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The neurogenic component appears to be an integral part of the “mosaic” of factors underlying chronic hypertension. Studies in many animal models have shown a critical interaction between the renin-angiotensin and the sympathetic nervous systems and have demonstrated the presence of an angiotensin-sensitive neural structure in the brain. The implications of these findings for human essential hypertension are discussed.

The hemodynamic changes accompanying experimental neurogenic hypertension due to sinoaortic denervation were measured in unanesthetized dogs for 3 weeks with chronically implanted arterial catheters and aortic flow transducers. Hypertension was modest, the average increase in mean arterial pressure being 31 ± 5 (SE) mm Hg. In about half of the dogs it was due predominantly to increase in cardiac output and in the others to increase in peripheral resistance; one factor or the other tended to maintain the hypertension in each dog throughout the experiments. Arterial pressure became extremely labile during the first few days after denervation and remained so during the entire experiment. This lability was closely correlated with environmental stimuli; rather minor distractions caused a sharp fall in pressure due variably to decrease in both cardiac output and peripheral resistance; greater distractions or physical activity caused a rise in pressure due usually to increase in peripheral resistance. Mean arterial pressures were higher when measured by transcutaneous puncture of a femoral artery, presumably because of the necessity of restraint and the discomfort associated with passage of a needle. Before sinoaortic denervation, arterial pressures fell to basal levels during sleep. After denervation, unexpectedly and for an undetermined cause, pressures rose to very high levels during sleep; the rises were consistently due to increase in peripheral resistance. Awakening was accompanied by a sharp fall in pressure and peripheral resistance.

The synthetic octapeptide angiotonin evoked systolic and diastolic pressure responses in anesthetized and unanesthetized dogs identical with those due to a natural, largely decapeptide, angiotonin, and responses to both angiotonins were modified in the same manner by a variety of procedures. Infusion of synthetic angiotonin caused hypertension sustained for the durations of the infusions and tachyphylaxis was not observed. Induced tachyphylaxis to a crude renin preparation was accompanied by loss of response to both synthetic and natural angiotonin but not to norepinephrine.

Arterial pressure response to serotonin depends largely upon four main actions of the drug: direct vasoconstriction, a von Bezold-like reflex, transient ganglion blockade and peripheral inhibition of neurogenic vasoconstriction. The relative prominence of these actions differs depending upon the dose of serotonin, species tested and degree of pre-existing neurogenic vasoconstriction.

High spinal cord section caused reduction of stroke volume, cardiac output, aortic pressure, and increase in heart rate. Peripheral resistance was little changed. With time, arterial pressure and heart rate recovered to near control levels; stroke volume, cardiac output, and peripheral resistance tended to increase. Recovery of arterial pressure was due either to increase in peripheral resistance or increase in cardiac output. Elimination of essentially all efferent sympathetic activity caused little or no decrease in peripheral resistance; the small decrease in arterial pressure was accounted for by decrease in stroke volume and cardiac output. Atropine given well after recovery from operation increased heart rate, cardiac output, and aortic pressure while stroke volume decreased. The increase in blood pressure was due to increased cardiac output. Tetraethylammonium chloride given after atropine showed that cardiovascular denervation was essentially complete. Induction of experimental renal hypertension caused marked rise in peripheral resistance without change in stroke volume, heart rate, and cardiac output. Since cardiovascular denervation was complete, the hypertension was of humoral origin.

Since vascular responsiveness to adrenaline, noradrenaline, renin and angiotonin is reduced by suppression of thyroidal function in normotensive dogs, it was a possibility that in neurogenic and renal hypertensive animals suppression of thyroidal function might be associated with decrease in arterial pressure. This possibility was not confirmed, hypertension persisting unaltered in both groups of hypertensive animals over long periods of observation. Changes in vascular reactivity were slight in comparison with those associated with the athyroid state in normotensive dogs.

At least four mechanisms contribute to the increased responsiveness to pressor drugs caused by ganglioplegic agents: 1) Elimination of parasympathetic reflexes alone was found to have a prominent effect on pressor responsiveness, especially to norepinephrine. 2) Elimination of sympathetic compensatory reflexes caused the expected increase in responsiveness. 3) Tetraethylammonium had a direct effect on blood vessels of the dog's perfused hind limb that resulted in sensitization to norepinephrine, though not to angiotensin; this direct effect of the ganglioplegic was similar to that produced by surgical denervation. 4) Tetraethylammonium caused enhancement of response to epinephrine but not to norepinephrine in pithed cats and this effect seems best explained by a blocking action of the ganglioplegic on adrenergic vasodilator receptors. Because of the participation of these different mechanisms, ganglioplegics and surgical denervation do not necessarily affect pressor responsiveness in the same manner. Additionally, the different mechanisms involved account for the various degrees of augmentation of response to different pressor drugs since the latter have their major actions on different portions of the cardiovascular system. Responsiveness may vary greatly during a single experiment and also from day to day; this variability is due in large part to the nervous system since it is abolished by cervical section of the spinal cord.

1. Infusion of angiotensin into both vertebral arteries or into a lateral cerebral ventricle of dogs anaesthetized with morphine-chloralose elicited a centrally mediated rise in blood pressure. 2. Heat coagulation of the area postrema and immediately adjacent structures abolished the pressor response to infusion of angiotensin into the circulation of the vertebral arteries, but did not alter the pressor response when the peptide was delivered into a cerebral lateral ventricle; transection of the midbrain eliminated the latter response but not the former. 3. It is concluded that there are at least two areas in the dog's brain that respond to angiotensin by inducing a raised blood pressure.

Systemic pressor responses occurred consistently 5 to 15 minutes following reduction of renal perfusion pressure and were accompanied by the appearance of pressor material in renal vein blood. The pressor material is probably angiotensin formed from renin released by the kidney, since its activity was not affected by protein precipitation, was eliminated by incubation with chymotrypsin, and since it caused enhanced pressor responses to tyramine, all of which are characteristic of angiotensin. Activity was unaffected by pharmacologic blockade of response to norepinephrine and serotonin. Its renal origin is indicated by the greater amount of pressor activity in renal venous than in arterial blood throughout the systemic pressor responses. Smaller amounts of pressor material, also with properties of angiotensin, were found in thoracic duct lymph. They did not contribute materially to the systemic pressor response since external drainage of all lymph did not modify the response, and since the time course of the response correlated with an increase in pressor activity in renal vein blood but not in lymph. The late appearance of angiotensin in thoracic duct lymph is probably due to renin secretion by the kidney into renal lymph rather than transfer from circulating blood; activity did not appear in lymph when renin was infused intravenously in amounts that caused rises in systemic pressure comparable to those produced by reduction of renal perfusion pressure. The results indicate that during short periods of reduced renal perfusion pressure, renin is released in larger amounts in blood than in lymph.

The results of these experiments indicate that the carotid and aortic baroceptor mechanisms are reset to the hypertensive pressure levels of animals with chronic perinephritic hypertension. Thus, seemingly, the buffer reflexes tend to maintain, rather than prevent, the chronic phase of renal hypertension and are, presumably, an important component in the mechanism of chronic renal hypertension.

Removal of the dog's liver only slightly reduced pressor-depressor responses to test drugs during several hours after operation in the majority of experiments. The perfused vascular bed of one hind leg of these preparations also showed relatively normal responsiveness to drug and reflex stimuli. Other experiments contrasted with these in that responses to test agents were greatly reduced, or lost, in company with enhanced response to the depressor action of TEAC and predominantly depressor response to serotonin which is characteristic when neurogenic vasoconstriction is increased, as after severe hemorrhage, but hemorrhage was probably not alone accountable for the unresponsive state following hepatectomy, nor could a number of other factors be proved causative. Removal of an organ so importantly concerned with detoxication failed to augment responses to vasoactive agents.

Increased vasomotor discharge induced by bleeding caused renal release of renin in anesthetized dogs whether or not there was measurable change in either arterial pressure or total renal blood flow. Release of renin was prevented by ganglion blockade or local anesthesia of the renal nerves. Hemorrhage-induced release of renin occurred more consistently in dogs fed a low-sodium diet than in those fed a standard kennel diet. Stimulation of sympathetic vasomotor discharge by occlusion of the common carotid arteries, while renal perfusion pressure was kept constant, also caused release of renin, as did infusions of norepinephrine, tyramine, or DMPP. Isoproterenol, angiotensin, vasopressin, serotonin, or acetylcholine infused into the renal artery did not cause release of renin. It is concluded that neural stimuli are capable of causing release of renin in the absence of gross change in renal perfusion pressure or flow.

In a majority of experiments on both dogs and cats, hypotensive doses of tetraethylam-monium chloride or mecamylamine caused no change or moderate increase in efferent electric activity in the largely preganglionic thoracic portion of the splanchnic nerve, and caused complete and prolonged elimination of efferent activity in the postganglionic inferior cardiac and renal nerves. Both drugs failed to suppress changes in splanchnic nerve activity that were elicited refiexly. These results imply strongly that both ganglion-blocking drugs, in dosage used intravenously to induce hypotension, act mainly through their peripheral effects rather than through one on central vasomotor synapses. In both dogs and cats, reserpine caused slowly progressive and marked diminution in efferent splanchnic nerve activity, which supports the hypothesis that the central action of this agent contributes to its hypotensive effect.

Arterial pressure response to intravenous infusion of serotonin in dogs and cats is usually a sustained fall; this differs from the usual response to a single quick injection of serotonin and suggests that the mechanisms controlling response are different depending upon the manner of administration of the drug. It is concluded that when serotonin is infused the depressor response has at least three main contributory mechanisms: a) release of endogenous histamine by serotonin; b) peripheral inhibition of neurogenic vasoconstriction; c) a dose-response relationship that, in some preparations, determines whether change in arterial pressure shall be a rise or fall. The response to intravenous infusion of serotonin in three hypertensive patients was different from that in normotensive dogs and cats or neurogenic hypertensive dogs. These patients responded with a small, sustained rise in arterial pressure. Infusion of either histamine or serotonin in dogs caused similar changes in response to other drugs: those to DMPP were strikingly augmented and those to noradrenaline were moderately increased in both dogs and cats. Responses to angiotonin, barium chloride, and Aramine were essentially unchanged. The depressor action of the histamine releasing drug, 48/80, or histamine, was sharply reduced or abolished.

THE carotid sinus did not achieve its rightful place in the scheme of things until 1923, when Hering described the carotid sinus reflex. But it was Soma Weiss and James Baker who brought to it a cl...

1.1. DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) stimulated sympathetic ganglia more powerfully than nicotine and tetramethylammonium iodide and had less ganglion paralyzing action than nicotine in dogs, cats, rabbits and man. It differed from nicotine also in that its vasopressor action was largely independent of carotid and aortic chemoreceptor function. Respiratory stimulation, however, depended in part upon stimulation of these chemoreceptors. 2.2. The pressor effect of DMPP depended upon release of epinephrine and/or norepinephrine from the adrenal glands and liver and stimulation of sympathetic ganglia with resultant vasoconstriction and cardioacceleration. The drug had no prominent direct action on blood vessels, at least in the perfused denervated dog's leg. 3.3. Stimulation of parasympathetic ganglia caused initial transient bradycardia and fall in blood pressure that tended to inhibit the pressor action of DMPP. This opposing action was especially prominent after spinal cord section at C 6 and was eliminated by atropine or section of the vagus nerves. 4.4. Section of the spinal cord at C 6 or paravertebral sympathectomy augmented the pressor action of DMPP, since these procedures also augment the pressor action of epinephrine and nor-epinephrine. 5.5. TEAC, nicotine and hexamethonium all inhibited the ganglion-stimulating action of DMPP. The adrenergic blocking agents, priscoline, regitine and RO 2-3248, inhibited the pressor action of DMPP to a degree directly dependent on the inhibition of pressor response to nor-epinephrine. 6.6. Response to DMPP was not altered by production of chronic neurogenic hypertension in dogs by section of the carotid sinus and aortic depressor nerves. But during the acute hypertension immediately following section of the buffer nerves the late sustained pressor action of DMPP was often replaced by a pronounced depressor effect. The significance of this difference is unknown, other than it may be listed with other observations suggesting that the two forms of hypertension depend on different mechanisms. 7.7. DMPP has proved useful in the diagnosis of pheochromocytoma because of its strong and specific action on ganglia and adrenal medullary tissue. It ensures a high secretory activity of the tumor, the effect of which is specifically inhibited by adrenergic blocking agents.

Puromycin infused into a renal artery (10–125 μg/kg/min for 20 min) of anaesthetized dogs consistently reduced renin activity in samples of renal venous blood when kidneys were perfused at lowered pressures. It did not affect the smaller amounts of renin present in the renal venous effluent from kidneys perfused at normal pressures. Since renin is a protein and puromycin is known to inhibit protein synthesis in vitro , it seemed logical to attribute reduction of renin-release by puromycin to inhibition of renin synthesis. But because of the early reduction of renin-release in most kidneys perfused at lowered pressures, it is probable that another mechanism is involved. However, puromycin had no effect in vitro either on the amount of angiotensin formed when it was added to incubation mixtures containing known amounts of dog renin and its substrate, or on the appearance of renin from isolated slices of dogs' kidney cortex incubated in Kreb's buffer solution.

Renin secretion was found to be controlled by a renal baroreceptor rather than by ischemia. Development of a sensitive assay technique that detects renin in small quantities of renal venous and peripheral arterial plasma has permitted the demonstration that the rate of renin secretion varies inversely with the level of arterial pressure independently of renal blood flow. When mean renal perfusion pressure was reduced 5 to 40 mm Hg by a constricting band around the aorta above the level of the renal arteries, increased renin secretion commenced within 60 seeonds. Reductions of this magnitude did not necessarily cause mean perfusion pressure to fall below control levels of diastolic perfusion pressure. Rises in perfusion pressure had the reverse effect, reducing the rate of renin secretion again without measurable change in renal blood flow. Compression of the kidney within an oncometer by an applied forece of from 15 to 40 mm Hg also caused increases in the rate of renin secretion in the absence of change in total renal blood flow. Reduction of pulse pressure alone did not provoke secretion of renin, nor did reduced oxygen tension, or renal ischemia. Rise in perfusion pressure due to occlusion of the common carotid arteries was associated with reduction in the rate of renin secretion. A small amount of renin was secreted continuously under the conditions of these experiments; physiologic changes in mean perfusion pressure served to alter the rate. This suggests that a renal baroreceptor mechanism regulates renin secretion under normal circumstances and that arterial pressure tends to stabilize at a level at which renin secretion is minimal.

SUMMARY 1. Synthetic angiotensin I1 was infused chronically through catheters implanted into a vertebral artery and an external jugular vein of unanaesthetized dogs. Arterial pressure was recorded daily from an indwelling catheter in the abdominal aorta before, during and after the infusions. 2. Infusion of angiotensin 1 pg kg-' day-' into a vertebral artery caused mean arterial pressure to increase by an average of 12 mmHg in five dogs, and the rise was sustained throughout the infusion period of 7 days in all dogs. 3. When the infusion rate of angiotensin was increased to 10 pg kg-' day-', arterial pressure during vertebral artery infusion rose initially to a slightly greater extent but decreased at the end of the infusion, indicating tachyphylaxis. 4. During infusion of angiotensin into the vertebral circulation, arterial pressure rose rather than fell during sleep; awakening was accompanied by sharp fall in pressure. 5. It is concluded that there is an area in the central nervous system responsive to angiotensin that can cause a sustained rise in arterial pressure. Arterial pressure is increased in rabbits (Dickinson & Yu, 1967; Rosendorff, Lowe, Lavery & Cranston, 1970), dogs (Scroop & Lowe, 1969; Ferrario, Dickinson & McCubbin, 1970) and man (Ueda, Uchida, Ueda, Gondaira & Katayama, 1969) when angiotensin is infused into a vertebral artery in amounts that are ineffective when given intravenously. It is not known if this action of angiotensin is involved in the initiation, or maintenance, of renal hypertension. The experiments reported here were done to determine whether or not continuous infusion of small amounts of angiotensin into the vertebral arteries of unanaesthetized dogs could cause a rise in arterial pressure that would be sustained for days.

Pentobarbital anesthesia produces an important change in the dog's arterial pressure response to TEAC. Without anesthesia, the response, instead of being sharply depressor, is characteristically pressor, or biphasic and mainly pressor. Only occasionally is it depressor. Small doses of TEAC more often elicited depressor responses than did large ones. Mecamylamine, hexamethonium and chlorisondamine usually also failed to cause appreciable lowering of arterial pressure in unanesthetized dogs, but did not show as much pressor activity as did TEAC. Responses to TEAC in hypertensive conscious man showed considerable variability, but the overall pattern of response tended more to resemble that of anesthetized than that of unanesthetized dogs. Atropine caused narrowing of pulse pressure, tachycardia, little change in mean pressure, and the response to TEAC to become mainly depressor—though not to the same degree as did pentobarbital. The greatly augmented depressor activity of ganglion blocking agents after pentobarbital anesthesia probably depends in large part upon nearly complete inhibition of parasympathetic cardioinhibitory activity by the anesthetic agent, and upon partial suppression of sympathetic compensatory reflexes by the ganglion blocking action of pentobarbital. Cardiovascular reactivity measurements are closely dependent on the conditions of the experiment and anesthesia is one of the most important of these conditions.

Tetraethylammonium, hexamethonium, chlorisondamine or mecamylamine suppressed the dog's carotid occlusion reflex well before appearance of maximum augmentation of responses to pressor drugs. The reflex usually returned to near control values despite continued administration of ganglioplegics, while augmented responsiveness persisted or became more marked. An antipseudocholinesterase or prostigmine restored the suppressed reflex without loss of augmented responsiveness. Electroneurographic measurements of efferent spontaneous activity in postganglionic renal nerves revealed synaptic pathways resistant to blockade: a small amount of activity persisted during tolerance to ganglioplegics and showed reflex changes. Similar measurements of spontaneous and evoked potentials in the inferior cardiac nerve showed no synaptic activity during tolerance. Augmentation of response to pressor drugs by ganglioplegics does not depend wholly upon loss of compensatory reflexes; peripheral sensitization is probably another mechanism concerned. Maintenance of arterial pressure and persistence of cardiovascular reflexes during tolerance to ganglioplegics appear to depend upon transmission of a relatively few impulses over pathways resistant to blockade and upon peripheral sensitization to the presumably smaller amounts of norepinephrine released from nerve endings.

Angiotensin has an effect on the sympathetic nervous system which results in an enhanced response to agents and procedures that cause release of endogenous norepinephrine while having little or no effect on response to exogenous norepinephrine. The effect is peripheral, it does not appear to involve sensitization of norepinephrine receptors, it is dependent upon a functionally intact sympathetic nervous system, and it appears unrelated to the direct vasoconstrictor action of angiotensin. The response to tyramine is increased in both acute and chronic renal hypertension; this suggests that only very small amounts of angiotensin, difficult to detect by present assay methods, continue to have an effect on the sympathetic nervous system in chronic renal hypertension. By intensifying the effect of normal neurogenic vasomotor activity, this action of angiotensin, along with the upward shift of threshold and range of response of the carotid sinus buffer mechanism, might account to a major degree for the large neurogenic component of chronic renal hypertension.

Reserpine, serotonin, norepinephrine, 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine had qualitatively the same cardiovascular effects when they were injected into a lateral ventricle or into the cisterna magna. All lowered arterial pressure, usually caused bradycardia despite prior section of the vagus nerves, and caused marked inhibition of the pressor response to occlusion of the common carotid arteries. Essentially the same results were obtained in unanesthetized as in anesthetized dogs. On a weight basis, norepinephrine was the more active amine tested and 5-hydroxytryptophan was more active than serotonin and 3,4 dihydroxyphenylalanine. Reserpine injected centrally had an effect equivalent to that of 20 or more times larger dosage given intravenously. All drugs were more active against the response to carotid occlusion than against the reflex pressor response to stimulation of a cut central end of a sciatic or vagus nerve. Decreased afferent electric activity of the carotid sinus nerve accompanied lowering of arterial pressure following central injection of small dosage, or intravenous injection of large dosage, of 5-hydroxytryptophan, indicating that the cardiovascular effects are not due to a direct action of 5-hydroxytryptophan on carotid sinus baroceptors. Central injection of an amine oxidase inhibitor, beta-phenylisopropylhydrazine, markedly augmented and prolonged the cardiovascular effects of the amines and of reserpine as well. These results are all consistent with, though they do not validate, the premise that the acute cardiovascular effects of reserpine are mediated centrally by serotonin and/or norepinephrine, either released from a bound and inactive to a free and active form, or formed by decarboxylation of their respective amino acids.

Natural decapeptide or synthetic octapeptide angiotonin was ineffective in lowering arterial pressure or decreasing the carotid occlusion response when injected into the carotid sinus adventitia. Injection of synthetic octapeptide angiotonin into the lumen of the carotid sinus after tying its branches decreased the carotid occlusion response but the effect depended on dosage many times the pressor activity of 1 γ of norepinephrine which elicited a comparable effect.

Pressor response to injection of renin is reduced or abolished during adrenal insufficiency without concurrent change in response to angiotonin and other drugs. Selective loss of response to renin is considered to result from depletion of available renin-substrate by endogenous renin; when release of endogenous renin is precluded by nephrectomy, adrenalectomy does not cause diminution of response to renin. The increase in response to angiotonin and renin that follows nephrectomy is not prevented by adrenalectomy.

Though single injections of angiotensin cause extreme rise in arterial pressure, infusion fails to elevate pressure to the degree usually found in experimental renal hypertension. The maximal pressure level obtainable by infusing angiotensin into anesthetized dogs was approximately the same in different dogs and was independent of the initial pressure. The vagus nerves did not importantly influence the "ceiling" response but if arterial pressure was then elevated by carotid occlusion the ceiling was raised. The combination of renal artery constriction and infusion of angiotensin failed to give a higher ceiling than angiotensin alone. In dogs with chronic renal hypertension the ceiling was higher than in normal dogs, presumably because of an upward shift in the range of response of cardiovascular reflexes. The results support the view that compensatory cardiovascular reflexes and tachyphylaxis to large amounts of infused angiotensin suppress the response and that these factors are much less effective in limiting response to quick injection.

Bilateral nephrectomy selectively augments reactivity to pressor drugs and affects that to angiotonin the most prominently. This change is not mediated through the central nervous system, does not depend upon mechanical exclusion of the renal vascular bed, and is not modified by change in sodium intake. The inhibitory action on pressor responsiveness is independent of renal excretory function.

Several vasoconstrictor drugs and reserpine administered into a cerebral lateral ventricle inhibited the reflex pressor response to occlusion of the common carotid arteries in both anesthetized and unanesthetized dogs. This effect was opposed by central administration of the vasodilator drugs, nitroprusside and histamine. Serotonin, norepinephrine and their precursors, 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine, and reserpine caused lowering of arterial pressure and slowing of heart rate as well as inhibition of the carotid occlusion response; angiotensin and vasopressin did not. The central inhibitory effect of norepinephrine was opposed by phentolamine; that of 5-hydroxytryptophan was not affected by lysergic acid diethylamide or its brom derivative. Cooling of cerebrospinal fluid, which presumably caused local vasoconstriction, also caused inhibition of the carotid occlusion response, hypotension and bradycardia, and these effects were counteracted by central injection of vasodilator drugs. Warming of cerebrospinal fluid, presumably associated with local vasodilation, opposed the central inhibitory effect of vasoconstrictor drugs and of reserpine. In view of the consistently opposite effects of vasoconstrictor and vasodilator drugs and procedures on central vasomotor sympathetic activity, it is tentatively concluded that these effects depend on change in local blood flow. The acute cardiovascular effects of reserpine of central origin are probably due to local decrease of tissue perfusion caused by serotonin, norepinephrine or other vasoconstrictor agent released from a bound to an active form.

The response of the arterial pressure to a variety of drugs acting on different parts of the vascular tree has been employed to determine the contrasting mechanisms of chronic hypertension experimentally produced in dogs. The results suggest that the pattern of response depends on the state of the extrinsic regulatory mechanisms of the blood vessels rather than on intrinsic change in vascular musculature. Contrasting with chronic renal hypertension, greatly increased vasomotor function causes increased peripheral resistance in chronic neurogenic hypertension. The hypertension seems to us to be due more to this increase in resistance than to increased cardiac output. The pattern of vascular responsiveness in acute hypertension is different from the chronic and emphasizes the importance of distinguishing between the two phases of hypertension.

The renal pressor system exerts a dramatic effect on body fluid volumes when the thoracic sympathetic chains are removed in dogs. This effect was demonstrated in experiments designed originally to determine the influence of cardiac sympathectomy on the increase in cardiac output that precedes development of renal hypertension. While removal of the cardiac sympathetic nerve supply did not prevent the increase in cardiac output after wrapping one kidney in cellophane, a modest rise in blood pressure was accompanied by a remarkable 46 ± 8 (S.E.) % (p

SUMMARY 1. When angiotensin was infused at low rates into the vertebral arteries of anaesthetized dogs, it raised the blood pressure. When infused at similar rates intravenously or into the internal carotid artery it either did not change blood pressure, or raised it only very slightly. The difference in response was highly significant over the range of 1-50 ng kg- ' min- '. 2. During intravenous infusion at higher rates, angiotensin usually produced the well-known reflex bradycardia and fall of cardiac output, but on infusion into the vertebral arteries it rapidly raised systemic arterial pressure, often increased heart rate, and usually produced a transient increase of cardiac output. 3. Angiotensin by both routes raised peripheral resistance, but noradrenaline, by contrast, produced the same response whether it was given into the vertebral arteries or into a vein. 4. These observations suggest that part of the pressor effect of intravenous angiotensin may be mediated by a direct stimulation of some part of the hind brain. There are several means by which angiotensin may raise systemic arterial pressure. In addition to its direct arterial vasoconstrictor action, it can release catecholamines from the adrenal medulla (Braun-Menhdez, Fasciolo, Leloir & Muiioz, 1940), stimulate or facilitate transmission in sympathetic ganglia (Lewis & Reit, 1966) and enhance the peripheral vasoconstrictor response to endogenously released noradrenaline (McCubbin & Page, 1963a, b). In very large doses it was reported, 9 years ago, to cause central stimulation of the sympatho-adrenal system when infused into the the dog's cerebral circulation which was isolated and perfused from another animal (Bickerton & Buckley, 1961). The special importance of the vertebral artery territory in mediating the central stimulatory effects of angiotensin, and the extreme sensitivity to angiotensin when given into the vertebral artery, was first observed in conscious rabbits (Dickinson, 1965; Yu & Dickinson, 1965) and in anaesthetized rabbits after blood

Using direct electroneurographic technics, it is shown that the carotid sinus baroceptor reflexes adapt or reset to the higher pressure levels of chronic renal hypertension. They remain functional at the higher pressure level and thus act to maintain rather than to oppose it. This provides a satisfactory explanation for the presence of significant neurogenic vasoconstriction in chronic hypertension. Experiments on acutely hypertensive dogs indicate that the resetting process starts quite early but seems to lag behind the rise in arterial pressure.

Small reductions in renal perfusion pressure to levels still within a physiologic range, which did not reduce renal blood flow, caused the kidney to release renin. Renin appeared in much larger amounts in renal-vein blood than in renal lymph. Release of reruin appears to be mediated by a renal baroceptor rather than by ischemia.

Both before and after pentobarbital anesthesia, cardiovascular responsiveness to norepinephrine, epinephrine and serotonin was increased and that to angiotensin was decreased when experimental renal hypertension was first elicited. Response to tyramine was strikingly enhanced. Several weeks later, during the chronic phase of hypertension, there was a slight and scarcely significant heightened response to norepinephrine, a clearly increased response to tyramine, and no change in that to serotonin, dimethylphenylpiperazinium iodide, and 3-hydroxy-phenyl-ethanolamine HCl. Study of the problem of variability of responsiveness showed relatively little difference in mean response to any of five pressor drugs with or without anesthesia and after sham operation. Hypertension produced by infusion of angiotensin into normal anesthetized dogs did not change the response to norepinephrine but more than doubled that to tyramine. When acute renal hypertension was produced in the same dogs, angiotensin infusion failed to cause further change in response to either substance. Infusion of angiotensin into dogs with chronic renal hypertension caused increased response to tyramine but not to norepinephrine. The perfused hind legs of dogs with acute renal hypertension showed clearly reduced responses to angiotensin with no concurrent change in responses to norepinephrine. The pressor response to serotonin was increased while that to tyramine was unchanged. During chronic hypertension responses were like the normal values. Hypertension caused by infusion of angiotensin decreased greatly the vasoconstrictor response to superimposed injections of angiotensin into the perfused leg circuit while norepinephrine responses were unchanged. Response to another peptide, vasopressin, was reduced like that to angiotensin. These studies suggest that during acute renal hypertension increased quantities of angiotensin are present and that there is a decrease in neural tone. The finding that during the chronic phase of hypertension, the response to tyramine alone remained elevated, suggests the presence of small amounts of angiotensin, i.e., enough to increase the pressor effectiveness of endogenous norepinephrine released by tyramine. During the chronic phase of hypertension, peripheral resistance appears relatively more dependent on neural control.

The tail-cuff method for measuring blood pressure in awake rats, while used as a standard procedure, is not as reliable as is often assumed. Tail-cuff measurements made daily in trained, unanaesthetized rats with chronically implanted aortic catheters did not correlate significantly with simultaneously-recorded intra-arterial pressure. On the other hand, correlation between direct and indirect measurements improved when rats were anaesthetized with ether. Constriction of the tail artery during measurement of arterial pressure could account for the lack of correlation. To examine this possibility, simultaneous measurements were made in unanaesthetized rats after intraperitoneal injection of pressor doses of noradrenaline. During the first 20 min, elevation of arterial pressure caused by injected noradrenaline was clearly evident with either method of measurement. After this, in most experiments, tail pressure either diminished, or could not be detected, while intra-arterial pressure remained high. When sympathetic vasomotor activity was increased in anaesthetized rats by bilateral carotid occlusion, similar results were obtained. These findings indicate that tail-cuff measurements are not valid in certain circumstances in unanaesthetized rats.