Search

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.

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.

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.

The serum lipoproteins and cholesterol were studied in dogs after bilateral nephrectomy. In most cases the animal's life was prolonged by dialysis. Cholesterol and the lower density lipoproteins increased and remained elevated while the high density –S 1–10 fraction usually decreased moderately. Dogs fed a high protein diet exhibited similar but more pronounced lipid changes and arteriolar necrosis, and no correlation was found between elevation of blood pressure and lipid concentration. Ureteral ligation elicited qualitatively similar lipid changes to arenal dogs fed raw kidneys. As one control, well nourished dogs unfed for 5 days showed no significant serum lipid changes. It is suggested that, by analogy, the postnephrectomy lipid pattern may be in part due to action of products of adrenal cortical stimulation.

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.

Atropine inhibited the contractile response of isolated guinea pig ileum to angiotensin by 60–70%. This inhibition could be reversed with neostigmine. Morphine, which is known to prevent the release of acetylcholine from the nerve endings, also inhibited the response to angiotensin. The response to bradykinin under the same circumstances was not altered, nor was the response of the uterus to angiotensin and bradykinin. Except for tetraethylammonium chloride (TEAC), the quaternary nitrogen blocking agents had no effect on the ileal response to angiotensin. TEAC potentiated the response of the ileum to both angiotensin and bradykinin, even after the administration of atropine. Depolarizing doses of nicotine and tetramethylammonium chloride inhibited the response of the ileum to angiotensin without altering the response to bradykinin. Results thus suggest that angiotensin acted both by stimulating ganglion cells and smooth muscle. In the intestines, the ganglion stimulating effect was preponderant. Bradykinin, on the other hand, acted on smooth muscle cells only. TEAC potentiation of the response to the polypeptides was by direct action on the smooth muscle independent of its ganglion blocking effect.

The effect of 5-methoxy-N:N-dimethyltryptamine on the conditioned avoidance response of trained rats was compared quantitatively, using a shuttle-box, with that of several substituted tryptamines and LSD-25. 5-Methoxy-N:N-dimethyltryptamine, at a dose level of 19 µm/kg, had a pronounced effect on the conditioned avoidance response, much more pronounced than that due to the known psychotomimetic substituted tryptamines: N:N-dimethyltryptamine, N:N-diethyltryptamine, and 5-hydroxy-N:N-dimethyltryptamine (bufotenine) at the higher dose level of 25 µm/kg. A similar response was elicited by LSD-25 at a dose level of 6 µm/kg. Both hydroxyindole-O-methylase and an enzyme capable of N-methylating indoleethylamines occur in mammals. This circumstance makes it possible to form 5-methoxy-N:N-dimethyltryptamine from such substrates as serotonin. The pronounced behavioral effect of this and similar methoxyindolealkylamine suggests that abnormal tryptophan metabolism could result in mental disturbance.

When postheparin plasma was incubated with a coconut oil substrate, a decrease in optical density and an increase in unesterified fatty acids occurred. The increase in unesterified acids was prevented by previous intravenous injection of Triton to rats. Addition of post-Triton plasma to a system containing postheparin plasma and coconut oil emulsion inhibited the lipoprotein lipase activity. Incubation of Triton with coconut oil substrate before addition of postheparin plasma caused inhibition of lipoprotein lipase activity. It is concluded that inhibition of lipoprotein lipase activity by Triton is due to modification of the substrate such that the enzyme can no longer act. Further, it is suggested that the chief cause of Triton hyperlipemia is coating of the plasma lipoproteins by Triton resulting in their faulty catabolism.

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.

Evidence has been presented previously indicating that angiotensin acts indirectly on guinea pig intestines by stimulating the ganglion cells of Auerbach's plexus. Further studies have shown that the adrenergic nerves are not directly involved in this mechanism, although adrenergic blocking agents suppress the response to angiotensin, probably by acting directly on the cell membrane. Epinephrine, and to a lesser extent norepinephrine and isoproterenol, inhibited the contraction of ileum and uterus to angiotensin, and to electrical stimulation, possibly by reversing or blocking sodium or potassium ion flux across the cell membrane resulting from the action of the peptide. Most of the adrenergic blocking agents studied, with the exception of Dibenamine, also inhibited the response to angiotensin. Reserpine, guanethidine, and bretylium block its action, possibly by releasing catecholamines from bound tissue stores, and phentolamine and piperoxane, by their sympathetic actions imitating the catecholamines.