Elevated Pulmonary Vascular Tone Research Articles

Care for patients with ventricular assist devices and suspected COVID-19 infection.

Care for patients with ventricular assist devices and suspected COVID-19 infection.

Pulmonary Responses to Selective Phosphodiesterase-5 and Phosphodiesterase-3 Inhibitors

To compare the direct pulmonary vasodilating activity and specificity of phosphodiesterase-5 (zaprinast) and phosphodiesterase-3 (milrinone) inhibitors on the pulmonary vascular (PV) bed of the spontaneously breathing cat with an intact chest. Prospective, randomized animal study. Laboratory of university hospital. Experiments were performed in vivo in intact-chest, spontaneously breathing cats with controlled pulmonary blood flow and constant left atrial pressure. The responses to intralobar injections of zaprinast and milrinone were investigated at low PV tone. PV tone was then increased by intralobar arterial infusion of a thromboxane A(2) mimic, U46619. Animals received intralobar bolus injections of zaprinast or milrinone, followed by continuous IV infusion of the drug, which was administered in incremental doses titrated to produce a 20% reduction in mean systemic arterial pressure. At low PV tone, zaprinast, but not milrinone, decreased lobar arterial pressure (LoAP). At elevated PV tone, both drugs caused dose-dependent decreases in LoAP; however, milrinone caused significantly less pulmonary vasodilation. Dose-related decreases in mean systemic arterial pressure were observed with milrinone, but not with zaprinast. When the continuous IV infusion was titrated to produce a 20% reduction in mean systemic arterial pressure, the decreases in lobar arterial pressure with zaprinast infusion were significantly greater than those produced by milrinone. These data show that zaprinast and milrinone exert a direct in vivo vasodilator effect on the PV bed at low (zaprinast) and elevated (zaprinast and milrinone) PV tone; however, at elevated PV tone, the pulmonary vasodilator effect was greater with zaprinast then with milrinone. This suggests that phosphodiesterase-5 inhibitors may potentially offer a therapeutic alternative in the management of acute pulmonary hypertension.

Decreased Basal Production of Nitric Oxide in Patients With Heart Disease

The pathophysiologic role of nitric oxide (NO) released in the lung is not well understood. To determine whether the production of endogenous NO is correlated with any hemodynamic parameters, we measured the amount of NO released from the lung tissue of patients with heart disease. Twenty patients (14 with ischemic heart disease, 4 with dilated cardiomyopathy, and 2 with mitral stenosis) and 16 normal control subjects were enrolled in the study. We measured exhaled air samples by using a method developed in our laboratory. The NO release rate from the lungs was calculated from the amount of exhaled NO and the duration of the exhalation. The rate of NO release was significantly lower in the patients with moderate-to-severe heart failure (New York Heart Association [NYHA] II or III) than in those with mild heart failure (NYHA I) or in normal control subjects. The rate of NO release was positively correlated with the cardiac index (r=0.50, p<0.05), and was negatively correlated with either the systemic (r= -0.58, p<0.01) or pulmonary vascular resistance (r=-0.45, p<0.05). In the patients with moderate-to-severe heart failure, the amount of NO released and the oxygen tension in the pulmonary artery were significantly lower compared with those parameters in patients with mild heart failure. Results suggest that the basal production of endogenous NO in the lung tissue of patients with heart failure is impaired, perhaps leading to the elevated pulmonary vascular tone seen in patients with moderate-to-severe heart failure.

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.

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.

Purinergic responses in the feline pulmonary vascular bed

AbstractAdenosine and ATP produce dose‐dependent, tone‐dependent response in the pulmonary vascular (PV) bed, under conditions of controlled pulmonary blood flow and constant left atrial pressure in vivo in intact‐chest, spontaneously breathing cats. At low, resting PV tone, adenosine produces dose‐dependent vasoconstrictor responses by acting on “A1‐like” adenosine receptors which activate a phospholipase and thromboxane release. ATP Produces dose‐dependent vasoconstrictor responses, in part, following its metabolism to adenosine, by acting on “A1‐like” adenosine receptors and by acting on P2x receptors. At elevated PV tone, data to date support that adenosine and ATP produce dose‐dependent vasodilator responses by acting on A2 and P2Y receptors, respectively. Mechanisms to explain how a change in vascular tone alters the response of the vascular bed to a substance are not known. Moreover, the role of purinoceptors in pulmonary vascular disease is not known. Identification of selective pharmacological probes for purinoceptors in the pulmonary vascular bed is necessary to investigate their role in the development of pulmonary hypertension of acute and chronic lung disease. © 1993 Wiley‐Liss, Inc.

Amrinone Reduces Pulmonary Vascular Resistance Elevated by U46619 in Isolated Perfused Lungs

The effects of amrinone on pulmonary vascular resistance (PVR) were studied in an isolated, perfused rabbit lung model where all the major determinants of PVR were controlled. In this preparation, the alveolar oxygen and carbon dioxide tensions, vascular pH and vascular oxygen and carbon dioxide tensions, and zonal conditions of the lung and phasic variations of pulmonary artery pressures could be precisely measured and controlled. Measurements of PVR were made by a complete determination of the pulmonary pressure-flow curve and determination of the PVR under identical flow conditions for all studies. This approach allowed a more precise determination of the primary effects of amrinone on normal and elevated PVR than has been previously possible. We found that amrinone in final concentrations of either 4 or 8 micrograms/ml had no effect on basal PVR and no effect on lung water weight to dry ratios. When PVR was elevated by the addition of the thromboxane A2 mimetic U46619, amrinone reduced the PVR by 27% at a final concentration of 4 micrograms/ml and by 74% at a final concentration of 8 micrograms/ml. We conclude that in the doses tested, amrinone has no effects on basal PVR but is able to reduce elevated PVR in a dose-dependent manner. These results are the first to demonstrate clearly that amrinone has the ability to reduce elevated pulmonary vascular tone through a direct mechanism and not through secondary effects on other determinants of PVR such as left atrial pressure (Pla), increased cardiac output with resultant vascular recruitment, or increases in mixed venous oxygen tension. The possible implications for the clinical use of amrinone in situations of elevated PVR are discussed.

Effects of substance P and calcitonin gene-related peptide on the pulmonary circulation

To assess the in vivo effects of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) on the pulmonary vascular bed, the hemodynamic responses to both CGRP and SP were examined in the in situ-perfused lung lobe of open-chest anesthetized pigs. Peptides were infused into the lobar artery under conditions of elevated pulmonary vascular tone by prostaglandin F2 alpha (PGF2 alpha, 20 micrograms/min). Pulmonary airway lobar dynamic compliance (Cdyn) and airway resistance (Re) were computed from simultaneously measured airway pressure and airflow entering the lobe through a Carlens endobronchial divider. PGF2 alpha infusion slightly reduced Cdyn (-20%) and increased Re (+11%) while lobar arterial pressure rose from 14 +/- 1 to 31 +/- 2 mmHg (n = 12). In these conditions, lobar artery infusion of SP (0.5-50 pmol/min) or CGRP (15-5,000 pmol/min) produced a dose-dependent decrease in the pressor response to PGF2 alpha, reaching -54 +/- 3 and -64 +/- 7%, respectively, without alterations in lung mechanics. On a molar basis, SP was more effective than CGRP; its vasodilatory effect was more rapid and of shorter duration. Higher CGRP infusion rates were not studied because of marked systemic hypotension. SP infused at 150, 500, and 1,000 pmol/min significantly reduced Cdyn by 12 +/- 2, 24 +/- 4, and 62 +/- 7%, respectively, but also induced a rise in lobar arterial pressure and a fall in systemic arterial pressure. The results show that both SP and CGRP are potent pulmonary vasodilators. In contrast to CGRP, which did not affect lung mechanics, high infusion rates of SP decreased Cdyn and increased Re.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary vasodilator responses to atrial natriuretic factor and sodium nitroprusside

The objective of this study was to determine the direct actions of atrial natriuretic factor (ANF) on the pulmonary vascular bed and to compare these actions with those of sodium nitroprusside (SNP). The responses to incremental infusion rates of 1, 5, 10, and 50 ng.kg-1.min-1 synthetic human ANF and to 1-2 micrograms.kg-1.min-1 SNP were examined in the in situ autoperfused lung lobe of open-chest anesthetized pigs under conditions of normal and elevated pulmonary vascular tone. During basal conditions, ANF and SNP caused small but significant reductions in pulmonary artery pressure (Ppa) and pulmonary venous pressure (Ppv) with no change in lobar vascular resistance (LVR). When pulmonary vascular tone was increased by prostaglandin F2 alpha (20 micrograms/min), ANF infusion at doses greater than 1 ng.kg-1.min-1 decreased Ppa and LVR in a dose-related fashion. Infusion of 50 ng.kg-1.min-1 ANF and of 2 micrograms.kg-1.min-1 SNP maximally decreased Ppa, from 33 +/- 3 to 20 +/- 2 mmHg (P less than 0.001) and from 31 +/- 4 to 18 +/- 1 mmHg (P less than 0.001), respectively. At these doses, ANF reduced systemic arterial pressure by only 11.5 +/- 3% compared with 34 +/- 4% decreased with SNP (P less than 0.001). The results indicate that ANF, similarly to SNP, exerts a direct potent vasodilator activity in the porcine pulmonary vascular bed, which is dependent on the existing level of vasoconstrictor tone.

肺循環とプロスタノイド 特に低酸素性肺血管収縮におけるプロスタノイドの関与

Hypoxic pulmonary vasoconstriction (HPV) is known to be an important physiological response to preserve an appropriate ventilation-perfusion ratio in the lung. The precise mechanism of HPV remains to be controversial, but recently the role of prostaglandins for mediating and/or modulating HPV has been emphasized. From this viewpoint, we studied the effect of PAF on HPV in anesthetized, open chest mongrel dogs. HPV was assessed by the change of total pulmonary resistance (TPR, PPA-PLA/QAO) . After the stable condition was established, 15-min exposure to 10% O2 followed by 15-min exposure to 100% O2 was repeated 6 times.In control group (N=5), spontaneous potentiation of HPV was observed during the 1st to the 5th hypoxic exposures, but an attenuation was occurred in the 6th hypoxic exposure.In PAF treatment group (N=5), the 6th hypoxic exposure was performed during continuous infusion of PAF at the dose of 33 ng/kg/min for 30 min (totally 1μg/kg) . This group showed no attenuation but potentiation of HPV in the 6th hypoxic exposure.Pretreatment with CV-3988 (10mg/kg), a specific antagonist of PAF, blocked the potentiating effect on HPV induced by PAF but pretreatment with OKY-046 (10mg/kg), a specific thromboxane synthetase inhibitor, did not block the effect of PAF.It is suggested that PAF, at the dose of 1μg/kg, acts as vasoconstrictor even in the condition of elevated pulmonary vascular tone induced by HPV in mongrel dogs.