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.

Mechanosensitive afferents of femoral-saphenous vein

1987 ◽  
Vol 252 (2) ◽  
pp. R367-R370 ◽  
Author(s):  
P. W. Davenport ◽  
F. J. Thompson
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Contractile Response ◽  
Blocking Agent ◽  
Urotensin Ii ◽  
Dibutyryl Cyclic Amp ◽  
Maximal Contraction ◽  
Channel Blocking ◽  
Apparent Concentration ◽  
Small Contraction

Urotensin II (U II) caused marked concentration-dependent contractions of helical strips from several major arteries of the rat. The thoracic aorta was most sensitive; the apparent concentration of U II producing half-maximal contraction was 6.8 X 10(-10) M. Papaverine, dibutyryl cyclic AMP, forskolin, and nitroprusside antagonized the contractile responses to U II at the apparent concentrations producing 50% inhibition (IC50) of 7.6 X 10(-6), 2.1 X 10(-4), 2.5 X 10(-6), and 1.5 X 10(-8) M, respectively. Verapamil, a calcium channel-blocking agent, partially inhibited the contractile response to U II at IC50 = 6.5 X 10(-6) M. Maximal relaxation, i.e., a complete inhibition, could not be obtained even at a concentration of 3 X 10(-5) M verapamil. Cyproheptadine reduced the U II-induced contraction at higher concentrations. Phentolamine (10(-5) M), propranolol (10(-5) M), atropine (10(-4) M), tetrodotoxin (10(-6) M), burimamide (10(-5) M), and indomethacin (10(-5) M) did not change the U II-induced contraction. At higher concentration, U II (10(-8) M) induced a small contraction of aortic strips in Ca2+-free Krebs Henseleit solution similar to that of norepinephrine, but the U II-induced contraction was not inhibited by phentolamine or propranolol. The action of U II did not require the presence of endothelial cells. It is concluded that U II acts on vascular smooth muscle and induces the contraction partly through intracellular Ca2+ mobilization but mainly by stimulating the influx of extracellular Ca2+ via potential dependent and potential independent calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

The Haemodynamic Consequences of Adaptive Structural Changes of the Resistance Vessels in Hypertension

1971 ◽  
Vol 41 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Björn Folkow
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Muscle Activity ◽  
Flow Resistance ◽  
Smooth Muscles ◽  
Vascular Smooth Muscles ◽  
Resistance Increase ◽  
Vascular Bed ◽  
Resistance Vessels ◽  
Vascular Beds

It is generally accepted that a rise in systemic flow resistance constitutes the essential background of the increased arterial blood pressure in well-established hypertension, though the early ‘labile’ phases of essential hypertension in particular may exhibit a pattern simulating a moderately intense defence reaction, with enhanced cardiac output and muscle blood flow as the most characteristic features, apart from the rise in blood pressure. With respect to the increased flow resistance in the well-established phase, it is accepted that the vessels respond readily, and apparently normally, to vasodilator substances, from which the correct conclusion has been drawn that the resistance increase cannot be ascribed to any sclerotic narrowing of the resistance vessels (Pickering, 1968). However, this observation has also generally led to the assumption that an increased smooth-muscle tone of the resistance vessels must be the explanation of the increased flow resistance and, despite the fact that there are numerous reports of medial hypertrophy in the precapillary resistance vessels for instance (Pickering, 1968), the possible haemodynamic consequences of such a type of structural vascular adaptation has hardly been considered at all. Instead the debate has mainly been concerned about whether the assumed increase of vascular tone is due to enhanced myogenic activity, to an increased neurogenic and/or hormonal exogenous stimulation of the vascular smooth muscles or whether these muscles might exhibit an enhanced sensitivity or ‘reactivity’ to such extrinsic stimuli. In other words, if summarized in a diagram relating the extent of active smooth-muscle shortening to the degree of resistance increase in an idealized resistance vessel (Fig. 1), an increased smooth muscle activity, whatever its background, would mean a shift from the normal resting equilibrium at point O to a point B along the curve N. However, one cannot safely deduce levels of vascular smooth-muscle activity between different individuals, or vascular beds, by simply assuming that they are proportional to the respective levels of current flow resistance. In each individual, or vascular bed, one must first relate the actual resistance level to that present when the vascular smooth muscles are completely inactive; i.e. when the resistance vessels are maximally dilated and exposed to the same amount of distending pressure. This latter resistance value provides the necessary ‘baseline’, or an equivalent of fully relaxed muscle length for a particular vascular bed, from which its current level of smooth muscle activity has to be judged in terms of the ratio between these two resistance values. This is simple and straightforward reasoning, but surprisingly enough studies along these lines were apparently not performed systematically until our group used this approach in analyses of the level of ‘basal tone’ in different vascular beds or individuals (Celander & Folkow, 1953; Löfving & Mellander, 1956; Folkow, 1956).

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.

Contraction of major artery segments of rat by fish neuropeptide urotensin II

1987 ◽  
Vol 252 (2) ◽  
pp. R361-R366 ◽  
Author(s):  
H. Itoh ◽  
Y. Itoh ◽  
J. Rivier ◽  
K. Lederis
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Contractile Response ◽  
Blocking Agent ◽  
Urotensin Ii ◽  
Dibutyryl Cyclic Amp ◽  
Maximal Contraction ◽  
Channel Blocking ◽  
Apparent Concentration ◽  
Small Contraction

Urotensin II (U II) caused marked concentration-dependent contractions of helical strips from several major arteries of the rat. The thoracic aorta was most sensitive; the apparent concentration of U II producing half-maximal contraction was 6.8 X 10(-10) M. Papaverine, dibutyryl cyclic AMP, forskolin, and nitroprusside antagonized the contractile responses to U II at the apparent concentrations producing 50% inhibition (IC50) of 7.6 X 10(-6), 2.1 X 10(-4), 2.5 X 10(-6), and 1.5 X 10(-8) M, respectively. Verapamil, a calcium channel-blocking agent, partially inhibited the contractile response to U II at IC50 = 6.5 X 10(-6) M. Maximal relaxation, i.e., a complete inhibition, could not be obtained even at a concentration of 3 X 10(-5) M verapamil. Cyproheptadine reduced the U II-induced contraction at higher concentrations. Phentolamine (10(-5) M), propranolol (10(-5) M), atropine (10(-4) M), tetrodotoxin (10(-6) M), burimamide (10(-5) M), and indomethacin (10(-5) M) did not change the U II-induced contraction. At higher concentration, U II (10(-8) M) induced a small contraction of aortic strips in Ca2+-free Krebs Henseleit solution similar to that of norepinephrine, but the U II-induced contraction was not inhibited by phentolamine or propranolol. The action of U II did not require the presence of endothelial cells. It is concluded that U II acts on vascular smooth muscle and induces the contraction partly through intracellular Ca2+ mobilization but mainly by stimulating the influx of extracellular Ca2+ via potential dependent and potential independent calcium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Segmental vascular reactivity subsequent to sympathectomy

1963 ◽  
Vol 204 (6) ◽  
pp. 1145-1150 ◽  
Author(s):  
David G. Reynolds ◽  
Charles J. Imig
Keyword(s):  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Reactivity ◽  
Small Vessel ◽  
Intravenous Injections ◽  
Vascular Bed ◽  
Vascular Beds

The effect of sympathectomy on the vascular bed of the dog was studied by analyzing segmental resistance changes occurring in response to intra-arterial injections of epinephrine and norepinephrine. The results indicate that the increase in total vascular bed reactivity is caused by sensitization of only the small vessel and venous segments. In an attempt to test the possibility that vascular smooth muscle develops supersensitivity in a manner similar to that which causes skeletal muscle supersensitivity, experiments were done on dogs which received intravenous injections of norepinephrine (0.5 µg/kg) every 8 hr for 2 weeks following sympathectomy. This procedure resulted in an increase in sensitivity of the arterial and venous segments in both the control and sympathectomized legs. Since this behavior was seen in both the denervated and innervated vascular beds no definite conclusions could be reached.

scholarly journals Binding and effects of KATP channel openers in the vascular smooth muscle cell line, A10

1997 ◽  
Vol 122 (6) ◽  
pp. 1119-1126 ◽  
Author(s):  
Ulrich Russ ◽  
Friedrich Metzger ◽  
Elisabeth Kickenweiz ◽  
Annette Hambrock ◽  
Peter Krippeit-Drews ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Cell Line ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Katp Channel ◽  
Muscle Cell Line ◽  
Katp Channel Openers

Presence of Postsynaptic α2-Adrenoreceptors of Predominantly Extrasynaptic Location in the Vascular Smooth Muscle of the Dog Hind Limb

1980 ◽  
Vol 59 (s6) ◽  
pp. 225s-228s ◽  
Author(s):  
S. Z. Langer ◽  
R. Massingham ◽  
N. B. Shepperson
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Antihypertensive Agent ◽  
Hind Limb ◽  
Blocking Agent ◽  
Sympathetic Stimulation ◽  
Vascular Bed ◽  
Pressor Responses

1. In the autoperfused hind limb of the dog prazosin (10μg/kg intravenously) markedly antagonized responses to lumbar sympathetic stimulation, whereas responses to injected nor-adrenaline were largely unaffected. 2. In β-adrenoreceptor- and ganglion-blocked animals, the hind limb pressor responses to phenylephrine were antagonized to a greater degree by prazosin than responses to injected noradrenaline. 3. Rauwolscine, a selective α2-adrenoreceptor-blocking agent, antagonized responses to the α2-adrenoreceptor agonist guanabenz, but not those to phenylephrine. 4. Hind limb pressor responses to noradrenaline were significantly inhibited by rauwolscine and further reduced by prazosin. 5. These results demonstrate that in this vascular bed α1- and α2-adrenoreceptors are located postsynaptically. Furthermore the results suggest that neuronally released noradrenaline acts mainly upon α1-adrenoreceptors, whereas exogenous noradrenaline acts upon α1- and α2-adrenoreceptors. 6. It is suggested that this selectivity of prazosin in blocking the vasoconstriction to neuronally-released noradrenaline may in part explain the effectiveness of this drug as an antihypertensive agent.

Design, Synthesis and Biological Evaluation of Benzopyran Derivatives as KATP Channel Openers

2010 ◽  
Vol 7 (6) ◽  
pp. 415-420 ◽  
Author(s):  
Jinpei Zhou ◽  
Hai Qian ◽  
Huibin Zhang ◽  
Hui Gao ◽  
Wenlong Huang ◽  
...  
Keyword(s):  
Katp Channel ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Synthesis And Biological Evaluation ◽  
Katp Channel Openers

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.

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