The cerebral blood distribution in dogs and cats. An anatomical and functional study.

On the basis of corrosion preparations and of microsphere studies, the following characteristics of the canine and feline cerebral circulation were observed. (1) In cats, a greater part of the vertebral arterial blood goes to the brain and it is more specifically restricted to the ponto-medullary and cerebellar structures. These structures received approximately 3 times more microspheres in cats than in dogs. (2) In dogs, an important amount of vertebral blood goes to the neck muscles, and the intracranial vertebral blood supply is spread over a greater area of the brain, including the thalamo-hypothalamic and posterior cortical zone. (3) In cats the thalamo-hypothalamic area receives a greater amount of blood via the common carotid artery than in dogs. (4) In both animal species, the vascular connections between the left and right side of the brain are more extensive in the vertebral than in the carotid bed. However, for either vascular bed, a more important left to right transmission was found in the dog.

The prevention of Ca2+ overload in vascular smooth muscle by flunarizine as detected by Laser Microprobe Mass Analysis (LAMMA).

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.

Double-blind comparison of ketanserin with placebo in patients with essential hypertension.

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)

Intermittent claudication--pathophysiological considerations.

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.

Proceedings: The effects of hypothalamic and reflexogenic hypertension on renal and femoral circulation.

In anaesthetized dogs, electrical stimulation of the median posterior hypothalamus provoked hypertension accompanied by a decrease of renal blood flow and an increase of femoral blood flow. Similar hypothalamic reactions occurred after bilateral cervical vagotomy or after atropine, 2 mg/kg i.v. During reflexogenic hypertension induced by bilateral carotid occlusion in bivagotomized dogs, the renal and femoral blood flows were not significantly modified. The decrease of the renal blood flow and the increase of the femoral blood flow, during hypothalamic stimulation were greatly reduced or reversed after R 28935 equals erythro-1-(1--e12-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidaxolinone, 80 mug/kg i.v., but not after clonidine, 5 mug/kg i.v.

Hypothalamic depressor reactions in anaesthetized dogs after baroreceptor exclusion and during norepinephrine infusions.

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.

Distribution of the blood flow supplied by the vertebral artery in rats: anatomical, functional and pharmacological aspects.

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.

Influence of guanethidine on the nicotinic effects of acetylcholine in atropinized dogs.

The influence of guanethidine on the nicotinic effects of acetylcholine was studied in anaesthetized atropinized dogs. Guanethidine (5 mg/kg i.v.) reversed the initial nicotinic pressor reaction, abolished the accompanying femoral vasoconstriction and reduced the increase of mean aortic flow. Therefore, nicotinic hypotension after guanethidine was due to a decrease of the peripheral vascular resistance. The height of the second pressor reaction was hardly affected by guanethidine. This drug inhibited the increases in mean aortic flow and heart rate but not the elevation of peripheral resistance, occurring at the secone nicotinic pressor phase. The present findings support the assumption that the initial hypertension is due to increased sympathetic outflow towards heart and vessels, whereas the second hypertension is due to adrenal medullary stimulation. The neurogenic femoral vasodilation at the onset of the second nicotinic pressor phase was blocked by guanethidine, which also inhibited the catecholamine-induced neurogenic vasodilation. These antagonisms may result from the interference of guanethidine with noradrenaline re-uptake.

Influence of electrical stimulation of the posterior hypothalamus on musculocutaneous and renal circulation in anesthetized dogs.

Hypertension and tachycardia were consistently induced by electrical stimulation of the median posterior hypothalamus in dogs under chloralose anesthesia, curarized and artificially ventilated. When renal and femoral vascular beds were perfused at a constant blood flow, the renal perfusion pressure markedly increased, whereas only minor variations of the femoral perfusion pressure occurred. When the renal and femoral vessels were perfused by the heart at the prevailing blood pressure, peri-arterial electromagnetic flow measurements revealed that renal flow decreased and that femoral flow increased during hypothalamic hypertension, both before and after vagotomy. In the same animals, no significant changes of renal or femoral flow occurred during reflexogenic hypertension induced by carotid occlusion. These marked hemodynamic differences between the reflexogenic and the hypothalamic type of hypertension were consistently and repeatedly observed. The indications that baroreflex counter-regulation and ganglionic inhibition due to elevated catecholaminemia contribute to the relative lack of femoral vasoconstriction during hypothalamic hypertension, are discussed.

Vascular and noradrenalic reactions in the musculocutaneous bed during hypothalamic stimulation.

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.

Characteristics of hypotension elicited by electrical stimulation of the lateralhypothalamusin anaesthetized dogs.

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.

Antihypertensive activity of erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-ET]-4-piperidyl)-2-benzimidazolinone (R 28935).

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.

Unusual mechanism of hypotensive activity exerted by erytrho-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-ET-a1-4-piperidyl)-2-benzimidazolinone (R 28935).

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.