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Biomedical subjects

I C Ehrhart

Publications and source records attributed to I C Ehrhart.

At least 19 recordsLinked to original sources
PubMed2001

Pentoxifylline rescue preserves lung function in isolated canine lungs injured with phorbol myristate acetate.

OBJECTIVE: We hypothesized that pentoxifylline, administered after phorbol myristate acetate (PMA), would diminish the severity of lung injury. SETTING: Animal research laboratory. DESIGN: Comparative study. SUBJECTS: Mongrel dogs (n = 33). INTERVENTIONS: Baseline measurements were obtained from the isolated blood-perfused dog lung lobes after 1 h of stable perfusion and ventilation. Four different measures of lung compliance were obtained along with WBC and neutrophil counts. Pulmonary vascular resistance (PVR) and capillary filtration coefficient (Kf) were calculated, and the ratio of a normalized maximal enzymatic conversion rate to the Michaelis-Menten constant (Amax/Km) was used to assess perfused capillary surface area. The control lobes (n = 8) were ventilated and perfused for an additional 40 min while the injured lobes (n = 17) received PMA (0.1 microg/mL of perfusate). The pentoxifylline-protected lobes (n = 8) were treated with pentoxifylline (1 mg/mL of perfusate) 10 min after injury with PMA. All measurements were then repeated. MEASUREMENT AND MAIN RESULTS: The three groups did not differ significantly at baseline. The control lobes remained relatively stable over time. The injured lobes demonstrated marked deterioration in compliance: 8.79 +/- 0.7 to 5.97 +/- 0.59 mL/cm H(2)O (p < 0.05) vs 10.1 +/- 1.0 to 8.07 +/- 0.72 mL/cm H(2)O and 9.6 +/- 1.1 to 9.9 +/- 0.85 mL/cm H(2)O in the control and protected lobes, respectively. Both groups receiving PMA had similar drops in WBC and neutrophil counts, but the pentoxifylline-protected lobes had preservation of all four compliance measures. PVR increased from 37.8 +/- 1.8 to 118.6 +/- 12.7 cm H(2)O/L/min (p < 0.05) in the injured lobes vs 35.4 +/- 0.5 to 36.3 +/- 2.8 cm H(2)O/L/min and 40.4 +/- 0.04 to 46.7 +/- 2.8 cm H(2)O/L/min (p < 0.05) in the control and protected lobes, respectively. Kf increased < 25% in the protected group but more than tripled in the injured group. Amax/Km dropped from 559 +/- 36 to 441 +/- 33 mL/min (p < 0.05) in the injured lobes vs 507 +/- 14 to 490 +/- 17 mL/min and 609 +/- 34 to 616 +/- 37 mL/min in the control and pentoxifylline-protected lobes, respectively. CONCLUSIONS: The use of pentoxifylline as a rescue agent prevented the PMA-induced deterioration of lung compliance, vascular integrity, and endothelial metabolic function in this acute lung injury model, despite significant pulmonary neutrophil sequestration.

Animals↗
PubMed2000

Effect of nitrite on endothelial function in isolated lung.

Nitrated tyrosine, implicated in protein dysfunction, is increased in various tissues in association with diverse pathological processes. Angiotensin converting enzyme (ACE) is a luminal vascular endothelial enzyme whose dysfunction is an early sign of endothelial injury. ACE contains a tyrosine critical for its enzymatic activity. Others have shown that nitrite exacerbates the ACE dysfunction of cultured endothelial cells in contact with activated polymorphonuclear neutrophils (PMN). We hypothesized that exogenous nitrite would enhance endothelial ACE dysfunction associated with PMN activation in the isolated lung. Rats received lipopolysaccharide (LPS) 2 h prior to isolated lung perfusion with Ficoll containing buffer. Either formyl-Met-Leu-Phe (fMLP, 10(-7) M) or phorbol myristate acetate (PMA, 10(-7) M) was used to activate PMN in lungs treated or not treated with 300-microM nitrite. A first pass indicator dilution method and first order reaction kinetics were used to determine ACE activity, while lung Ficoll content served as an index of vascular permeability. Both fMLP and PMA decreased endothelial ACE activity and increased pulmonary artery pressure, edema and vascular permeability. Exogenous nitrate did not potentiate the decrease in ACE activity, the lung injury or nitrotyrosine immunoreactivity of lung homogenates. In contrast to observations in cultured endothelial cells, our findings in the whole lung are compatible with the speculation of others that the rat lung has an unidentified factor, which minimizes accumulation of nitrated proteins.

Animals↗
PubMed1999

Vascular recruitment increases evidence of lung injury.

OBJECTIVE: Changes in pulmonary blood flow rate can alter the size of the perfused pulmonary capillary surface area. We tested the hypothesis that full recruitment of the pulmonary vascular bed may decrease evidence of lung injury by recruiting less injured capillaries. We also tested the hypothesis that endothelial ectoenzyme activity is an earlier indicator of lung injury than are permeability measures. DESIGN: Isolated canine lung lobes were perfused with autologous blood at constant blood flows of either 2.05+/-0.04 L/min (SEM) (high flow, full recruitment, n = 12) or 0.600 +/- 0.004 L/min (low flow, 33% full recruitment, n = 12) after lung injury to determine the effect of vascular recruitment on measures of injury. SETTING: Research laboratory at a medical university. SUBJECTS: Lung lobes were obtained from 36 mongrel dogs of either gender. INTERVENTIONS: Lung injury was induced by adding phorbol myristate acetate (PMA) to the blood perfusing the isolated lung. MEASUREMENTS AND MAIN RESULTS: Indicator dilution methods were used to measure single pass hydrolysis of 3[H]-benzoyl-Phe-Ala-Pro, a synthetic substrate for angiotensin converting enzyme, and calculate the modified first order kinetic parameter corresponding to the ratio of a normalized maximal enzymatic conversion rate (A(max)) to the Michaelis-Menten constant (K(m)), i.e., A(max)/K(m), before and after PMA. At a given flow rate, the decrease in A(max)/K(m)serves as an index of vascular injury. PMA decreased A(max)/K(m), percent metabolism, and fractional substrate utilization, and increased permeability, vascular resistance, and vascular pressures regardless of flow rate. The decrease in enzyme activity was detected earlier than the increase in permeability. CONCLUSION: The greater percentage decrease in percent metabolism and fractional substrate utilization and the earlier appearance of increased permeability during high flow indicates that increasing blood flow three-fold recruited injured vessels and/or increased vascular injury by increasing vascular perfusion pressures.

Animals↗
PubMed1998

Ventilation above closing volume reduces pulmonary vascular resistance hysteresis.

The aim of this study was to determine the relationship of pulmonary vascular resistance (PVR) hysteresis and lung volume, with special attention to the effects of ventilation around closing volume (CV). Isolated, blood-perfused canine left lower lung lobes (LLL) were incrementally inflated and deflated. Airway and pulmonary artery pressures (PAP) were recorded after each stepwise volume change. Constant blood flow was provided (600 ml/min) and the pulmonary vein pressure (PVP) was held constant at 5 cm H2O. PAP changes, therefore, were a direct index of PVR changes. Group 1 lobes underwent a full inflation from complete collapse to total lobe capacity (TLC) followed by a full deflation. Group 2 lobes underwent two deflation/inflation cycles, after an initial full inflation. These cycles, both beginning at TLC, had deflation end above and below CV, respectively. Significant PVR hysteresis was noted when the first inflation and deflation were compared. The maximum difference in PAP on deflation was 3.3 cm H2O or 11%. The mean decrease was 2.7 cm H2O for 18 lobes (p < 0.0001). The PAPs on all subsequent inflations or deflations that began above CV remained 9% lower than the initial inflation (n = 9, p < 0.0001), but were not different from each other. However, the final inflation which began from below CV resulted in a 30% return of PVR hysteresis (mean increase in PAP of 0.8 cm H2O, n = 7, p < 0.004). We conclude that there is hysteresis in the PVR response during ventilation, with decreased PVR during deflation relative to the initial inflation, that this hysteresis is absent when lung volume is maintained greater than CV, and that hysteresis returns when inflation occurs after deflation below CV.

Air Pressure↗
PubMed1997

Endothelial ectoenzyme assays estimate perfused capillary surface area in the dog lung.

Whether the pulmonary vascular bed accommodates flow-induced increases in blood volume mainly through recruitment of previously unperfused capillaries or distension of already perfused vessels remains controversial. The modified first order reaction parameter of an enzyme and substrate, Amax/K(m), is, under nontoxic conditions, proportional to enzyme mass. Thus for ACE, an endothelium-bound ectoenzyme uniformly distributed along the luminal surface of the pulmonary capillary bed, Amax/K(m) is proportional to the dynamically perfused capillary surface area (PCSA). We estimated single-pass translobar hydrolysis and calculated the corresponding Amax/K(m) values of the synthetic ACE substrate 3H-benzoyl-Phe-Ala-Pro (BPAP), under first-order reaction conditions, in isolated blood-perfused dog lung lobes. We additionally studied blood flow distribution using radioactive microsphere techniques. Experiments were performed under zone III conditions over a wide range of lobar blood flow rates (Qb). As Qb was increased, Amax/K(m) rose linearly, while lobar vascular resistance (LVR) decreased, suggesting capillary recruitment rather than distension. Single pass BPAP hydrolysis (v approximately 2.9 at resting Qb) was not altered over a wide range of Qb, indicative of unchanging capillary transit times. When full capillary recruitment was achieved (at Qb > 70 ml/min/g lung wet weight), further Qb elevations failed to increase Amax/K(m), but decreased BPAP hydrolysis, denoting shorter transit times through the fully recruited capillary bed. Our data indicate that, as previously shown for rabbit lung, in this canine model, increases in pulmonary blood volume are mainly accommodated through recruitment of previously unperfused capillaries throughout the entire lung.

Animals↗
PubMed1996

Measurement of pulmonary blood flow by fractal analysis of flow heterogeneity in isolated canine lungs.

Regional heterogeneity of lung blood flow can be measured by analyzing the relative dispersion (RD) of mass (weight)-flow data. Numerous studies have shown that pulmonary blood flow is fractal in nature, a phenomenon that can be characterized by the fractal dimension and the RD for the smallest realizable volume element (piece size). Although information exists for the applicability of fractal analysis to pulmonary blood flow in whole animal models, little is known in isolated organs. Therefore, the present study was done to determine the effect of blood flow rate on the distribution of pulmonary blood flow in the isolated blood-perfused canine lung lobe by using fractal analysis. Four different radiolabeled microspheres (141Ce, 95Nb, 85Sr, and 51Cr), each 15 microns in diameter, were injected into the pulmonary lobar artery of isolated canine lung lobes (n = 5) perfused at four different flow rates (flow 1 = 0.42 +/- 0.02 l/min; flow 2 = 1.12 +/- 0.07 l/min; flow 3 = 2.25 +/- 0.17 l/min; flow 4 = 2.59 +/- 0.17 l/min), and the pulmonary blood flow distribution was measured. The results of the present study indicate that under isogravimetric blood flow conditions, all regions of horizontally perfused isolated lung lobes received blood flow that was preferentially distributed to the most distal caudal regions of the lobe. Regional pulmonary blood flow in the isolated perfused canine lobe was heterogeneous and fractal in nature, as measured by the RD. As flow rates increased, fractal dimension values (averaging 1.22 +/- 0.08) remained constant, whereas RD decreased, reflecting more homogeneous blood flow distribution. At any given blood flow rate, high-flow areas of the lobe received a proportionally larger amount of regional flow, suggesting that the degree of pulmonary vascular recruitment may also be spatially related.

Animals↗
PubMed1994

Effect of high blood flow on pulmonary vascular permeability to protein.

The elevated cardiac output associated with exercise increases lung lymph flow and may increase extravascular lung water. However, it is not known if extremely elevated cardiac output alters pulmonary vascular permeability. The hematocrit-protein method was used to determine the solvent drag reflection coefficient, an index of vascular permeability to proteins, in the isolated blood-perfused canine lung lobe. Microvascular pressure was obtained by double vascular occlusion. Lobes filtered fluid during perfusion at normal flow, 0.451 +/- 0.005 l/min (LF; n = 8), or high flow, 2.319 +/- 0.080 l/min (HF; n = 7). In the LF, venous pressure was elevated to 19.0 +/- 0.5 Torr to induce filtration, whereas Pv was 3.3 +/- 0.1 Torr in the HF. In HF vs. LF, respectively, arterial pressure was 61.4 +/- 7.1 vs. 28.0 +/- 1.0 Torr (P < 0.05), microvascular pressure was 31.9 +/- 3.0 vs. 22.2 +/- 0.9 Torr (P < 0.05), and sigma was 0.52 +/- 0.07 vs. 0.51 +/- 0.02 (P > 0.05). The fivefold increase in blood flow did not alter pulmonary vascular permeability to proteins; however, the capillary filtration coefficient was fivefold greater in the HF vs. LF group (0.328 +/- 0.059 vs. 0.067 +/- 0.007; P < 0.002). These data are compatible with enzyme activity measures indicating a direct linear relationship between blood flow rate and perfused pulmonary microvascular surface area. Although the data do not rule out the possibility of increased pulmonary vascular permeability to water during very elevated blood flow rates, the greater filtration rate during elevated flow is more likely related to increases in both microvascular pressure and surface area.

Animals↗
PubMed1993

Segmental vascular pressures in lung embolism.

Average microvascular filtration pressure and vascular permeability measures were obtained in 100-microns glass bead-embolized dog lung lobes randomly assigned to groups in which isolated perfusion was designed to produce weight gain (edema groups) or no weight gain (isogravimetric groups). The solvent drag reflection coefficient (sigma), an index of vascular permeability, was obtained during edema formation, whereas isogravimetric capillary pressure was obtained during isogravimetry. Vascular permeability increased in response to embolism, because sigma was 0.53 +/- 0.03 vs. 0.80 +/- 0.05 (P < 0.005) in embolized and control lobes, respectively. Vascular occlusion methods indicated the greatest resistance increase in response to embolism in the vascular segment represented by Pao--Pdo (arterial occlusion pressure--double occlusion pressure). Because papaverine vasodilation reduced total vascular resistance (RT; P < 0.05) by decreasing Pao (P < 0.01) without altering Pdo, the RT increase in response to embolism was likely due to both vasoconstriction and obstruction. Because Pdo approximated capillary pressure at isogravimetry, Pdo appears to estimate average filtration pressure in both embolized (n = 6) and control lungs (n = 6). Arterial pressure was 56.2 +/- 13.6 vs. 17.6 +/- 1.5 cmH2O (P < 0.01) in embolized (n = 5) and control lobes (n = 6), respectively, whereas Pdo values of 16.1 +/- 1.5 vs. 12.4 +/- 0.8 (P < 0.05) suggested relatively little increase in filtration pressure in response to embolism. If the beads obstructed 100-microns vessels, the vascular segment represented by Pao--Pdo, the major site of vasoconstriction as well as mechanical obstruction, likely includes 100-microns arteries.

Animals↗
PubMed1992

Effect of methylene blue on vasoreactivity in dog lung.

We examined the effect of methylene blue (MB), a putative inhibitor of guanylate cyclase (GC) activation by endothelium-derived relaxing factor (EDRF) and nitrovasodilator compounds, on vascular tone and reactivity to vasoactive substances in the isolated, blood-perfused canine lower left lung lobe. Lobar vascular resistance was partitioned into arterial and venous segments by venous outflow occlusion. Because MB did not alter vasoconstriction to either serotonin or acetylcholine (P greater than 0.05) except after cyclooxygenase inhibition (COI), we determined the effectiveness of MB as an inhibitor of GC activation by nitrovasodilators. Lobes were given graded bolus doses of nitroglycerin (GTN), sodium nitroprusside (SNP), and bradykinin (BK) at baseline vascular tone, after COI, and after vascular tone was raised by either U-46619, a thromboxane analogue, or MB infusion. GTN and BK but not SNP induced dose-dependent vasodilation when vascular tone was raised by U-46619. However, when vascular tone was increased to a similar level by 30 mg MB and 0.5 mg/min infusion, vasodilation to GTN, SNP, and BK was enhanced from U-46619 infusion. In contrast to MB, NG-nitro-L-arginine, a putative inhibitor of EDRF synthesis, diminished vasodilation to BK in cyclooxygenase-inhibited lobes with elevated vascular tone. Because MB potentiated vasodilation to GTN, SNP, and BK, it is questionable whether MB is an effective inhibitor of vasodilation to nitrovasodilators or BK in the isolated, blood-perfused canine lung.

Acetylcholine↗
PubMed1992

Pressure-dependent increase in lung vascular permeability to water but not protein.

Simultaneous measures of vascular permeability to fluid (capillary filtration coefficient, Kf) and to plasma proteins (solvent drag reflection coefficient, sigma) were obtained over venous pressures (Pv) from 14 to 105 Torr in the isolated ventilated canine lung lobe (n = 70) pump perfused with autologous blood. The sigma was obtained from the relative increase in the concentration of plasma proteins vs. erythrocytes during fluid filtration. Kf's were obtained from two gravimetric methods as well as from change in hematocrit. All Kf's increased (P less than 0.05) as Pv was increased. However, sigma averaged 0.59 +/- 0.01 (range 0.54-0.67) and was unchanged (P greater than 0.05) by elevation of Pv over 20-105 Torr. In 44 lobes where all three Kf measures were obtained, gravimetric measures of Kf did not differ (P greater than 0.05) and were highly correlated with Kf obtained from hematocrit change, Vf Kf (P less than 0.001). However, both weight-based Kf's exceeded Vf Kf (P less than 0.05), suggesting that fluid filtration was overestimated by rate of lung weight gain or underestimated by hematocrit change. Increased permeability to water but not to protein over Pv from 20 to 105 Torr indicates that permeability to both can change independently and is counter to the theory that elevated vascular pressure "stretches" vascular pores.

Animals↗
PubMed1992

Effects of different cyclooxygenase inhibitors on the segmental distribution of pulmonary vascular resistance in the dog.

An increase in pulmonary vascular resistance (PVR) after cyclooxygenase inhibition (COI) is well documented in the dog, but the site of vasoconstriction to chemically distinct cyclooxygenase inhibitors is largely unknown. The purpose of the present study was to examine and compare equimolar concentrations of three chemically unrelated cyclooxygenase inhibitors, indomethacin (INDO; n = 6), meclofenamate (MECLO; n = 6) and ibuprofen (IBU; n = 5), upon the longitudinal distribution of PVR in the isolated canine lower left lung lobe perfused at constant flow with autologous blood. At successive increases in the blood concentration of each cyclooxygenase inhibitor, PVR was partitioned into upstream (arterial, Ra), middle (Rm) and downstream (venous, Rv) resistance by arterial and venous flow occlusion with capillary pressure estimated by a double flow occlusion technique. All three cyclooxygenase inhibitors produced significant pulmonary vasoconstriction with the largest increase in PVR after INDO (104 +/- 21%) and the smallest after IBU (69 +/- 10%). The PVR increase in the INDO and MECLO group was related to an elevation in both Ra (p less than 0.01) and Rv (p less than 0.01), whereas only Rv was increased by IBU (p less than 0.01). While none of the cyclooxygenase inhibitors increased Rm (p greater than 0.05), capillary pressure was increased from pretreatment levels by each cyclooxygenase inhibitor. Although each of the three chemically distinct cyclooxygenase inhibitors raised PVR, the segmental distribution of PVR and the magnitude of the capillary pressure increase varied at equimolar blood concentration.

Animals↗
PubMed1992

Effect of aspirin on vascular tone and reactivity to vasoactive amines in the dog lung.

The effect of increasing blood levels of aspirin on pulmonary hemodynamics and pressor response to vasoactive amines was examined in the isolated canine lung lobe, blood perfused at constant flow. At steady state lobar vascular resistance (LVR), lobes were challenged with either 250 micrograms serotonin (5-HT; n = 4), 5.0 mumol acetylcholine (ACh; n = 4) or 50 micrograms norepinephrine (NE; n = 4) before and after blood aspirin concentration [ASA] was incrementally increased from 17 to 3140 microM. LVR was partitioned into arterial (Ra) and venous (Rv) segments by venous outflow occlusions 20 min after each ASA addition and at the peak of the pressor response to each amine. ASA treatment was associated with a dose-related 105% increase in LVR (P < 0.01) accounted for by a 154% increase in Ra (P < 0.01) and a 70% increase in Rv (P < 0.01) at 3150 microM ASA (n = 12). In spite of increased vascular tone, higher [ASA] also potentiated increases in both pulmonary arterial pressure and LVR to both 5-HT and NE whereas only Ra increased with ACh challenge. Thus, the increase in pulmonary vascular tone and reactivity to vasoactive amines is positively correlated with blood aspirin levels in the dog.

Animals↗
PubMed1991

Relationship of fluid filtration to lung vascular pressure during edema.

Effect of edema on the relationship between rate of fluid filtration and vascular pressure was studied in ventilated isolated dog lung lobes blood-perfused at constant flow. Constant rate of lobe weight gain (S), representing transvascular fluid flux, was obtained at different venous pressures (Pv) as Pv was increased stepwise from 2 to 40 and then similarly decreased from 40 to 2 Torr (n = 6). In another group (n = 6), edema was maximized by reversing the sequence of Pv change; S was obtained during similar Pv steps as Pv was decreased from 40 to 2 and then returned to 40 Torr. In both groups, delta S was disproportionately greater for delta Pv at higher Pv's, with S vs. Pv fit by an exponential curve (P less than 0.001). The exponential relationship was independent of lung hydration inasmuch as greater edema on the second limb of Pv change did not alter the curve (P greater than 0.05). At 144% weight gain, interstitial compliance was 55.5 +/- 26.8 ml.100 g-1.Torr-1 (n = 10). Interstitial pressure reportedly remains constant, i.e., fails to increase to further buffer fluid filtration, after transition of the lung interstitium from low to high compliance at approximately 40% lung weight gain. If so, then the exponential S vs. Pv relationship observed in the present study at elevated interstitial compliance does not appear related to tissue pressure-buffering effects.

Animals↗
PubMed1991

Modulation of vascular reactivity to serotonin in the dog lung.

Experiments were conducted to compare the effects of cyclooxygenase inhibition (COI) on vascular reactivity to serotonin (5-HT) in the isolated blood-perfused canine left lower lung lobe (LLL) and in isolated canine intrapulmonary lobar artery rings with and without a functional endothelium. LLLs (n = 6), perfused at constant blood flow, were challenged with bolus doses of 50, 100, and 250 micrograms 5-HT before COI, after COI with 45 microM meclofenamate, and after infusion of prostacyclin (PGI2) during COI. Lobar vascular resistance was segmentally partitioned by venous occlusion. Pulmonary arterial pressure increased from 13.5 +/- 1.0 to 16.3 +/- 0.8 cmH2O (P less than 0.01) after COI but declined to 13.1 +/- 1.1 cmH2O (P less than 0.01) subsequent to PGI2 infusion (91.3 +/- 14.5 ng.min-1.g LLL-1). The pulmonary arterial pressure changes were related to changes in postcapillary resistance. The dose-dependent pressor response to 5-HT was potentiated by COI (P less than 0.01) but reversibly attenuated (P less than 0.05) by PGI2 infusion. Isolated intrapulmonary artery rings (2-4 mm diam) exhibited a dose-related increase in contractile tension to 5-HT. The response to 5-HT was enhanced (P less than 0.05) in rings devoid of a functional endothelium. However, COI (10 microM indomethacin) did not alter (P greater than 0.05) the dose-related increase in contractile tension to 5-HT in rings with an intact endothelium. Our results suggest that both PGI2 and endothelium-derived relaxing factors modulate pulmonary vascular reactivity to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Multiple muscarinic receptor subtypes in the canine pulmonary circulation.

The vascular response to the muscarinic receptor agonist acetylcholine (ACh) in the presence of selected antagonists was examined in the isolated blood-perfused canine left lower lung lobe under conditions of normal (resting) and elevated vascular tone. At normal vascular tone, ACh (1-5 mumol) produced a dose-dependent increase in pulmonary arterial pressure (Ppa), total pulmonary vascular resistance (PVR), and downstream resistance (Rds) without altering upstream resistance (Rus). Pirenzepine (50 and 100 nM), the prototype M1-selective antagonist, and gallamine, an M2-selective antagonist, as well as atropine (50 nM) and secoverine (100 nM), nonselective antagonists, attenuated (P less than 0.05) the ACh-induced increase in Ppa and Rds. With elevated vascular tone induced by serotonin infusion, ACh produced a dose-dependent increase in Ppa in 19 of 25 lobes, although Rus decreased while Rds increased in all lobes. At high vascular tone, pirenzepine or gallamine attenuated the ACh-induced increase in Rds, whereas Rus was not affected. Secoverine and atropine antagonized ACh-induced increases in both Rds and Rus. The pA2 values (i.e., the negative log antagonist concentration requiring a doubling of ACh dose for an equivalent increase in Rds) for gallamine, pirenzepine, secoverine, and atropine were 6.1 +/- 0.1, 7.4 +/- 0.1, 8.3 +/- 0.2, and 10.2 +/- 0.3, respectively. These results suggest that 1) ACh increases PVR in the dog by constricting the venous segments (downstream) of the pulmonary circulation via activation of pulmonary vascular muscarinic receptors under conditions of both normal and elevated vascular tone, 2) both M1- and non-M1-muscarinic receptor subtypes appear to participate in mediating the ACh-induced increase in Rds, and 3) ACh moderately relaxes the upstream (arterial) vessels, especially under conditions of elevated tone.

Acetylcholine↗
PubMed1990

Verapamil inhibition of serotonin-induced vasoconstriction in dog lung.

The effect of the voltage-dependent calcium channel blocker verapamil on serotonin (5-HT)-induced vasoconstriction and segmental distribution of vascular resistance was examined in isolated, blood-perfused dog left lower lung lobe. 5-HT, 250 micrograms, increased lobar vascular resistance (LVR) by 47.3 +/- 6.5 cm H2O (n = 7), accounted for by a 30.8 +/- 4.3 and 16.4 +/- 2.8 cm H2O increase in upstream (Ra) and downstream (Rv) resistance, respectively. However, the increase in LVR, Ra, and Rv to 5-HT was significantly attenuated as verapamil concentration was increased from 1.2 to 100 microM. The verapamil concentration that inhibited 50% of LVR response (ED50) to 5-HT was 12.1 +/- 5.5 microM. The LVR response to 50, 100, and 250 micrograms 5-HT was reduced after 12.5 microM verapamil by 41 +/- 4.4, 43 +/- 3.8, and 43 +/- 5.0%, respectively. The increase in Ra to 50, 100, and 250 micrograms 5-HT was reduced by 57 +/- 6.7, 57 +/- 4.6, and 51 +/- 7.2%, respectively, by 12.5 microM verapamil, with Rv reduced by 32 +/- 3.9% only at 250 micrograms 5-HT. The alpha-adrenergic receptor antagonist, phentolamine (10 microM) reduced the pressor response to norepinephrine (NE) by 97% but reduced the Ppa increase to 250 micrograms 5-HT by only 29 +/- 10% and did not alter the pressor response to 5 mmol KCl. A verapamil concentration of 105 microM was required to inhibit 50% of the control pressor response to KCl. Our results suggest that the entry of extracellular calcium is important for 5-HT-evoked contractions of canine pulmonary vascular smooth muscle.

Animals↗
PubMed1990

Prostacyclin production with serotonin, increased flow, or elevated venous pressure in dog lung.

The lung may release prostacyclin (PGI2) in response to humoral or mechanical stimuli. We measured 6 keto-PGF1 alpha as an index of PGI2 production during serotonin (5-HT) infusion, elevated venous pressure (Pv), or increased blood flow (Q) in the isolated canine lower left lung lobe (LLL). Lobar vascular resistance (LVR) was partitioned into arterial (Ra), middle (Rm), and venous (Rv) components by arterial and venous occlusions. The infusion of 55-210 micrograms/min 5-HT (n = 9) was associated with concomitant increases in PGI2 production and dose-related increases in pulmonary arterial pressure (Pa) and LVR. 5-HT increased Ra at each infusion rate, whereas Rm was not changed and Rv was increased only at the highest infusion rate. When Pa was increased by stepwise elevations in Pv from 3.7 to 19.1 cmH2O (n = 8) or by increases in Q from 250 to 507 ml/min (n = 5) to match the Pa increase observed during 5-HT infusion, PGI2 production was not altered. Increases in Pv reduced LVR largely by decreasing Ra, whereas increases in Q reduced LVR without changing Ra, Rm, or Rv. Infusion of 5-HT when Pa was held constant by reduction in blood flow (n = 6) did not increase PGI2. Thus infusion of 5-HT at a normal blood flow rate increased PGI2 formation in the isolated blood-perfused dog lung lobe. The results also suggest that sustained mechanical effects related to increased venous pressure or elevated blood flow are not associated with a sustained elevation of PGI2 formation.

6-Ketoprostaglandin F1 alpha↗