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Vasopressin
Abstract
Vasopressin is a hormone that is essential for both osmotic and cardiovascular homeostasis. A deficiency of vasopressin exists in some shock states and replacement of physiological levels of vasopressin can restore vascular tone. Vasopressin is therefore emerging as a rational therapy for vasodilatory shock. In this article we review the rationale and summarize the evidence for using vasopressin in vasodilatory shock states, such as septic shock. We then highlight the areas of uncertainty in using vasopressin for septic shock and summarize the reasons for clinical equipoise. We close by suggesting that further randomized controlled trials of vasopressin in septic shock are required before vasopressin is used routinely for management of septic shock.
Rats have been widely used as one of the most common laboratory animals for biological research, because their physiology, pathology, and behavioral characteristics are highly similar to humans. Recent developments in rat genetic modification techniques have now led to further their utility for a broad range of research questions, including the ability to specifically label individual neurones, and even manipulate neuronal function in rats. We have succeeded in generating several transgenic rat lines that enable visualization of specific neurones due to their expression of fluorescently-tagged oxytocin, vasopressin, and c-fos protein. Furthermore, we have been able to generate novel transgenic rat lines in which we can activate vasopressin neurones using optogenetic and chemogenetic techniques. In this review, we will summarize the techniques of genetic modification for labeling and manipulating the specific neurones. Successful examples of generating transgenic rat lines in our lab and usefulness of these rats will also be introduced. These transgenic rat lines enable the interrogation of neuronal function and physiology in a way that was not possible in the past, providing novel insights into neuronal mechanisms both in vivo and ex vivo.
To determine if horses before undergoing anesthesia for surgical correction of colic would have lower plasma arginine vasopressin (AVP) concentrations than healthy horses undergoing anesthesia for arthroscopic surgery, and would not increase their plasma AVP concentrations in response to anesthesia and surgery.
Prospective clinical study.
University teaching hospital.
Fourteen horses with colic and 8 healthy horses.
Horses with colic underwent anesthesia and surgery for alleviation of colic, and healthy horses underwent anesthesia and surgery for arthroscopy.
Plasma AVP was measured perioperatively in horses with colic and in healthy horses. Before anesthesia, and 30 and 60 minutes after induction, horses with colic had greater median plasma AVP concentrations than control horses (P<or=0.001); thereafter during anesthesia differences in AVP concentrations between the 2 groups were not significant. In the control group, plasma AVP concentration increased during 120 minutes of anesthesia; no such increase occurred in colic horses.
Compared with healthy horses, horses with colic had higher preanesthesia plasma AVP concentrations that did not increase further in response to anesthesia and surgery. Exogenous AVP is associated with decreased splanchnic perfusion in a variety of animal species and, therefore, could be detrimental to horses with colic. Thus, it may be inappropriate to use exogenous AVP in support of blood pressure in anesthetized horses with colic. Further studies are warranted to define appropriate indications for the use of AVP in horses with colic.
Arginine vasopressin (AVP), an endogenous hormone with vasopressor properties, may be inadequately secreted during episodes of intradialytic hypotension (IDH).
To evaluate this, we performed a prospective, observational pilot study of 20 chronic hemodialysis patients assessing the baseline AVP level and trend of AVP with ultrafiltration in patients with a diagnosis of IDH compared with patients without IDH. Ten symptomatic IDH patients and 10 controls were enrolled and matched for age, gender, and dialysis vintage. AVP levels were obtained hourly throughout the dialysis session and during hypotensive episodes.
We observed that IDH patients experienced greater decreases in both systolic and diastolic blood pressure during the dialysis session despite equivalent ultrafiltration in both groups. AVP concentration did not increase in the IDH patients (5.0 +/- 1.8) compared with controls (6.4 +/- 6.0) (P = 0.5) despite hypotensive events.
This study suggests that symptomatic IDH patients are unable to mount an appropriate increase in AVP secretion in the setting of hypotension. These findings support the possibility of AVP as a mechanism driven therapy for patients with symptomatic IDH.
We tested the effects of continuous infusion of N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on cardiovascular performance and pulmonary gas exchange in patients with hyperdynamic septic shock.
Prospective clinical study.
ICU of a university hospital.
Eleven critically ill patients with severe refractory septic shock.
Standard hemodynamic measurements were made and blood samples taken before, during, and after 12 h of continuous infusion of 1 mg/kg/h of L-NAME.
Continuous infusion of L-NAME increased mean arterial pressure (MAP) from 65+/-3 (SEM) to 93+/-4 mm Hg and systemic vascular resistance (SVR) from 962+/-121 to 1,563+/-173 dyne x s x cm(-5)/m2. Parallel to this, cardiac index (CI) decreased from 4.8+/-0.4 to 3.9+/-0.4 L/min/m2 and myocardial stroke volume (SV) was reduced from 43+/-3 to 34+/-3 mL/m2. Left ventricular stroke work was increased in the first hour of L-NAME infusion from 31+/-3 to 43+/-4 g x m/m2 (all p<0.01 compared with baseline). Heart rate, cardiac filling pressures, and right ventricular stroke work did not change significantly (p>0.05). L-NAME increased the ratio of arterial PO2 to the fraction of inspired O2 from 167+/-23 to 212+/-27 mm Hg (p<0.05). Venous admixture (QVA/QT) was reduced from 19.4+/-2.6% to 14.2+/-2.1% (p<0.05) and oxygen extraction ratio increased from 21.1+/-2.4% to 25.3+/-2.7% (p<0.05). Oxygen delivery (DO2) was reduced following L-NAME, whereas oxygen uptake and arterial lactate and pH were unchanged.
Prolonged inhibition of NO synthesis with L-NAME can restore MAP and SVR in patients with severe septic shock. Myocardial SV and CI decrease, probably as a result of increased afterload, since heart rate and stroke work were not reduced. L-NAME can improve pulmonary gas exchange with a concomitant reduction in QVA/QT. L-NAME did not promote anaerobe metabolism despite a reduction in DO2.
Arginine vasopressin in physiological concentrations potentiated the vascular effects of various vasoconstrictor agents. By using the isolated rat mesenteric artery preparation, the pressor effects of norepinephrine, angiotensin II, and potassium chloride were all significantly increased when vasopressin was added to the perfusion buffer. Cortisol and lithium both inhibited the potentiating effect of vasopressin but had no effect on the control pressor response to norepinephrine. When the vascular effects of norepinephrine were first blocked with indomethacin and then restored by the addition of prostaglandin E2, the potentiation by vasopressin was almost completely prevented. This suggests that vasopressin may be acting by stimulating prostaglandin biosynthesis. Cortisol and lithium may exert their inhibitory effects by preventing the activation of prostaglandin synthesis by vasopressin. These findings may be of clinical significance because the phenomena occur well within the range of vasopressin levels found in human plasma.
The non-osmotic release of arginine vasopressin (AVP) is associated with the concomitant activation of the renin-angiotensin and sympathetic nervous systems. In vivo studies suggest that a positive interaction may occur between AVP and angiotensin II (Ang II), and other Ca2+ mobilizing hormones. In the present study, the cellular mechanisms of this interaction between AVP and Ang II in vascular smooth muscle cell (VSMC) were examined. These results support the existence of a positive interaction between AVP and Ang II on Ca2+ mobilization in VSMC. In fact, the challenge of VSMC with combined AVP and Ang II, in a range from 5 x 10(-11) to 10(-8) M, enhanced cytosolic free Ca2+ ([Ca2+]i) and 45Ca2+ efflux in a more than additive manner. This potentiation, which was not dependent of the presence of extracellular calcium, correlated with an increased VSMC shape change. Moreover, the combination of subthreshold doses of AVP and Ang II (5 x 10(-11) M), which do not release Ca2+ alone, evoked a Ca2+ mobilizing response. A subthreshold dose of Ang II also shifted to the left the concentration-response curve of the AVP-mediated 45Ca2+ efflux. Since there were no changes in receptor binding of either hormone by the other hormone and the interaction of the two hormones on the production of inositol phosphatides was additive, the AVP and AII positive interaction on Ca2+ mobilization on VSMC may occur at the level of the intracellular Ca2(+)-releasing mechanism itself. Such an interaction can occur at hormone concentrations below the Ca2+ release threshold and may explain an increased functional response to the combination of pressor hormones compared to that of each hormone alone.
The effect of a moderate hemorrhage on plasma antidiuretic hormone and plasma renin activity was studied in normal human blood donors. An average blood loss of 9.9% of estimated blood volume in 24 subjects caused no significant change in either plasma antidiuretic hormone or plasma renin activity. Systolic and diastolic blood pressure and heart rate also were unchanged by the hemorrhage. It thus appears that the ADH response to hemorrhage in humans is no more sensitive than it is in the dog where often 10-20% of the estimated blood volume must be removed by hemorrhage before an increase in plasma ADH concentration is detectable. In addition, the data confirm previous reports which demonstrated that hemorrhage of this magnitude does not alter plasma renin activity.
We have previously observed that arginine vasopressin (AVP)-induced pulmonary vasodilation is attenuated by nitric oxide (NO) synthesis inhibition; however, blockade of the response is incomplete even at very high doses of the inhibitor. Thus it was hypothesized that the remaining vasodilation might be due to release of an endothelium-derived hyperpolarizing factor acting to open vascular smooth muscle K+ channels. Lungs were isolated from male Sprague-Dawley rats and perfused at constant flow with physiological saline solution containing 4% albumin. After equilibration, lungs were treated with either glibenclamide (50 microM), Ba2+ (100 microM), tetraethylammonium (10 mM), or the respective vehicle and were then constricted with the thromboxane mimetic U-46619. Upon development of a stable degree of vasoconstriction, AVP (2.5 x 10(-9) M) was administered and its vasodilator action noted. AVP caused an approximately 60% reversal of U-46619 vasoconstriction in control lungs, and this response was not affected by any of the K+ channel blockers. In contrast, administration of the NO synthesis inhibitor N omega-nitro-L-arginine (L-NNA; 300 microM) significantly attenuated AVP-induced dilation to approximately 25%. The addition of K+ channel blockers did not further diminish the vasodilatory response in L-NNA-treated lungs. In conclusion, these results suggest that ATP- and Ca(2+)-sensitive K+ channels are not involved in the pulmonary vasodilatory response to AVP.
Mature coronary collateral arteries are hyperresponsive to vasopressin; in contrast, contractile responses of collaterals to endothelin are attenuated. Our goal was to determine the cellular mechanisms underlying these differences in reactivity using two sizes of canine collateral arteries isolated from hearts subjected to chronic coronary occlusion.
Contractile responses to vasopressin (100 mmol/L) were enhanced threefold to fourfold in near-resistance (approximately 200 microns lumen diameter) and conduit (approximately 500 microns lumen diameter) collateral arteries compared with similarly sized noncollateral coronary arteries (P < .01). In contrast, contractions of both sizes of collaterals in response to endothelin (0.01 to 30 nmol/L) were smaller than responses of size-matched noncollateral arteries (P < .05). Pretreatment with either indomethacin (5 mumol/L), a cyclooxygenase inhibitor, or NG-nitro-L-arginine methyl ester (100 mumol/L), a nitric oxide synthase inhibitor, did not alter the relative responsiveness of collateral arteries to vasopressin or endothelin compared with noncollateral arteries. Vasopressin produced greater increases of intracellular free Ca2+ (measured by use of fura-2 microfluorometry and Ca(2+)-dependent 42K+ efflux) in smooth muscle of collateral arteries than in smooth muscle of noncollateral arteries (P < .05). Surprisingly, endothelin-induced increases of Ca2+ were not different in smooth muscle of collateral and noncollateral arteries (P > .05).
We conclude that altered contractile responsiveness of collateral arteries to vasopressin and endothelin does not result from altered synthesis/release of nitric oxide or prostaglandins. Parallel enhancement of vasopressin-mediated Ca2+ and contractile responses suggests increases in vasopressin receptor number, affinity, and/or efficiency of coupling mechanisms in collateral smooth muscle. The dissociation between endothelin-induced contractile and Ca2+ responses of collaterals indicates that the mechanisms involved in increasing Ca2+ sensitivity of contractile proteins during endothelin stimulation may be altered in collateral arteries.
We tested whether activation of K(ATP) channels contributes to vasodilatation and end-organ hypoperfusion in severe hemorrhagic shock (HS). Anesthetized juvenile pigs were hemorrhaged to a portal blood flow of 45% of baseline for 45 min and then resuscitated with Ringer lactate (RL; 100% volume of shed blood; n = 10) or RL in combination with the K(ATP)-channel antagonist glibenclamide (10 mg/kg iv bolus injection; n = 10). Addition of glibenclamide to the resuscitation fluid caused a sustained recovery of systemic blood pressure, cardiac index, portal blood flow, renal blood flow, renal cortical ATP concentration, and ileal mucosal P(CO2). Treatment with RL alone caused only a partial and transient hemodynamic and metabolic benefit. Glibenclamide treatment of sham-shocked control pigs (n = 6) transiently increased mesenteric and systemic vascular resistance. Inhibition of K(ATP)-channel activity in HS, which effectively and safely restores systemic hemodynamics, regional perfusion, and tissue metabolism, is a potentially novel therapeutic approach to the management of severe HS.