Analysis of responses to kallidin, DABK, and DAK in feline hindlimb vascular bed

1995 ◽  
Vol 269 (6) ◽  
pp. H2057-H2064
Author(s):  
J. A. Santiago ◽  
E. A. Garrison ◽  
H. C. Champion ◽  
R. E. Smith ◽  
O. Del Rio ◽  
...  
Keyword(s):  
Time Course ◽  
Blocking Agent ◽  
Constant Flow ◽  
Flow Conditions ◽  
B1 Receptor ◽  
Vascular Bed ◽  
Channel Blocking ◽  
Kinin B1 Receptor ◽  
B2 Receptors ◽  
Dose Dependent

Responses to kallidin, des-Arg9-bradykinin (DABK), and des-Arg10-kallidin (DAK) were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. Injections of kallidin, DABK, and DAK into the hindlimb perfusion circuit produced dose-dependent vasodilator responses in the hindlimb vascular bed. Vasodilator responses to kallidin and bradykinin (BK) were similar in magnitude and time course, and both peptides were approximately 100-fold more potent than DABK or DAK. Responses to kallidin were decreased by the kinin B2 antagonist, HOE 140, whereas responses to DABK and DAK were reduced by des-Arg9[Leu8]BK, a kinin B1-receptor antagonist. N omega-nitro-L-arginine methyl ester (L-NAME) reduced vasodilator responses to kallidin, DABK, and DAK, whereas meclofenamate, atropine, and U-37883A, a vascular selective ATP-sensitive K+ (K+ATP) channel-blocking agent, did not alter responses to the three peptides. These data suggest that both kinin B1 and B2 receptors are normally present in the hindlimb vascular bed. These data also suggest that kinin B1 and B2 receptor-mediated vasodilator responses are mediated by the release of nitric oxide and that the activation of K+ATP channels or muscarinic receptors, or the release of vasodilator prostaglandins play little if any role in mediating responses to kallidin, DABK, or DAK in the hindlimb vascular bed of the cat.

Daltroban blocks thromboxane responses in the pulmonary vascular bed of the cat

1992 ◽  
Vol 72 (6) ◽  
pp. 2305-2310 ◽  
Author(s):  
J. S. Hood ◽  
B. D. Nossaman ◽  
I. N. Ibrahim ◽  
T. J. McMahon ◽  
C. R. Babycos ◽  
...  
Keyword(s):  
Platelet Activating Factor ◽  
Blocking Agent ◽  
Constant Flow ◽  
Flow Conditions ◽  
Response Curves ◽  
Receptor Blocking ◽  
Vascular Bed ◽  
Txa2 Receptor ◽  
The Right ◽  
Pulmonary Vascular Bed

The influence of daltroban (BM13.505; SK&F 96148), a thromboxane (Tx) A2-receptor-blocking agent, on responses to the TxA2 mimics U-46619 and U-44069 was investigated in the pulmonary vascular bed of the intact-chest cat under constant-flow conditions. Daltroban (5 mg/kg iv) had no significant effect on mean baseline vascular pressures but significantly decreased responses to the TxA2 mimics without altering responses to prostaglandin (PG) F2 alpha or PGD2 or the PGD2 metabolite 9 alpha, 11 beta-PGF2. Dose-response curves for U-46619 and U-44069 were shifted to the right in a parallel manner, and daltroban had no significant effect on responses to norepinephrine, serotonin, angiotensin II, BAY K 8644, endothelin-(ET) 1, ET-2, or platelet-activating factor (PAF). After administration of daltroban, responses to U-46619 returned to 50% of control in 90 min and responses to the PG and TxA2 precursor arachidonic acid were decreased significantly. These results suggest that daltroban selectively antagonizes TxA2-receptor-mediated responses in a competitive and reversible manner. These data provide support for the hypothesis that discrete TxA2 receptors unrelated to receptors stimulated by PGF2 alpha, PGD2, or 9 alpha, 11 beta-PGF2 are present in the pulmonary vascular bed of the cat. The present data suggest that pulmonary vasoconstrictor responses to PAF and ET peptides are not dependent on activation of TxA2 receptors in the cat.

Use of ionic currents to identify and estimate parameters in models of channel blockade

1990 ◽  
Vol 259 (2) ◽  
pp. H626-H634
Author(s):  
C. F. Starmer ◽  
V. V. Nesterenko ◽  
F. R. Gilliam ◽  
A. O. Grant
Keyword(s):  
Time Course ◽  
Experimental Studies ◽  
Ionic Currents ◽  
Blocking Agent ◽  
Model Parameters ◽  
Protein Conformations ◽  
Channel Blockade ◽  
Channel Blocking ◽  
Individual Contributions ◽  
Modulated Receptor

Models of ion channel blockade are frequently validated with observations of ionic currents resulting from electrical or chemical stimulation. Model parameters for some models (modulated receptor hypothesis) cannot be uniquely determined from ionic currents. The time course of ionic currents reflects the activation (fraction of available channels that conduct in the presence of excitation) and availability of channels (the ability of the protein to make a transition to a conducting conformation and where this conformation is not complexed with a drug). In the presence of a channel blocking agent, the voltage dependence of availability appears modified and has been interpreted as evidence that drug-complexed channels exhibit modified transition rates between channel protein conformations. Because blockade and availability both modify ionic currents, their individual contributions to macroscopic conductance cannot be resolved from ionic currents except when constant affinity binding to a bindable site is assumed. Experimental studies of nimodipine block of calcium channels and lidocaine block of sodium channels illustrate these concepts.

N omega-nitro-L-arginine selectively inhibits vasodilator responses to acetylcholine and bradykinin in cats

1991 ◽  
Vol 260 (3) ◽  
pp. H1025-H1029 ◽  
Author(s):  
J. A. Bellan ◽  
R. K. Minkes ◽  
D. B. McNamara ◽  
P. J. Kadowitz
Keyword(s):  
Receptor Agonist ◽  
Vascular Tone ◽  
Nitroso Compound ◽  
Constant Flow ◽  
Flow Conditions ◽  
Relaxing Factor ◽  
Thromboxane Receptor ◽  
Vascular Bed ◽  
Resistance Vessels ◽  
Regulation Of Vascular Tone

The effects of N omega-nitro-L-arginine (nitroarginine), an inhibitor of endothelium-dependent relaxing factor (EDRF) production, on vascular tone and responses to vasodilator and vasoconstrictor agents were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, infusion of nitroarginine into the hindquarters vascular bed caused a significant increase in systemic arterial and hindquarters perfusion pressures. During infusion of nitroarginine, hindquarters vasodilator responses to acetylcholine and bradykinin were reduced significantly whereas vasodilator responses to isoproterenol, PGE1, nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate were not altered. Infusion of nitroarginine significantly enhanced vasoconstrictor responses to the thromboxane receptor agonist U 46619 and to phenylephrine. The results of these studies are consistent with the hypotheses that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine, and that EDRF production may play a role in the regulation of vascular tone and in the mediation of responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, in resistance vessels in the hindquarters. These data support the concept that EDRF is very likely an endogenous nitrovasodilator derived from L-arginine in the hindquarters vascular bed of the cat.

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.

Effects of U-37883A, a vascular selective KATP+ channel antagonist, in the pulmonary and hindlimb circulation

1996 ◽  
Vol 271 (6) ◽  
pp. L924-L931 ◽  
Author(s):  
B. J. DeWitt ◽  
D. Y. Cheng ◽  
T. J. McMahon ◽  
J. R. Marrone ◽  
H. C. Champion ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Katp Channel ◽  
Blocking Agent ◽  
Vasodilator Agents ◽  
Vascular Bed ◽  
Pulmonary Vasodilator ◽  
Channel Blocking ◽  
Vascular Beds ◽  
Resting Tone ◽  
Katp Channel Openers

The effects of the vascular selective nonsulfonylurea guanidine ATP-sensitive K+ (KATP+) channel-blocking agent U-37883A on vasodilator and vasoconstrictor responses were investigated in the pulmonary and hindlimb vascular beds of the cat. Under elevated tone conditions, both U-37883A and the sulfonylurea KATP+ antagonist, glibenclamide, attenuated pulmonary vasodilator responses to the KATP+ channel openers without altering responses to vasodilator agents that are reported to act by KATP(+)-independent mechanisms. However, under low resting-tone conditions, U-37883A enhanced pulmonary vasoconstrictor responses to the thromboxane mimic U-46619 and to prostaglandin (PG) F2 alpha and PGD2, whereas glibenclamide antagonized responses to U-46619 and the vasoconstrictor PG. In the hindlimb vascular bed, U-37883A and glibenclamide had no effects on responses to U-46619 in doses that inhibited vasodilator responses to the KATP+ channel opener levcromakalim. U-37883A and glibenclamide had no significant effect on baseline tone in the pulmonary or hindlimb vascular beds, and neither U-37883A nor glibenclamide altered pulmonary vasodilator responses to PGE1. The results of the present investigation show that U-37883A and glibenclamide, agents that are used in the study of vascular smooth muscle KATP+ channel mechanisms and attenuate vasodilator responses to the KATP+ channel openers, have pronounced effects on thromboxane/PG receptor-mediated vasoconstrictor responses in the pulmonary vascular bed of the cat.

Bradykinin-induced mesenteric vasodilation is mediated by B2-subtype receptors and nitric oxide

1993 ◽  
Vol 264 (3) ◽  
pp. G492-G496 ◽  
Author(s):  
R. Berguer ◽  
O. D. Hottenstein ◽  
T. E. Palen ◽  
J. M. Stewart ◽  
E. D. Jacobson
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Mesenteric Artery ◽  
Pressure Transducer ◽  
Doppler Velocimetry ◽  
Pulsed Doppler ◽  
Synthesis Inhibitor ◽  
B1 Receptor ◽  
B2 Receptors ◽  
Dose Dependent

We investigated mechanisms mediating bradykinin (BK)-induced anterior mesenteric artery (AMA) vasodilation in anesthetized rats. The velocity of blood flowing (VBF) in the AMA was measured with pulsed Doppler velocimetry, and arterial pressure (BP) was measured with a pressure transducer. Drugs were infused through an intra-aortic catheter positioned proximal to the AMA origin. AMA conductance (C) was calculated from mean VBF/BP and expressed as percent of control C. BK infusion (10-1,000 ng.kg-1.min-1) increased C significantly (Cmax = 201 +/- 18%, ED50 = 100 ng.kg-1.min-1, P < 0.01 for all doses). A B2-subtype receptor antagonist, D-Arg,[Hyp3,Thi5.8,D-Phe7]BK, administered at 10(5) ng.kg-1.min-1 before or during BK infusion, inhibited the vasodilation by 73 +/- 7 and 103 +/- 7%, respectively. A nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine, administered at 5.0 mg/kg 15 min before BK, inhibited the hyperemia by 61 +/- 8%. Neither a B1-receptor antagonist nor intrajejunal capsaicin inhibited BK-induced vasodilation. BK-evoked, dose-dependent, mesenteric vasodilation in rats appears to be mediated partly by B2-receptors and endogenous NO generation.

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.

Role of K+ATP channels and EDRF in reactive hyperemia in the hindquarters vascular bed of cats

1995 ◽  
Vol 269 (5) ◽  
pp. H1704-H1712 ◽  
Author(s):  
R. K. Minkes ◽  
J. A. Santiago ◽  
T. J. McMahon ◽  
P. J. Kadowitz
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Reactive Hyperemia ◽  
Blocking Agent ◽  
Aortic Blood Flow ◽  
Constant Flow ◽  
Nitric Oxide Release ◽  
Vascular Bed ◽  
Vasoconstrictor Response ◽  
S Period

The mechanism underlying reactive hyperemia was investigated in the feline hindquarters vascular bed under natural- and constant-flow conditions. A 30-s occlusion of the distal aorta produced a marked hyperemic increase in distal aortic blood flow that was attenuated by the ATP-sensitive K+ (K+ATP) channel blocking agent, glibenclamide. When blood flow to the hindquarters vascular bed was held constant with a pump, interruption of blood flow for 5- to 90-s periods produced reactive vasodilator responses that increased in magnitude and duration as the period of ischemia increased. The magnitude and duration of the reactive vasodilator responses were reduced by K+ATP channel antagonists and an inhibitor of nitric oxide synthase, whereas indomethacin had no significant effect. In the pulmonary vascular bed, under constant-flow, elevated tone conditions, a 30-s period of ischemia produced a small reactive vasodilator response and a larger secondary vasoconstrictor response. The present data suggest that reactive hyperemia in the hindquarters vascular bed is mediated by the opening of K+ATP channels and nitric oxide release and that the reactive hyperemic response is not pronounced in the pulmonary circulation.

Relation between intestinal blood flow and oxygen uptake

1982 ◽  
Vol 242 (3) ◽  
pp. G202-G208 ◽  
Author(s):  
P. R. Kvietys ◽  
D. N. Granger
Keyword(s):  
Blood Flow ◽  
Oxygen Uptake ◽  
Perfusion Pressure ◽  
Constant Flow ◽  
Flow Conditions ◽  
Venous Outflow ◽  
Flow Rates ◽  
Dose Dependent ◽  
Oxygen Difference

In autoperfused and pump-perfused preparations of canine ileum, arterial pressure, venous outflow pressure, blood flow, and arteriovenous oxygen difference were measured while blood flow was altered either mechanically or by graded intra-arterial infusions of isoproterenol, adenosine, or 2,4-dinitrophenol. In pump-perfused preparations, mechanical alterations in blood flow resulted in opposite changes in arteriovenous oxygen difference, so that ileal oxygen uptake was independent of blood flow over the range of 30-140 ml.min-1.100 g-1. Only at flow rates below 30 ml.min-1.100 g-1 was oxygen uptake dependent on blood flow. Isoproterenol, adenosine, and dinitrophenol produced dose-dependent increases in blood flow under free-flow conditions and decreases in perfusion pressure under constant-flow conditions. Ileal oxygen uptake was not affected by isoproterenol, decreased by adenosine, and increased by dinitrophenol. The effects of these drugs on intestinal oxygen uptake are in accord with their effects on oxygen consumption in vitro. These results suggest that vasodilators will not alter intestinal oxygen uptake in autoperfused preparations in which oxygen uptake is independent of blood flow, unless they exert an effect on oxidative metabolism.

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