Constant Left Atrial Pressure Research Articles

Effects of commonly used inotropes on myocardial function and oxygen consumption under constant ventricular loading conditions.

Inotropic medications are routinely used to increase cardiac output and arterial blood pressure during critical illness. However, few comparative data exist between these medications, particularly independent of their effects on venous capacitance and systemic vascular resistance. We hypothesized that an isolated working heart model that maintained constant left atrial pressure and aortic blood pressure could identify load-independent differences between inotropic medications. In an isolated heart preparation, the aorta and left atrium of Sprague Dawley rats were cannulated and placed in working mode with fixed left atrial and aortic pressure. Hearts were then exposed to common doses of a catecholamine (dopamine, epinephrine, norepinephrine, or dobutamine), milrinone, or triiodothyronine (n = 10 per dose per combination). Cardiac output, contractility (dP/dtmax), diastolic performance (dP/dtmin and tau), stroke work, heart rate, and myocardial oxygen consumption were compared during each 10-min infusion to an immediately preceding baseline. Of the catecholamines, dobutamine increased cardiac output, contractility, and diastolic performance more than clinically equivalent doses of norepinephrine (second most potent), dopamine, or epinephrine (P < 0.001). The use of triiodothyronine and milrinone was not associated with significant changes in cardiac output, contractility or diastolic function, either alone or added to a baseline catecholamine infusion. Myocardial oxygen consumption was closely related to dP/dtmax (r(2) = 0.72), dP/dtmin (r(2) = 0.70), and stroke work (r(2) = 0.53). In uninjured, isolated working rodent hearts under constant ventricular loading conditions, dobutamine increased contractility and cardiac output more than clinically equivalent doses of norepinephrine, dopamine, and epinephrine; milrinone and triiodothyronine did not have significant effects on contractility.

An Analysis of Responses to Defibrotide in the Pulmonary Vascular Bed of the Cat

Defibrotide is a polydisperse mixture of single-stranded oligonucleotides with many pharmacologic properties and multiple actions on the vascular endothelium. Responses to defibrotide and other vasodepressor agents were evaluated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure. Lobar arterial pressure was increased to a high steady level with the thromboxane A2 analog U-46619. Under increased-tone conditions, defibrotide caused dose-dependent decreases in lobar arterial pressure without altering systemic arterial and left atrial pressures. Responses to defibrotide were significantly attenuated after the administration of the cyclooxygenase inhibitor sodium meclofenamate. Responses to defibrotide were also significantly attenuated after the administration of both the adenosine 1 and 2 receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine and 8-(3-chlorostyryl)caffeine. Responses to defibrotide were not altered after the administration of the vascular selective adenosine triphosphate-sensitive potassium channel blocker U-37883A, or after the administration of the nitric oxide synthase inhibitor L-N-(1-iminoethyl)-ornithine. These data show that defibrotide has significant vasodepressor activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to defibrotide are partially dependent on both the activation of the cyclooxygenase enzyme and adenosine 1 and 2 receptor pathways and independent of the activation of adenosine triphosphate-sensitive potassium channels or the synthesis of nitric oxide in the pulmonary vascular bed of the cat.

Hemodynamic response to exercise and head-up tilt of patients implanted with a rotary blood pump: a computational modeling study.

The present study investigates the response of implantable rotary blood pump (IRBP)-assisted patients to exercise and head-up tilt (HUT), as well as the effect of alterations in the model parameter values on this response, using validated numerical models. Furthermore, we comparatively evaluate the performance of a number of previously proposed physiologically responsive controllers, including constant speed, constant flow pulsatility index (PI), constant average pressure difference between the aorta and the left atrium, constant average differential pump pressure, constant ratio between mean pump flow and pump flow pulsatility (ratioP I or linear Starling-like control), as well as constant left atrial pressure ( P l a ¯ ) control, with regard to their ability to increase cardiac output during exercise while maintaining circulatory stability upon HUT. Although native cardiac output increases automatically during exercise, increasing pump speed was able to further improve total cardiac output and reduce elevated filling pressures. At the same time, reduced venous return associated with upright posture was not shown to induce left ventricular (LV) suction. Although P l a ¯ control outperformed other control modes in its ability to increase cardiac output during exercise, it caused a fall in the mean arterial pressure upon HUT, which may cause postural hypotension or patient discomfort. To the contrary, maintaining constant average pressure difference between the aorta and the left atrium demonstrated superior performance in both exercise and HUT scenarios. Due to their strong dependence on the pump operating point, PI and ratioPI control performed poorly during exercise and HUT. Our simulation results also highlighted the importance of the baroreflex mechanism in determining the response of the IRBP-assisted patients to exercise and postural changes, where desensitized reflex response attenuated the percentage increase in cardiac output during exercise and substantially reduced the arterial pressure upon HUT.

An Analysis of Responses to Levosimendan in the Pulmonary Vascular Bed of the Cat

Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart failure. We investigated the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase, adenosine triphosphate (ATP)-dependent potassium channels, or both. We investigated responses to the calcium sensitizer levosimendan in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was increased to a high steady level with the thromboxane A(2) analog U-46619. Under increased-tone conditions, levosimendan caused dose-related decreases in lobar arterial pressure without altering systemic arterial and left atrial pressure. Responses to levosimendan were significantly attenuated, although not completely, after the administration of U-37883A, a vascular selective nonsulfonylurea ATP-sensitive K(+)-channel-blocking drug. Responses to levosimendan were not significantly different after the administration of the nitric oxide synthase inhibitor L-N(5)-(1-iminoethyl)-ornithine or the cyclooxygenase inhibitor sodium meclofenamate or when lung ventilation was interrupted. These data show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to levosimendan are partially dependent on activation of ATP-sensitive K(+) channels and independent of the synthesis of nitric oxide, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the cat. Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart-failure treatment. The lung circulation affects both right- and left-sided heart failure. Levosimendan decreased lobar arterial pressure via a partial K(+)(ATP) (potassium channel sensitive to intracellular adenosine triphosphate levels)-dependent mechanism. These data suggest that, in addition to calcium-sensitizing activity, levosimendan decreases pulmonary resistance, which may also aid in the treatment of heart failure.

An Analysis of Responses to Levosimendan in the Pulmonary Vascular Bed of the Cat

Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart failure. We investigated the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase, adenosine triphosphate (ATP)-dependent potassium channels, or both. We investigated responses to the calcium sensitizer levosimendan in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was increased to a high steady level with the thromboxane A2 analog U-46619. Under increased-tone conditions, levosimendan caused dose-related decreases in lobar arterial pressure without altering systemic arterial and left atrial pressure. Responses to levosimendan were significantly attenuated, although not completely, after the administration of U-37883A, a vascular selective nonsulfonylurea ATP-sensitive K+-channel-blocking drug. Responses to levosimendan were not significantly different after the administration of the nitric oxide synthase inhibitor l-N5-(1-iminoethyl)-ornithine or the cyclooxygenase inhibitor sodium meclofenamate or when lung ventilation was interrupted. These data show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to levosimendan are partially dependent on activation of ATP-sensitive K+ channels and independent of the synthesis of nitric oxide, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the cat.

Milrinone, not epinephrine, improves left ventricular compliance after cardiopulmonary bypass

Objective: To compare the effects of milrinone versus epinephrine administered after cardiopulmonary bypass (CPB) on left ventricular compliance. Design: Prospective and randomized. Setting: University-affiliated hospital. Participants: Twenty consenting adult patients. Interventions: Patients undergoing aortocoronary bypass surgery were randomized to receive 50 μkg/kg of milrinone (group M; n = 10) or 0.03 μkg/kg/min of epinephrine (group E; n = 10) shortly after separation from CPB. Left ventricular compliance was assessed by observing changes in left ventricular end-diastolic area (LVEDA) in the short-axis view with transesophageal echocardiography, while maintaining a constant left atrial pressure. Measurements were performed (1) before CPB, (2) after separation from CPB, and (3) after either milrinone or epinephrine. Measurements and Main Results: Baseline LVEDA decreased by 20% after CPB in the milrinone group (from 16.6 ± 3.1 cm2 to 14.3 ± 2.4 cm2; p < 0.05) and by 22% in the epinephrine group (from 19.4 ± 4.1 cm2 to 17.2 ± 3.8 cm2; p < 0.05). LVEDA increased by 15% after milrinone (from 14.3 ± 2.4 cm2 to 15.6 ± 2.8 cm2; p < 0.05) but remained unchanged after epinephrine (from 17.2 ± 3.8 cm2 to 17.1 ± 4.2 cm2; p = ns). Conclusions: Left ventricular compliance was decreased after CPB. The administration of milrinone, but not epinephrine, was associated with a partial return to prebypass values. The exact mechanism of action remains to be determined. Copyright © 2000 by W.B. Saunders Company

Analysis of responses to adrenomedullin-(13-52) in the pulmonary vascular bed of rats.

The effects of human adrenomedullin-(13-52) [hADM-(13-52)] were investigated in the rat pulmonary vascular bed and in isolated rings from the rat pulmonary artery (PA). Under conditions of controlled blood flow and constant left atrial pressure when tone was increased with U-46619, injection of hADM-(13-52) produced dose-related decreases in lobar arterial pressure. Pulmonary vasodilator responses in the intact rat and vasorelaxant responses to hADM-(13-52) in rat PA rings were inhibited by NG-nitro-L-arginine methyl ester (L-NAME) and L-N5-(1-iminoethyl)-ornithine hydrochloride (L-NIO). Vasorelaxant responses to hADM-(13-52) were also inhibited by methylene blue, endothelium removal, hADM-(26-52), and iberiotoxin, whereas meclofenamate, calcitonin gene-related peptide-(8-37) [CGRP-(8-37)], glibenclamide, and apamin were without effect. Because vasorelaxant responses to NS-1619, a large-conductance Ca(2+)-activated K+ channel agonist, were not altered by L-NAME and vasorelaxant responses to acetylcholine and CGRP were not altered by hADM-(26-52), the present data suggest that ADM-(13-52) acts on a receptor in the pulmonary vascular bed that is coupled to endothelial nitric oxide release. These data suggest that this nitric oxide release may lead to guanosine 3',5'-cyclic monophosphate-dependent K+ channel activation, which produces a pulmonary vasorelaxant response through hyperpolarization of vascular smooth muscle cells. The present data suggest that ADM-(13-52) modulates receptor-mediated, but not voltage-dependent, pulmonary vascular contraction by influencing Ca2+ influx. These results suggest that the ADM fragment, hADM-(13-52), acts as an endothelium-dependent vasodilator agent in the pulmonary vascular bed of the rat.

Novel catheterization technique for the in vivo measurement of pulmonary vascular responses in rats.

A novel cardiac catheterization technique was devised to investigate the pulmonary arterial pressure-blood flow relationship in intact spontaneously breathing rats (ISBR) under physiological conditions with constant left atrial pressure and controlled blood flow within the normal range. Observations using this new technique in vivo were contrasted with data derived with isolated perfused rat lungs in vitro. Unlike results in in vitro isolated perfused rat lungs, the pressure-flow curves in vivo were curvilinear, with pulmonary artery pressure increasing more rapidly at low pulmonary blood flows of 4-8 ml/min and less rapidly at higher flow rates. Pressure-flow curves were reproducible and were not altered by 1-1.5 h of arrested perfusion, cyclooxygenase blockade, or perfusion with aortic or mixed venous blood. In contrast to results in in vitro isolated perfused rat lungs, NG-nitro-L-arginine methyl ester (L-NAME) increased pulmonary arterial pressure at all but the lowest flow rates with a slight effect on the curvilinear pressure-flow relationship. L-NAME reversed pulmonary vasodilator responses to acetylcholine and bradykinin and enhanced the pulmonary vasodilator response to nitroglycerin. The present data suggest that actively induced pulmonary hypertension is under greater control by endothelium-derived relaxing factor (EDRF). Unlike previous results in in vitro perfused rat lungs, results in ISBR demonstrate that the pulmonary vasodilator response to adrenomedullin-(13-52) is not mediated by calcitonin gene-related peptide receptors, which are not coupled to the release of EDRF. These results indicate that this novel technique may provide a useful model for the study of the pulmonary circulation in the intact chest rat.

Pharmacologically Induced Heart Failure for the Evaluation of Circulatory Assistance.

For the evaluation of the hemodynamic interaction between the natural heart and an assist device, a reversible pharmacological model based on the channel blocker Verapamil under hyperkalemia, was developed for deterioration of left ventricular function. Four calves weighing 70-90 kg underwent standard implantation for left atrioaortal assist (BioMedicus, BP-80), pump anesthesia (oxygen/isoflurane [1%]; 8 mg/kg of BW/h keta-mine), and of ventricular demand pacing at 120 bpm. Left atrial pressure (LAP), ventricular pressure (LVP), aortic pressure (AoP), pulmonary arterial (Qpulm) pressures, and graft flow (Qgraft) were monitored. The hemodynamic effects of anesthetic overdose (2% Isoflurane) were compared with those of Verapamil (Isoptin: 0.2 mg/kg BW/h 5 mmol/kg of BW/h of KC1) medication. Both regimens caused a decrease in AoP to ≤50%. For Isoflurane, a slight reduction in cardiac output (CO) of 10% at a nearly constant LAP and a strong decrease of the peripheral resistance (Rperi) of 35% could be seen where Isoptin caused a significant reduction in CO of 40% at an increased LAP (+ 25%) and changes in Rperi of <10%. Because the vascular tonus remains nearly constant, the hemodynamic effects are controllable and reversible (antagonized with calcium chloride); thus we conclude that Verapamil administration under hyperkalemia conditions is a proper model for mimicking congestive heart failure with low systemic side effects.

Pharmacological probes for A1 and A2 adenosine receptors in vivo in feline pulmonary vascular bed.

Under conditions of controlled pulmonary blood flow and constant left atrial pressure, adenosine produces dose-dependent, tone-dependent responses in the pulmonary vascular (PV) bed of intact-chest, spontaneously breathing cats. The potency profile for adenosine receptor agonists to produce vasoconstriction at low baseline PV tone is 5'-(N-ethylcarboxamido)adenosine > or = CGS-21680 > or = 2-chloroadenosine (2-CADO) > or = [R]-N6-(2-phenylisopropyl)adenosine (R-PIA) > or = N6-cyclopentyladenosine > adenosine > > CV-1808. After an increase in PV tone with the use of an intralobar infusion of the thromboxane mimic U-46619, the potency profile for adenosine receptor agonists to produce vasodilation at elevated PV tone is 2-CADO > or = CV-1808 > or = CGS-21680 > R-PIA > or = adenosine. The selective A1 adenosine receptor antagonists xanthine amine congener (XAC) and 8-cyclopentyl-1,3-dipropylxanthine (DP-CPX) significantly antagonize the vasoconstrictor responses of adenosine and R-PIA at low baseline PV tone while having less effect on the vasodilator responses of adenosine, 2-CADO, and R-PIA at elevated PV tone. DPCPX antagonizes the vasoconstrictor responses of CGS-21680 at low baseline PV tone. The nonselective A1 and A2 adenosine receptor antagonist BWA-1433U significantly antagonizes vasoconstrictor responses of R-PIA and vasodilator responses of adenosine, 2-CADO, and R-PIA. These data support that adenosine produces vasoconstriction at low baseline PV tone and vasodilation at elevated PV tone in the feline PV bed by acting on A1 and A2 adenosine receptors, respectively. Compared with the adenosine receptor agonists tested in this in vivo model, R-PIA and CV-1808 are the most selective adenosine receptor agonists for A1 and A2 adenosine receptors, respectively, in the feline PV bed. R-PIA, CV-1808, DPCPX, and XAC may be used in this in vivo model to define the roles of A1 and A2 adenosine receptors in acute lung injury and pathophysiological changes in the pulmonary vasculature associated with pulmonary hypertension and edema formation in the same animal model.

Role of G proteins in the vasodilator response to endothelin isopeptides in vivo

The purpose of the present study was to determine the influence of pertussis toxin (PTX) on the pulmonary and systemic vasodilator responses to endothelin (ET) isopeptides in the intact cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by an intralobar arterial infusion of U-46619, intralobar arterial bolus injections of ET-1, ET-2, and ET-3 decreased lobar arterial pressure and systemic vascular resistance in a dose-related manner. The vasodilator responses to ET-1 and ET-2 in the cat lung were abolished by PTX pretreatment, whereas PTX pretreatment did not alter the pulmonary vasodilator response to ET-3 and cromakalim, a specific ATP-sensitive potassium (KATP) channel activator, and the systemic vasodilator responses to all ET isopeptides studied. Glipizide, an inhibitor of KATP channels, inhibited the pulmonary vasodilator responses to ET-1, ET-2, and ET-3, whereas the systemic vasodilator responses to these isopeptides were not changed. The present data are the first to provide a functional correlate in vivo suggesting the existence of different signal transduction mechanisms for two pulmonary vascular ET receptor subtypes, ETA-like that is PTX sensitive and has greater sensitivity to ET-1 and ET-2 (than to ET-3) and ETc-like that is PTX insensitive and has sensitivity to ET-3 (than to ET-1 and ET-2). However, both ET-receptor subtypes promote vasodilation in the adult pulmonary vascular bed by activating KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Tone-dependent responses of histamine in feline pulmonary vascular bed

Under conditions of controlled pulmonary blood flow and constant left atrial pressure, histamine produced tone-dependent responses in the pulmonary vascular (PV) bed of intact-chest, spontaneously breathing cats. At low, baseline PV tone, histamine produced dose-dependent increases in mean lobar arterial pressure that were antagonized by the selective histamine H1-receptor antagonist, diphenhydramine. The cyclooxygenase inhibitor, meclofenamate, and the thromboxane A2 (TxA2) receptor antagonist, SQ-29548, had no effect on these vasoconstrictor responses of histamine. After an increase in PV tone with an intralobar arterial infusion of a TxA2 mimic, U-46619, histamine produced vasodilator responses at low doses, biphasic vasodilator/vasoconstrictor responses at midrange doses, and vasoconstrictor responses at high doses. Diphenhydramine antagonized vasoconstrictor responses and the vasodilator responses of low to midrange doses and enhanced vasodilator responses of high doses of histamine at elevated PV tone. Selective H2-receptor antagonists, ranitidine and meclofenamate, and selective H3-receptor antagonist, thioperamide, did not antagonize vasodilator responses of histamine. H1- and H2-receptor antagonism was more effective in reducing the vasodilator responses of histamine at elevated PV tone than H1-receptor antagonism alone. These data support that histamine produces vasoconstrictor responses at low baseline and elevated PV tone by acting on H1 receptors that do not induce the release of vasoconstrictor prostanoids. At elevated PV tone, histamine produces vasodilation by acting on H1 receptors that are not coupled to the release of vasodilator prostaglandins and also, in part, by acting on H2 receptors.

Starling resistor vs. distensible vessel models for embolic pulmonary hypertension

We investigated whether the Starling resistor model (Mitzner et al. J. Appl. Physiol. 51: 1065-1071, 1981) or a distensible vessel model (Haworth et al. J. Appl. Physiol. 70: 15-26, 1991) best describes pulmonary vascular pressure-flow (Q) relationships in embolic pulmonary hypertension. Mean pulmonary arterial pressure (Ppa)-Q plots at constant left atrial pressure (Pla) and Ppa-Pla plots at constant Q were investigated in seven dogs before and after 500-micron glass bead pulmonary embolism. Embolization to a mean angiographic obstruction of 78% increased the slope and extrapolated pressure intercept (P(i)) of Ppa-Q plots and increased the inflection point of Ppa-Pla plots, above which an increase in Pla is transmitted to Ppa in a ratio of approximately 1:1. The Starling resistor and the distensible vessel model provided a reasonably good fit to the Ppa-Q and Ppa-Pla coordinates before and after embolism. However, contrary to the prediction of the Starling resistor model, no correlation was found between the inflection point of Ppa-Pla plots and P(i). We therefore conclude that an increased closing pressure is unlikely to contribute to embolic pulmonary hypertension.

Influence of [formula omitted] methyl ester, LY83583, glybenclamide and L158809 on pulmonary circulation

The effects of N ω- nitro- L-arginine methyl ester, an inhibitor of nitric oxide synthase; 6-anilino-5,8-quinolinedione (LY83583), an inhibitor of soluble guanylate cyclase; glybenclamide, a ATP-sensitive K + channel blocking agent; and 5,7-dimethyl-2-ethyl-3-[[2′-(1 H-tetrazol-5-yl)-[1,1′]-biphenyl-4-yl]methyl]-3 H-imidazo[4,5- b]pyridine (L158809), an angiotensin II type I receptor antagonist, on the response to ventilatory hypoxia were investigated in the isolated blood-perfused rat lung. Under conditions of controlled pulmonary blood flow, and constant left atrial pressure, injections of glybenclamide into the pulmonary arterial perfusion circuit significantly increased baseline pulmonary arterial perfusion pressure, whereas administration of N ω- nitro- L- arginine methyl ester produced smaller increases in baseline tone. Ventilatory hypoxia (3% O 2-5% CO 2-92% N 2) significantly increased pulmonary arterial perfusion pressure and the response was reproducible with respect to time. Following administration of N ω- nitro- L-arginine methyl ester or LY83583, the response to hypoxia was significantly increased, whereas the response to hypoxia was not changed by glybenclamide or atropine. N ω- Nitro- L-arginine methyl ester also significantly enhanced pressor responses to angiotensin II, but had no effect on the pressor response to serotonin. When pulmonary vascular tone was increased with hypoxia, vasodilator responses to acetylcholine were inhibited by N ω- nitro- L-arginine methyl ester and vasodilator responses to levcromakalim were reduced by glybenclamide. In addition, L158809 did not alter the pressor response to hypoxia, whereas responses to angiotensin II were reduced in a selective manner. The present data demonstrate that glybenclamide, and to a smaller extent, N ω- nitro- L-arginine methyl ester, significantly increased baseline pulmonary arterial pressure, suggesting that activation of ATP-sensitive K + channels, and to a smaller extent, tonic release of nitric oxide, modulate baseline tone in the pulmonary circulation of the rat. The results of the present study also show that N ω- nitro- L-arginine methyl ester and LY83583 enhance the pressor response to hypoxia, but that glybenclamide and L158809 have no effect on the response to hypoxia, suggesting that the response to hypoxia is modulated by nitric oxide production and the activation of soluble guanylate cyclase, but not by alterations in ATP-sensitive K + channel activity or changes in angiotensin II levels in the isolated blood-perfused rat lung.

Analysis of responses to bradykinin in the pulmonary vascular bed of the cat.

Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K+ATP channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine benzyl ester and N omega-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of angiotensins I, II, and III in pulmonary vascular bed of the rat.

The inhibitory effects of losartan (Dup 753), a nonpeptide angiotensin (ANG) II-type 1 receptor antagonist, on responses to ANG I, II, and III were investigated in the isolated perfused lung of the rat. Under conditions of constant pulmonary blood flow and left atrial pressure, injections of ANG I, II, and III into the pulmonary arterial perfusion circuit caused dose-related increases in pulmonary arterial pressure. Responses to ANG I, II, and III were reproducible with respect to time, and Dup 753, in a dose of 3 nM/ml injected into the perfusion circuit, decreased responses to the three peptides. Dup 753 had no significant effect on pressor responses to norepinephrine, serotonin, or BAY K 8644, and Dup 753 had no significant effect on mean baseline pulmonary arterial or airway pressure. Captopril and enalaprilat, ANG II-converting enzyme inhibitors, decreased the pressor response to ANG I while increasing the pressor response to ANG II and III. In addition, responses to ANG I, II, and III were similar when compared on a molar basis, suggesting the three peptides had similar pressor activity in the isolated perfused rat lung. Pressor responses to the angiotensin peptides were greater compared with responses to pressor agents that increase vascular resistance by various mechanisms, and Dup 753 did not significantly alter the pressor response to ventilatory hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Optimal shape of prosthesis for tricuspid valve replacement

To develop an optimal prosthesis for use in the tricuspid valve, we determined the change in cardiac performance associated with the change in shape of the anulus of the tricuspid valve using a metal ring of variable flat ratio (defined as the long/short axis). In experiment I in an isolated autoperfusion model with six dogs, the left ventricular stroke work under a constant left atrial pressure of 7 mm Hg were, in grams per beat per minute, 11.88 +/- 0.52 with a flat ratio of 1.0, 11.88 +/- 0.70 with a flat ratio of 1.3, 16.23 +/- 0.61 with a flat ratio of 1.6, and 11.22 +/- 0.38 with a flat ratio of 2.3 (mean +/- standard error of the mean). The volume was significantly higher with a flat ratio of 1.6 than with the other ratios (p < 0.05). In experiment II with six dogs in vivo, the blood flow of the pulmonary trunk artery was 0.57 +/- 0.03 L/min with a flat ratio of 1.0, 0.66 +/- 0.03 L/min with a flat ratio of 1.6, and 0.58 +/- 0.03 L/min with a flat ratio of 2.3; the flow was significantly larger with a ratio of 1.6 than with the other ratios (p < 0.05). Right ventriculography was performed in five dogs. The percentage of radial shortening of the apex close to the acute margin was 19.4% +/- 3.1% with a flat ratio of 1.0 and 49.2% +/- 5.1% with a flat ratio of 1.6 (p < 0.05). In conclusion, the best hemodynamic results were obtained with a flat ratio of 1.6, which showed more advantageous hemodynamics than do the ratios of conventional circular prostheses.

Functional evidence for different endothelin receptors in the lung

The present study was undertaken to compare and contrast the characteristics of the pulmonary and systemic vascular responses to endothelin (ET) isoforms in the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone (PVT) was actively increased by intralobar infusion of U-46619, intralobar arterial bolus injections of 1 microgram ET-1, 1 microgram ET-2, or 3 micrograms ET-3 markedly decreased lobar arterial pressure, systemic arterial pressure, and systemic vascular resistance. After seven repeated injections of ET-1 or ET-2 to separate groups of cats, pulmonary and systemic responses were largely reversed from vasodilation to vasoconstriction. In contrast, the pulmonary vasodilator response to ET-3 remained intact after multiple ET-3 injections, whereas its systemic vasodilator response was lost. Repeated intralobar arterial bolus injections of ET-1, ET-2, or ET-3 also caused the loss of pulmonary vasodilation to subsequent doses of ET-1, ET-2, or sarafotoxin 6b but not to ET-3. The present data suggest that the pulmonary and systemic vasodilator responses to ET-1 and ET-2 undergo tachyphylaxis and cross-tachyphylaxis. In contrast, the pulmonary vasodilator response to ET-3, unlike its systemic vasodilator response, is resistant to tachyphylaxis and cross-tachyphylaxis. The present data provide a functional correlate for the existence of at least two ET receptor subtypes, ETA-like and ETC-like receptors, in the adult pulmonary vascular bed.

A distensible vessel model applied to hypoxic pulmonary vasoconstriction in the neonatal pig.

Recently, we presented a simple two-parameter distensible vessel model as a potential tool for characterizing pulmonary vascular pressure vs. flow curves under zone 3 conditions (Linehan et al. J. Appl. Physiol. 73: 987-994, 1992). One parameter, alpha, represents the distensibility of the resistance vessels as the fractional change in vessel diameter per Torr change in pressure, and the other parameter, R0, represents the vascular resistance that would exist if the resistance vessels were at their respective diameters obtained if the vascular pressure were zero. The objective of the present study was to determine whether this distensible vessel model was capable of describing the pressure vs. flow data obtained during hypoxia vasoconstriction and under control conditions in isolated lungs from neonatal pigs. The piglet lungs were perfused with autologous blood, and the pulmonary arterial pressure was measured over a range of flow rates from 15 to 250 ml.min-1 x kg-1 at constant left atrial (3 Torr) pressure. The model provided a reasonable fit to the data under both conditions. Hypoxia resulted in a significant increase in R0, from 0.39 +/- 0.10 Torr.ml-1 x min.kg during control conditions to 1.41 +/- 0.46 Torr.ml-1 x min.kg during hypoxia. alpha was 2.4 +/- 0.4%/Torr under control conditions and 2.0 +/- 0.4%/Torr during hypoxia, but this difference was not statistically significant. The results suggest that the distensible vessel model may be useful for interpreting pressure-flow data in terms of changes in geometry and distensibility of the resistance vessels in response to a vasoconstrictor stimulus such as hypoxia.

Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed.

The influence of Zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, was investigated in the pulmonary vascular bed of the cat under conditions of controlled blood flow and constant left atrial pressure. Under baseline conditions, injections of Zaprinast into the perfused lobar artery produced small decreases in lobar arterial pressure without altering systemic arterial or left atrial pressure. When tone was increased with U-46619, Zaprinast caused larger dose-dependent decreases in lobar arterial pressure without altering left atrial pressure. The decreases in lobar arterial pressure were reduced significantly by treatment with the nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the guanylate cyclase inhibitor methylene blue. Under elevated tone conditions, efferent vagal stimulation and intralobar injections of acetylcholine, substance P, NO solution, and the S-nitrosothiols [S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-L-cysteine (CysNO)] decreased lobar arterial pressure in a frequency-dependent and dose-related manner. After treatment with Zaprinast, the decreases in lobar arterial pressure in response to efferent vagal stimulation, the endothelium-dependent vasodilators, and the nitrovasodilators were not changed, whereas the duration of the vasodilator responses as measured by the half times was increased significantly. Vasodilator responses to adenosine, albuterol, and pinacidil were not altered by Zaprinast. These data suggest that cGMP hydrolysis in the lung is rapid and that endothelium-derived NO is important in stimulating basal cGMP production and in regulating vascular tone.(ABSTRACT TRUNCATED AT 250 WORDS)