J. W. McCubbin

Baroceptor Function in Chronic Renal Hypertension

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.

Cardiovascular Effects of Angiotensin Mediated by the Central Nervous System

• During recent years the nature of the considerable contribution of the sympathetic nervous system to renal hypertension has become somewhat more clear, due in part to the unexpected discoveries that angiotensin is not simply a direct vasoconstrictor agent but is almost ubiquitous in its actions. Among these actions are several on the sympathetic nervous system that appear to intensify its effects on the peripheral vascular system. It stimulates release of catechols from the adrenal medulla (1); at certain dose levels it facilitates ganglionic transmission (2); and it sensitizes the neurovascular effector so that the effects of sympathetic vasomotor discharge are augmented (3). This latter effect may depend in part on prevention of reuptake of released norepinephrine (4). For a long time it was considered unlikely that angiotensin had any effect on the central nervous system since theoretically it does not cross the blood-brain barrier. Then Bickerton and Buckley (5), in 1961, cross-perfused the head of a recipient dog, isolated from its own circulation and connected to the body only by the spinal cord, with blood from a donor animal. When angiotensin was injected into the circulation of the donor animal it raised the systemic arterial pressure in the recipients trunk as well as in the donor animal. Because

Control of Renin Secretion

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.

Neural Stimulation of Release of Renin

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.

The Variable Arterial Pressure Response to Serotonin in Laboratory Animals and Man

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.

Arterial Hypertension Elicited by Subpressor Amounts of Angiotensin

Long-term infusion of amounts of angiotensin insufficient at the beginning to raise arterial pressure results, after several days in sustained arterial hypertension in unanesthetized dogs. This hypertension is to a large degree dependent on environmental stimuli, and results chiefly from increase in peripheral resistance. As in dogs with renal hypertension, there is increased pressor responsiveness to tyramine. This indirect action of angiotensin to increase total peripheral resistance and arterial pressure by an action on the sympathetic nervous system, along with an upward resetting of the carotid sinus buffering mechanism, might logically account for the neural component of chronic renal hypertension. Such a proposal integrates the humoral and neural elements of the mosaic describing the mechanisms of tissue perfusion.

Renal Pressor System and Neurogenic Control of Arterial Pressure

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.

Ability of Serotonin and Norepinephrine to Mimic the Central Effects of Reserpine on Vasomotor Activity

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.

Hemodynamic Characteristics of Chronic Experimental Neurogenic Hypertension in Unanesthetized Dogs

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.

Neurogenic Component of Chronic Renal Hypertension

Infusion of angiotensin or renin in small quantities affects the sympathetic nervous system so that responses are increased to either drugs or reflexes that cause release of norepinephrine at nerve endings. Response to injected norepinephrine is relatively unchanged. This action of angiotensin is dependent upon an intact sympathetic nervous system. The direct vasoconstrictor action of angiotensin is not an essential part of the enhanced response. The phenomenon was shown to have relevance to acute and chronic experimental renal hypertension in dogs by the fact that in both the pressor response to tyramine was enhanced. We believe that the ability of angiotensin to intensify the effect of normal neurogenic vasomotor activity, along with an upward reset of the carotid sinus buffer mechanism, might account importantly for the neurogenic component of renal hypertension.