Vasopressin-mediated forearm vasodilation in normal humans. Evidence for a vascular vasopressin V2 receptor.

Arginine vasopressin (AVP) is a potent vasopressor and antidiuretic neurohormone. However, when administered intravenously to humans, AVP causes forearm vasodilation. This effect has been attributed to sympathetic withdrawal, secondary to AVP-induced sensitization of baroreceptors. The possibility that AVP also causes forearm vasodilation directly has not been examined. Accordingly, the direct effect of AVP was determined by studying the forearm blood flow (FBF) response to intraarterial (IA) AVP infusion (0.01-1.0 ng/kg per min). Infusion of IA AVP increased FBF (96%) in the infused arm, but not the control arm, in a dose-dependent manner. The role of specific AVP V1 receptors in mediating this FBF response was determined before and after pretreatment with a V1 antagonist (AVP-A). AVP-A alone had no effect on FBF, but coadministration of AVP and AVP-A potentiated the vasodilatory response (223%). IA infusion of the V2 agonist, 1-desamino[8-D-arginine] vasopressin, caused a dose-dependent increase in FBF. These findings suggest that AVP causes direct, dose-dependent vasodilation in the human forearm that may be mediated by V2 vasopressinergic receptors. In contrast, AVP infusion caused digital vasoconstriction that was blocked by AVP-A, whereas dDAVP did not affect digital blood flow. Thus, AVP induces regionally selective vascular effects, with concurrent forearm vasodilation and digital vasoconstriction.     

Spontaneous gasping produces carotid blood flow during untreated cardiac arrest

We have shown previously that arginine vasopressin (AVP) given during sinus rhythm increases mean arterial blood pressure (MAP) and left anterior descending (LAD) coronary artery cross sectional area. AVP was assumed to result in vasodilatation via activation of the endothelial nitric oxide system. The purpose of the present study was to assess the effects of AVP before and after NO-inhibition. Nine domestic pigs were instrumented for measurement of haemodynamic variables using micromanometer-tipped catheters, and measurement of LAD coronary artery cross sectional area employing intravascular ultrasound (IVUS). Haemodynamic variables, LAD coronary artery cross sectional area and cardiac output were measured at baseline, 90 s and 5, 15, and 30 min after AVP (0.4 U kg (-1) IV) before and after blockade of nitric oxide synthase with N(G)-nitro L-arginine methyl ester (L-NAME). Compared with baseline, AVP significantly increased MAP after 90 s (89+/-4 versus 160+/-5 mm Hg), increased LAD coronary artery cross sectional area (11.3+/-1 versus 11.8+/-1 mm(2)) and decreased cardiac index (138+/-6 versus 53+/-6 mL/min kg(-1)). After blockade of nitric oxide synthase, AVP significantly increased MAP after 90 s (135+/-4 versus 151+/-3 mm Hg), increased LAD coronary artery cross sectional area (8.7+/-1 versus 8.9+/-1 mm(2)), and significantly decreased cardiac index (95+/-6 versus 29+/-4 mL/min kg (-1)). IMPLICATIONS: During sinus rhythm, AVP increased MAP and LAD coronary artery cross sectional area, but decreased cardiac index.     

Pharmacological characterization of FE 202158, a novel, potent, selective, and short-acting peptidic vasopressin V1a receptor full agonist for the treatment of vasodilatory hypotension

FE 202158, ([Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin, where Hgn is homoglutamine and iPr is isopropyl), a peptidic analog of the vasoconstrictor hormone [Arg(8)]vasopressin (AVP), was designed to be a potent, selective, and short-acting vasopressin type 1a receptor (V(1a)R) agonist. In functional reporter gene assays, FE 202158 was a potent and selective human V(1a)R agonist [EC(50) = 2.4 nM; selectivity ratio of 1:142:1107:440 versus human vasopressin type 1b receptor, vasopressin type 2 receptor (V(2)R), and oxytocin receptor, respectively] contrasting with AVP's lack of selectivity, especially versus the V(2)R (selectivity ratio of 1:18:0.2:92; human V(1a)R EC(50) = 0.24 nM). This activity and selectivity profile was confirmed in radioligand binding assays. FE 202158 was a potent vasoconstrictor in the isolated rat common iliac artery ex vivo (EC(50) = 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED(50) = 4.0 versus 3.4 pmol/kg/min for AVP). The duration of its vasopressor effect by intravenous bolus in rats was as short as AVP at submaximally effective doses. FE 202158 had no V(2)R-mediated antidiuretic activity in rats by intravenous infusion at its ED(50) for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 seems suitable for treatment of conditions where V(1a)R activity is desirable but V(2)R activity is potentially deleterious, such as vasodilatory hypotension in septic shock. In addition to the desirable selectivity profile, its short-acting nature should allow dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety.     

Role of arginine vasopressin and angiotensin II in cardiovascular responses to combined acute hypoxemia and hypercapnic acidosis in conscious dogs.

The physiological relationship of increased circulating angiotensin II and vasopressin to circulatory changes during combined hypoxemia and hypercapnic acidosis is unclear. To evaluate the role(s) of angiotensin II and vasopressin, seven unanesthetized female mongrel dogs with controlled sodium intake (80 meq/24 h X 4 d) were studied during 40 min of combined acute hypoxemia and hypercapnic acidosis (PaO2, 36 +/- 1 mmHg; PaCO2, 55 +/- 2 mmHg; pH = 7.16 +/- 0.04) under the following conditions: (a) intact state with infusion of vehicles alone; (b) beta-adrenergic blockade with infusion of d,l-propranolol (1.0 mg/kg bolus, 0.5 mg/kg per h); of the vasopressin pressor antagonist d-(CH2)5Tyr(methyl)arginine-vasopressin (10 micrograms/kg); and (d) simultaneous vasopressin pressor and angiotensin II inhibition with the additional infusion of 1-sarcosine, 8-alanine angiotensin II (2.0 micrograms/kg per min). The rise in mean arterial pressure during the combined blood-gas derangement with vehicles appeared to be related to increased cardiac output, since total peripheral resistance fell. Beta-adrenergic blockade abolished the fall in total peripheral resistance and diminished the rise in cardiac output during combined hypoxemia and hypercapnic acidosis, but the systemic pressor response was unchanged. In addition, the rise in mean arterial pressure during the combined blood-gas derangement was unaltered with vasopressin pressor antagonism alone. In contrast, the simultaneous administration of the vasopressin pressor and angiotensin II inhibitors during combined hypoxemia and hypercapnic acidosis resulted in the abrogation of the overall systemic pressor response despite increased cardiac output, owing to a more pronounced fall in total peripheral resistance. Circulating catecholamines were increased during the combined blood-gas derangement with vasopressin pressor and angiotensin II blockade, suggesting that the abolition of the systemic pressor response in the last 30 min of combined hypoxemia and hypercapnic acidosis was not related to diminished activity of the sympathetic nervous system. These studies show that vasopressin and angiotensin II are major contributors to the systemic pressor response during combined acute hypoxemia and hypercapnic acidosis.     

Acute effects of mildly intoxicating levels of alcohol on left ventricular function in conscious dogs.

We assessed the effect of alcohol, before and after autonomic blockade, on left ventricular (LV) performance in conscious dogs. 10 animals were instrumented to determine LV volume from ultrasonic LV internal dimensions and measure LV pressure with a micromanometer. The animals were studied in the conscious state after full recovery from the operation. Blood alcohol was undetectable before and 67 +/- 14 mg/dl (mean +/- SD) at 20 min after alcohol administration. In response to alcohol, the LV systolic pressure was reduced slightly, the left ventricular end-diastolic pressure increased slightly. The maximum time derivative of LV pressure (dP/dtmax) and stroke volume were decreased. The end-systolic volume (VES), as well as effective arterial elastance, were significantly increased. There was no significant change in heart rate. Variably loaded pressure-volume loops were generated by acute caval occlusion before, immediately, and 20 min after the intravenous infusion of alcohol (0.2 g/kg). Three measures of LV performance were derived from these variably loaded pressure-volume loops: the end-systolic pressure-volume relation; the stroke work-end-diastolic volume relation; and maximum dP/dt-VED relation. The slopes of all three relations were significantly decreased in response to alcohol, and all three relations were shifted toward the right, indicating a depression of LV contractile performance. Similar, but greater depressions of LV performance with alcohol were observed following autonomic blockade. LV performance was restored by infusing dobutamine. We conclude that mildly intoxicating levels of alcohol (blood concentration less than 100 mg/dl) are capable of producing LV contractile depression in conscious animals, which is more marked after autonomic blockade. This suggests that patients with impaired LV function should avoid even small amounts of alcohol.     

Role of vasopressin in response to intrarenal infusions of alpha-2 adrenoceptor agonists

Previous studies have indicated that the effects of renal alpha-2 adrenoceptor stimulation are mediated through the blockade of the renal effects of vasopressin. If this premise is correct then 1) specific antagonists of the antidiuretic effect of vasopressin (V2 antagonists) should mimic alpha-2 adrenoceptor stimulation and 2) in the presence of V2 antagonists, the diuretic and natriuretic effect of clonidine should be attenuated. The renal effects of [d(CH2)5,D-Ile2,Ile4]AVP, a specific V2 antagonist, were studied. On the day of the experiment, uninephrectomized rats were anesthetized, and the carotid artery and jugular vein were cannulated for recording blood pressure and saline infusion, respectively. The left kidney was exposed and the ureter cannulated. A 31-gauge needle was advanced into the renal artery to permit direct i.r. infusion of study drugs. Bolus doses of the V2 antagonist (0, 1, 3, 10, or 30 nmol/kg i.v.) produced a dose-related increase in urine volume and free water clearance at all doses tested. Sodium excretion increased only at the higher doses (10 and 30 nmol/kg). This dose-related dissociation in water and then sodium excretion is similar to that observed after i.r. clonidine infusions. In the presence of the V2 antagonist, clonidine (3 micrograms/kg/min) had no effect on urine volume or free water clearance but significantly decreased the excretion of sodium from control. These results demonstrate that V2 antagonists mimic the effects of i.r. clonidine. As well, in the absence of vasopressin (V2 antagonism), the effects of clonidine are attenuated. Moreover, they are also consistent with not only an antidiuretic role for endogenous vasopressin but also an antinatriuretic one.     

Evidence for a role of endorphins in the cardiovascular pathophysiology of primate shock

Using the opiate receptor antagonist naloxone, we tested the hypothesis that endorphins act on opiate receptors to cause cardiovascular depression in primate shock. Mean arterial pressure (MAP), cardiac output, and left ventricular contractility (LV dP/dtmax) were measured in 34 anesthetized cynomolgus monkeys. Hemorrhagic shock was induced by bleeding into a heparinized reservoir to achieve (t = 0) and maintain MAP at 45 mm Hg. At t = 60 min, the reservoir was clamped and the animals were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 5) or 0.9% NaCl as a control (n = 5). There were no significant differences in the cardiovascular responses to naloxone and saline when acid-base balance and core body temperature were not controlled. Pressor responses to naloxone, however, were present in proportion to arterial pH and body temperature. When these factors were controlled, naloxone (n = 6) significantly increased MAP and LV dP/dtmax by 48% and 83%, respectively, whereas saline (n = 6) had no significant effect. Blood was reinfused at t = 120 min, and survival rate at 72 h was significantly (p = .01) higher with naloxone (3/6) than saline controls (0/6). In the endotoxic shock model, cynomolgus monkeys were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 6) or 0.9% NaCl (n = 6) when MAP reached 75 mm Hg or its nadir 60 to 90 min after Escherichia coli endotoxin, 5 mg/kg iv. Naloxone significantly increased MAP and LV dP/dtmax by 24% and 22%, respectively, whereas saline had no effect. Survival rate at 48 h was significantly (p = .01) higher with naloxone (6/6) than saline (1/6). Plasma beta-endorphin and beta-lipotropin concentrations rose three to five-fold in both shock models and were not affected by treatment. We conclude that endorphins are activated in primate shock and act on opiate receptors to contribute to the cardiovascular depression found with hemorrhage and endotoxemia.     

Development of a Rate Adaptive Pacemaker Based on the Maximum Rate-of-Rise of Right Ventricular Pressure (RV dP/dtmax)

The maximum rate of rise of right ventricular pressure (RV dP/dtmax) may change in response to physiological stress and thereby provide an appropriate parameter upon which to base rate adaptive pacing. Initial feasibility testing was carried out in six patients using externally closed loop rate adaptive pacing with a pressure sensing lead (Model 6220) and an investigational VVI pulse generator (Medtronic, Model 2451). During exercise, maximum positive RV dP/dtmax increased from 223 +/- 55 to 405 +/- 181 mmHg.sec.1 (P less than 0.05). Based on these results, rate adaptive pulse generators using maximum positive RV dP/dt were implanted in 12 patients (Medtronic, Model 2503). Exercise treadmill testing in the VVI mode resulted in heart rates ranging from 69 +/- 6 beats/min at rest to 79 +/- 14 beats/min (n = 12; P greater than 0.05). In contrast, VVIR mode pacing rates ranged from 71 +/- 11 beats/min to 115 +/- 24 beats/min (n = 17; P less than 0.05). Holter recording showed heart rates ranging from 51 +/- 6 to 110 +/- 22 beats/min during activities of normal daily living (n = 9; P less than 0.05). Passive postural tilt resulted in rates of 69 +/- 8 beats/min in the supine position increasing to 74 +/- 14 beats/min with 60 degrees upright tilt (n = 16; P greater than 0.05). With up to 5-year follow-up data, there have been no late failures of pacing but one lead showed insulation failure with over- and undersensing after 4.5 years. A number of deficiencies were identified in the prototypes leading to modifications of a subsequent generation of rate responsive pacemaker based on RV dP/dtmax. These initial data demonstrate that rate adaptive pacing based on RV dP/dtmax responds in a physiological manner. This rate responsive system is of particular interest as it is based on a beat-to-beat parameter of cardiac mechanical function.     

Effect of vasopressin on cardiovascular and renal functions and ANP release under plasma volume expansion.

To assess the mechanisms whereby arginine vasopressin (AVP) increases atrial natriuretic peptide (ANP) release and to examine whether AVP-mediated ANP release affects the effect of AVP on the cardiovascular and renal function, AVP was infused continuously at a rate of 20 ng.kg-1.min-1 for 75 min following 200 ng/kg bolus injection under stepwise increases in plasma volume in anesthetized dogs. Moreover, the effect of an AVP antagonist, a V1 blocker, 1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid)-2-(o-methyl)tyrosine AVP (TMeAVP), on these parameters was also investigated. In the control study, saline alone was infused. AVP infusion increased total peripheral resistance (TPR), pulmonary capillary wedge pressure (PCWP), and plasma ANP, but decreased cardiac index (CI) and heart rate (HR) without increases in mean arterial blood pressure (MABP). Stepwise rises in plasma volume further increased plasma ANP, CVP, CI and PCWP, but gradually decreased TPR. TMeAVP curtailed AVP-induced increases in TPR and plasma ANP as well as decreases in CI and HR. The replacement of ANP to prevent a fall in plasma ANP following TMeAVP never affected cardiovascular function. AVP infusion increased plasma volume accompanied by a fall in urinary Na excretion (UNaV) and urine flow (UF) under the stepwise plasma volume expansion compared to the control group, but did not affect mean circulatory filling pressure (MCFP). ANP administration enhanced UNaV and UF and decreased MCFP. These results indicate that AVP may preferentially increases ANP release via the increased cardiac afterload, not preload, but increased plasma ANP per se may not be involved directly in the AVP-induced cardiac suppression.     

Vasopressin inhibits sympathetic ganglionic transmission but potentiates sympathetic neuroeffector responses in hindlimb vasculature of rabbits

To determine whether vasopressin (AVP) affects vasoconstrictor responses to electrical stimulation of sympathetic nerves or i.a. norepinephrine (NE), changes in perfusion pressure were measured during lumbar sympathetic nerve stimulation (LSNS, 1-8 Hz), or administration of NE (50-200 ng), in the isolated constant-flow perfused hind limb of chloralose-anesthetized rabbits (n = 7), before and after i.a. infusion of AVP (0.65 mU/kg/min). AVP significantly potentiated responses to LSNS (relative potency (RP) = 1.59) and to NE (RP = 5.17). The potentiation of LSNS and NE by AVP infusion was abolished by the AVP V1 antagonist, d(CH2)5[Tyr(Me)2]AVP, 400 ng, total dose (n = 6). Because there was a significant difference between the RP of LSNS (stimulation of both preganglionic and postganglionic nerves) and NE (direct effect on the vascular smooth muscle), we verified whether this difference might represent disparate actions of AVP on the ganglia and/or sympathetic neuroeffector sites. To evaluate responses to stimulating only the postganglionic sympathetic nerves, we repeated the above study in animals pretreated with a supramaximal dose of the ganglionic blocking agent hexamethonium (25 mg/kg i.v.). After ganglionic blockade the responses to LSNS were reduced to 22% of control. In the presence of ganglionic blockade, AVP potentiated responses to LSNS (RP = 4.09) (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunohistochemical localization of V2 vasopressin receptor along the nephron and functional role of luminal V2 receptor in terminal inner medullary collecting ducts.

We investigated immunohistochemical localization of V2 vasopressin receptor along the nephron using a specific polyclonal antibody. Staining was observed in some of thick ascending limbs and all of principal and inner medullary collecting duct (IMCD) cells. Not only basolateral but also luminal membrane was stained in collecting ducts, especially in terminal IMCD (tIMCD). To learn the functional role of luminal V2 receptor in tIMCD, we studied the luminal effects of arginine vasopressin (AVP) on osmotic water permeability (Pf), urea permeability (Pu), and cAMP accumulation using isolated perfused rat tIMCD. In the absence of bath AVP, luminal AVP caused a small increase in cAMP accumulation, Pf and Pu, confirming the presence of V2 receptor in the lumen of tIMCD. In contrast, luminal AVP inhibited Pf and Pu by 30-65% in the presence of bath AVP by decreasing cAMP accumulation via V1a or oxytocin receptors and by an unknown mechanism via V2 receptors in the luminal membrane of tIMCD. These data show that V2 receptors are localized not only in the basolateral membrane but also in the luminal membrane of the distal nephron. Luminal AVP acts as a negative feedback system upon the basolateral action of AVP in tIMCD.     

Antidiuretic effects of a nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to rats

OPC-51803 is the first nonpeptide vasopressin (AVP) V(2)-receptor-selective agonist. Its pharmacological profile, including antidiuretic action and receptor binding, was characterized using conscious Brattleboro rats with hereditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations from the liver and kidney, OPC-51803 displaced the [(3)H]AVP binding to V(2)-receptors (K(i) = 49.8 +/- 8.1 nM) more greatly than that to V(1a)-receptors (K(i) = 1061 +/- 60 nM), showing a 21 times higher affinity for V(2)-receptors. At single oral doses of 0.003 to 0.3 mg/kg in female Brattleboro rats, OPC-51803 decreased urine volume (from 10.8 +/- 1.1 to 0.5 +/- 0.2 ml during 0-2 h postdosing) and increased urinary osmolality (from 114 +/- 9 to 432 +/- 114 mOsm/kg) in a dose-dependent manner. During the period of 4-week treatment with OPC-51803, significant and constant antidiuresis was observed. In male Sprague-Dawley rats with normal plasma AVP levels, OPC-51803 at 0.03 to 0.3 mg/kg also produced a dose-dependent antidiuretic action (urine volume: from 2.6 +/- 0.6 to 1.1 +/- 0.2 ml at 0-4 h postdosing). Few changes in urinary parameters, serum parameters, or plasma hormone levels were observed. OPC-51803 did not change blood pressure or heart rate, or inhibit AVP-induced pressor response even at 30 mg/kg p.o. These results demonstrate that OPC-51803 is a V(2)-selective agonist that produces a significant antidiuretic action after single and multiple oral dosing in AVP-deficient and normal AVP states. The data suggest that OPC-51803 is a useful therapeutic drug in the treatment of hypothalamic diabetes insipidus, nocturnal enuresis, and some kinds of urinary incontinence.     

血管加压素对心肺转流术后血管麻痹综合征患者血流动力学的影响

目的评价血管加压素对心肺转流术(CPB)后血管麻痹综合征患者血流动力学的影响。方法选取CPB下心脏手术后发生血管麻痹综合征患者14例,分为去甲肾上腺素(NE)组(NE组)和血管加压素(AVP)组(AVP组)。NE组患者输注NE维持平均动脉血压>65 mmHg,当NE输注速率>0.4μg/(kg.min)则加用AVP 0.01～0.04 U/min;AVP组患者输注AVP0.01～0.04 U/min,必要时使用NE维持患者平均动脉血压>65 mmHg。于血管麻痹综合征诊断时(T1,基础值)、注药后24 h(T2)、48 h(T3)、72 h(T4)分别记录两组患者心率(HR)、平均动脉压(MAP)、平均肺动脉压(MPAP)、心排血量(CO)、肺毛细血管楔压(PCWP)、中心静脉压(CVP)及尿量,计算体循环血管阻力(SVR)及肺循环血管阻力(PVR)。并记录儿茶酚胺药物使用量及不良反应。结果两组患者年龄、体重、性别构成比,术前EF、术前治疗用药情况、CPB时间、主动脉阻断时间比较差异无统计学意义(P>0.05)。两组患者血压维持稳定。与NE组比较,AVP组SVR T2时增加;HR T2～3时显著降低(P<0.05);NE需要量T2～4明显降低(P<0.05);尿量明显增加(P<0.05)。结论 AVP可以改善CPB术后血管麻痹综合征患者的血流动力学。     

Inhibition of adenosine deaminase attenuates endotoxin-induced release of cytokines in vivo in rats.

The purpose of this study was to investigate in vivo the effects of modulating the adenosine system on endotoxin-induced release of cytokines and changes in heart performance and neurohumoral status in early, profound endotoxemia in rats. Time/pressure variables of heart performance and blood pressure were recorded continuously, and plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 1-beta (IL-1beta), plasma renin activity (PRA), and catecholamines were determined before and 90 min after administration of endotoxin (30 mg/kg of lipopolysaccharide, i.v.). Erythro-9[2-hydroxyl-3-nonyl] adenine (EHNA; an adenosine deaminase inhibitor) had no effects on measured time-pressure variables of heart performance under baseline conditions and during endotoxemia, yet significantly attenuated endotoxin-induced release of cytokines and PRA. Pretreatment with the non-selective adenosine receptor antagonist DPSPX not only prevented the effects of EHNA but also increased the basal release of cytokines and augmented PRA. At baseline, caffeine (a non-selective adenosine receptor antagonist) increased HR, +dP/dtmax, heart rate x ventricular pressure product (HR x VPSP) and +dP/dtmax normalized by pressure (+dP/dtmax/VPSP), and these changes persisted during endotoxemia. Caffeine attenuated endotoxin-induced release of cytokines and augmented endotoxin-induced increases in plasma catecholamines and PRA. Pretreatment with propranolol abolished the effects of caffeine on heart performance and neurohumoral activation during the early phase of endotoxemia. 6N-cyclopentyladenosine (CPA; selective A1 adenosine receptor agonist) induced bradicardia and negative inotropic effects, reduced work load (i.e., decreased HR, VPSP, +dP/dtmax, +dP/dtmax/VPSP and HR x VPSP) and inhibited endotoxin-induced tachycardia and renin release. CGS 21680 (selective A2A adenosine receptor agonist) decreased blood pressure under basal condition but did not potentiate decreases in blood pressure during endotoxemia. CGS 21680 completely inhibited endotoxin-induced release of TNFalpha, augmented sympathetic activity and PRA, and increased +dP/dtmax and +dP/dtmax/VPSP in the absence and presence of endotoxin. The present study provides strong evidence that inhibition of adenosine deaminase reduces cytokine release in vivo without producing significant hemodynamic and cardiac effects during the early phase of profound endotoxemia in rats. The augmented neurohumoral activation induced by caffeine is associated with decreased cytokine release induced by endotoxin. Further studies are warranted to determine the impact of these effects on cardiac function and hemodynamics in the late phase of endotoxemia.     

Blocking effects of V1 (OPC-21268) and V2 (OPC-31260) antagonists on the negative inotropic response to vasopressin in isolated dog heart preparations.

We investigated the effects of V1 IOPC-21268, 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2( 1H)- quinolinone) and V2 (OPC-31260, 5-dimethylamino-1[4-(2-methylbensoylamino)benzoyl]-2,3,4,5-tetrahy dro-1H- benzazepine) vasopressin receptor antagonists on the negative inotropic response to arginine vasopressin (AVP) in the isolated perfused heart preparations of the dog. AVP (7.5-750 pmol) decreased the atrial and ventricular contractile force when the preparation was perfused with constant pressure or constant flow. AVP induced a small increase in sinus rate. Desmopressin, a selective vasopressin V2 agonist, did not change the sinus rate and atrial or ventricular contractile force. OPC-21268 (0.01-3 mumol) and OPC-31260 (0.01-1 mumol) induced a small negative inotropic effect. Both OPC-21268 and OPC-31260 inhibited the negative inotropic response to AVP in a dose-dependent manner. The doses of 50% inhibition (ID50) for OPC-21268 and OPC-31260 on the inotropic effect were 0.30 +/- 0.16 mumol and 0.084 +/- 0.034 mumol, respectively. Neither OPC-21268 nor OPC-31260 affected the acetylcholine-, adenosine- or norepinephrine-induced inotropic and chronotropic effects. It has been reported that the concentration of OPC-21268 that displaced 50% of specific AVP binding is 0.4 microM for V1 receptors and > 100 microM for V2 receptors and the concentration of OPC-31260 is 0.01 microM for V2 receptors and 1 microM for V1 receptors. We, therefore, suggest that AVP directly causes negative inotropic effects mediated at least in part by V1 receptors in the dog heart.     

Characteristic cardiovascular effects of RA642, a pyrimido-pyrimidine derivative, in anesthetized dogs

The hemodynamic effects of RA642, a pyrimido-pyrimidine derivative, were studied in dogs anesthetized with pentobarbital. The i.v. injection of RA642 (0.25 mg/kg) produced significant increases in systemic blood pressure (from 126 +/- 5 to 152 +/- 7 mm Hg 10 min after injection), cardiac output (from 1.37 +/- 0.11 to 2.07 +/- 0.11 liters/min) and left ventricular dP/dt (from 4658 +/- 557 to 6628 +/- 912 mm Hg/sec). Blood flow in coronary, renal and superior mesenteric arteries increased significantly after the injection (from 62 +/- 5 to 79 +/- 6 ml/min, from 142 +/- 5 to 174 +/- 5 ml/min and from 205 +/- 16 to 248 +/- 10 ml/min 10 min after the injection, respectively). Total peripheral and pulmonary vascular resistance were reduced significantly (from 7320 +/- 510 to 5980 +/- 512 dyn X sec/cm5 and from 250 +/- 10 to 220 +/- 12 dyn X sec/cm5, respectively, 10 min after injection). There were no significant changes in heart rate, pulmonary arterial pressure, pulmonary capillary wedge pressure or central venous pressure. With either pretreatment using hexamethonium or with the administration of phenoxybenzamine and propranolol together, hemodynamic effects caused by RA642 did not occur. With pretreatment using atropine, RA642 caused a significant increase in the heart rate. Perfusion pressure in an isolated hind-limb was reduced by the direct administration of RA642 into the perfusion circuit in a dose-dependent way. The vasodilating effect of this compound was prevented by pretreatment with papaverine but not with propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noncompetitive blockade of vasopressin-1 receptors in rat tail artery

To study vasopressin-1 receptor-mediated contraction of the isolated rat tail artery, pseudoirreversible blockade was produced by incubating tissues with 10 nM 1-beta-mercapto,beta,beta,cyclopentamethylene propionic acid, 2(O-me)tyrosine,-8-D-arginine vasopressin and 1.2 mM magnesium. Concentration-response curves to vasopressin agonists were constructed before and during exposure to 1-beta-mercapto,beta,beta,cyclopentamethylene propionic acid, 2(O-me)tyrosine,-8-D-arginine vasopressin, and at three time points after washing out the antagonist. EC50 values (-log M) for arg-vasopressin (AVP, 8.02 +/- 0.16) and arg-vasotocin (AVT, 9.51 +/- 0.12) were unaltered after exposure to the antagonist and washing of the tissues. The control EC50 for lys-vasopressin (LVP, 8.33 +/- 0.09) was significantly lower than after blockade (P less than .05). At each time point after blockade, the intrinsic activity of LVP was greater than either AVP or AVT. Increasing the ambient magnesium ion concentration greater than 1.2 mM did not alter responses to vasopressin agonists. Reducing the ambient magnesium ion from 1.2 mM to zero increased the EC50 values for all vasopressin agonists by 6- to 20-fold, but had no effect on maximal response size, nor on the concentration-response curve for norepinephrine. Pseudoirreversible blockade performed in the absence of magnesium also increased the EC50 for LVP but not for AVP or AVT after exposure to the antagonist. We conclude that LVP has greater efficacy than AVP and AVT at vasopressin receptors in rat tail artery, and that magnesium ions affect only agonist affinity but not efficacy at this vasopressin-1 receptor.     

Shen-fu injection attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest

To investigate the effect of Shen-Fu injection (SFI) for the management of postresuscitation myocardial dysfunction in a porcine model of cardiac arrest. Ventricular fibrillation was induced electrically in anesthetized domestic swine. After 4 min of untreated ventricular fibrillation, cardiopulmonary resuscitation was initiated. Sixteen successfully resuscitated pigs were randomized to receive a continuous infusion of either SFI (0.24 mg/min) or saline placebo for 6 h, beginning 15 min after return of spontaneous circulation (ROSC). The SFI treatment produced better left ventricular +dP/dtmax, -dP/dtmax, cardiac output, and ejection fraction after ROSC. The SFI treatment also produced lower serum cardiac troponin I, lactate levels, and left ventricle malondialdehyde content after ROSC, whereas left ventricle superoxide dismutase, Na-K-ATPase, and Ca-ATPase activity were significantly increased in the SFI group when compared with saline group. The cardioprotective effect of SFI was further confirmed by myocardial ultrastructure examination. Shen-Fu injection can attenuate postresuscitation myocardial dysfunction through beneficial effects on energy metabolism and remarkable antioxidant capacity.     

A Prospective Study of Changes in Right Ventricular dP/dt During Ventricular Tachycardia

The automatic implantable cardioverter defibrillator (AICD) has significantly decreased mortality in high risk ventricular tachycardia (VT) patients. The AICD provides treatment based on ventricular rate, sometimes leading to high energy shocks in conscious patients with stable VT, or patients with sinus or supraventricular tachycardia. Other physiological parameters, such as maximal positive and negative systolic right ventricular (RV) dP/dt (RV + dP/dtmax, RV - dP/dtmax, respectively), may be included in detection algorithms for future implantable defibrillators. We studied frequency band limited positive and negative RV dP/dtmax before, during, and after 13 episodes of VT lasting at least 40 beats in duration in nine male patients. The mean (+/- SEM) RV + dP/dtmax, dropped by 120 +/- 28 mmHg/sec (P less than 0.001) during the first five beats of VT. RV + dP/dtmax then slowly rose toward baseline levels until a significant overshoot occurred during the first ten beats following VT termination (delta = 234 +/- 58 mmHg/second, P less than 0.002). RV + dP/dtmax correlated poorly with mean arterial pressure (r = 0.32, P greater than 0.1), systolic blood pressure (r = 0.19, P greater than 0.1), and VT cycle length (r = 0.34, P greater than 0.1). Conversely, RV - dP/dtmax rose during the first ten beats of VT (74 +/- 27 mmHg/sec, P greater than 0.05) and then slowly drifted back toward baseline levels. Like RV + dP/dtmax, RV - dP/dtmax overshot baseline levels during the recovery phase (-108 +/- 48 mmHg/sec, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasopressin receptor antagonists: mechanisms of action and potential effects in heart failure

Increased arginine vasopressin (AVP) secretion in heart failure may lead to vasoconstriction, left ventricular remodeling, and water retention-actions that promote afterload, preload, and hyponatremia and thereby cause disease progression. Interfering with AVP-mediated signaling pharmacologically may be beneficial in heart failure. Selective antagonism of the vasopressin 2 (V2) receptor may facilitate a safe diuresis and normalize low serum sodium levels, as demonstrated in preliminary clinical trials. Pure V2 antagonism, however, may stimulate AVP secretion and enhance V1a signaling, while pure V1a receptor antagonism may lead to unwanted V2 stimulation and secondary water retention and volume expansion. Combined V1a and V2 receptor antagonism could potentially prove advantageous as a therapy for heart failure by acting synergistically to facilitate diuresis and improve hemodynamics.