Decrease In Mean Aortic Pressure Research Articles

Sildenafil for congenital heart diseases induced pulmonary hypertension, a meta-analysis of randomized controlled trials

BackgroundSildenafil was first prescribed for angina pectoris and then for erectile dysfunction from its effects on vascular smooth muscle relaxation and vasodilatation. Recently, sildenafil has been proposed for congenital heart diseases induced pulmonary hypertension, which constitutes a huge burden on children's health and can attribute to fatal complications due to presence of unoxygenated blood in the systemic circulation. Therefore, our meta-analysis aims to further investigate the safety and efficacy of sildenafil on children population.MethodsWe searched the following electronic databases: PubMed, Cochrane CENTRAL, WOS, Embase, and Scopus from inception to April 20th, 2022. Randomized controlled trials that assess the efficacy of using sildenafil in comparison to a placebo or any other vasodilator drug were eligible for inclusion. The inverse variance method was used to pool study effect estimates using the random effect model. Effect sizes are provided in the form of mean difference (MD) with 95% confidence intervals (CI).ResultsOur study included 14 studies with (n = 849 children) with a mean age of 7.9 months old. Sildenafil showed a statistically significant decrease over placebo in mean and systolic pulmonary artery pressure (PAP) with MD -7.42 (95%CI [-13.13, -1.71], P = 0.01) and -8.02 (95%CI [-11.16, -4.88], P < 0.0001), respectively. Sildenafil revealed a decrease in mean aortic pressure and pulmonary artery/aortic pressure ratio over placebo with MD -0.34 (95%CI [-2.42, 1.73], P = 0.75) and MD -0.10 (95%CI [-0.11, -0.09], P < 0.00001), respectively. Regarding post corrective operations parameters, sildenafil had a statistically significant lower mechanical ventilation time, intensive care unit stay, and hospital stay over placebo with MD -19.43 (95%CI [-31.04, -7.81], s = 0.001), MD -34.85 (95%CI [-50.84, -18.87], P < 0.00001), and MD -41.87 (95%CI [-79.41, -4.33], P = 0.03), respectively. Nevertheless, no difference in mortality rates between sildenafil and placebo with OR 0.25 (95%CI 0.05, 1.30], P = 0.10) or tadalafil with OR 1 (95%CI 0.06, 17.12], P = 1).ConclusionSildenafil is a well-tolerated treatment in congenital heart diseases induced pulmonary hypertension, as it has proven its efficacy not only in lowering both PAP mean and systolic but also in reducing the ventilation time, intensive care unit and hospital stay with no difference observed regarding mortality rates.

Chronic maternal hypercortisolemia models stress-induced adverse birth outcome and altered cardiac function in newborn lambs.

Maternal stress in pregnancy is thought to be a contributing factor in adverse pregnancy outcomes, including stillbirth and prematurity. Previous studies in our laboratory have shown that chronic elevation in maternal cortisol concentration in ewes (by maternal infusion of 1 mg/kg/day) during the late gestation increased the incidence of stillbirth and altered fetal heart rate and blood pressure at birth. We designed the current study to test the effect of chronically elevated maternal cortisol on fetal cardiac adaption from in utero life to ex utero life. The combined risk of stillbirth or prematurity was significantly greater in the pregnancies with maternal hypercortisolemia; in this cohort, 40% of the lambs of cortisol-infused ewes died in utero or at birth compared with 25% of lambs of control ewes, and 24% of lambs of cortisol-infused ewes were born preterm, whereas no lamb was born preterm in the control group. Compared with control lambs, the lambs of cortisol-infused ewes born at full term exhibited a significant increase in mean aortic pressure just before birth and a significant decrease in mean aortic pressure that was evident during the first 9 h after birth. The QT interval was decreased before birth and increased immediately after birth in the newborns of cortisol-treated ewes compared with control lambs. These findings suggest that excess in utero corticosteroid exposure adversely affects fetal cardiac adaptation to extrauterine life and that chronic maternal stress or hypersecretion of corticosteroids may contribute to adverse obstetric outcomes.

Systemic vascular effects of acute electrical baroreflex stimulation.

We intended to determine if acute baroreflex activation therapy (BAT) increases venous capacitance and aortic conductance. BAT is effective in resistant hypertension, but its effect on the systemic vasculature is poorly understood. Left ventricular (LV) and aortic pressures and subdiaphragmatic aortic and caval flows (ultrasonic) were measured in six anesthetized dogs. Changes in abdominal blood volume (Vabdominal) were estimated as the integrated difference in abdominal aortic inflow and caval outflow. An electrode was implanted on the right carotid sinus. Data were measured during control and BAT. Next, sodium nitroprusside (SNP) was infused and BAT was subsequently added. Finally, angiotensin II (ANG II) was infused, and three increased BAT currents were added. We found that BAT decreased mean aortic pressure (PAo) by 22.5 ± 1.3 mmHg (P < 0.001) and increased aortic conductance by 16.2 ± 4.9% (P < 0.01) and Vabdominal at a rate of 2.2 ± 0.6 ml·kg(-1)·min(-1) (P < 0.01). SNP decreased PAo by 17.4 ± 0.7 mmHg (P < 0.001) and increased Vabdominal at a rate of 2.2 ± 0.7 ml·kg(-1)·min(-1) (P < 0.05). During the SNP infusion, BAT decreased PAo further, by 26.0 ± 2.1 mmHg (P < 0.001). ANG II increased PAo by 40.4 ± 3.5 mmHg (P = 0.001). When an increased BAT current was added, PAo decreased to baseline (P < 0.01) while aortic conductance increased from 62.3 ± 5.2% to 80.2 ± 3.3% (P < 0.05) of control. Vabdominal increased at a rate of 1.8 ± 0.9 ml·kg(-1)·min(-1) (P < 0.01), reversing the ANG II effects. In conclusion, BAT increases arterial conductance, decreases PAo, and increases venous capacitance even in the presence of powerful vasoactive drugs. Increasing venous capacitance may be an important effect of BAT in hypertension.

SKA‐31, a positive modulator of SKCa and IKCa channels, increases systemic conductance and lowers arrterial pressure in an anesthetized pig model

SKA‐31 regulates microvascular tone, tissue perfusion and blood pressure by acting on endothelial SKCa and IKCa channels. In this study, we have examined the hemodynamic effects of SKA‐31 in comparison to the established vasodilator sodium nitroprusside (SNP) in anesthetized domestic pigs. We measured left ventricular (LV), aortic and inferior vena cava (IVC) pressures and monitored levels of blood flow in the ascending aorta, right carotid, left anterior descending coronary and left renal arteries during acute intravenous infusions of SKA‐31 (0.1 to 5 mg/kg), followed by a single dose of SNP (5 μg/kg). SKA‐31 dose‐dependently and reversibly decreased mean aortic pressure (mPAO) to a level comparable to that produced by SNP (−23±3 vs. −28±4 mmHg). Mean IVC pressure did not change. Both SKA‐31 (1 to 5 mg/kg doses) and SNP increased systemic conductance, along with coronary and carotid artery conductances; renal conductance did not change. There was no change in LV stroke volume (SV) for any infusion, and heart rate was not altered following SKA‐31 administration (132±14 vs. 128±13 bpm). With no change in SV, the significant decrease in LV stroke work (SW) observed with either SKA‐31 or SNP was largely attributed to decreased mPAO. In summary, SKA‐31 significantly decreased mPAO by increasing systemic conductance, and did not appear to reduce cardiac contractility. Supported by the CIHR (JVT and APB) and the NIH (HW).

The hypotensive effect of intravenous amiodarone is sustained throughout the maintenance infusion period

1. Hypotension frequently occurs with use of intravenous amiodarone and is managed by slowing the rate of administration. This response has been attributed to the cosolvents in the formulation and is believed to be solely related to the initial loading dose. The present study was performed to determine whether intravenous amiodarone-induced hypotension persists beyond the loading dose and into the maintenance infusion period and also whether hypotension occurs with maintenance level dosing alone. 2. Anaesthetized beagle dogs (n = 7/group) were instrumented to assess haemodynamics. Animals were treated with the human-equivalent dosing regimen (loading dose followed by maintenance infusion) of intravenous amiodarone or control (5% dextrose in water). 3. No haemodynamic changes were observed in the control group during the 6 h study. In contrast, administration of the standard intravenous amiodarone regimen produced rapid and significant decreases in mean aortic pressure, cardiac output and maximum rate of change of left ventricular pressure that persisted throughout the 6 h maintenance infusion period. Administration of amiodarone as the maintenance infusion dose alone produced haemodynamic changes that were similar in magnitude to those observed with administration of the full dosing regimen, but were delayed in onset by approximately 60 min. 4. Dosing with a cosolvent-free formulation of amiodarone (PM101) caused no haemodynamic effects during the 6 h dosing period, indicating that the cardiodepressant effects of intravenous amiodarone were due to its cosolvents. 5. These data suggest that consideration should be given to intravenous amiodarone as a potential cause for sustained hypotension during prolonged infusion.

PM101: A cyclodextrin-based intravenous formulation of amiodarone devoid of adverse hemodynamic effects

Intravenous amiodarone (Amiodarone IV) is widely used to treat cardiac arrhythmias. The most frequent clinical adverse event associated with Amiodarone IV administration is systemic hypotension which has been attributed to the cosolvents used in the formulation, polysorbate 80 and benzyl alcohol. To minimize hypotension Amiodarone IV is diluted in 5% dextrose in water prior to administration and slowly infused. PM101 is a novel intravenous formulation that uses sulfobutylether-7-beta-cyclodextrin to solubilize amiodarone, and thus should be devoid of the untoward hemodynamic effects associated with polysorbate 80 and benzyl alcohol. Beagle dogs ( n = 7/group) were anesthetized with morphine and α-chloralose and instrumented to assess aortic blood pressure, cardiac output, cardiac contractility, and heart rate. Animals were treated with the U.S. approved human-equivalent loading dose (2.14 mg/kg) of Amiodarone IV, PM101, and their respective vehicle controls. Administration of Amiodarone IV rapidly and significantly decreased mean aortic pressure, cardiac output, and cardiac contractility. A significant increase in heart rate was also observed as was a transient, but not significant, decrease in systemic vascular resistance. A similar pattern of rapid and significant hemodynamic changes was produced by the Amiodarone IV Vehicle (polysorbate 80/benzyl alcohol) alone. In marked contrast, PM101 and its vehicle produced no significant hemodynamic effects. This study provides a useful model for the continued search for a safe and effective intravenous amiodarone formulation devoid of the hypotensive risk associated with the current commercial formulation.

Effects of Exogenous Sphinganine, Sphingosine, and Sphingosine-1-Phosphate on Relaxation and Contraction of Porcine Thoracic Aortic and Pulmonary Arterial Rings

Fumonisin mycotoxicosis in pigs causes a decrease in mean aortic pressure, an increase in mean pulmonary arterial pressure, and increases in serum concentrations of sphinganine (3.2 microM) and sphingosine (1.4 microM). To determine a causal relationship between the hemodynamic changes and sphingolipid alterations, we examined the in vitro effects of sphinganine, sphingosine, and sphingosine-1-phosphate on porcine aortic and pulmonary arterial rings. Both sphinganine and sphingosine relaxed un-contracted and phenylephrine-contracted aortic rings at > or = 10 microM and > or = 1 microM, respectively. Sphingosine (> or = 10 microM) relaxed un-contracted and phenylephrine-contracted pulmonary arterial rings, whereas sphingosine-1-phosphate (10 microM) contracted pulmonary arterial rings. Sphingosine (3 microM) also impaired the contractile response of pulmonary artery rings to 60 mM KCl. The results suggested that the systemic hypotension caused by fumonisin is mediated, in part, by increases in serum sphinganine and sphingosine concentrations, and the pulmonary hypertension is mediated, in part, by increased sphingosine-1-phosphate concentrations.

Enhanced Hypotensive Effects of the Essential Oil ofOcimum gratissimumLeaves and its Main Constituent, Eugenol, in DOCA-Salt Hypertensive Conscious Rats

The cardiovascular effects of intravenous (i.v.) treatment with the essential oil of Ocimum gratissimum (EOOG) and its main constituent, eugenol (Eug) were investigated in the experimental model of deoxycorticosterone acetate (DOCA-salt)-hypertensive rats. In both conscious DOCA-salt hypertensive rats and their uninephrectomized controls, i.v. bolus injections of EOOG (1 - 20 mg/kg) or Eug (1 - 10 mg/kg) induced dose-dependent hypotension and bradycardia. Treatment with DOCA-salt significantly enhanced the maximal decreases in mean aortic pressure (MAP) elicited by hexamethonium (30 mg/kg, i.v.) as well as the hypotensive responses to both EOOG and Eug without affecting the bradycardia. However, the enhancement of EOOG-induced hypotension in hypertensive rats remained unaffected by i.v. pretreatment with either hexamethonium (30 mg/kg) or methylatropine (1 mg/kg). These results show that i.v. treatment with EOOG or Eug dose-dependently decreased blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement appears related mainly to an increase in EOOG-induced vascular smooth relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model.

Intra‐aortic Balloon Pumping: Does Posture Matter?

The effect of the posture of semirecumbent patients on the hemodynamics and performance of intra-aortic balloon (IAB) were studied in vivo and in vitro. An IAB was inserted into a glass tube filled with saline, fully inflated and deflated using an intra-aortic balloon pump (IABP). Three successive cycles were filmed at 125 frames/s with the tube positioned at various angles between 0 degrees (horizontal) and 90 degrees (vertical). Pressure and flow were measured distal to both ends of the balloon. In parallel, coronary left anterior descending (LAD) flow velocity and aortic pressure were recorded in 6 patients using IABP, postcardiac surgery in the intensive care unit. Recordings were made when the patient was lying horizontally (recumbent) and when the patient's torso was inclined at 30 degrees to the horizontal (semirecumbent). With the tube horizontal, the inflation was effectively uniform along the length of the balloon. At all other angles, the higher end of the balloon inflated first, and mean pressure and flow measured distal to the higher end of the balloon were less than those measured at 0 degrees . Mean aortic pressure and LAD flow decreased by 10 +/- 2% (P = 0.001) and 15 +/- 3% (P = 0.001), respectively, when the patient was semirecumbent compared to when the patient was recumbent. The decreased mean aortic pressure and LAD flow velocity suggests that unless patients using IABP are required to be semirecumbent, it may be best to position them horizontally to gain the full benefits of balloon counter pulsation to the coronary circulation.

Involvement of nitric oxide in the mediation of the hypotensive action of the essential oil of Mentha x villosa in normotensive conscious rats.

Recently, we showed that intravenous (i.v.) treatment with the essential oil of Mentha x villosa (EOMV) in pentobarbitone-anaesthetised rats decreased blood pressure; the effect occurred independently of the presence of an operational central autonomic drive to the cardiovascular system. This finding suggested that the hypotensive activity of EOMV may result from its vasodilatory effects directly upon vascular smooth muscle. The present study examines this possibility and whether EOMV-induced hypotension is mediated, at least in part, by an endothelial L-arginine/nitric oxide pathway. In conscious rats, i.v. injections of bolus doses (1 to 20 mg/kg) of EOMV elicited immediate and dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR). Pretreatment with i.v. hexamethonium (30 mg/kg) reduced the EOMV-induced bradycardia without affecting the hypotension. However, i.v. pretreatment with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl (L-NAME, 20 mg/kg), reduced partially, but significantly, the maximal percent decreases in MAP elicited by EOMV without affecting the bradycardia. In rat isolated thoracic aorta preparations, EOMV (1 - 130 microg/ml) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction. This smooth muscle-relaxant activity of EOMV was significantly reduced by the incubation of endothelium-intact rings with L-NAME (20 microM), as evidenced by the significant enhancement in the IC50 for EOMV-induced reduction of potassium-induced contraction (133.8 +/- 26.5 vs. 65.2 +/- 8.2 microg/ml in the absence of L-NAME). Furthermore, the vasorelaxant effects of EOMV in endothelium-denuded aortic rings were also significantly reduced (IC50 = 109 +/- 10 microg/ml), compared to those observed in segments with intact endothelium (IC50 = 61 +/- 13 microg/ml). These results show that i.v. treatment with EOMV dose-dependently decreases blood pressure in conscious rats, and that this action is due to an active vascular relaxation rather than withdrawal of sympathetic tone. Released nitric oxide from vascular endothelial cells appears partially involved in the aortic relaxation induced by EOMV and in turn in the mediation of EOMV-induced hypotension. They further support the concept that EOMV-induced hypotension and bradycardia occurred independently.

Cardiovascular effects of the essential oil of Mentha x villosa in DOCA-salt-hypertensive rats.

The present study investigated the effects of chronic treatment with deoxycorticosterone-acetate (DOCA)-salt on cardiovascular responses to intravenous (i.v.) injection of the essential oil of Mentha x villosa (EOMV) in conscious rats. In both DOCA-salt-hypertensive and uninephrectomized control, conscious rats, i.v. bolus injections of EOMV (1 to 20 mg/kg body wt.) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-dependent manner. Treatment with DOCA-salt significantly enhanced EOMV-induced decreases in MAP, without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. injection of the ganglion blocker, hexamethonium (30 mg/kg body wt.), were significantly greater in DOCA-salt-hypertensive than in control rats. In DOCA-salt-hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg body wt.) reduced the bradycardia elicited by EOMV (1 to 20 mg/kg body wt.) without affecting the enhancement of EOMV-induced hypotension. These results show that i.v. treatment with EOMV decreases blood pressure in conscious DOCA-salt-hypertensive rats dose-dependently, and that this action is enhanced when compared with uninephrectomized controls. This enhancement could be related mainly to an increase in EOMV-induced vascular smooth muscle relaxation, rather than to enhanced sympathetic nervous system activity in this hypertensive model.

Cardiovascular effects of beta 3‐adrenoceptor stimulation in perinephritic hypertension

A new beta 3-adrenoceptor (beta3-AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the beta3-AR agonist, SR58611 in normal and hypertensive dogs. In protocol 1, SR58611 was infused in normal dogs after placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB. In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensive dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 +/- 32 to 125 +/- 35 mmHg; - 26%, P < 0.0001), that was greater than in normal dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0.0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an effect not observed in normal dogs. Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.

Vasodilator responses of coronary conduit and resistance arteries to continuous nitroglycerin infusion in humans: a Doppler guide wire study.

To examine the responses of coronary conduit and resistance arteries to the continuous i.v. administration of nitroglycerin in 15 patients with atypical chest pain, we measured coronary blood flow velocity in the left anterior descending coronary artery using a Doppler guide wire and the lumen diameter and cross-sectional area by quantitative coronary angiography. Systolic flow, diastolic flow, total coronary flow, and coronary vascular resistance were calculated. Stepwise increases in dose of nitroglycerin resulted in significant dose-dependent decrease in mean aortic pressure (p < 0.01) and increase in lumen diameter (p < 0.05). After nitroglycerin administration of 0.5 microg/kg/min, systolic flow decreased significantly by 89.9+/-15.7% (p < 0.01), and diastolic flow increased significantly by 74.2+/-37.1% (p < 0.05). Total coronary flow did not change significantly with the various doses of nitroglycerin. However, coronary vascular resistance decreased significantly at concentrations greater than 0.5 microg/kg/min nitroglycerin. Continuous nitroglycerin infusion did not reduce either diastolic or total coronary blood flow despite a significant reduction in coronary perfusion pressure. These results indicate that subendocardial blood flow might be maintained during continuous i.v. infusion of nitroglycerin within the clinical dose range.

Cardiovascular responses to intrathecal dopamine receptor agonists in conscious DOCA-salt hypertensive rats.

Previous studies have demonstrated that in conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats, the hypotensive action of intravenous (i.v.) bromocriptine, a selective dopamine D2 receptor agonist, was mediated partly by peripheral and partly by spinal dopamine D2 receptor stimulation, and that this effect was greater and longer-lasting than that in uninephrectomized control rats. To determine whether this amplification results partly from a putative spinal hypersensitivity phenomenon, cardiovascular responses to intrathecal (i.t.) administration of apomorphine and quinpirole were studied in conscious, 4-week DOCA-salt hypertensive rats and compared with those in uninephrectomized control rats. In both groups, upper thoracic (T2-T4) i.t. injections of apomorphine (9.1, 45.5 and 91.1 microg/rat) induced immediate and dose-dependent decreases in mean aortic pressure (MAP) and heart rate (HR), while i.t. quinpirole (38.4 microg/rat) induced only bradycardia. Neither magnitude nor duration of these responses was enhanced in DOCA-salt hypertensive rats when compared to control rats. In DOCA-salt hypertensive rats, apomorphine-induced hypotension and bradycardia remained unaffected by i.v. (500 microg/kg) pretreatment with domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. However, i.t. (40 microg/rat at T2-T4) pretreatment with domperidone significantly reduced apomorphine-induced hypotension, but fully suppressed bradycardia elicited by either apomorphine or quinpirole. These results demonstrated that in conscious DOCA-salt hypertensive rats, intrathecally-injected apomorphine or quinpirole decreased MAP and/or HR through a spinal D2 dopaminergic mechanism, as previously demonstrated in normotensive intact rats. Since both magnitude and duration of these responses were unchanged with respect to uninephrectomized control rats, enhancement of the hypotensive effect of intravenously-administered bromocriptine in DOCA-salt hypertensive rats does not appear to involve spinal dopamine D2 receptors.

The cause of the difference between the arterial baroreceptor reflex under natural pulsatile circulation and under nonpulsatile systemic circulation

In a previous study we investigated the relation between afferent and efferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation using total left heart bypass. The results indicated that the regulation of the arterial baroreceptor reflex was converted under nonpulsatile systemic circulation, and we inferred that a possible reason for this conversion was the transformation in discharge of the afferent activity of the arterial baroreceptor reflex that took place under nonpulsatile systemic circulation. In the present study we tested this hypothesis by sectioning carotid sinus and aortic depressor nerves and electrically stimulating bilateral aortic depressor nerves under anesthesia in five rabbits (400 spikes for 20s, with 0.02ms pulse width and 8 V amplitude), while recording changes in aortic pressure, mean aortic pressure, and heart rate. Continuous stimulation was taken as discharge of the afferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation, and periodic stimulation was taken as discharge under natural pulsatile circulation. Aortic pressure, mean aortic pressure, and heart rate decreased under both continous and periodic stimulation. The decreases in mean aortic pressure and heart rate during continuous stimulation were significantly lower than those during periodic stimulation. Our results suggest that the transformation in discharge of the afferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation may have played an important causative role in the conversion of the regulation of the arterial baroreceptor reflex under nonpulsatile systemic circulation.

Preserved vasodilator effect of bradykinin in dogs with heart failure.

In heart failure (HF), vasoconstrictor systems are activated and endothelium-derived vasodilation is blunted. Bradykinin, a potent vasodilator, may play an important role in this setting. However, it is not known whether its vasodilator effect is modified in HF. Fourteen chronically instrumented dogs were studied in the control state and in pacing-induced HF (250 bpm for 3 weeks). The dose-dependent decrease in mean aortic pressure (MAP) induced by acetylcholine was significantly blunted in HF. In contrast, in both control and HF, bradykinin infusion caused similar dose-dependent decreases in MAP and increases in cardiac output (CO). This vasodilator effect of exogenous bradykinin was potentiated similarly in both states by enalaprilat, which blocks both angiotensin conversion and bradykinin degradation. For evaluating the role of endogenous bradykinin, the effects of enalaprilat were compared with those of ciprokiren, a pure renin inhibitor. In control, ciprokiren did not produce any effect. Enalaprilat, however, produced a significant decrease in MAP and a significant increase in CO, which were attributed to the inhibition of bradykinin degradation, because these effects were absent after pretreatment with Hoe 140 (a bradykinin B2 receptor antagonist). In contrast, in HF, vasodilator effects of ciprokiren were observed, but enalaprilat produced larger changes in MAP and CO, and after Hoe 140, the hemodynamic effects of enalaprilat were significantly decreased, showing the effects of endogenous bradykinin, which were similar to those measured in control. In this model of HF with a blunted endothelium-derived vasodilation, the vasodilator effects of exogenous and endogenous bradykinin are preserved. These results suggest that bradykinin may play an important role in HF, in which vasoconstriction is present and endothelium-dependent vasodilation is blunted.

Hypotensive action of bromocriptine in the DOCA-salt hypertensive rat: contribution of spinal dopamine receptors.

To assess the role of spinal dopamine receptors in mediation of hypotension induced by systemic administration of the dopamine D2 receptor agonist, bromocriptine, conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rats were pretreated with either intravenous (i.v.; 500 micrograms/kg) or intrathecal (i.t.; 40 micrograms/rat at T9-T10) domperidone, a selective dopamine D2 receptor antagonist that does not cross the blood-brain barrier. In DOCA-salt hypertensive rats, i.v. administration of a sub-maximal dose of bromocriptine (150 micrograms/kg) induced a significant decrease in mean aortic pressure (MAP) which was greater and longer lasting than that in uninephrectomized control rats. Intravenous or i.t. pretreatment with domperidone reduced partially, but significantly, the hypotensive effect of bromocriptine (reduction of about 57% and 45% of the maximal effect, respectively). The remaining responses observed during the 60 min postinjection period were still statistically significant as compared with vehicle injection. In contrast, the bromocriptine-induced hypotension was fully abolished by i.v. pretreatment with metoclopramide (300 micrograms/kg), a dopamine D2 receptor antagonist that crosses the blood-brain barrier, or by combined pretreatment with i.v. and i.t. domperidone. These results suggest that, in DOCA-salt hypertensive rats, the hypotension induced by i.v. bromocriptine is mediated partly through a peripheral D2 dopaminergic mechanism and partly through stimulation of spinal dopamine D2 receptors, has been demonstrated in conscious normotensive rats.

Neonatal piglet model of intraaortic balloon pumping: Improved efficacy using echocardiographic timing

Background. Pediatric intraaortic balloon pumping (IABP) has met with little success because of technical difficulty in tracking rapid heart rates. This study was designed to evaluate the efficacy of M-mode echocardiography for IABP timing in a neonatal piglet model. Methods. Two groups of piglets underwent mitral valve avulsion to create a model of shock. Group 1 (n = 8; mean weight, 7.7 ± 1.8 kg) underwent IABP timed with both the ascending aortic pressure and M-mode echocardiogram. Group 2 (n = 6; mean weight, 7.5 ± 1.4 kg) underwent two separate periods of IABP: one with echocardiographic timing and the second using standard timing points from the femoral arterial pressure tracing and electrocardiogram. Measurements included ascending aortic flow, left anterior descending arterial flow, ascending aortic pressure, left atrial pressure, and heart rate. Results. Mitral valve avulsion produced a shock model with a significant decrease in mean aortic pressure and aortic flow and a significant increase in left atrial pressure and heart rate. Compared with the shock state, IABP in group 1 animals resulted in a significant increase in aortic flow (353 ± 152 versus 454 ± 109 mL/min; p < 0.05) and a significant decrease in left atrial pressure (23 ± 6 versus 17 ± 7 mm Hg; p < 0.05). Group 2 animals with echocardiogram-timed IABP had significantly increased aortic flow (365 ± 106 versus 458 ± 107 mL/min; p < 0.05) and mean aortic pressure (43 ± 11 versus 52 ± 8 mm Hg; p < 0.05). However, standard-timed IABP failed to show any improvement. Conclusions. In piglets with rapid heart rates, echocardiogram-timed IABP results in increased aortic flow and pressure and decreased left atrial pressure compared with standard-timed IABP.

Haemodynamic effects of a sixty minute infusion of dopamine hydrochloride in horses anaesthetised with halothane.

To describe the haemodynamic effects of a 60 min infusion of dopamine 4 microg/kg bwt/min during halothane anaesthesia, 7 mature Thoroughbred horses were studied. The infusion began 1 h after induction of anaesthesia by romifidine (100 microg/kg) and ketamine (2.2 mg/kg bwt). Throughout the period of dopamine infusion and for 30 min after its discontinuation, the horses were ventilated by intermittent positive pressure to maintain PaCO2 between 4.6-5.4 KPa. Inspired halothane concentration was adjusted to maintain an end tidal halothane concentration of 0.9%. Haemodynamic variables were measured using intracardiac strain gauge transducers sited in the left and right ventricle, aorta, and pulmonary artery. Left ventricular pressure was differentiated to obtain maximal rate of increase of intraventricular pressure (LVdp/dtmax). Transoesophageal Doppler echocardiography was performed to measure maximum aortic blood flow velocity (vmax) and acceleration (dv/dtmax), left ventricular velocity time integral (vTI) and cardiac output (CO), and left ventricular pre-ejection period (PEP) and ejection time (ET). Measurements were made during the 60 min infusion, and for 30 min after the infusion was discontinued. Infusion of dopamine 4 microg/kg/min significantly decreased mean aortic pressure, while left and right ventricular end-diastolic pressure and mean pulmonary artery pressure remained unchanged. There was a small, but significant, increase in heart rate during dopamine infusion. Maximum acceleration of aortic blood flow, CO and vTI were also significantly increased by dopamine infusion. Maximal rate of increase of intraventricular pressure (LVdp/dtmax) was significantly decreased 10 min after commencing infusion, but then returned to baseline for the remainder of the study. Left ventricular pre-ejection period (PEP) decreased during dopamine infusion whilst ejection time (ET) significantly increased. All measured variables except LVET had returned to baseline values within 30 min of discontinuing the infusion. This study demonstrated beneficial effects of dopamine infusion upon left ventricular systolic function. However, the therapeutic value of the drug is likely to be limited in clinical anaesthesia due to the simultaneous falls in arterial blood pressure which accompany its administration.

Additional hypotensive effect of endothelin-1 receptor antagonism in hypertensive dogs under angiotensin-converting enzyme inhibition.

Endothelin-1 (ET-1) may play a role in hypertension. ET-1 receptor antagonism by bosentan lowers blood pressure in hypertension. We evaluated whether the effect of bosentan is still observed under ACE inhibitors (ACEI). Thirty anesthetized and 18 conscious hypertensive dogs were studied randomly. Anesthetized dogs were divided into 4 groups: group 1 received cumulative doses of bosentan (bolus+30-minute infusion: 0.1 mg/kg+/-0.23 mg/kg per hour to 3 mg/kg+/-7 mg/kg per hour); group 2, the same dose-responses after 1 mg/kg enalaprilat; group 3, the vehicle after enalaprilat; and group 4, the dose responses to bosentan followed by enalaprilat. The conscious dogs were divided into 3 groups: group 5 received 2 cumulative doses of bosentan; group 6, the vehicle; and group 7, enalaprilat alone. In groups 1 and 2, bosentan produced dose-related decreases (P=.0001) in left ventricular systolic pressure and mean aortic pressure (AOP). In group 1, bosentan decreased mean AOP by 22%. In group 2, enalaprilat decreased mean AOP by 25% (from 173+/-26 to 130+/-25 mm Hg; P<.005); an additional 18% decrease was obtained with bosentan, the mean AOP reaching 98+/-21 mm Hg (P<.01). In group 3, the effect of enalaprilat alone was a 22% decrease in mean AOP (P<.005). The additive effect of the bosentan-ACEI association was also observed in group 4. In group 5, bosentan reduced mean AOP by 20% (P<.005), whereas mean AOP remained unchanged in group 6. The effect of ACEI alone (group 7) was similar to that of bosentan. Bosentan produces an additional hypotensive effect to that of ACEI, which opens new therapeutic perspectives.