Comparative effects of L-NNA and alkyl esters of L-NNA on pulmonary vasodilator responses to ACh, BK, and SP

1994 ◽  
Vol 266 (6) ◽  
pp. H2416-H2422 ◽  
Author(s):  
D. Y. Cheng ◽  
B. J. DeWitt ◽  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Substance P ◽  
Vagal Stimulation ◽  
Benzyl Ester ◽  
No Synthase ◽  
Flow Conditions ◽  
Inhibitory Effects ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Benzyl Esters ◽  
Pulmonary Vascular Bed

The comparative effects of the nitric oxide (NO) synthase inhibitors N omega-nitro-L-arginine (L-NNA), N omega-nitro-L-arginine methyl ester (L-NAME), and N omega-nitro-L-arginine benzyl ester (L-NABE) on baseline tone and on vasodilator responses to acetylcholine (ACh), bradykinin (BK), and substance P (SP) were compared in the pulmonary vascular bed of the cat under constant flow conditions. After administration of the NO synthase inhibitors in intravenous doses of 100 mg/kg, the increase in lobar arterial pressure and the attenuation of vasodilator responses to ACh, BK, and SP were similar, whereas responses to adenosine and felodipine, endothelium-independent vasodilator agents, were not altered. In addition to inhibiting responses to ACh, BK, and substance P, the NO synthase inhibitors enhanced vasodilator responses to S-nitroso-N-acetylpenicillamine and NO. Moreover, atropine inhibited pulmonary vasodilator responses to ACh but not to SP or BK, and L-NAME or L-NABE had no effect on the decrease in heart rate in response to efferent vagal stimulation, a muscarinic receptor-mediated response that is independent of NO release. The similar inhibitory effects of L-NNA, L-NAME, and L-NABE on vasodilator responses to ACh, BK, and SP suggest that the L-arginine analogue, L-NNA, as well as the methyl and benzyl esters of L-NNA are useful probes for studying NO-mediated endothelium-dependent responses in the pulmonary vascular bed of the intact-chest cat.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of L-N5-(1-iminoethyl)-ornithine on tone and endothelium-dependent vasodilator responses

1997 ◽  
Vol 273 (3) ◽  
pp. L588-L594 ◽  
Author(s):  
B. J. DeWitt ◽  
H. C. Champion ◽  
J. R. Marrone ◽  
D. B. McNamara ◽  
T. D. Giles ◽  
...  
Keyword(s):  
Methyl Ester ◽  
Substance P ◽  
Arterial Pressure ◽  
Inhibitory Effect ◽  
Benzyl Ester ◽  
Inhibitory Effects ◽  
Synthesis Inhibitor ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pulmonary Vascular Bed

The effects of the nitric oxide (NO) synthesis inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO) on baseline tone and on responses to the endothelium-dependent vasodilator agents were investigated in the pulmonary vascular bed of the cat under constant-flow conditions. When administered in doses of 1 and 5 mg/kg i.v., L-NIO inhibited pulmonary vasodilator responses to acetylcholine, bradykinin, and substance P but did not alter vasodilator responses to adenosine, pinacidil, or adrenomedullin. L-NIO in doses of 1-10 mg/kg i.v. did not significantly affect baseline lobar arterial pressure, and when administered in doses of 10-30 mg/kg i.v. the inhibitory effect on responses to bradykinin and substance P was not greater than that observed when the lower doses of L-NIO were administered. L-NIO in doses of 5-30 mg/kg i.v. reduced plasma reactive nitrogen intermediate levels. The inhibitory effects of L-NIO were similar to the inhibitory effects of N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, and N omega-nitro-L-arginine benzyl ester. The highest dose of L-NIO studied (30 mg/kg i.v.) caused a significant increased in lobar arterial pressure, and the administration of N omega-nitro-L-arginine methyl ester (100 mg/kg i.v.) caused a significant increase in lobar arterial pressure in animals previously treated with L-NIO (1 mg/kg i.v.). The results of the present study show that the effects of L-NIO on endothelium-dependent vasodilator responses and on baseline tone can be separated and may be interpreted to suggest that basal release of NO does not play an important role in the maintenance of baseline tone in the pulmonary vascular bed of the cat.

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)

Analysis of responses to substance P in the pulmonary vascular bed of the cat

1993 ◽  
Vol 264 (2) ◽  
pp. H394-H402 ◽  
Author(s):  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Substance P ◽  
Guanylate Cyclase ◽  
Left Atrial ◽  
Soluble Guanylate Cyclase ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Synthesis Inhibitor ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Pulmonary Vascular Bed

Responses to substance P were investigated in the pulmonary vascular bed of the cat with controlled pulmonary blood flow and constant left atrial pressure. Under baseline conditions, intralobar injections of substance P caused small, inconsistent reductions in lobar arterial pressure (AP) and significant reductions in mean systemic AP without affecting left atrial pressure. Decreases in lobar AP were significant and dose related when lobar vascular resistance was increased with U-46619, a thromboxane A2 mimetic. When compared with other vasodilator agents, the order of potency was substance P approximately bradykinin > pituitary adenylate cyclase activating polypeptide (PACAP) > acetylcholine (in nmol). Pulmonary vasodilator responses to substance P were unchanged by administration of atropine, glibenclamide, or sodium meclofenamate or when airflow to the left lower lung lobe was interrupted by bronchial occlusion. The NO synthesis inhibitor, N omega-nitro-L-argininemethyl ester (L-NAME), and the soluble guanylate cyclase inhibitor, methylene blue (MB), selectively inhibited pulmonary vasodilator responses to substance P and to acetylcholine. MB or L-NAME had no significant effect on pulmonary vasodilator responses to albuterol, lemakalim, or PACAP, whereas MB inhibited and L-NAME enhanced vasodilator responses to NO and sodium nitroprusside. The present investigation demonstrates that, when tone is increased experimentally, substance P has potent pulmonary vasodilator activity, and responses are not dependent on changes in bronchomotor tone, on the activation of muscarinic receptors or ATP-sensitive K+ channels, or on the release of a dilator prostaglandin but do involve, at least in part, endothelium-derived NO release and soluble guanylate cyclase activation.

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.

Pulmonary vasodilation to adrenomedullin: a novel peptide in humans

1995 ◽  
Vol 268 (6) ◽  
pp. H2211-H2215 ◽  
Author(s):  
J. Heaton ◽  
B. Lin ◽  
J. K. Chang ◽  
S. Steinberg ◽  
A. Hyman ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasodilation ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Cgrp Receptor Antagonist ◽  
Pulmonary Vascular Bed

The present study investigates the effects of human adrenomedullin (ADM) on the pulmonary vascular bed of isolated, blood-perfused rat lung. Because pulmonary blood flow and left atrial pressure were constant, changes in pulmonary arterial pressure directly reflect changes in pulmonary vascular resistance. Under conditions of resting (low) pulmonary vasomotor tone, intra-arterial bolus injections of ADM-(1-52) and two truncated sequences of ADM-(1-52) [ADM-(1-12) and ADM-(13-52)] did not alter pulmonary arterial pressure. When pulmonary vasomotor tone was increased by U-46619, a thromboxane A2 mimic, intra-arterial bolus injections of ADM-(1-52) and ADM-(13-52) at similar doses produced similar, dose-dependent reductions in pulmonary arterial pressure. On a molar basis, ADM-(1-52) had greater pulmonary vasodilator activity than isoproterenol. In contrast, ADM-(1-12) had no activity. When pulmonary vasomotor tone was actively increased to the same level using KCl, the pulmonary vasodilator activity of ADM-(13-52) was decreased 10-fold. The present data demonstrate that ADM-(1-52) dilates the pulmonary vascular bed and suggest that the pulmonary vasodilator activity of ADM is greater on pulmonary blood vessels preconstricted through a receptor-dependent mechanism. Because meclofenamate, nitro-L-arginine methyl ester, methysergide, BW A-1433U83, U-37883A, and calcitonin gene-related peptide [CGRP-(8-37)], a CGRP-receptor antagonist, did not alter the pulmonary vasodilator response to ADM-(1-52), the present data suggest that ADM dilates the pulmonary vascular bed independently of cyclooxygenase products, endothelium-derived relaxation factor, serotoninergic receptors, adenosine1 purinoreceptors, ATP-dependent potassium channels, and CGRP receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative responses to endothelin-2 and sarafotoxin 6b in the pulmonary vascular bed of the cat

1991 ◽  
Vol 69 (2) ◽  
pp. 211-214 ◽  
Author(s):  
R. K. Minkes ◽  
B. D. Nossaman ◽  
P. Kvamme ◽  
P. J. Kadowitz
Keyword(s):  
Arterial Pressure ◽  
Systemic Arterial Pressure ◽  
Significant Activity ◽  
Constant Flow ◽  
Carboxy Terminus ◽  
Flow Conditions ◽  
Vascular Bed ◽  
Natural Flow ◽  
Pulmonary Arterial ◽  
Pulmonary Vascular Bed

Pulmonary vascular responses to endothelin-2 and sarafotoxin 6b were investigated in the feline pulmonary vascular bed under natural flow and constant flow conditions. Injections of endothelin-2 and sarafotoxin 6b in a dose of 0.3 nmol/kg iv increased pulmonary arterial and left atrial pressures and cardiac output, and caused a biphasic change in calculated pulmonary vascular resistance. Endothelin-2 caused a biphasic change in systemic arterial pressure, while sarafotoxin 6b only decreased arterial pressure. Under constant flow conditions in the intact-chest cat, injections of endothelin-2 and sarafotoxin 6b in doses of 0.1–1 nmol into the perfused lobar artery increased lobar arterial pressure in a dose-related manner but were less potent than the thromboxane A2 mimic, U46619. An ET analog with only the Cys1–Cys15 disulfide bond and an amidated carboxy terminus had no significant activity in the pulmonary vascular bed. The present data show that endothelin-2 and sarafotoxin 6b have significant vasoconstrictor activity in the pulmonary vascular bed of the cat.Key words: pulmonary circulation, endothelin-2, sarafotoxin 6b.

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

1991 ◽  
Vol 70 (2) ◽  
pp. 947-952 ◽  
Author(s):  
H. L. Lippton ◽  
G. A. Cohen ◽  
I. F. McMurtry ◽  
A. L. Hyman
Keyword(s):  
Vascular Response ◽  
Vasomotor Tone ◽  
Prostaglandin I2 ◽  
Pulmonary Vasodilation ◽  
Vasodilator Response ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Spontaneously Breathing ◽  
Pulmonary Vascular Bed

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)

Inhibitory effects of DuP 753 and EXP3174 on responses to angiotensin II in pulmonary vascular bed of the cat

1992 ◽  
Vol 73 (5) ◽  
pp. 2054-2061 ◽  
Author(s):  
T. J. McMahon ◽  
A. D. Kaye ◽  
J. S. Hood ◽  
R. K. Minkes ◽  
B. D. Nossaman ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Dose Response ◽  
Inhibitory Effect ◽  
Response Relationship ◽  
Norepinephrine Release ◽  
Inhibitory Effects ◽  
Dose Response Relationship ◽  
Vascular Bed ◽  
The Right ◽  
Pulmonary Vascular Bed

The effects of the non-peptide antagonist DuP 753 and its metabolite EXP3174 on responses to angiotensin II were investigated in the pulmonary vascular bed of the intact-chest cat. Under conditions of controlled blood flow and constant left atrial pressure, injections of angiotensin II into the perfused lobar artery caused dose-related increases in lobar arterial pressure. Responses to angiotensin II were reproducible and were not changed by meclofenamate or prazosin, indicating that prostaglandin or norepinephrine release does not mediate or modulate pulmonary vascular responses to the peptide. DuP 753 (1–5 mg/kg iv) decreased responses to angiotensin II in a competitive manner, and the duration of the blockade was related to dose of the antagonist. DuP 753 had no significant effect on responses to U-46619, norepinephrine, serotonin, endothelin-1, vasopressin, or BAY K 8644. EXP3174 also decreased responses to angiotensin II without altering responses to agents that act by a variety of mechanisms. The inhibitory effect of EXP3174 (1 mg/kg iv) was not overcome by angiotensin II in the range of doses studied, and the shift to the right of the dose-response curve was nonparallel, suggesting that the blockade was noncompetitive. The blockade was long in duration, and, when the dose of EXP3174 was decreased to 0.1 mg/kg iv, the blockade was surmounted and the shift to the right of the dose-response relationship was parallel. DuP 753 and EXP3174 had little effect on mean baseline pressures in the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

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 SQ 30741 on thromboxane receptor-mediated responses in the feline pulmonary vascular bed

1991 ◽  
Vol 71 (5) ◽  
pp. 2012-2018 ◽  
Author(s):  
T. J. McMahon ◽  
J. S. Hood ◽  
B. D. Nossaman ◽  
I. N. Ibrahim ◽  
C. J. Feng ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Blocking Agent ◽  
Maximal Response ◽  
Flow Conditions ◽  
Thromboxane Receptor ◽  
Vascular Bed ◽  
Vessel Elements ◽  
Txa2 Receptor ◽  
The Right ◽  
Pulmonary Vascular Bed

The effects of SQ 30741, a thromboxane A2 (TxA2) receptor blocking agent, on responses to the TxA2 mimic, U-46619, were investigated in the pulmonary vascular bed of the intact-chest cat under constant-flow conditions. The administration of SQ 30741 in doses of 1–2 mg/kg iv markedly reduced vasoconstrictor responses to U-46619 without altering responses to prostaglandin (PG) F2 alpha or PGD2 and serotonin. SQ 30741 had no significant effect on mean vascular pressures in the cat, and the dose-response curve for U-46619 was shifted to the right in a parallel manner with a similar apparent maximal response. In addition to not altering responses to PGF2 alpha, PGD2 alpha, or serotonin, SQ 30741 (2 mg/kg iv) was without significant effect on pulmonary vasoconstrictor responses to the PGD2 metabolite 9 alpha, 11 beta-PGF2, norepinephrine, angiotensin II, BAY K 8644, endothelin 1, or endothelin 2. Although responses to vasoconstrictor agents, which act through a variety of mechanisms, were not altered, responses to the PG and TxA2 precursor, arachidonic acid, were reduced significantly. The duration of the TxA2 receptor blockade was approximately 30 and 75 min at the 1- and 2-mg/kg iv doses of the antagonist, respectively. The present data show that SQ 30741 selectively blocks TxA2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed. These data suggest that responses to arachidonic acid are due in large part to the formation of TxA2 and that discrete TxA2 receptors unrelated to receptors activated by PGD2 or PGF2 alpha are most likely located in resistance vessel elements in the feline pulmonary vascular bed.

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