Influence of inhibitors of prostaglandin synthesis on the canine pulmonary vascular bed

1975 ◽  
Vol 229 (4) ◽  
pp. 941-946 ◽  
Author(s):  
PJ Kadowitz ◽  
BM Chapnick ◽  
PD Joiner ◽  
AL Hyman
Keyword(s):  
Blood Flow ◽  
Arterial Pressure ◽  
Vascular Resistance ◽  
Airway Pressure ◽  
Left Atrial ◽  
Prostaglandin Synthesis ◽  
Left Atrial Pressure ◽  
Small Arteries ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

The effects of two chemically dissimilar inhibitors of prostaglandin (PG) synthesis on vascular resistance and responses to pressor and depressor hormones were evaluated in the canine pulmonary vascular bed. Indomethacin or meclofenamate, 2.5-5 mg/kg iv, increased lobar arterial pressure. Since lobar blood flow was held constant and left atrial pressure did not change, the rise in pressure reflects an increase in vascular resistance. The rise in lobar pressure after indomethacin occurred in the absence of a change in lobar venous or translobar airway pressure. This agent enhanced the response to angiotensin but not to norepinephrine. Meclofenamate decreased responses to both agents. Indomethacin enhanced the dilator response to PGE1 and both indomethacin and meclofenamate increased the response to PGF2alpha. These data indicate that the rise in resistance after indomethacin or meclofenamate was the result of vasoconstriction in vessels upstream to the small veins, presumed to be small arteries. These data are consistent with the hypothesis that under resting conditions synthesis of a dilator prostaglandin may be important for the maintenance of the pulmonary vascular bed in a dilated state. However, results of the present study are not consistent with the postulate that prostaglandins modulate responses to norepinephrine but suggest that indomethacin and meclofenamate interfere with the inactivation of PGF2alpha and PGE1 in the lung.

Methylene blue inhibits neurogenic cholinergic vasodilator responses in the pulmonary vascular bed of the cat

1992 ◽  
Vol 263 (5) ◽  
pp. L575-L584 ◽  
Author(s):  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Methylene Blue ◽  
Arterial Pressure ◽  
Guanylate Cyclase ◽  
Left Atrial ◽  
Vagal Stimulation ◽  
Stimulus Frequency ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

The effects of methylene blue, an inhibitor of soluble guanylate cyclase, on pulmonary vasodilator responses to efferent vagal stimulation were investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. In animals pretreated with reserpine or phenoxybenzamine, under elevated tone conditions, efferent vagal stimulation at frequencies of 2-16 Hz caused stimulus-frequency-dependent decreases in lobar arterial pressure and pulmonary lobar vascular resistance. The vasodilator response to vagal stimulation was reproducible, blocked by atropine, and reduced by methylene blue. Intralobar infusion of methylene blue increased lobar arterial pressure without significantly altering systemic arterial or left atrial pressure. Methylene blue had no significant effect on vasodilator responses to isoproterenol, albuterol, atriopeptin III, lemakalim, adenosine, ATP, and pituitary adenylate cyclase-activating polypeptide-27 but significantly decreased vasodilator responses to acetylcholine, nitric oxide (NO), sodium nitroprusside, and the S-nitrosothiol, S-nitroso-N-acetyl-penicillamine. The effects of methylene blue on responses to vagal stimulation were reversible and were similar with the addition of a NO synthase inhibitor. The present data suggest that vasodilator responses to cholinergic nerve stimulation involve an increase in the production of guanosine 3',5'-cyclic monophosphate in the pulmonary vascular bed. These results provide additional evidence to support the hypothesis that neurogenically released acetylcholine induces endothelium-dependent, muscarinic, guanylate cyclase-mediated vasodilation.

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

1993 ◽  
Vol 74 (4) ◽  
pp. 1704-1711 ◽  
Author(s):  
T. J. McMahon ◽  
L. J. Ignarro ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Left Atrial ◽  
Vascular Tone ◽  
Vagal Stimulation ◽  
Phosphodiesterase Inhibitor ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Synthesis Inhibitor ◽  
Vascular Bed ◽  
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)

Analysis of responses to sarafotoxin 6a and sarafotoxin 6c in the pulmonary vascular bed of the cat

1991 ◽  
Vol 71 (5) ◽  
pp. 2019-2025 ◽  
Author(s):  
T. J. McMahon ◽  
J. S. Hood ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Left Atrial ◽  
Lower Lobe ◽  
Thromboxane A2 ◽  
Aortic Pressure ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Lung Lobe ◽  
Vascular Bed ◽  
Pulmonary Vascular Bed

Pulmonary vascular responses to sarafotoxins 6a and 6c (S6a and S6c) were investigated in the intact-chest cat under constant flow conditions. Injections of S6a and S6c into the perfused lobar artery caused dose-related increases in lobar arterial pressure, increased left atrial pressure, and produced biphasic changes in systemic arterial (aortic) pressure. When left atrial pressure was maintained constant, injections of S6a, S6c, and endothelin 1 (ET-1) caused dose-related increases in lobar arterial pressure. The increases in lobar arterial pressure in response to S6a and S6c were not altered by treatment with a cyclooxygenase inhibitor or a thromboxane receptor blocking agent. Increases in lobar arterial pressure in response to S6a and S6c were not altered when airflow to the left lower lung lobe was interrupted by bronchial occlusion, and pressor responses were not diminished when the left lower lobe was perfused with low-molecular-weight dextran. Under conditions of controlled blood flow and constant left atrial pressure, S6a, S6b, S6c, and ET-1 had similar pressor activity, whereas the thromboxane A2 mimic, U-46619, had far greater activity when compared on a nanomolar basis. The present studies demonstrate that S6a and S6c have significant vasoconstrictor activity in the feline pulmonary vascular bed. These data suggest that pulmonary vasoconstrictor responses to the endothelin peptides are not dependent on release of cyclooxygenase products and the activation of thromboxane A2 receptors, alterations in bronchomotor tone, or interaction with formed elements in blood.

Regional blood volume distribution during positive and negative airway pressure breathing in supine humans

1993 ◽  
Vol 75 (4) ◽  
pp. 1740-1747 ◽  
Author(s):  
J. Peters ◽  
B. Hecker ◽  
D. Neuser ◽  
W. Schaden
Keyword(s):  
Heart Rate ◽  
Blood Flow ◽  
Arterial Pressure ◽  
Vascular Resistance ◽  
Airway Pressure ◽  
Left Ventricular ◽  
Whole Body ◽  
Blood Content ◽  
Calf Blood Flow ◽  
Negative Airway Pressure

To assess the effects of continuous positive (CPAP) or negative airway pressure (CNAP) breathing (+/- 10#x2013;12 cmH2O, duration 25 min) on blood content in the body's capacitance vasculature, regional distribution of labeled red blood cells was evaluated in seven spontaneously breathing supine volunteers. Counts were acquired by whole body scans and detectors overlying the liver, intestine, left ventricle, and lower arm, and arterial pressure, heart rate, calf blood flow and vascular resistance, hematocrit, vasopressin, and atrial natriuretic peptide plasma concentrations were also obtained. With CPAP, thoracic, cardiac, and left ventricular counts diminished significantly by 7#x2013;10%, were accompanied by significant increases in counts over both the gut and liver, and remained decreased during CPAP but reversed to baseline with zero airway pressure. Calf blood flow and vascular resistance significantly decreased and increased, respectively, whereas limb counts, arterial pressure, heart rate, and hormone concentrations remained unchanged. With CNAP, in contrast, regional counts and other variables did not change. Thus, moderate levels of CPAP deplete the intrathoracic vascular bed and heart, shifting blood toward the gut and liver but not toward the limbs. No short-term compensation increasing cardiac filling during CPAP was seen. In contrast, CNAP did not alter intrathoracic or organ blood content and, therefore, does not simply mirror the effects evoked by CPAP.

Pulmonary vasodilator responses to vasoactive intestinal peptide in the cat

1985 ◽  
Vol 58 (5) ◽  
pp. 1723-1728 ◽  
Author(s):  
P. A. Nandiwada ◽  
P. J. Kadowitz ◽  
S. I. Said ◽  
M. Mojarad ◽  
A. L. Hyman
Keyword(s):  
Arterial Pressure ◽  
Vasoactive Intestinal Peptide ◽  
Vascular Resistance ◽  
Vascular Tone ◽  
Base Line ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Adrenergic Mechanism ◽  
Pulmonary Vascular Bed

We investigated the effects of vasoactive intestinal peptide (VIP) in the feline pulmonary vascular bed under conditions of controlled pulmonary blood flow when pulmonary vascular tone was at base-line levels and when vascular resistance was elevated. Under base-line conditions, VIP caused small but significant reductions in lobar arterial pressure without affecting left atrial pressure. Decreases in lobar arterial pressure in response to VIP were greater and were dose related when lobar vascular resistance was increased by intralobar infusion of U 46619, a stable prostaglandin endoperoxide analogue. Acetylcholine and isoproterenol also caused significant decreases in lobar arterial pressure under base-line conditions, and responses to these agents were enhanced when lobar vascular tone was elevated. Moreover, when doses of these agents are expressed in nanomoles, acetylcholine and isoproterenol were more potent than VIP in decreasing lobar arterial pressure. Responses to VIP were longer in duration with a slower onset than were responses to acetylcholine or isoproterenol. Pulmonary vasodilator responses to VIP were unchanged by indomethacin, atropine, or propranolol. The present data demonstrate that VIP has vasodilator activity in the pulmonary vascular bed and that responses are dependent on the existing level of vasoconstrictor tone. These studies indicate that this peptide is less potent than acetylcholine or isoproterenol in dilating the feline pulmonary vascular bed and that responses to VIP are not dependent on a muscarinic or beta-adrenergic mechanism or release of a dilator prostaglandin.

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin

1991 ◽  
Vol 71 (5) ◽  
pp. 2026-2031 ◽  
Author(s):  
T. J. McMahon ◽  
J. S. Hood ◽  
J. A. Bellan ◽  
P. J. Kadowitz
Keyword(s):  
Methyl Ester ◽  
Left Atrial ◽  
Vascular Tone ◽  
Control Period ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pressor Responses ◽  
Pulmonary Vascular Bed

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3′,5′-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.

Nisoldipine inhibits vasoconstrictor responses in the cat pulmonary vascular bed

1989 ◽  
Vol 66 (6) ◽  
pp. 2885-2890 ◽  
Author(s):  
P. J. Kadowitz ◽  
H. L. Lippton ◽  
J. A. Bellan ◽  
A. L. Hyman
Keyword(s):  
Arterial Pressure ◽  
Vascular Resistance ◽  
Blocking Agent ◽  
Systemic Arterial Pressure ◽  
Calcium Entry ◽  
Bay K 8644 ◽  
Vascular Bed ◽  
Adrenoceptor Agonists ◽  
Thromboxane Receptors ◽  
Pulmonary Vascular Bed

The influence of nisoldipine, a dihydropyridine calcium entry antagonist, on vascular resistance and vasoconstrictor responses was investigated in the feline pulmonary vascular bed under conditions of controlled blood flow. The calcium channel blocking agent caused a small reduction in lobar vascular resistance and blocked pulmonary vasoconstrictor responses to BAY K 8644, an agent which promotes calcium entry. The calcium entry blocking agent also reduced pulmonary vasoconstrictor responses to methoxamine and to BHT 933, alpha 1- and alpha 2-adrenoceptor agonists, and to U 46619, an agent which mimics the actions of thromboxane A2. Although there was a marked difference in vasoconstrictor potency in the pulmonary vascular bed, responses to the thromboxane mimic and to the alpha 1- and alpha 2-adrenoceptor agonists were reduced by approximately the same extent. The increases in systemic arterial pressure in response to BAY K 8644, methoxamine, and BHT 933 were also reduced by nisoldipine, and the calcium entry antagonist reduced systemic arterial pressure and systemic vascular resistance. The results of the present study suggest that an extracellular source of calcium is required for the maintenance of vascular tone and for the expression of vasoconstrictor responses, resulting from activation of alpha 1- and postjunctional alpha 2-adrenoceptors and thromboxane receptors in the feline pulmonary vascular bed.

Analysis of responses to bradykinin and influence of HOE 140 in the isolated perfused rat lung

1994 ◽  
Vol 266 (6) ◽  
pp. H2452-H2461 ◽  
Author(s):  
B. D. Nossaman ◽  
C. J. Feng ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Receptor Antagonist ◽  
Airway Pressure ◽  
Pulmonary Arterial Pressure ◽  
Rat Lung ◽  
Vascular Bed ◽  
Pulmonary Arterial ◽  
Hoe 140 ◽  
Airway Responses ◽  
Pulmonary Vascular Bed

The inhibitory effects of HOE 140, a novel bradykinin B2 receptor antagonist, on pulmonary vascular and airway responses to bradykinin (BK) were investigated under conditions of controlled pulmonary blood flow and ventilation and constant left atrial pressure in the isolated blood-perfused rat lung. Under baseline conditions, BK produced dose-related increases in pulmonary arterial perfusion pressure without changing airway pressure. However, when pulmonary arterial pressure was raised to a high steady level, increases in pulmonary arterial pressure in response to BK were enhanced and BK then produced dose-related increases in airway pressure. Responses to BK were reproducible with respect to time and were not different when the inspired fraction of O2 was 0.21 or 0.95 and HOE 140 was 0.8 nM/ml (50 micrograms/kg) and decreased both pulmonary vascular and airway responses to the peptide. HOE 140 had no significant effect on pulmonary vascular responses to angiotensin II, serotonin, nitric oxide, sodium nitroprusside, albuterol, or pinacidil. Additionally, in these experiments, HOE 140 had no effect on the pulmonary arterial pressor response to ventilatory hypoxia. These results suggest BK has significant vasoconstrictor and bronchoconstrictor effects that are mediated by B2 receptors and are dependent on the baseline level of tone in the airways and in the pulmonary vascular bed. The present results suggest that HOE 140 is a highly selective, BK B2 receptor antagonist in the pulmonary vascular bed of the rat. These data also suggest that HOE 140 may be a useful probe for studying the role of BK in the pulmonary vascular bed in physiological and pathophysiological conditions.

Methylene blue selectively inhibits pulmonary vasodilator responses in cats

1989 ◽  
Vol 66 (3) ◽  
pp. 1513-1517 ◽  
Author(s):  
A. L. Hyman ◽  
P. J. Kadowitz ◽  
H. L. Lippton
Keyword(s):  
Methylene Blue ◽  
Arterial Pressure ◽  
Left Atrial ◽  
Vascular Tone ◽  
Aortic Pressure ◽  
Base Line ◽  
Control Value ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pulmonary Vascular Bed

The effects of methylene blue on vascular tone and the responses to pressor and depressor substances were investigated in the constricted feline pulmonary vascular bed under conditions of controlled blood flow and constant left atrial pressure. When tone was elevated with U46619, intralobar injections of acetylcholine, bradykinin, nitroglycerin, isoproterenol, epinephrine, and 8-bromoguanosine-3′,5′-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intralobar infusions of methylene blue elevated lobar arterial pressure without altering base-line left atrial or aortic pressure, heart rate, or cardiac output. When methylene blue was infused in concentrations that raised lobar arterial pressure to values similar to those attained during U46619 infusion, the pulmonary vasodilator responses to acetylcholine, bradykinin, and nitroglycerin were reduced significantly, whereas vasodilator responses to isoproterenol, epinephrine, and 8-bromo-cGMP were not altered. Moreover, the pressor responses to angiotensin II and BAY K 8644 during U46619 infusion and during methylene blue infusion were similar. The enhancing effects of methylene blue on vascular tone and inhibiting effects of this agent on responses to acetylcholine, bradykinin, and nitroglycerin were reversible. These responses returned to control value when tone was again increased with U46619, 30–45 min after the methylene blue infusion was terminated. The present data are consistent with the hypothesis that cGMP may play a role in the regulation of tone in the feline pulmonary vascular bed and in the mediation of vasodilator responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, and to nitrogen oxide-containing vasodilators such as nitroglycerin.

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

1994 ◽  
Vol 266 (6) ◽  
pp. H2256-H2267 ◽  
Author(s):  
B. J. DeWitt ◽  
D. Y. Cheng ◽  
T. J. McMahon ◽  
B. D. Nossaman ◽  
P. J. Kadowitz
Keyword(s):  
Methylene Blue ◽  
Arterial Pressure ◽  
Left Atrial ◽  
Soluble Guanylate Cyclase ◽  
Phosphodiesterase Inhibitor ◽  
Benzyl Ester ◽  
No Synthase ◽  
Vascular Bed ◽  
Steady Level ◽  
Pulmonary Vascular Bed

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)

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