RSR-13, an allosteric effector of hemoglobin, increases systemic and iliac vascular resistance in rats.

Tissue O2 delivery in excess of metabolic demand may be a factor in the development of high vascular resistance in experimental models of volume-expanded hypertension. This hypothesis was previously tested in rats with an exchange transfusion of red blood cells treated with inositol hexaphosphate or an intravenous infusion of RSR-4, allosteric effectors of hemoglobin. The binding of these drugs with hemoglobin effect a conformational change in the molecule, such that the affinity for O2 is reduced. However, in both preparations, the changes in vascular resistance could have been nonspecific. The present studies used intravenous infusions of RSR-13, which did not share some of the problematic characteristics of RSR-4 and inositol hexaphosphate. Conscious instrumented rats (an electromagnetic flow probe on ascending aorta or an iliac, mesenteric, or renal Doppler flow probe) were studied for 6 h after an RSR-13 infusion of 200 mg/kg in 15 min. This dose significantly increased arterial P50 (PO2 at which hemoglobin is 50% saturated) from 38 +/- 0.8 to 58 +/- 1.4 mmHg at 1 h after the start of the infusion. In the 3rd h cardiac output fell significantly from a control value of 358 +/- 33 to 243 +/- 24 ml.kg-1.min-1 and total peripheral resistance significantly increased from 0.31 +/- 0.03 to 0.43 +/- 0.04 mmHg.ml-1.kg.min. Cardiac output and P50 returned toward control over the next few hours. Neither cardiac output nor total peripheral resistance changed in the group of rats receiving vehicle alone. In a separate group of rats, iliac flow decreased significantly to 60% of control and iliac resistance increased to 160% of control. Iliac flow increased significantly in the group of rats that received vehicle only. Although the mechanism of these changes has not been established, these results suggest that a decreased O2 affinity leads to an increased total peripheral resistance and regional vascular resistance and support the hypothesis that O2 plays a role in the metabolic autoregulation of blood flow.

Low-affinity hemoglobin increases tissue PO2 and decreases arteriolar diameter and flow in the rat cremaster muscle.

The hypothesis that tissue oxygen delivery in excess of metabolic demand results in vasoconstriction and reduced blood flow was tested in the cremaster muscle of anesthetized Sprague-Dawley rats by studying the effects of an intravenous infusion of RSR-13, an allosteric effector of hemoglobin. RSR-13 reduces the affinity of hemoglobin for oxygen, causing a right shift in the oxygen dissociation curve. Thus, oxygen delivery to the tissues was increased without elevations in blood flow or blood pressure. Tissue PO2, arteriolar diameter, and RBC velocity were measured and volume flow was calculated from diameter and RBC velocity in third-order arterioles. In rats receiving RSR-13 at a rate of 200 mg kg-1 in 15 min (n = 18) P50 (the PO2 at which hemoglobin is 50% saturated) increased from 36 +/- 1 to 52 +/- 3 mm Hg, and tissue PO2 increased to a maximum of 146 +/- 12% above its control value. P50 and tissue PO2 did not change in the control group (n = 8) receiving vehicle at a rate equivalent to that in the experimental group. In a separate group of rats receiving RSR-13 (n = 7), P50 increased from 38 +/- 1 to 51 +/- 3 mm Hg, calculated arteriolar flow decreased from 9 +/- 3 to a minimum of 1.4 +/- 1 nl sec-1, and arteriolar diameter decreased from 27 +/- 3 to a minimum of 13 +/- 3 micrograms P50, volume flow, and arteriolar diameter did not change in the control group (n = 10). These results suggest that an increased tissue oxygen delivery, caused by a right shift in the oxygen dissociation curve, may cause an increase in vascular resistance independent of an elevated blood flow.

Identification of a putative microvascular oxygen sensor.

The vascular response to changes in oxygen levels in the blood and tissue is a highly adaptive physiological response that functions to match tissue oxygen supply to metabolic demand. Defining the cellular mechanisms that can sense physiologically relevant changes in PO2 and adjust vascular diameter are vital to our understanding of this process. A cytochrome P450 (P450) enzyme of the 4A family of omega-hydroxylases was localized in renal microvessels, renal cortex, and a striated muscle microvascular bed (cremaster) of the rat. In the presence of molecular oxygen, this P450 enzyme catalyzes formation of 20-HETE from arachidonic acid (AA). Prior studies have shown that 20-HETE potently contracts renal and cerebral arteries and arterioles. The present study demonstrates that 20-HETE constricts striated muscle arterioles as well. In both intact renal microvessels and enriched renal cortical microsomal enzyme preparations, the formation of 20-HETE was linearly dependent on PO2 between 20 and 140 mm Hg. Homogenates of cremaster tissue produced 20-oxygen HETE when incubated with AA. They also expressed message for P450 4A enzyme, as determined by Southern and Western blots. Administration of 17-octadecynoic acid (17-ODYA), which is a P450 4A inhibitor, attenuated the constriction of third-order cremasteric arterioles in response to elevation of superfusion solution PO2 from approximately equal to 3 to 5 mm Hg to approximately equal to 35 mm Hg. 17-ODYA had no effect on basal vascular tone or response of cremaster arterioles to vasoactive compounds. These results demonstrate the existence of P450 omega-hydroxylase activity and 20-HETE formation in the vasculature and parenchyma of at least two microvascular beds. Our data suggest that a P450 enzyme of the 4A family has the potential to function as an oxygen sensor in mammalian microcirculatory beds and to regulate arteriolar caliber by generating 20-HETE in an oxygen-dependent manner.

The effect of intracarotid vasopressin infusion on ACTH release in neurohypophysectomized, conscious dogs.

Neurohypophysectomy (NHX) attenuates the adrenocorticotropic hormone (ACTH) response to arterial hypotension but not corticotropin-releasing hormone (CRH) or insulin-induced hypoglycemia in conscious dogs. The purpose of the present study was to determine if increasing vasopressin (AVP) in the cephalic circulation by carotid infusion normalizes the ACTH response to hypotension attenuated by NHX. Five male, conditioned dogs underwent controlled, acute decreases in arterial pressure (by approximately 25 mmHg) by infusion of sodium nitroprusside (NP) before and > 4 wk after selective NHX. ACTH increased from 40 +/- 3 to 242 +/- 79 pg/ml during NP in the intact state. This response was greatly attenuated after NHX (peak ACTH 81 +/- 15 pg/ml). Simultaneous intravenous infusion of AVP (12.5 ng/min) had a small, augmenting effect on the ACTH response to NP (peak ACTH 120 +/- 27 pg/ml). Intracarotid AVP (12.5 ng/min) greatly augmented the ACTH response to NP (peak ACTH 202 +/- 26 pg/ml) such that it was no longer different from the intact response. Neither intravenous nor intracarotid AVP infusion per se had a great effect on ACTH. A normal ACTH response to hypotension requires an intact neurohypophysis and is mediated by a cephalic action of magnocellular AVP.

Vasopressin-induced changes in cardiac vagal tone and oxygen consumption in dogs.

Experiments were conducted in 63 dogs to determine whether stimulation of vagal tone contributes to the decrease in O2 consumption (VO2) that results from arginine vasopressin (AVP) administration. Vagal stimulation with pilocarpine did not reduce VO2 in conscious dogs. In anesthetized dogs, bilateral electrical cervical efferent vagal stimulation lowered both cardiac output (CO; by 46%) and VO2 (by 22%) over the first 5 min. Between 7 and 11 min of stimulation, CO remained decreased, but VO2 returned to control. Significant increases in left atrial pressure, bradycardia, and a fall in mean arterial pressure accompanied vagal stimulation. All these effects of cervical vagal stimulation were abolished by cardiac denervation and also by pacing. Administration of a selective AVP V1 agonist led to significant reductions of CO and VO2. Cardiac denervation prevented the decrease in VO2 induced by AVP infusion, but not the decrease in CO. During AVP infusions, pacing at a rate slightly higher than control heart rate did not prevent the fall in CO or in VO2, whereas pacing at 150 beats/min prevented part of the fall in VO2. Sinoaortic denervation or atropine treatment prevented the decrease in VO2 resulting from AVP infusion. The combination of alpha- and beta-blockade did not affect the CO or the VO2 response to AVP infusion, nor did naloxone treatment. The administration of atrial or ventricular extracts, but not that of alpha-human atrial natriuretic peptide, led to a significant reduction in VO2. These results are compatible with the hypothesis that AVP infusion increases vagal tone to the heart, which, possibly as a result of increased left atrial pressure and reduced heart rate, may release a factor reducing VO2.

L-NAME antagonizes vasopressin V2-induced vasodilatation in dogs.

Experiments were performed in conscious chronically instrumented dogs to study the mechanism of hemodynamic effects mediated by selective vasopressin V2 agonists. In one group of dogs (n = 5) instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter), the infusion of NG-nitro-L-arginine methyl ester (L-NAME; 20 or 40 micrograms.kg-1 x min-1) prevented or significantly inhibited the increase in cardiac output, heart rate and systemic conductance induced by injections of 1-desamino-8-D-arginine vasopressin (DDAVP, desmopressin) and 4-valine-8-D-arginine vasopressin (VDAVP), two selective V2 agonists. L-NAME infusion did not modify the aortic adenosine 3',5'-cyclic monophosphate increase induced by DDAVP infusion. In a second group of dogs similarly prepared (n = 4), the administration of L-arginine (10 mg.kg-1 x min-1) at the same time as that of L-NAME (20 micrograms.kg-1 x min-1) completely prevented the hemodynamic effects of L-NAME and restored the response to DDAVP administration. In a third group of dogs (n = 4), the infusion of a bradykinin B2 antagonist, at a rate that significantly inhibited the cardiac output, heart rate, and blood pressure responses to bradykinin, did not modify the hemodynamic response to DDAVP infusion. We conclude that the hemodynamic effects of selective V2 agonists in dogs are not mediated by bradykinin release but instead via a V2-like receptor on endothelial cells that triggers the release of nitric oxide.

Hemodynamic changes induced by low blood oxygen affinity in dogs.

Increased tissue oxygen delivery may play a role in the increased vascular resistance that develops in volume-expanded hypertension. This hypothesis was tested by decreasing the affinity of hemoglobin for oxygen in dogs to increase unloading of oxygen to the tissues. Six chronically instrumented dogs were studied before and for 7 days after partial exchange transfusion with red blood cells modified by incorporation of inositol hexaphosphate, which, 1 h after exchange, increased the PO2 value at which hemoglobin is half-saturated with oxygen (P50) to 38.8 +/- 2.1 mmHg from a control value of 31 +/- 1.5 mmHg. Cardiac output (electromagnetic flowmeter) fell to 92.5 +/- 7.4 ml.kg-1.min-1 after 2-4 h from control values between 120.2 +/- 5.7 and 125.8 +/- 4.6 ml.kg-1.min-1. One day later, cardiac output was still significantly decreased to 104.0 +/- 5.9 ml.kg-1.min-1. As P50 returned to control over the next few days, so did cardiac output. Two to four hours after exchange, total peripheral resistance was increased to 1,144 +/- 73 mmHg.l-1.kg.min from control values between 762 +/- 26 and 790 +/- 32 mmHg.l-1.kg.min. It was still increased to 993 +/- 51 mmHg.l-1.kg.min after 1 day. Oxygen consumption did not change significantly. Cardiac output and peripheral resistance changes were significantly different from those measured in a control group of six dogs receiving exchange transfusion with sham-shifted red blood cells without significant P50 changes. These results suggest that an increase in tissue oxygen delivery can raise total peripheral resistance in dogs in the absence of primary changes in fluid volumes, blood flow, or blood pressure.

cAMP and extrarenal vasopressin V2 receptors in dogs.

The effect of vasopressin analogues on plasma adenosine 3',5'-cyclic monophosphate (cAMP) concentration was examined in a group of five conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter). These dogs were infused for 20 min with a selective antidiuretic (V2) agonist, desamino-8-D-arginine vasopressin (DDAVP, 10 ng.kg-1 x min-1). This infusion was repeated on another day in the presence of the combined V1-V2 antagonist d(CH2)5-D-Tyr(Et)-4-valine,8-arginine vasopressin. The dogs also received an infusion of the selective V1 agonist 2-phenylalanine,8-ornithine oxytocin (Phe-OrnOT) at a rate of 10 ng.kg-1 x min-1. The effect of these infusions was compared with those of an isotonic saline infusion. Plasma cAMP measured in the aorta remained unchanged during all infusions but that of the selective V2 agonist DDAVP alone, during which it increased significantly from 22.4 +/- 0.8 to 32.6 +/- 4.6 and 37.0 +/- 4.1 pmol/ml after 10 and 20 min, respectively. In the plasma sampled from the inferior vena cava caudal to the renal veins, cAMP increased during DDAVP infusion from 22.2 +/- 2.5 to 39.2 +/- 3.8 and 36.0 +/- 4.0 pmol/ml after 10 and 20 min, respectively. The infusion of DDAVP was later given to the same dogs under anesthesia after bilateral nephrectomy, which did not modify the effect of DDAVP on arterial plasma cAMP. In another group of four conscious dogs, infusion of DDAVP at the same rate did not induce significant changes in plasma catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric modifiers of hemoglobin: 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity of hemoglobin in red cell suspensions, in whole blood, and in vivo in rats.

Two new potent allosteric effectors of hemoglobin, RSR-4 [2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]-2- methylpropionic acid] and RSR-13 [2-[4-[[(3,5-dimethlanilino)carbonyl]methyl]-phenoxy]-2-methylp rop ionic, are compared to the previously reported compounds L3,5 and L3,4,5 [Lalezari, I., Lalezari, P., Poyart, C., Marden, M., Kister, J., Bohn, B., Fermi, G., & Perutz, M. F. (1990) Biochemistry 29, 1515]. Unlike L3,5 and L3,4,5, RSR-4 and RSR-13 are less impeded by physiological concentrations of serum albumin. RSR-4 has also been shown to be more effective than L3,5 in shifting the allosteric equilibrium of bovine Hb toward the low-affinity T-state. X-ray crystal studies show that both RSR-4 and RSR-13 bind to only one pair of symmetry-related sites in the Hb central water cavity whereas previous studies on L3,5 and L3,4,5 demonstrated a second pair of symmetry-related binding sites near Arg 104 beta. Three major interactions between these allosteric effectors and Hb include the acid group with the guanidinium group of C-terminal Arg 141 alpha, the effector's amide oxygen with the ammonium ion of Lys 99 alpha, and the phi electrons of the halogenated or methylated aromatic ring and Asn 108 beta. No explanation has been found for the difference in number of binding sites observed for RSR-4 and RSR-13 (two sites) compared to L3,5 and L3,4,5 (four sites); also no correlation has been made between the number of binding sites and degree of allosteric shift in the oxygen equilibrium curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced oxygen consumption induced by vasopressin in dogs depends on systemic administration.

1. Arginine vasopressin reduces whole-body oxygen consumption in conscious dogs. To determine whether this decrease could result from limited oxygen delivery, studies were performed in two groups of chronically instrumented dogs. 2. In the first group (n = 7), vasopressin was infused at a rate of 18.5 pmol min-1 kg-1 while the animals were breathing 10% oxygen. Hypoxaemia alone (arterial partial pressure of oxygen 4.67 kPa) decreased whole-body oxygen delivery by 30%. The fall in whole-body oxygen consumption induced by vasopressin during hypoxaemia was not different from that measured under normoxic conditions, even though whole-body oxygen delivery was more reduced. 3. In a second group of seven dogs, hindquarter blood flow (electromagnetic flowmeter on lower abdominal aorta) and oxygen consumption (blood flow multiplied by arteriovenous oxygen difference) were measured as infusions of vasopressin were given either systemically or into the lower abdominal aorta. Systemic vasopressin infusions at 0.92, 4.6 and 18.5 pmol min-1 kg-1 reduced hindquarter blood flow, oxygen delivery and oxygen consumption, but the decreases in blood flow and oxygen delivery were dose-related whereas that in oxygen consumption was not. Intra-arterial infusions of vasopressin that increased venous concentrations as much as or more than systemic infusion of 0.92 pmol of vasopressin min-1 kg-1 had no effect on oxygen consumption, even though the higher intra-arterial rate reduced blood flow and oxygen delivery as much as the systemic infusion. Thus systemic but not locally administered vasopressin reduced hindquarter oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamics, fluid volume, and hormonal responses to chronic high-salt intake in dogs.

The sequential hemodynamics, fluid and electrolyte balances, and the hormonal responses to a 7-day high-salt (NaCl) intake were investigated in sodium-depleted conscious dogs (n = 6). Studies were carried out in metabolic cages mounted on sensitive load cells, which enabled continuous 24 h/day monitoring of total body weight (TBW) as an index of changes in body water. Beat-by-beat hemodynamics were determined 24 h/day. Water (700 ml/day iv) intake was maintained constant. Daily fluid and electrolyte balances and hormonal analyses were performed. An increase of daily salt intake from 8 to 120 meq increased TBW 251 +/- 44 g (P less than 0.05), which was sustained thereafter. Average 24-h mean arterial pressure (MAP) and heart rate (HR) remained unchanged. Average cardiac output (CO) increased 11% (P less than 0.05) above control values by day 2, while total peripheral resistance (TPR) decreased proportionally. CO and TPR returned to control values only when low salt was resumed. Blood volume (BV) was unchanged on day 2 as indicated by direct measurement of BV (51Cr-labeled red blood cells) or by analysis of plasma protein concentration. A 92-meq (P less than 0.05) sodium retention was observed initially, and plasma sodium concentration increased slightly. Plasma renin activity, angiotensin II, and aldosterone levels decreased significantly, whereas vasopressin and atrial natriuretic peptide levels remained unchanged. In summary, chronic high-salt intake resulted in a net retention of water and sodium with no changes in MAP, HR, or BV. The rise in CO was offset by a reduction in TPR, which appeared at least in part related to angiotensin II suppression.

Regional autoregulatory responses during infusion of vasoconstrictor agents in conscious dogs.

We investigated pressure-dependent autoregulatory responses in mesenteric, iliac, and renal vascular beds of conscious dogs during intravenous infusion of angiotensin II, phenylephrine, or arginine vasopressin at rates which increased arterial pressure by 20-40 mmHg. The arteries supplying these beds were instrumented with an electromagnetic flow probe, a nonoccluding catheter, and an electromagnetic flow probe, a nonoccluding catheter, and an occluder cuff connected with a servo-amplifier, which enabled us to return perfusion pressure to control levels during infusion of the vasoconstrictor agents. We attempted to differentiate between the increase in vascular resistance due to the direct effect of the vasoconstrictor agent and the increase induced by an autoregulatory response induced by elevations of aortic perfusion pressure. We measured a strong degree of autoregulation in the renal vascular bed with a fractional compensation value close to 1. Moderate autoregulation occurred in the mesenteric vascular bed, where the compensation was 0.4-0.5 with angiotensin II and phenylephrine and between 0.74 and 0.94 with vasopressin. No autoregulatory capacity could be demonstrated in the hindlimb. The findings indicate that, under conditions of increased systemic blood pressure, both the renal and the mesenteric vascular beds contribute to the increase in total peripheral resistance by pressure-dependent vasoconstrictor responses.

Interaction between V1 and V2 effects in hemodynamic response to vasopressin in dogs.

We investigated in conscious, chronically instrumented dogs whether actions mediated by V1 receptors affect cardiovascular effects elicited by V2-like receptors in response to vasopressin or vasopressin analogues. Infused arginine vasopressin (AVP) (220 pg.kg-1.min-1) did not have any significant effect on arterial pressure, cardiac output (CO), and heart rate (HR) when it was preceded by administration of a V1 receptor antagonist. However, when the same antagonist was administered 1 h after the start of the same infusion of AVP, CO, and HR increased significantly above control pre-AVP values, and total peripheral resistance (TPR) fell significantly below control. When a combined V1+V2 receptor antagonist was administered after 1 h of AVP infusion at the same rate, CO, HR, and TPR returned to, but not beyond, control values. When a selective V1 agonist was infused for 1 h, the administration of a V1 antagonist also returned hemodynamic values to, but not beyond, control. These results suggest that 1-h administration of AVP sensitized V2-like receptors to moderate levels of circulating AVP. In another set of experiments, the administration of a selective V1 agonist blunted significantly the CO and HR increase as well as the decrease in TPR normally associated with injection of a selective V2 agonist. However, administration of phenylephrine did not reduce these V2-mediated effects. We conclude that there are significant interactions between V1 and V2-like receptors in the cardiovascular system of conscious dogs, whereby V1 effects appear to 1) immediately antagonize the action of V2 agonists and 2) sensitize the organism to cardiovascular effects mediated by V2-like receptors after a prolonged exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasopressin reduces oxygen uptake in intact dogs but not in sinoaortic-denervated dogs.

We have investigated the effect of infusions of arginine vasopressin on cardiac output and O2 uptake in the presence and in the absence of sinoaortic reflexes to better understand the mechanism of the exaggerated decrease in cardiac output elicited by vasopressin. Chronically instrumented dogs received, on separate days, 30-min infusions of vasopressin (0.2, 1, 5, 20, and 60 ng.kg-1.min-1), phenylephrine (1, 3, and 10 micrograms.kg-1.min-1), and angiotensin II (ANG II) (10, 20, and 50 ng.kg-1.min-1). These infusions all increased mean arterial pressure to a maximum of 63 +/- 8.2 mmHg during the highest phenylephrine infusion rate. Vasopressin reduced cardiac output (electromagnetic flowmeter) more than the other vasoconstrictors for equivalent increases in arterial pressure. Vasopressin also produced dose-dependent decreases in O2 uptake, measured by collection of expired air. Such decreases were not observed with the other two agents. On the contrary, ANG II and phenylephrine increased O2 uptake significantly when they decreased cardiac output the most. The decrease in O2 uptake induced by vasopressin was significantly correlated with the decrease in cardiac output. Pretreatment of the dogs with atropine prevented the decrease in O2 uptake and blunted the fall in cardiac output induced by vasopressin at a rate of 5 ng.kg-1.min-1. In dogs surgically deprived of sinoaortic receptors, vasopressin given at 1 and 5 ng.kg-1.min-1 failed to reduce O2 uptake and cardiac output significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral vasodilatation induced by a vasopressin analogue with selective V2-agonism in dogs.

The selective V2-agonist 4-valine-8-D-arginine vasopressin (VDAVP) increases cardiac output and heart rate and decreases total peripheral resistance in dogs. The mechanism of these hemodynamic effects was examined in the present studies. When infused into the left coronary artery of six conscious dogs for 1 h, VDAVP (10 ng.kg-1.min-1) increased cardiac output and decreased total peripheral resistance more than when given intravenously in the same animals. Administration of VDAVP into the carotid circulation elicited effects that did not differ significantly from those after intravenous infusion at the same rate in six conscious dogs. After destruction of the central nervous system in five dogs anesthetized with pentobarbital, VDAVP failed to increase cardiac output and heart rate but lowered mean arterial pressure and total peripheral resistance. Finally, infusion of VDAVP into the femoral artery of six anesthetized dogs increased femoral blood flow at rates of 1, 5, and 10 ng.kg-1.min-1, whereas none of these rates increased femoral blood flow when given intravenously. Thus the hemodynamic effects of VDAVP appear to result primarily from a peripheral vasodilatory action, with possible contribution from a positive inotropic effect. We found no evidence that central effects of VDAVP were importantly involved in its cardiovascular action.

V1 vs. combined V1+V2 vasopressin blockade after hemorrhage in conscious dogs.

We examined the hypothesis that V2-like receptors might contribute to the hemodynamic response seen after blockade of the vasoconstrictor (V1) effect of arginine vasopressin (AVP) in nonhypotensive hemorrhage. Seven chronically instrumented dogs were bled 15 ml/kg within 15 min on two different days, at least 3 days apart, and then injected either with the V1 antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)2-(O-methyl)tyrosine]AVP [d(CH2)5Tyr(Me)AVP, 10 micrograms/kg] or with the combined V1+V2 antagonist [1(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)2-(O-ethyl)-D-tyrosine)4-valine]AVP [d(CH2)5-D-Tyr-(Et)VAVP (10 micrograms/kg)]. Mean arterial pressure, heart rate, and cardiac output (electromagnetic flowmeter) were measured before as well as after hemorrhage and for 10 min after antagonist administration. Both antagonists given after hemorrhage significantly decreased mean arterial pressure as well as total peripheral resistance and increased cardiac output. The V1 antagonist also increased heart rate significantly. No significant hemodynamic changes were measured in another group of six dogs in the absence of antagonist treatment. Although hemodynamic changes tended to be greater with the V1 antagonist than with the combined V1+V2 antagonist, a significant difference between the two analogues was established only for heart rate. These results indicate that in hemorrhage interaction with V2-like receptors plays only a modest role in the hemodynamic changes after V1 blockade in conscious dogs, contrary to what was found in dehydration.

Vasodilation induced by a specific vasopressin V2 agonist in dogs.

Vasopressin V2 agonists increase cardiac output and lower total peripheral resistance within minutes when infused into conscious dogs. The purpose of this study was to determine the mechanisms of these haemodynamic effects. Two groups of dogs were studied. In the first group, six dogs were instrumented for the measurement of mean arterial pressure and cardiac output (electromagnetic flowmeter) at least 1 week before the experiment. They were then anaesthetized with pentobarbital and the central nervous system was destroyed. Mean arterial pressure was maintained with an infusion of noradrenaline. After it had remained stable for 30 min the dogs received an intravenous infusion of 4-valine-8-D-arginine vasopressin (VDAVP), a specific V2 agonist, 10 ng/kg per min. Mean +/- s.e.m. arterial pressure fell from 97.6 +/- 1.8 to 69.1 +/- 2.5 mmHg, but cardiac output did not change significantly. Total peripheral resistance fell from 1322.5 +/- 151 to 859.7 +/- 84.9 units. Thus, VDAVP exerts haemodynamic effects in the absence of the central nervous system and appears to act primarily as a vasodilator. A second group of six anaesthetized dogs was studied in which femoral blood flow was measured with an electromagnetic flow probe during intravenous and intrafemoral arterial infusion of VDAVP, 10 ng/kg per min. Blood flow increased by 27.9 +/- 5.4 ml/min from a control value of 65.1 +/- 12.6 ml/min with intra-arterial infusion of VDAVP, but did not change significantly with intravenous infusion. Mean arterial pressure remained unchanged under both conditions.(ABSTRACT TRUNCATED AT 250 WORDS)