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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.

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.

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.

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.

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.

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.