Vasopressin analogues with selective pressor activity

Extracellular recordings were obtained from a class of nonpyramidal neurones in hippocampal slices. Oxytocin applied to the bath at concentrations of 1 nM or greater excited these cells. This effect was reversibly antagonized by a synthetic structural analogue known to block the peripheral endocrine effects of oxytocin. The effect of oxytocin was mimicked by a selective oxytocic agonist and, with less potency, by vasopressin and by other structural analogues. The potencies of oxytocin, vasopressin, and of these analogues in the hippocampus correlated well with their uterotonic activities but not with their vasopressor or antidiuretic activities. The data suggest that a class of hippocampal neurones is endowed with receptors for oxytocin that are similar to those of uterine smooth muscle cells.Vasopressin and oxytocin are peptide hormones that are synthesized in neuronal cell bodies located in the hypothalamus and are carried by axoplasmic transport to the neurohypophysis, from which they are released into the general circulation in response to appropriate stimuli. In addition, they are also present in nerve fibers in various areas within the central nervous system (1). A calcium-dependent, depolarization-induced release of these peptides can be demonstrated from some areas of the brain where axons immunoreactive for vasopressin and oxytocin have been shown to terminate synaptically on neuronal elements (2, 3). This suggests that oxytocin and vasopressin, in addition to their general hormonal effects, might act as neurotransmitters or neuromodulators in the brain.It has been shown that vasopressin and oxytocin increase the rate of firing of a class of neurones in the CAl area of hippocampal slices. This electrophysiological response was not due to the peptides interacting with a receptor resembling the renal antidiuretic vasopressin receptor (4). However, at least two other types of endocrine receptors for neurohypophyseal hormones have been recognized. One is the vasopressor receptor, present on vascular smooth muscle cells and on liver cells, which triggers the vasopressor and glycogenolytic effects of vasopressin in these tissues (5-8). The other is an oxytocic receptor (9), which triggers the contractile response of the uterus to oxytocin. In this study, we attempted to assess whether receptors for oxytocin and vasopressin are similar in such widely different parts of the body as the brain and peripheral tissues responsive to these hormones. Because both vasopressin and oxytocin excited hippocampal neurones, it was possible that oxytocic receptors, vasopressor receptors, or a mixed novel class of receptors for neurohypophyseal peptides were involved. In theory, it should be possible to elucidate this point by using specific vasopressor antagonists and oxytocic antagonists. However, available antagonists are not truly specific and act on both vasopressor and oxytocic receptors (10). In contrast, highly selective oxytocic agonists are available (11). Therefore, we used a number of compounds possessing ...

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“…hBerde et al (19). Activities are from assays on a new synthesis of this peptide (unpublished data).…”

Section: Resultsmentioning

confidence: 99%

Characterization of a uterine-type oxytocin receptor in the rat hippocampus.

Mühlethaler¹,

Sawyer²,

Manning³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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“…Ornipressin (ornithine-8-vasopressin) is a synthetic derivative of arginine vasopressin, the antidiuretic hormone, with comparable vasoconstrictor potency. 8 Studies in healthy subjects have shown that the iv administration of ornipressin, at doses similar to those used in the current study, is associated with a moderate increase in arterial pressure and systemic vascular resistance, with mild reductions in heart rate and cardiac output. 9 with arginine vasopressin and other derivatives, the vascular territories that are more sensitive to the vasoconstrictor effects of ornipressin are the skin and, especially, the splanchnic circulation.…”

Section: Discussionmentioning

confidence: 99%

“…The present study is designed to test this hypothesis. A combination of ornipressin, a potent vasoconstrictor drug, [8][9][10] and albumin was administered to improve effective arterial blood volume. …”

mentioning

confidence: 99%

Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion

et al. 1998

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Hepatorenal syndrome is caused by a marked vasoconstriction of the renal circulation. It is suggested that the renal vasoconstriction is related to an overactivity of vasoconstrictor systems secondary to a vasodilation of the arterial circulation that causes a reduction in effective arterial blood volume. To test this hypothesis, 16 cirrhotic patients with hepatorenal syndrome were treated with a combination of ornipressin, a potent vasoconstrictor agent, and plasma volume expansion with albumin to improve effective arterial blood volume. The combined treatment was administered either for 3 or 15 days (8 patients each), and the effects on renal function, vasoactive systems, and systemic hemodynamics were assessed. The 3-day treatment with ornipressin and albumin was associated with a normalization of the overactivity of renin-angiotensin and sympathetic nervous systems, a marked increase in atrialnatriuretic peptide levels, and only a slight improvement in renal function. However, when ornipressin and albumin were administered for 15 days, a remarkable improvement in renal function was observed, with normalization of serum-creatinine concentration, a marked increase in renal plasma flow and glomerular filtration rate, and a persistent suppression in the activity of vasoconstrictor systems. However, 3 of 8 patients on 15-day therapy treatment had to be discontinued because of ischemic complications. In conclusion, the decrease in effective arterial blood volume and the activation of vasoconstrictor systems play a crucial role in the pathogenesis of hepatorenal syndrome. Although the prolonged administration of ornipressin combined with plasma volume expansion reverses hepatorenal syndrome, this treatment should be used with great caution in clinical practice because of the risk of ischemic complications. (HEPATOLOGY 1998;27:35-41.)Hepatorenal syndrome (HRS) is a common and severe complication of patients with advanced cirrhosis, which is characterized by impaired renal function, marked abnormalities in the arterial circulation, and activity of endogenous vasoactive systems. [1][2][3][4][5] In the kidney, marked renal vasoconstriction results in reduced renal perfusion and low-glomerular filtration rate, whereas the extrarenal hemodynamics are characterized by low-systemic vascular resistance, and arterial hypotension. Although HRS is of functional origin and is theoretically reversible, no medical therapy has so far been shown to reverse renal hypoperfusion in these patients. 1,[4][5][6] The pathogenesis of HRS is not completely understood. It has been proposed that HRS represents the extreme expression of the underfilling of the arterial circulation, secondary to a vasodilation located mainly in the splanchnic vascular bed. 2,7 This vasodilation would cause a reduction in effective arterial blood volume with subsequent activation of vasoconstrictor systems, mainly the renin-angiotensin-aldosterone system and the sympathetic nervous system, that would promote renal vasoconstriction. If this is the case, the impro...

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“…All peptides were coded arbitrarily, so the substance tested was unknown to the observer. The Kimbrough et al, 1963Botos et al, 1979Berde et al, 1964Gillessen and du Vigneaud, 1970Gillessen and du Vigneaud, 1970Chan and du Vigneaud, 1962Smith et al, 1980Fenier et al, 1965Walter et al, 1976Sawyer et al, 1974Botos et al, 1979Manning et al, 1984Bankowski et al, 1978Kruszynski et al, 1980 late Dr. Roderich Walter and the late Dr. Vincent du Vigneaud, Cornell the Spearman's rank-difference correlation method (Guilford, 1956). Universitv.…”

Section: Methodsmentioning

confidence: 99%

A V1-like receptor mediates vasopressin-induced flank marking behavior in hamster hypothalamus

Albers¹,

Pollock²,

Simmons³

et al. 1986

J. Neurosci.

110

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A vasopressin-sensitive mechanism within the medial preoptic area-anterior hypothalamus (MPOA-AH) appears to be essential for expression of a complex behavior involved in olfactory communication in Golden hamsters called flank marking. The present study investigated whether the induction of flank marking by arginine-vasopressin (AVP) within the MPOA-AH is mediated by a receptor that is more similar to the vasopressor (Vl) or the antidiurectic (V2) AVP receptor. Adult male hamsters were anesthetized and implanted with a 26 gauge guide cannula stereotaxically aimed at the MPOA-AH and then microinjected with analogs of vasopressin, oxytocin, and selective Vl and V2 antagonists. Hamsters were tested for flank-marking behavior during a 5 or 10 min observation period following the injection of peptlde in a vehicle of 100 nl of saline. None of the 15 analogs of AVP and oxytocin produced more flank marking than the 50.8 + 16.2 and 76.8 f 4.4 (mean f SEW, II = 4) flank marks observed following injection of AVP at the 1 or 10 ng dose, respectively. The number of flank marks produced by each analog was found to be highly related to the pressor activity of that analog at both the 1 ng (p = +0.74, p < 0.01) and 10 ng (p = +0.82, p < 0.01) doses. In contrast, no statistically reliable relationship between flank marking and the antidiuretic activity of these analogs was found at either dose (1 ng: p = +O.O7,p > 0.05; 10 ng: p = +O.lO,p > 0.05). In a second series of studies, microinjection of 2 different Vl antagonists into the MPOA-AH significantly (p < 0.005) inhibited flank marking in response to AVP. However, microinjection of a V2 antagonist or saline did not inhibit flank marking. These data indicate that the receptors mediating the induction of 'flank marking within the MPOA-AH are more similiar to Vl (pressor) receptors than to V2 (antidiuretic) receptors. Scent marking is a major form of communication in mammals.Odors deposited in the environment can serve a variety of social functions from attracting mates to repelling competitors (Yahr, 1984). In the Golden hamster (Mesocricetus auratus), one form of scent marking, termed flank gland marking, is accomplished by rubbing a dorsal flank gland against vertical objects in the environment. Flank gland marking is commonly observed in both male and female hamsters and can be elicited by the odors of other hamsters and aggression during social encounters (Johnston, 1975).Several lines of evidence now indicate that neurons within the medial preoptic area-anterior hypothalamus (MPOA-AH) Received Dec. 2, 1985; revised Jan. 20, 1986; accepted Jan. 22, 1986. We wish to thank Professor Maurice Manning for providing several vasopressin analogs and for his comments on the manuscript. This work was supported by NIH Grants (to H.E.A.) and HD-18022 (to C.F.F. are critical for the expression of scent marking behavior. Lesions that destroy the MPOA-AH severely reduce scent-marking behavior in several mammalian species (Hart, 1974;Hart and Voith, 1978;Yahr, 1984). Implants of testoster...

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Vasopressin analogues with selective pressor activity

Cited by 57 publications

References 11 publications

Characterization of a uterine-type oxytocin receptor in the rat hippocampus.

Characterization of a uterine-type oxytocin receptor in the rat hippocampus.

Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion

A V1-like receptor mediates vasopressin-induced flank marking behavior in hamster hypothalamus

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