The rise and fall of blood pressure and cognitive function: implications for sex differences in brain health.

1. I.v. injection of 1 or 3 micrograms capsaicin led to a triphasic blood pressure response in Sprague-Dawley rats but, in contrast to Wistar rats, did not affect heart rate and respiration. The blood pressure response was a sequence of fall (A), return to normal levels or slight rise (B), and fall (C) in blood pressure. The blood pressure response to capsaicin remained unchanged after treatment with adrenoceptor or cholinoceptor antagonists. 2. The initial fall in blood pressure (A) was absent after bilateral vagotomy and in the pithed rat. The delayed fall in blood pressure (C) remained unchanged after vagotomy, but was absent after neonatal capsaicin pretreatment and in the pithed rat. Effect B was not diminished after vagotomy or despinalization: it was augmented in rats treated neonatally with capsaicin. 3. I.a. injection of capsaicin into the hind leg caused a reflex fall in blood pressure which was changed to a reflex rise in rats treated with capsaicin as neonates. 4. The initial and the delayed fall in blood pressure after i.v. injection of capsaicin seems to be reflex responses to stimulation of capsaicin-sensitive small diameter afferent fibres. The intermediate rise in blood pressure appears to result mainly from a direct short vasoconstriction by capsaicin.

1. In cats anaesthetized with pentobarbitone, the fluid spaces in and around the brain stem were perfused from the third ventricle to the foramen magnum with artificial cerebrospinal fluid (c.s.f.) flowing usually at the rate of 5 ml/minute. Test solutions were substituted for the artificial c.s.f. without switching artifact for periods varying from 5 to 60 seconds. Observations were made on respiratory excursions, end-expiratory% CO(2) and arterial blood pressure.2. Perfusion with sucrose solution equiosmolar with the c.s.f. produced no respiratory or cardiovascular response. Replacement of sodium with potassium (60 to 133 mM) resulted in a prompt but mild respiratory stimulation and a delayed fall in blood pressure associated with a slowing of the heart beat. Replacement of sodium with magnesium (40 to 131 mM) resulted in a late prolonged apneustic depression of breathing and in an early but slight reduction in blood pressure.3. Procaine (1 to 50 mg/ml) elicited a respiratory response similar to that of excess magnesium; however, an initial rise in blood pressure to as high as 200 mmHg was evoked with procaine. Nicotine (0.05 to 0.5 mg/ml) produced an immediate brief bradypnea followed by a vigorous and slowly reversing hyperpnea accompanied most often by a fall in blood pressure. Tachyphylaxis was observed in the response to nicotine. Noradrenaline (0.001 and 0.1 mg/ml) did not produce any effect, and it did not alter the responses elicited by procaine and nicotine given by perfusion either simultaneous with or subsequent to the noradrenaline. Acetylcholine (0.5 mg/ml) produced weak transient respiratory stimulation and a small fluctuation in blood pressure which disappeared in repeated tests. Methacholine (1 mg/ml) caused a brief hyperpnea and a fall in blood pressure both of which were abolished after atropine (0.2 mg) was injected into the third ventricle. Pilocarpine (10 mg/ml) elicited no change in respiration or blood pressure. Respiratory and cardiovascular effects produced by strychnine (1 mg/ml) were attributable non-specifically to convulsive movements of the animal. Ethamivan (1 mg/ml) produced a single deep breath and a slowly reversing rise in blood pressure. Cyanide (0.5 mg/ml) barely stimulated the respiration but it produced a long lasting rise in blood pressure. Ethyl alcohol (0.1 ml/ml) elicited brisk though brief respiratory stimulation and a short lasting fall in blood pressure.4. It was shown that the effects of procaine and nicotine were not qualitatively altered when the perfusion effluent was collected through a ventral craniotomy instead of the cisterna magna.

Received September 14, 2004; revision received January 31, 2005; accepted March 9, 2005. “We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time” — —T.S. Eliot, Four Quartets Syncope, defined as transient loss of consciousness and postural tone with spontaneous recovery, has both challenged and perplexed physicians since the dawn of recorded time. The earliest written accounts come from Hippocrates, and the word syncope itself is derived from an old Greek term meaning “to cut short” or “interrupt.” Recurrent episodes of syncope may result from a large number of different disorders, all of which cause a transitory reduction in cerebral blood flow sufficient to disturb the normal functions of the brain. Over the last 2 decades, considerable attention has been given to types of syncope that occur due to a centrally mediated (or “reflex”) fall in systemic blood pressure, a condition that has been referred to as vasovagal (and later neurocardiogenic) syncope. However, research into the nature of this disorder revealed that it is but one aspect of a broad and varied group of disturbances in the normal functioning of the autonomic nervous system (ANS), each of which may result in orthostatic intolerance, hypotension, and ultimately syncope. Continued investigations into the nature of these similar yet different disorders has led to the development of a system of classification that attempts to more accurately reflect our understanding of these conditions and their interrelationships.1 The present system of classification has proven both functional and clinically relevant and includes a group of disorders that most investigators have thought to be principally autonomic in nature. Because both the cardiologist and the cardiac electrophysiologist frequently are expected to both diagnose and treat these conditions, the following …

1. In cats anaesthetized with pentobarbitone sodium, atropinized by i.v. atropine methyl nitrate and artificially ventilated, experiments were carried out (a) to localize the site where glycine acts on the ventral surface of the medulla when, on topical application through paired Perspex rings caudal to the trapezoid bodies, it produces a fall in arterial blood pressure, (b) to compare the effects of uni- and bilateral application, and (c) to study the blood pressure effects produced by electrolytic lesions of the glycine-sensitive areas.2. Blood pressure fell only a little on unilateral application of glycine through one of the Perspex rings, but a pronounced fall occurred on its bilateral application. The fall was too large to be explained by two minimal responses added together. Thus the application of glycine to one side potentiated the depressor effect of glycine applied to the other side.3. By moving the paired Perspex rings rostrally or caudally to different positions on the medulla and determining for each position the effectiveness of glycine, the glycine-sensitive areas were found to be restricted to a 1.5 mm wide strip situated 1-2.5 mm caudal to the trapezoid bodies. By making electrolytic lesions within the limits of this strip the glycine-sensitive areas were found to be not wider than 1.5 mm in the mediolateral direction and to be situated about 4 mm lateral to the mid line. Histologically, such lesions involved the cells of the parvicellular part of the lateral reticular nucleus.4. Placing an electrode, with a diameter of 1 mm, under light pressure on the glycine-sensitive area produced a short-lasting steep rise in blood pressure. The same effect was produced when a current was passed through the electrode to destroy the underlying tissue, but after its destruction the passage of current no longer produced the pressor effect.5. Once the glycine-sensitive area of one side was destroyed, glycine applied to the destroyed area through one of the Perspex rings no longer produced its small depressor effect, but when applied to the intact area of the other side, a pronounced fall in blood pressure occurred. Thus unilateral destruction had the same effect as unilateral glycine application. It potentiated the depressor effect of glycine applied to the other side.6. Following unilateral destruction of the glycine-sensitive area there was only a small fall in blood pressure; following its bilateral destruction blood pressure fell to a low level.7. It is concluded that the cells in the small circumscribed glycine-sensitive areas on the ventral surface of the medulla may play a key role in the maintenance of arterial blood pressure and that the cells of one side are sufficient for this function.

To evaluate mechanisms responsible for differences between patients showing a nocturnal fall in blood pressure ("dippers") and those showing no such fall in blood pressure ("nondippers"), we performed 24-hour (h) ambulatory blood pressure monitoring in 25 patients with untreated essential hypertension who were 37-49 years of age (16 men and 9 women). The diagnosis of essential hypertension was based on the patients' history, physical examination, routine laboratory tests, and intravenous pyelography. Blood pressure was measured by sphygmomanometer and by noninvasive ambulatory monitoring for 24 h. Exercise was performed on a supine bicycle ergometer. The initial workload was 50 W and was increased progressively by 25 W at 3-min intervals. Plasma and urinary norepinephrine levels were measured by high-performance liquid chromatography. Dippers were defined as patients with a difference of > 10 mmHg in the systolic BP or > 5 mmHg in the diastolic BP between daytime and nighttime. Eleven patients were dippers and 14 patients were nondippers. There was a positive correlation between the nocturnal fall in blood pressure and the rise in blood pressure during exercise (r = 0.54, p < 0.01), and the increase during exercise was greater in dippers than in nondippers. There was also a significant positive correlation between the urinary norepinephrine level and the fall in blood pressure at night (r = 0.75, p < 0.01). A significant increase in plasma norepinephrine during exercise was found in dippers, as compared with nondippers. These results suggest that in patients with hypertension a nocturnal fall in blood pressure is closely related to the blood-pressure response to exercise, and that the attenuation of sympathetic nervous activity might play an important role in the nocturnal decrease in blood pressure.

1. The fall in arterial blood pressure with bradycardia that occurs on injection of clonidine into the cerebral ventricles and into the cisterna magna is attributed to an action on ;chemosensitive zones' situated at the ventral surface of the brain stem. This conclusion is based on the following results obtained in cats anaesthetized with pentobarbitone sodium.2. The fall in blood pressure no longer occurs on injection of clonidine (10 to 100 mug) into the cerebral ventricles when the passage of clonidine into the subarachnoid space is prevented by cannulation of the aqueduct. In this condition, the injections produce instead a rise in blood pressure.3. Applied bilaterally, by means of perspex rings, to the ventral surface of the brain stem, clonidine (10 mul of a 50 to 1,000 mug/ml solution placed in each ring) produces a fall in blood pressure with bradycardia, but only when the perspex rings cover the ;chemosensitive zones' from which changes in blood pressure and heart rate are obtained with various drugs.

The significance of the state of the central autonomic nervous system for quantitative and qualitative aspects of some cardiovascular reactions

Summary.The effects of tributyrin on circulation and respiration have been studied by injection of a tributyrin emulsion.On intravenous injection, the effect of tributyrin on circulation is characterized by rapidly appearing bradycardia and a fall in blood pressure, followed by a rise in blood pressure.Bradycardia and the fall in blood pressure are inhibited by vagotomy and procaine. They do not appear with injection into the left ventricle, aorta or large arteries. The effect is probably‐elicited through receptors with afferent pathways in the vagus, and located to the right side of the heart or the lungs. The rise in blood pressure is largely due to contraction of peripheral blood vessels. This rise is not inhibited by tetraethylammonium, hexamethonium, dihydroergotamine, ergotamine or procaine.In the heart‐lung preparation, tributyrin decreases the heart action. The blood flow in the abdominal aorta is reduced, together with a rise in blood pressure after injection of tributyrin.The effect on respiration is characterized by apnoea with a rapid onset, followed by hyperpnoea. Apnoea is not elicited after vagotomy, but appears after administration of atropine or procaine. Injection into the left ventricle, aorta or large arteries does not produce apnoea. Apnoea is probably evoked via receptors in the right side of the heart or the lungs. The hyperpnoea is considered to be produced by central stimulation.Bradycardia, the fall in blood pressure and apnoea associated with injection of tributyrin seem to be elicited in the same way as the Bezold‐Jarisch reflex described earlier.Tributyrin is found to have neither an inhibitory nor a stimulating effect on the superior cervical ganglion.The LD50 of tributyrin on intravenous injection into mice is 320 ± 11 mg/kg.

1. In peptone shock there is a marked, precipitate fall in arterial pressure. At the same time there is a fall in venous pressure. 2. In experimental fat embolism, (a) the fall in blood pressure is always gradual; (b) approximately 1 cc. of oil for each pound of body weight must be injected before a lasting fall in arterial pressure is produced; (c) it makes only a slight difference whether this amount is injected in small doses at a time or in relatively large quantities; and (d) when the arterial pressure falls, but not till then, the venous pressure rises. 3. In peptone shock, dyspnea, by its suction and force-pump action upon the reservoir of stagnating blood in the liver, brings more blood to the heart and causes a rise in arterial pressure. By repeatedly inducing short periods of dyspnea at frequent intervals, permanently beneficial results are obtained and the life of the animal can be saved. 4. In experimental fat embolism, dyspnea will cause a rise in blood pressure. But permanently beneficial results have not been obtained by this method. If dyspnea is found to bring permanent improvement in surgical shock, it is indirect evidence that this condition is not due to fat embolism. Respiratory suction is probably not responsible for the rise in blood pressure in experimental fat embolism. It seems more likely that the dyspnea in some way facilitates the passage of blood through the embarrassed pulmonary circulation. Artificial respiration with a bellows will also frequently cause a rise in blood pressure in experimental fat embolism. 5. In peptone shock the respiration is usually not affected, although there is some evidence that the respiratory center may be in a state of increased irritability. In experimental fat embolism, in some animals a violent dyspnea develops spontaneously. This is usually accompanied by edema of the lungs. In other instances, an apnea occurs, even before the blood pressure has begun to decline.

Effect of hydrocortisone on streptokinase-induced hypotension in patients with acute myocardial infarction

1. Capsaicin treated rats, in which the function of substance P-containing primary sensory neurons was impaired, were used to investigate the function of afferent fibers within the splanchnic nerve. The effects of electrical stimulation of the splanchnic nerve either distal or proximal to the site of its transsection on blood pressure and heart rate were investigated. 2. Distal splanchnic nerve stimulation evoked an equal rise in blood pressure in capsaicin treated rats and in their controls. Distal splanchnic nerve stimulation did not cause plasma extravasation in the adrenal medulla, an effect which is produced by antidromic stimulation of cutaneous sensory nerves. Peripheral effects of stimulation of primary afferent fibers within the splanchnic nerve cannot be assumed from these experiments. 3. Proximal stimulation of the splanchnic nerve evoked a reflex fall in blood pressure but no bradycardia. The fall in blood pressure was absent in capsaicin treated rats, which indicates that this effect is mediated by primary afferent fibers. Since the reflex fall in blood pressure was abolished by adrenergic blockade with guanethidine, it can be explained by vasodilatation resulting from reduction of sympathetic vasoconstrictor tone.

The effects of single doses of DOCA or cortisone, with or without the addition of stilbœstrol, on the vascular responses of anæsthetized female rats to vasopressin and oxytocin were studied.DOCA reduced the sensitivity to the pressor action of vasopressin in all animals. An initial fall in blood pressure always preceded the rise. After DOCA the majority of animals responded to oxytocin with a small fall and then a rise in blood pressure. Cortisone increased the reactivity to vasopressin in all diœstrous females; during œstrus (natural or stilbœstrol‐induced) cortisone like DOCA reduced the sensitivity to vasopressin. The rise in pressure was, except, in the diœstrous females, preceded by a sharp fall. Most of the cortisonetreated animals responded to oxytocin by a rise usually preceded by a fall in blood pressure. In three females the blood pressure was unchanged after oxytocin, and in a few it fell with no subsequent rise. Animals showing a diphasic response to vasopressin and a pure depressor or a diphasic response to oxytocin were given dihydroergotamine (DHE) and atropine to see how far the responses depended on autonomic nervous activity. With few exceptions after DHE the depressor phase of the response was abolished and the pressor phase regularly potentiated. The main exceptions were cortisone‐treated œstrous rats and three of the six females treated with cortisone and stilbœstrol; in these DHE enhanced the depressor phase of the response to vasopressin and oxytocin, and atropine given later caused a further enhancement. The results are discussed in relation to the activity of the autonomic nervous system.

An analysis is presented of the blood pressure changes during anoxia, asphyxia, and oxygen administration, in 34 animal experiments. Similarly, in 30 human beings during decompression equivalent to altitudes ranging from 16,500 ft. to 29,000 ft., the blood pressure findings are correlated with the action of the heart and the state of the peripheral blood vessels, and the effect of subsequent administration of oxygen upon them is investigated.Sudden deprivation of oxygen leads to a vasoconstrictor response, which, in humans, manifests itself in facial pallor and elevation of the blood pressure. The administration of oxygen in the later stages of this response may produce a further transient elevation of the blood pressure, which is followed by a fall of blood pressure and slowing of the pulse. The rise of blood pressure caused by oxygen after a period of acute anoxia or asphyxia is due to an augmentation of the action of the heart and to an intensification of the vascular tone, the two phenomena contributing to the rise of blood pressure in a varying degree under different experimental conditions. In intact, anaesthetized cats the effect persists after adrenalectomy. In spinal preparations, previously kept on "minimal" respiration, the effect is greatly reduced by the removal of the suprarenal glands. The rise of blood pressure resulting from the administration of oxygen is abolished by the destruction of the spinal cord by pithing, and is therefore attributed to an excitation of the sympathetic centres. Evidence also is presented that suggests that the chemoreceptors participate in this response in intact anaesthetized animals.A protracted oxygen deficiency of a moderate degree leads to a vasodilator reaction. In human subjects it manifests itself in a gradual engorgement of the cutaneous blood vessels, often in a lowering of the blood pressure, and an increase of the pulse rate. Sudden administration of excessive quantities of oxygen under these conditions causes a further decline of blood pressure and a slowing of the pulse. An analysis of the fall of blood pressure caused by the administration of oxygen in conditions of prolonged hypo-oxygenation shows that it is not strictly related to changes in respiration or to acapnia, which occurs during breathing of air deficient in oxygen. Neither is it prevented by addition of carbon dioxide to the oxygen. However, under prevailing experimental conditions, this fall of blood pressure is almost invariably abolished by a bilateral vagotomy, is occasionally reduced by atropine, and is absent in spinal preparations, these observations indicating "that it is dependent on the functioning of the medullary reflex mechanisms.

The present study was undertaken to compare the antihypertensive effects of beta-blocking agents and to clarify the relations between antihypertensive effects and beta-blocking actions. In this study, blood pressure was measured by a direct cannulation of the abdominal aorta. Subcutaneous administration of carteolol and pindolol caused a significant fall in mean blood pressure in both normotensive and spontaneously hypertensive rats, whereas propranolol produced a rise in blood pressure. Maximum fall in blood pressure was observed 3 approximately 7 hr after the administration of carteolol and pindolol. In order to determine the beta-blocking action, changes in heart rate and blood pressure in response to isoproterenol (3 microgram/kg i.v.) were observed during the experiment. beta-Blocking action was found as early as 1 hr after subcutaneous administration. Carteolol showed the most effective blocking action throughout the experiment. Although beta-blocking agents lowered the blood pressure in this experiment, there was no apparent parallel between antihypertensive effects and beta-blocking action on the cardiac function.

1. Intravenous injection of anti‐angiotensin II causes a transient fall in the mean blood pressure of anaesthetized normal rats, showing that the angiotensin content in the blood plays a role for the normal blood pressure level. The subsequent return of the blood pressure to its initial level is probably caused by the cardio‐accelerator and pressor reflexes. The function of the baroreceptors is also thought to be the cause why a depressor effect of anti‐angiotensin is lacking in conscious normal rats. Lack of effect on anaesthetized nephrectomized rats conforms to the lack of angiotensin in their blood. The somewhat increased depressor response to anti‐angiotensin in rats with acute severe constriction of the renal arteries and the still more pronounced response in many (but not all) renal hypertensive rats conforms to increased plasma angiotensin in these rats. The somewhat decreased depressor response of ureterligated rats corresponds to their decreased sensitivity to angiotensin and renin. 2. Anti‐angiotensin causes a decreased response to injected angiotensin both in conscious normal and anaesthetized normal, nephrectomized, ureterligated and renal hypertensive rats, the sensitivity in several cases being reduced to less than 1 per cent. If angiotensin is continuously infused in doses of 9 ng/min, anti‐angiotensin will cause a fall of the blood pressure which in one half of the cases reaches the initial level, in the other half stops at a level above the initial, even when a second dose of anti‐angiotensin is injected. When anti‐angiotensin is given between two periods of continuous infusion of angiotensin, the second rise in blood pressure will be smaller, being up to 50 per cent of the first. 3. Anti‐angiotensin causes a decreased response to renin, but the above‐mentioned groups of rats do not react in the same way. In anaesthetized normal rats the sensitivity is reduced to about 5 to 10 per cent. Nephrectomized and ureterligated rats are still able to react with a pressor response to doses of renin which are without effect on the blood pressure of anti‐angiotensin pretreated normal rats. The maximum response of rats belonging in these two groups is, however, only up to 50 per cent of that found in non pretreated nephrectomized or ureterligated rats. If given shortly after renin, anti‐angiotensin injection will cause a rapid fall in the blood pressure to the initial level in normal and ureterligated rats, while there is only a partial return to a level markedly above the initial in nephrectomized rats.