting anaerobic metabolism will cause further vasodilatation. Both phenomena (exercise and reactive hyperemia) contribute to a maximal increase in local blood flow as soon as the exercise is stopped. If the local circulation is impaired by occluding arterial disease (eventually complicated by aggravating factors) the tolerance to skeletal work is lowered and the circulatory reserves are entirely exhausted as demonstrated by the ischemic exercise-test. In the case of a major obstruction and poor collateralisation, a "steel phenomenon" may occur. The pharmacotherapeutic possibilities to cope with in this situation are briefly discussed.
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In rats, the vertebral artery make only a minor contribution to the blood perfusion of the ponto-medullary area. This was measured with radioactive microspheres and was confirmed by methylmetacrylate casts and local injection of a centrally acting hypotensive drug.
Electrical stimulation of the lateral hypothalamus near the paraventricular nucleus hypothalami, resulted in : hypotension, light bradycardia, decrease of the left ventricular systolic pressure without increase of the left ventricular end-diastolic pressure or left ventricular output, femoral vasodilatation and occasionally renal vasodilatation. The hypotensive reactions were potentiated by baroreceptor deafferentation. They were not blocked by anticholinergic, antihistaminic or antidopaminergic agents.
The stimulation of the paraventricular hypothalamic centre inhibits the vasoconstriction of the peripheric arterioles and the myocardial effects elicited by endogenous or exogenous increased catecholaminaemia.
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When electrical stimulation is applied to the ventromedial hypothalamic zone one observes an increase in systemic blood pressure. There also occur blood pressure variations in the isolated femoral circuit: two distinct phenomena were observed. The early event, being either an increase or a decrease in peripheral resistance, is directly related to the amount of noradrenaline produced locally. The late event is due to catecholamines arriving from the general circulation. Inhibition of local catecholamine release through the baroreceptor reflex and inhibition of ganglionic transmission by a large and sudden increase in adrenaline blood levels do influence the response in the isolated femoral circuit. Moreover the peripheral vasomotor tonus seems to be influenced by yet another mechanism, independent of local catecholamine release. This delicate mechanism depends on the balance between the degree of excitation of hypothalamic pressor (medial) and depressor (lateral) zones.
Erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-ET]-4-piperidyl)-2-benzimidazolinone (R 28935), provokes marked antihypertensive effects lasting several hours in conscious SHR (0.63 to 40 mg/kg i.p.) and beagles with renal hypertension (1.25 mg/kg p.o.). In SHR, this compound induces much less bradycardia, compared to equiactive hypotensive doses of clonidine, guanethidine and propranolol. Significant postural hypotension during tilting, is induced by guanethidine and mecamylamine but not by R 28935. In anaesthetized beagles with renal hypertension, the lowering of the blood pressure by R 28935, (0.02-0.64 mg/kg i.v.) is associated with a considerable decrease in the total peripheral vascular resistance, whereas the myocardial function is not affected. R 28935 is considered a potent antihypertensive drug, with attractive haemodynamic characteristics.
In the dog, erythro-1-[2-(1,4benzodioxan-2-yl)-2-OH-ET]-4-piperidyl)-2-benzimidazolinone (R 28935) lowers the blood pressure for several hours at dosages of 80 mug/kg when injected intravenously, of 10 mug/kg when injected into the vertebral artery and of 1.25 mug/kg when injected suboccipitally. No alpha- or beta-receptor blocking activity can be elicited at these doses. The carotid occlusion reflex is markedly reduced by low doses of R 28935 (40 to 80 mug/kg i.v.), whereas the pressor response elicited by electrical stimulation of the hypothalamus remains unimpaired. The hypotensive effect of R 28935 is not antagonized by piperoxan, desmethylimipramine or nalorphine. This lowering of the blood pressure is associated with a decrease of the peripheral vascular resistance and with a slight tendency towards bradycardia. It is concluded that R 28935 is a potent blood pressure lowering drug, acting on the brain stem, presumably in the pontomedullary region--although the drug has no alpha-sympathomimetic activity.