Pressor Principle Research Articles

The Renin-Angiotensin System in the Twenty-first Century

Renin was discovered more than a century ago as a pressor principle in renal extracts. Subsequent research has revealed the renin-angiotensin system to be fascinatingly complex biochemically, with intriguing phylogenetic and evolutionary aspects. In the human species alone there is now seen to be very diverse physiological and pathophysiological involvement, and hence important therapeutic implications. In the present relatively brief review we shall consider current understanding of the renin-angiotensin system, certain of the more notable recent developments in our knowledge thereof, and what is likely to comprise some important avenues of future investigation. For more detailed information, including an extensive bibliography, the reader is referred to a two-volume treatise on the subject [1], plus two recent detailed reviews [2, 3].

Vasopressor activity in incubated plasma of normal and hypertensive pregnant women

The pressor activity generated in incubated plasma of nonpregnant, normal pregnant, and hypertensive pregnant women was measured by means of a sensitive bioassay technique. It was found that the plasma of normal pregnant women generated significantly higher amounts of active pressor principle than the plasma of nonpregnant women. The plasma of hypertensive pregnant women generated significantly lower amounts of active pressor principle than the plasma of normal pregnant women. Plasma obtained from the antecubital vein revealed no difference in pressor activity compared to plasma collected from the uterine vein at the time of cesarean section. These data suggest that active pressor principle is not involved in the pathogenesis of pregnancy-induced hypertension and that the pregnant uterus is not the source of active pressor principle.

Characterization of a vasopressor substance generated in human plasma by incubation

Incubation of human plasma at 37°C for several hours leads to the formation of a non-dialysable vasopressor substance termed the active pressor principle. Some of the chemical and physical natures of active pressor principle were investigated in anesthetized and ganglion blocked rats. It was found to have properties characteristic of protein. The substance was crudely purified to about 25-fold in alcoholic trichloroacetic acid solution after placing the plasma in a boiling water bath for 5 minutes (“active fraction”). After treatment of the vasoactive plasma or “active fraction” with Pronase, the pressor activity was almost abolished. The molecular weight of this fraction as determined by gel filtration was about 68,000. With addition of diisopropyl fluorophosphate before incubation of the plasma, no vasopressor substance was generated. After treatment of the rat with captopril, an angiotensin converting enzyme inhibitor, the pressor effect of incubated plasma was not inhibited. These findings suggest that a vasoactive protein, which is clearly different from renin, is generated during simple incubation of plasma, and that a serine protease is involved in the formation of this substance.

Effects of Pregnancy and Hormone Treatments on Pressor Activity of Incubated Rat Plasma

The pressor activity generated in incubated plasma of nonpregnant female and pregnant rats was measured by means of a sensitive bioassay technique. It was found that the plasma incubated for 12 hours on days 7, 14 and 19 of pregnancy generated significantly smaller amounts of the pressor substance than the incubated plasma of nonpregnant rats. Vasopressor activity of the plasma incubated for 12 hours from ovariectomized female rats treated with either estradiol (100 μg/kg), progesterone (2.5 mg/kg), or both were not different from control rats. These results indicate that pregnant rats are characterized by reduced amounts of the vasopressor substance, active pressor principle, and the amount of the principle seems to be regulated by neither estrogen nor progesterone in the rat.

Phylogeny of neurohypophyseal hormones. Vasopressin polymorphism in three kangaroo species.

The neurohypophyseal hormones of three species of Australian marsupials belonging to the family Macropodidae (Macropus rufus, Macropus giganteus, Macropus robustus) have been investigated. In these species three active peptides have been disclosed, one with oxytocic activity and two with pressor activity. The three hormones are present in all the individual glands which have been examined. Purification has been undertaken by ion-exchange chromatography and paper chromatoelectrophoresis. The more abundant of the pressor hormones (about 80% of the total pressor activity) has been identified as lysine-vasopressin by its biological properties, its chromatographic behaviour and its amino acid composition. The second pressor principle, more basic, has not yet been chemically characterized but its pharmacological properties and its chromatographic behaviour suggest that it is closely related or identical to arginine-vasopressin. Dimorphism of vasopressins seems peculiar to Metatheria since it has not been observed in Protheria and very rarely in Eutheria.

Increased pressor activity in incubated plasma of pregnant rabbits

A study to measure the pressor activity which is generated in incubated plasma of pregnant and nonpregnant rabbits was performed by means of a recently modified bioassay technique. It was found that plasma of normal pregnant rabbits generated significantly higher amounts of active pressor principle (APP) than those generated by plasma of nonpregnant rabbits. The possible relevance of these results to blood pressure regulation during normal and abnormal pregnancies is discussed.

Some properties of a high molecular vasopressor substance generated in human serum by incubation.

Incubation of human serum or plasma at 37°C leads to the formation of a non-dialysable vasoactive factor, which we have called active pressor principle (APP). The intravenous injection of incubated human serum into anesthetized ganglionic blocked rats causes a transient blood pressure increase similar to the response to angiotensin II. The pressure activity of incubated serum or plasma depends on temperature and time of the incubation. At 37 °C the activity reaches a maximum within 6 days. A slight decrease occurs after further incubation. At 4 °C very little APP is formed within several weeks; at 25 °C a maximum is reached after about 14 days of incubation. Incubation at 47 °C yields a maximum activity after 48 hours; further incubation induces a marked decrease in APP-concentration. During incubation of serum at 37 °C after addition of angiotensin II or noradrenaline, these substances are rapidly inactivated, whereas the APP-formation proceeds uninfluenced. After separation by means of gel filtration with

Studies on the pressor substances of the caudal neurosecretory system of teleost fish: bioassay and fractionation.

SUMMARY A method for the bioassay of the pressor substances in extracts of the urophyses of the teleost fish, Mugil auratus and Anguilla anguilla, is described. Ultracentrifugation, chromatography on Sephadex gel and treatment with trypsin and papain showed that the pressor principles are polypeptides. One fraction was protein-bound while two other fractions seem to be small molecules. Treatment with thioglycollate showed that disulphide bonds do not form an integral part of the active molecule. The possible function of these principles in the control of the caudal circulation is discussed.

Genetic influence on the development of renal hypertension in parabiotic rats. Evidence for a humoral factor.

The effects of several renal manipulations including uninephrectomy, unilateral renal artery constriction, and a combination of these two (Goldblatt procedure) were studied in two strains of rats with opposite constitutional predispositions to experimental hypertension. The protective value of intact renal tissue to protect against hypertension was shown to be genetically determined. The Goldblatt procedure carried out on only one member of a parabiotic pair induced hypertension in this operated rat but significant hypertension developed in the intact partner only when the operated animal belonged to the strain predisposed to hypertension. It was speculated that there were qualitative differences in the pressor signals of the two strains of rats. In the strain genetically predisposed to hypertension there are at least two pressor principles: (a) one which is common to both strains, not transmittable via the parabiosis junction and presumably related to the renin-angiotensin system; and (b) a second which is specific for the hypertension-prone strain and can be transmitted through the parabiosis junction. This transmittable agent is probably identical with the factor that produces salt hypertension and is associated with the salt-excreting mechanism.

Isolation of a non-dialysable active pressor principle from pig serum.

Isolation of a non-dialysable active pressor principle from pig serum.

Experimental Studies on the Influence of Hypertensive Substances in tne Cases of Adrenalectomized Animals.

Since the work of Helmer in 1947, many studies concerning the sustained pressor principle have been made in Japan. As well as renin, this substance has a hypertensive effect and up to date, it is believed to be produced by the convolution tubular of an ischemic kidney caused by the hypotension. However, investigations in re'acont yeas have cast some doubt upon the hypothesis that the sustained pressor principle is an end product of the ischemic kidney of hypotension. An attempt was made, therefore, to evaluate, the mechanism of its production in adrenalectomized rats with or without DOCA, and observed the blood sugar level, contractibility of the exstirpated intestine and the effect of tachyphylaxis. Contrary to the present hypothesis, it was found that the blood samples obtained from the adrenalectomized rats without DOCA before the apperance of the hypotension conlained the Sustained Pressor Pinciple. From the results in the Present study, it may be concluded that the sustained pressor principle is not necessarily produced under an ischemic kidney caused by the hypotension but is present in non-hypotensive kidney. Furthermore, the administration of DOCA will inhibit the production of this substance in adrenalectomized rats and this, may be postulated that some adrenal hormone plays an important role in the production of the Sustained Pressor Principle.

Effect of some preparations of adrenocorticotrophic hormone on the colour of Bufo arenarum Hensel.

SUMMARY In view of recent claims that intermedin and adrenocorticotrophic hormone (ACTH) are identical or closely related, a comparative study of their action on skin colour and the adrenals of the toad, Bufo arenarum Hensel, has been carried out. 1. Intermedin and ACTH darken the skin of the pale, hypophysectomized toad, but, weight for weight, intermedin is far more active than ACTH. Both preparations are more active than those of the pressor and oxytocic principles of the posterior pituitary. The melanotrophic action of ACTH does not depend on the presence of the adrenals or the sex of the toad. 2. Treatment with formaldehyde or boiling with sodium hydroxide, which are known to destroy the activity of the adrenocorticotrophic hormone, do not affect the action of ACTH on the skin; the latter treatment may even increase it. Boiling ACTH with acid does not affect its action on the colour of the skin. 3. Unlike ACTH, intermedin does not prevent atrophy of the adrenals after hypophysectomy or the development of asthenia. 4. It is concluded that the adrenocorticotrophic and chromatophorotrophic actions of the hypophysis are produced by two different substances.

Decreased resistance to hemorrhage in neurohypophysectomized dogs.

The diabetes insipidus dog is more susceptible to hemorrhage than the normal dog as determined by a standardized hemorrhage procedure. When aqueous pitressin is administered in subpressor dosages, this susceptibility to hemorrhage is reversed to or toward normal. Aqueous pitressin does not increase the intact dog's resistance to hemorrhage. The foregoing observations are interpreted as demonstrating that the neurohypophysial pressor principle serves a physiologic role in maintaining blood pressure during hemorrhage.

Clinical disorders of the neurohypophysis.

Excerpt Diabetes insipidus is the only clinical disorder generally conceded to be of neurohypophyseal origin, but accumulating evidence suggests that the neurohypophysis may have functions now scar...

An Examination of Factors Affecting the Precision of the Assay of the Oxytocic Hormone in Posterior Pituitary Lobe Preparations

Summary Work has been described which shows the errors which may be encountered under different experimental conditions of the uterine assay of oxytocin, or commercial posterior pituitary extracts where the ratio of oxytocin to vasopressin is not unity. By increasing the concentration of magnesium chloride in the British Pharmacopoeia 1948 Ringer’s solution, the response of the guinea-pig uterus to pitocin is increased. The response of the guinea-pig uterus to pitressin is also potentiated by increasing the concentration of magnesium chloride, but to a different extent than is pitocin. Different concentrations of calcium chloride in the Ringer’s solution produce potentiation to both pitocin and pitressin, but to different extents. The pressor principle does not produce any oxytocic effect on the uterus suspended in Ringer’s solution from which calcium chloride is absent. The absence of glucose from the Ringer’s solution produces rapid fatiguing of the uterine strip. Temperature regulation of the Ringer’s solution is very important. The sensitivity of uteri from guinea-pigs treated with stilbæstrol is greater than the uteri of progesterone-treated guinea-pigs to both pitocin and pitressin. The ratio of the sensitivity of uteri from progesterone-treated guinea-pigs to pitressin and pitocin is almost unity, whilst the ratio of sensitivity for the uteri of guinea-pigs treated with stilbæstrol indicates that the uteri are more sensitive to pitocin than to pitressin. Seasonal variation in the number of virgin albino guinea-pigs used per assay was not found to be significant. The ratio of oxytocin to vasopressin in the test samples must be the same as the ratio which is stated for the standard. The type of uterus and the physiological salt solution should be stated. It is recommended that the modification of Ringer’s solution proposed by the British Pharmacopoeia 1948 should be used for the guinea-pig assay, and that the uterus of the guinea-pig should be that of a virgin in diæstrus. The chicken blood depressor method offers many advantages over the isolated guinea-pig uterine method. It is cheaper and quicker to perform, and is more accurate in that narrow fiducial limits can be obtained. Until the chicken blood depressor method has been studied exhaustively in many laboratories engaged on the assay of the oxytocic principle, the guinea-pig uterine assay should be run in parallel with the former.

Observations on the “sustained pressor principle” in different animal species: Shipley, R. E., and Helmer, O. M.: Am. J. Physiol. 153:341 (May), 1948

Observations on the “sustained pressor principle” in different animal species: Shipley, R. E., and Helmer, O. M.: Am. J. Physiol. 153:341 (May), 1948

On the Influence of the Neurohypophyseal Principles on the Sodium Metabolism in the Axolotl (Amblystoma mexicanum)

Summary. The active uptake of sodium from dilute solutions of sodium chloride by the axolotl has been studied with radio‐sodium. The mean rate of uptake was found to be 68.7 μequiv. per day. The daily excretion of starving animals was found to be somewhat higher, viz. 94.6 μequiv. Injection of Insipidin, a pressor preparation from the neurohypophysis, induces a net uptake of sodium and chlorine lasting for several days. Studies with radio‐sodium revealed that the net uptake is due to an increased active uptake (the increase amounting to 200% of the normal sodium uptake), whereas the excretion is not depressed. Indeed, an increase in the excretion lasting for several hours after the injection was always seen. The oxytocic principle, represented by the preparation Pitupartin, induces a rapid net loss of sodium and chlorine lasting for 2–5 days. This loss was found to be due to an increased excretion, whereas the active sodium uptake was practically unaffected, apart from a short increase in the rate of uptake immediately after the injection. The injection into the animals of hypertonic sodium chloride solution calls forth an increase in the active uptake as well as in the excretion of sodium. After a few hours, both uptake and excretion as a rule returned to the normal level. The mere introduction of the injection needle produced a quite similar reaction. This pricking effect is easily distinguished from the pressor principle reaction on account of the short duration of the former. The results are discussed and it is concluded that the transient increase both in excretion after Insipidin and in uptake after Pitupartin may be due to the pricking effect, so that the pressor principle may be assumed to act upon the active salt uptake only, whereas the oxytocic principle mainly (or only) increases the rate of the salt excretion.

Injurious Action of Pitressin on the Rat Testis.

Some of the biological effects of adrenocorticotropic pituitary preparations suggested the presence of a pressor substance. A temporary prostration of the rats was observed invariably to follow injections of high levels of these partially purified preparations. Co-incidentally it was noted that there were injurious effects of high levels of these preparations on the testes of normal and hypophysectomized males. Two methods have been employed in the effort to determine whether the injurious effects on the testes may be referred to pressor principles. First, attempts were made to remove any pressor substance from ACT preparations and to compare the biological properties of the crude and purer materials. This phase of the subject will be discussed later. Second, effects of the pressor principle itself on the testis have been studied and are here reported.As a maximum of 5 dog pressor units per mg have been found in ACT preparations, pitressin† was injected into normal 40-day-was old male rats for a period of...

Purification of the Pressor Principle of the Posterior Lobe of the Pituitary Gland by Electrophoresis

Purification of the Pressor Principle of the Posterior Lobe of the Pituitary Gland by Electrophoresis

Further Observations on Elimination of Intestinal Gas Shadows in Roentgenography

From the time roentgen studies were first utilized as a method of observing the gall bladder and the genito-urinary tract, intestinal gas shadows have been disturbing elements on the roentgenogram. Every conceivable method has been clinically evaluated in an attempt to eliminate these shadows, which cause immeasurable confusion and errors of interpretation. Use of catharsis by administration of compound licorice powder, castor oil, and enemas has found wide use in the past. Regardless of the fact that many roentgenologists and urologists have felt, as we do, that there is more often an increased production of gas rather than an elimination, all of these measures have been tolerated because of the lack of anything better. Only recently has a real advance been made in overcoming this long-standing problem. In a recently published article, we described a method of eliminating objectionable intestinal gas shadows in roentgenography. At that time we reviewed results in a large series of patients who were subjected to roentgenologic study following the use of pitressin as a pre-examination agent. Continued use of the drug in an additional 1,000 cases, as a routine method of preparation, has convinced us that there is no other means at our disposal which will even approximate it in efficiency. Pitressin was isolated in 1928, and is the pressor principle of the pituitary gland. Combined with the oxytocic principle (alpha hypophamine), which acts on the uterine musculature, it appears as pituitrin. This latter drug had been used intermittently by many persons in attempts to discover a gas-dispelling agent; no amount of success has ever accompanied its use. The oxytocic element is too often contra-indicated. Pitressin, on the other hand, lends itself distinctively to use in the field of roentgenology. Its action is primarily on the smooth muscle of the intestinal tract and it is this factor that establishes its efficacy. The stimulation of the smooth muscle of the bowel with increase in muscular tonus induces elimination of feces and gas, thereby removing objectionable shadows and permitting satisfactory clarity on the roentgenogram. After rather sensational results in a few cases first studied in 1934, more careful analysis of the action of pitressin was undertaken and a method of administration was outlined. This was varied at intervals until what we considered the most effective combination of factors was achieved. Administration.—The following is the routine described in our previous paper; it has been in use at Receiving Hospital and the Alexander Blain Hospital for over two years. The night before examination, a cleansing enema is given. This is followed, in the morning, about one and one-half hours before the time set for roentgenography, by another enema.