L-NAME enhances responses to atrial natriuretic peptide in the pulmonary vascular bed of the cat.

This study investigated the hypothesis that atrial natriuretic peptide (ANP) responses are mediated by particulate guanylate cyclase in the pulmonary vascular bed of the cat. When tone in the pulmonary vascular bed was raised to a high steady level with the thromboxane mimic U-46619, injections of ANP caused dose-related decreases in lobar arterial pressure. After administration of HS-142-1, an ANP-A- and ANP-B-receptor antagonist, vasodilator responses to ANP were reduced. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) enhanced ANP vasodilator responses, suggesting that inhibition of NO modulates ANP responses. L-NAME administration with constant 8-bromo-cGMP infusion attenuated the increased vasodilator response to ANP, suggesting that supersensitivity to ANP occurs upstream to activation of a cGMP-dependent protein kinase. In pulmonary arterial rings, ANP produced concentration-related vasorelaxant responses with and without endothelium. Methylene blue, L-NAME, or N(omega)-monomethyl-L-arginine did not alter ANP vasorelaxant responses. These data show that ANP supersensitivity observed in the intact pulmonary vascular bed is not seen in isolated pulmonary arterial segments, suggesting that it may only occur in resistance vessel elements. These results suggest that ANP responses occur through activation of ANP-A and/or -B receptors in an endothelium-independent manner and are modulated by NO in resistance vessel elements in the pulmonary vascular bed of the cat.

The effect of prior hypothermia on the physiological response to norepinephrine.

OBJECTIVE: this study determines the effect of prior hypothermia on the cardiovascular responses to norepinephrine (NE) after rewarming. METHODS: the experiment was a 2x2 controlled design with four groups of feline animals. The two variables were the presence or absence of previous cooling, and the use or non-use of NE after rewarming. During the 'cooling' phase, animals were either cooled using an external arterial-venous femoral shunt to 30 degrees C or maintained at 37 degrees C. After 'rewarming' animals were stratified to receive either NE at rates to deliver 0.2, 1.0 or 5 microg/kg per h or normal saline infusions. Animals were instrumented to measure mean arterial pressure (MAP) and cardiac output (CO) and systemic vascular resistance (SVR) was calculated. RESULTS: there were no differences between groups at baseline and low dose NE (0.2 microg/kg per min). At 1.0 microg/kg per min, NE caused a significant increase in CO (P<0.01) and no effect of MAP or SVR in the rewarmed animals when compared with normothermic controls. In rewarmed animals 5.0 microg/kg per min NE caused a significant increase in CO (P<0.01) and no effect on MAP or SVR. In normothermic controls there was a significant increase in SVR (P=0.02) and MAP (P=0.05) and no effect on CO. CONCLUSION: this study shows that the effect of prior hypothermia on cardiovascular responses to moderate and high doses of NE is an improved CO with no affect on SVR and MAP. This could alter the clinical utility of NE in this situation.

The physiological response to norepinephrine during hypothermia and rewarming.

Our purpose was to determine if core hypothermia influences physiological responses to norepinephrine (NE); and if rewarming reverses these effects. Animals were instrumented to measure mean arterial pressure (MAP) and cardiac output (CO). Core temperature was manipulated from 37.5 degrees C (normothermia), to 30 degrees C (hypothermia) and the back to 37.5 degrees C (rewarming) using an external arterial-venous femoral shunt. At each of these temperatures, baseline CO and MAP were measured. Norepinephrine (NE) was infused at rates to deliver 0.2, 1.0, or 5 microg kg(-1) per h. At each dose CO and MAP was measured again. Systemic vascular resistance (SVR) was calculated using the formula (SVR = (MAP/CO) x 80). Eight animals underwent all three phases of the protocol. The response to NE during normothermia was a significant increase in MAP to doses of 1 microg kg(-1) per min (P < 0.01) and 5 microg kg(-1) per min (P < 0.01) and SVR to doses of 1 microg kg(-1) per min (P < 0.01) and 5 microg kg(-1) per min (P < 0.01). The response to NE during hypothermia was a significant increase in MAP only at doses of 1 microg kg(-1) per min (P = 0.03) and 5 microg kg(-1) per min (P = 0.01). The response to NE after rewarming was a significant increase in MAP only at a dose of 5 microg kg(-1) per min (P = 0.03). This study shows that core hypothermia causes a change in physiological response to NE that rewarming does not reverse.

Blood flow to the immature hip. Ultrasonic measurements in pigs.

We quantitatively analyzed blood flow through the major arteries supplying the pig's femoral head during various hip positions and following ligation of various vessels in order to identify the vascular abnormalities which may be responsible for the development of avascular necrosis during the treatment of developmental dysplasia of the hip. Our findings reveal that a decrease in total blood flow to the femoral head occurs when the hip is held in the frog leg position with ligation of the deep femoral artery and proximal ligation of the lateral femoral circumflex artery, and ligation of the deep femoral artery, together with the lateral femoral circumflex artery proximally. In contrast, neither distal ligation of the medial femoral circumflex artery nor lateral femoral circumflex artery alone nor holding the hip in the Lange position caused a statistically significant decrease in total flow. We also observed a unique steal effect on total proximal femoral blood flow, with the hip held in the frog leg position. In 4 of 7 pigs, we found a reversal of flow in the medial femoral circumflex artery.

Adrenomedullin mediates coronary vasodilation through adenosine receptors and KATP channels.

The following experiments were conducted to determine whether, and the mechanisms through which, endogenous peptides alter coronary artery blood flow. Ultrasonic transit time probes were placed around the ascending aorta and left anterior descending coronary artery in groups of anesthetized, open-chest dogs. A Millar pressure catheter monitored left ventricular developed pressure. Intracoronary artery bolus injections of adenosine (a purinergic receptor activator), pinacidil (a KATP channel activator), calcitonin gene-related peptide (CGRP; which causes vascular smooth muscle relaxation by intracellular increases in cyclic-AMP), and adrenomedullin (mechanism unknown) each significantly (P < 0.05, Student's t test) increased coronary blood flow in a dose-dependent fashion, without altering systemic hemodynamic measurements. Intracoronary artery injection of U37883A (a KATP channel antagonist) significantly (P < 0.05) blocked the coronary vasodilator responses to adenosine, adrenomedullin, and pinacidil. Intracoronary xanthine amine congener (an adenosine receptor antagonist) blocked only the responses to adenosine and adrenomedullin, not pinacidil. Intracoronary CGRP8-37 (CGRP receptor antagonist) blocked only the vasodilator response to CGRP. These data suggest that the coronary vasodilator effect of adrenomedullin is initiated first by activation of adenosine receptors, and subsequently through KATP channels-not by activation of CGRP receptors. That there were no changes in left ventricular developed pressure or in systemic hemodynamics after intracoronary artery infusions of adrenomedullin indicates that this endogenous peptide may have clinical utility in facilitating myocardial protection or preconditioning.

Characterization of alpha-adrenoceptor activity in term-newborn piglet mesentery.

For further characterization of neonatal mesenteric alpha 1-adrenoceptor populations, an extracorporeal perfusion circuit was established to control intestinal blood flow in 0-2 day old piglets. Activation of alpha 1-adrenoceptors was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intra-mesenteric arterial injection of methoxamine and noradrenaline. Peripheral intravenous injections of WB 4101 (a competitive alpha 1A-adrenoceptor antagonist), but not clorethylclonidine (CEC, an alpha 1B-adrenoceptor antagonist), significantly (P < 0.05, analysis of variance) blunted mesenteric vasoconstrictor responses to those agonists. That the mesenteric vasoconstrictor response to mesenteric plexus stimulation was unaltered by CEC, but was muted by both WB 4101 and SK&F 104856 (a post-junctional alpha 1- and alpha 2-adrenoceptor antagonist) suggests that pre- and post-junctional alpha 1A-adrenoceptors are present and functional at birth.

Effects of anti-inflammatory agents on hydrochloric acid-induced pulmonary injury.

To determine the effects of anti-inflammatory agents on hydrochloric acid lung injury, the heart and lungs were harvested from rats, placed in a lung chamber, constant flow perfused with whole blood, and ventilated. The following experiments were conducted: observation alone; intratracheal injection of normal saline; intratracheal hydrochloric acid; and intravenous meclofenamate or indomethacin before intratracheal hydrochloric acid. Wet-to-dry lung weights were measured. Peak airway pressures increased immediately (p < .001 vs. baseline; ANOVA) in all intratracheal groups, hydrochloric acid producing even greater (p < .05) increases than saline-effects unaltered by meclofenamate or indomethacin. The increased (p < .001 vs. baseline) 2-h pulmonary artery pressures in hydrochloric acid-treated groups were unaltered by meclofenamate or indomethacin. All hydrochloric acid-treated groups demonstrated increases (p < .05) in weight that were unchanged by meclofenamate or indomethacin. These data suggest that the beneficial effects of these medications described elsewhere, using a variety of in vivo lung injury experimental models, may be attributed to their experimental design, or to contributions from organs/systems outside the pulmonary circuit.

Effect of maturation on alpha-adrenoceptor activity in newborn piglet mesentery.

To characterize the mesenteric alpha1- and alpha2-adrenoceptor populations in newborn piglets, an extracorporeal circuit was established to control intestinal blood flow in 0- to 2-day old and 10- to 14-day old animals. In both groups, alpha-adrenoceptor activation was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intramesenteric arterial injection of alpha-adrenoceptor agonists. In the 10- to 14-day old piglets, mesenteric vasoconstrictor responses to alpha1-adrenoceptor agonists (methoxamine and norepinephrine) and an alpha2-adrenoceptor agonist (BHT-933) were each blunted (P < 0.05, analysis of variance) by peripheral intravenous injections of prazosin (an alpha1-adrenoceptor antagonist) and yohimbine (an alpha2-adrenoceptor antagonist), respectively. The mesenteric vasoconstrictor responses to those agonists were not significantly attenuated by prazosin or yohimbine in 0- to 2-day old animals, nor were they blunted by YM-12617 (alpha1-adrenoceptor antagonist) or idazoxan (alpha2-adrenoceptor antagonist)--compounds that are structurally unrelated to prazosin and yohimbine, respectively. In addition, mesenteric vasoconstrictor responses to other known vasoconstrictor agents--angiotensin II, neuropeptide Y, and a thromboxane A2 mimic (U-46619)--were not effected in either age group by prazosin or yohimbine, implying these agents act independently of alpha-adrenoceptor mechanisms. These data suggest that (1) there exists functional mesenteric alpha1- and alpha2-adrenoceptor-like activity in 10- to 14-day old piglets that, in 0- to 2-day old animals, is not specifically expressed; and (2) mesenteric alpha-adrenoceptor function becomes more selective as newborn piglets mature.

Burn edema reduction by methysergide is not due to control of regional vasodilation.

To determine the extent to which edema modulation by methysergide is due to a blunting of the regional vasodilator response to scald and/or local reduction of transvascular fluid flux, a canine hind limb lymphatic was cannulated. Femoral blood flow (Qa; ml/min), lymph flow (QL; microliter/min/100 g), and lymph-to-plasma protein ratios (CL/CP) were monitored in groups of five dogs before and 4 hr after 5-sec, 100 degrees C foot paw scald; high (1.0 mg/kg) or low (.5 mg/kg) dose of methysergide 30 min before scald. The compression on a clamp placed around the femoral artery in other dogs was adjusted after scald to simulate the blunting effect on Qa observed in methysergide treated dogs. Hind leg venous pressure was elevated to approximately = 40 mm Hg before experimentation until steady state QL and (CL/CP)min were reached. Protein reflection coefficient (sigma d; 1-C1/ CP) and fluid filtration coefficient (Kf) were calculated. Compared to preburn values, all groups showed significant (P < 0.002, analysis of variance) increases in CL/CP and Kf. Contrasted with the burn only group, methysergide blunted increases in Qa, Kf and paw weight gain in a dose-dependent fashion, with no effect on the reflection coefficient. Compression clamp control of femoral Qa caused no effects on permeability. Methysergide limits burn edema in a dose-related fashion, though not due to a blunting of the regional vasodilator response. Local, not regional, mechanism(s) likely mediate this response.

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)

Serotonin receptors regulate canine regional vasodilator responses to burn.

OBJECTIVE: To determine which serotoninergic receptor subtype(s) mediates the regional vasodilator response to scald injury. DESIGN: Prospective, randomized trial. SETTING: Microcirculation research laboratory. SUBJECTS: Anesthetized dogs. INTERVENTIONS: Mechanically ventilated dogs underwent cannulation of a brachial artery and placement of an ultrasonic flow probe around one femoral artery. All animals received a 2% to 3% body surface area partial thickness scald injury by immersing the paw ipsilateral to the instrumented femoral artery into 100 degrees C water for 5 secs. In one group of dogs, BMY 7378 (a serotoninergic1A receptor antagonist) was given by the peripheral intravenous route before burn. These results were compared with those findings obtained from a group of animals that received a burn only, and groups of animals given a peripheral intravenous injection of methysergide (a serotoninergic receptor antagonist) or ritanserin (a serotoninergic2 receptor blocking agent) before burn. Experiments were conducted for two postburn hours. MEASUREMENTS AND MAIN RESULTS: Burn injury caused a marked and persistent increase in regional (e.g., femoral artery) blood flow, an effect that was significantly blunted by preburn administration of the serotoninergic receptor antagonist, methysergide. Preburn administration of BMY 7378 increased baseline femoral blood flow by 13%, reflecting its known serotonin agonist properties. However, when compared with the mean postscald increases in femoral blood flow over baseline seen in scald only dogs and in animals given the serotoninergic2 receptor blocking agent, ritanserin (before scald), the BMY 7378-treated group demonstrated a significant (p < .001 by analysis of variance) 2-hr-postscald blunting of this femoral vasodilator response. CONCLUSION: These data suggest that serotoninergic1A-like receptors play an integral, albeit not an exclusive, role in blood flow regulation to the site of burn injury.

Effects of methysergide administration on edema formation at the site of scald.

Femoral blood flow (Qa), hind paw lymph flow (Qlym), and lymph-to-plasma protein concentration ratio (Clym/Cp) were monitored before and 4 h after 1) 5-s 100 degrees C paw scald, 2) methysergide (1 mg/kg iv) 20 min before scald, 3) methysergide 30 min after scald, and 4) methysergide only. Before experimentation, hind paw venous pressure was elevated and maintained until steady-state Qa, Qlym, and minimal Clym/Cp levels were reached. The reflection coefficient (sigma d) was determined as 1 - minimal Clym/Cp; the filtration coefficient (Kf) was calculated. Methysergide alone caused no changes. Increases in Qa, Qlym, Clym/Cp, and Kf were identified in all scald groups. Compared with scald only animals, pre- and postscald methysergide blunted the increases in Qa, Qlym, Kf, and paw weight gain without an effect on sigma d. These data demonstrate that methysergide reduces edema formation at the site of scald, perhaps by modulating the burn-induced vasodilator response and/or by limiting the burn-induced increase in microvascular surface area.

Influence of nifedipine, verapamil and diltiazem on pulmonary vascular resistance and vasoconstrictors in cats.

In the present study, the effects of three classes of L-type calcium channel-blocking agents, nifedipine, verapamil and diltiazem, on the lobar arterial pressure and the vasoconstrictor responses in the pulmonary vascular bed were compared to those of cromakalim, a KATP channel activator, in the anaesthetized cat under controlled pulmonary blood flow and constant left atrial pressure. These drugs were infused intralobarly in doses selected which did not raise left atrial pressure, change cardiac output or alter systemic arterial pressure. Intralobar bolus injections of calcium channel-blocking agents and of the K+ channel activator decreased the lobar arterial pressure in a dose-related manner when pulmonary vasomotor tone was actively elevated by intralobar arterial infusion of U46619. The pulmonary vasodilator response to these agents was accompanied by a dose-related decrease of systemic arterial pressure. In decreasing lobar arterial pressure at elevated pulmonary vasomotor tone, the order of potency was nifedipine > verapamil > diltiazem, whereas in reducing systemic arterial pressure, the order of potency was nifedipine > diltiazem > verapamil. The calcium channel-blocking agents were less active than the reference drug, cromakalim, in both vascular beds. Intralobar arterial infusions of nifedipine, verapamil and diltiazem, at the rates of 0.03 mumol/min, 0.2 mumol/min and 0.1 mumol/min, respectively, caused no changes in cardiac output and in systemic and pulmonary arterial pressure. Infusion of all three calcium-channel-blocking agents blocked the pulmonary vasoconstrictor responses to BAY K 8644 (calcium entry promoter) and U46619 (thromboxane A2 mimic). Nifedipine infusion also reduced the pulmonary vasoconstrictor responses to methoxamine and BHT933 (alpha 1- and alpha 2-adrenoceptor agonists, respectively), whereas verapamil infusion reduced the responses only to methoxamine. Infusion of diltiazem caused no significant decrease of responses to either alpha-adrenoceptor agonist. The results of the present study suggest that the dihydropyridine, nifedipine, is more potent than the non-dihydropyridines, verapamil and diltiazem, in reducing the pulmonary vascular resistance and more effective in inhibiting the vasoconstrictor responses to the alpha-adrenoceptor agonists, to U46619 and to BAY K 8644 in the feline pulmonary circulation at the infusion rates which cause no or little hemodynamic changes.

Analysis of regional hemodynamic regulation in response to scald injury.

Ultrasonic probes were placed around dog femoral arteries to record blood flow. Hind paw scalding with boiling water (5 s) caused a marked increase in ipsilateral femoral blood flow that persisted for the 2-h observation period. Contralateral femoral blood flow and systemic and pulmonary vascular resistances were unchanged. Compared to scald only animals, methysergide pretreatment diminished and shortened the femoral vasodilator response to scald (109 +/- 14 vs 243 +/- 27 ml/min at 5 min; 59 +/- 14 vs 191 +/- 31 ml/min at 2 h). Pretreatment with ritanserin, BW A1433U83, atropine, ICI 118551, diphenhydramine, ranitidine, meclofenamate, L-nitro-arginine methyl ester, 3-amino-1,2,4-triazine, and U 37883A had no effect on the increased femoral blood flow response to scald, suggesting this vasodilator response is not dependent upon activation of serotonergic2, adenosineA1, muscarinic, beta 2-adrenergic, histaminergic1 or histaminergic2 receptors, on cyclooxygenase products, endothelium-derived relaxing factor derived from nitric oxide (NO) synthase III, NO derived from NO synthase II, or KATP channels, respectively. Methysergide given after burn immediately reduced the augmented femoral blood flow to preburn levels, suggesting the vasodilator response to scald is mediated through continual activation of local serotonergic1-like receptors, which may be target site(s) for therapeutic interventions to influence burn-induced hemodynamic alterations.

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.

L-NAME enhances pulmonary vasoconstriction without inhibiting EDRF-dependent vasodilation.

The purpose of the present study was to determine the influence of NG-nitro-L-arginine methyl ester (L-NAME) on pulmonary vascular responses to endothelium-dependent relaxing factor- (EDRF) dependent and EDRF-independent substances in the pulmonary vascular bed of the anesthetized cat. Because pulmonary blood flow and left atrial pressure were kept constant, changes in lobar arterial pressure directly reflect changes in pulmonary vascular resistance. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of acetylcholine, bradykinin, serotonin, and 5-carboxyamidotryptamine (a serotonin1A receptor agonist) decreased lobar arterial pressure in a dose-related manner. The pulmonary vasodilator response to serotonin, but not to 5-carboxyamidotryptamine, acetylcholine, and bradykinin, was significantly decreased by L-NAME (100 mg/kg i.v.). Administration of ritanserin (0.5 mg/kg i.v.), but not L-arginine (1 g/kg i.v. with 60 mg.kg-1 x min-1 i.v. infusion), reversed the inhibitory effects of L-NAME on the pulmonary vasodilator response to serotonin and abolished the enhanced pulmonary vasoconstrictor response to (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoproprane hydrochloride (a serotonin2 receptor agonist) after L-NAME administration. In conclusion, the present experiments suggest that L-NAME inhibits the pulmonary vasodilator response to serotonin by increasing the sensitivity of serotonin2 receptor-mediated vasoconstriction and not by inhibiting EDRF formation. Because the pulmonary vasodilator responses to bolus administration of acetylcholine and bradykinin were not inhibited by L-NAME, these data suggest that L-NAME does not appear to be an adequate probe to study the role of endogenous EDRF in the adult feline pulmonary vascular bed in vivo.

Mechanisms of signal transduction for adenosine and ATP in pulmonary vascular bed.

The purpose of the present study was to investigate the contribution of pertussis toxin (PTX)-sensitive guanine nucleotide (G) proteins in the pulmonary vascular response to adenosine and ATP in the intact cat under conditions of controlled pulmonary blood flow and left atrial pressure. Adenosine, ATP, and beta-tau-ATP increased lobar arterial pressure in a dose-dependent manner. The pulmonary vasoconstrictor response to adenosine was abolished by BW 1433U, a specific purinergic receptor (P1) inhibitor, PTX pretreatment, indomethacin, and ONO 3708, a thromboxane A2 (TxA2) receptor antagonist. These data suggest that the pulmonary vasoconstrictor response to adenosine depends on activation of P1 purinergic receptors coupled to PTX-sensitive G proteins and subsequent metabolism of liberated arachidonic acid to form TxA2. Because each blocking agent studied produced similar reductions in the pulmonary vasoconstrictor response to ATP without altering the pulmonary vasoconstrictor response to beta-tau-ATP, the present data suggest that ATP constricts the pulmonary vascular bed, in part, by hydrolysis to adenosine. Moreover, the present study suggests that both A1 purinoceptors that are linked to PTX-sensitive G proteins as well as P2x purinoceptors receptors that are independent of PTX-insensitive G proteins mediate the pulmonary vasoconstrictor response to ATP in vivo.

Pulmonary vasodilation to endothelin isopeptides in vivo is mediated by potassium channel activation.

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of ET-1 (1 microgram), ET-2 (1 microgram), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg iv), indomethacin (2.5 mg/kg iv), and ICI 118551 (1 mg/kg iv) but was significantly diminished by glybenclamide (5 mg/kg iv). This dose of glybenclamide significantly diminished the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms) and cromakalim (10 and 30 micrograms), whereas pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 microgram), prostaglandin I2 (0.1 and 0.3 microgram), and isoproterenol (0.03 and 0.1 microgram) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data comprise the first publication demonstrating that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data further suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides does depend on the preexisting level of pulmonary vasomotor tone.(ABSTRACT TRUNCATED AT 250 WORDS)

Methylene blue prevents hypoxic pulmonary vasoconstriction in cats.

The influence of methylene blue, an inhibitor of soluble guanylate cyclase, on responses to ventilatory and precapillary hypoxia was investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. Because methylene blue increased vascular tone, responses to hypoxia were compared when lobar arterial pressure was raised to similar levels with U 46619 and with methylene blue. When lobar arterial pressure was raised with U 46619, ventilation with 7.5% O2 increased lobar arterial pressure significantly. Infusion of methylene blue in concentrations that raised lobar arterial pressure to a value similar to that attained with U 46619 prevented the pressor response to hypoxia, and a significant depressor response was unmasked. The depressor response to hypoxia in the methylene blue-treated animal was not altered by meclofenamate but was blocked by propranolol. A reduction in lobar arterial perfusate PO2 induces an increase in pulmonary vascular resistance in the cat, and this response was prevented by methylene blue. During methylene blue infusion, the vasodilator response to acetylcholine was reduced, whereas the response to isoproterenol was not altered. Although the response to hypoxia was prevented, the pressor response to prostaglandin F2 alpha was not changed. The response to ventilatory hypoxia was enhanced by propranolol or ICI 118551, suggesting that the response is modulated by circulating catecholamines that are probably of adrenal origin. The effects of methylene blue on vascular tone and responses to hypoxia and acetylcholine were reversible, and responses returned to control value after the infusion was terminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of responses to endothelins in the rabbit pulmonary and systemic vascular beds.

The effects of two isoforms of human endothelin (ET) on the pulmonary and systemic vascular beds were compared in the anesthetized intact-chest rabbit under conditions of constant pulmonary blood flow and left atrial pressure. Intralobar bolus injections of ET-1 (0.1-1 micrograms) and ET-3 (1-3 micrograms) produced modest vasoconstriction in the pulmonary vascular bed, whereas both peptides decreased systemic arterial pressure. The pulmonary vasoconstrictor response to ET-1 and ET-3 was inhibited by intralobar infusion of nitrendipine but was not altered by indomethacin. In contrast to the small effects of ET-1 and ET-3 on intact pulmonary resistance vessels, both peptides markedly contracted isolated pulmonary conductance vessels, with greater activity on venous than on arterial segments. Intravenous bolus injection of ET-1 (0.1-0.3 micrograms) or ET-3 (0.3-1 microgram) decreased systemic arterial pressure, increased cardiac output, and markedly decreased systemic vascular resistance. Higher doses of ET-1 produce a biphasic systemic vascular response with a prominent secondary pressor component. The present data suggest that the pulmonary vasoconstrictor activity of ET-1 is greater than that of ET-3 and their pressor activity depends on an extracellular source of calcium. The pulmonary and systemic hemodynamic effects of ET-1 and ET-3 in the rabbit do not depend on cyclooxygenase products. The systemic vasodilator response to ET-1 is not altered by first-pass lung transit. Furthermore the systemic vasodilator response to both peptides occurs independent of activation of muscarinic, beta 2-adrenergic, and platelet-activating factor receptors. Although ET-1 and ET-3 were initially reported as vasoconstrictor peptides, the present data suggest that, by having unique and potent systemic vasodilator activity, ET-1 and ET-3 act differently in the systemic and pulmonary vascular beds under resting conditions in the rabbit.