A comparison of the effects of acute verses chronic administration of phenoxybenzamine on pressor responses elicited by the selective α1-adrenoceptor agonist cirazoline in the pithed rat preparation

1992 ◽  
Vol 70 (6) ◽  
pp. 916-921 ◽  
Author(s):  
Reza Tabrizchi ◽  
Christopher R. Triggle
Keyword(s):  
Pressor Response ◽  
Chronic Administration ◽  
Inhibitory Effect ◽  
Acute Administration ◽  
Dependent Manner ◽  
Pithed Rat ◽  
Inhibitory Effects ◽  
Receptor Reserve ◽  
Pressor Responses ◽  
The Right

The effects of nifedipine on the pressor responses to cirazoline were examined in the pithed rat preparation that had received either acute or chronic phenoxybenzamine treatment. Phenoxybenzamine was administered, i.v., to conscious rats, either acutely at 0.01, 0.03, and 0.1 mg/kg, 60 min prior to the commencement of the experiments or chronically at 0.1, 0.3, and 1.0 mg/kg, once daily for 7 days. Nifedipine was administered i.a. (1.0 mg/kg) after the animals had been pithed. The acute or chronic administration of phenoxybenzamine alone displaced the dose–response curve to cirazoline to the right in a dose-dependent manner, while reducing the slope function and maximum response to the agonist. The combined effects of acute phenoxybenzamine and nifedipine produced an additive inhibitory effect on the pressor response elicited by cirazoline, which was most apparent following the removal of receptor reserve by acute phenoxybenzamine. The inhibitory effects of nifedipine and chronically administered phenoxybenzamine were additive at the lower administered doses of the alkylating agent but, in contrast with the effects of acute phenoxybenzamine, the enhanced inhibitory effects of nifedipine were reduced following the removal of receptor reserve. These results indicate that the chronic administration of phenoxybenzamine reduces the additive inhibitory effects of nifedipine and phenoxybenzamine that were observed following the acute administration of phenoxybenzamine.Key words: α1-adrenoceptors, vasoconstriction, subtypes, pithed rat, calcium channel antagonist.

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist clinically effective for the treatment of cerebral vasospasm. Part I: Inhibitory effect on endothelinA receptor—mediated contraction

2005 ◽  
Vol 102 (6) ◽  
pp. 1101-1107 ◽  
Author(s):  
Hartmut Vatter ◽  
Michael Zimmermann ◽  
Veronika Tesanovic ◽  
Andreas Raabe ◽  
Lothar Schilling ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Isometric Force ◽  
Inhibitory Effect ◽  
Affinity Constant ◽  
Dependent Manner ◽  
Content Type ◽  
The Right ◽  
Fine Print

Object. The central role of endothelin (ET)—1 in the development of cerebral vasospasm after subarachnoid hemorrhage is indicated by the successful treatment of this vasospasm in several animal models by using selective ETA receptor antagonists. Clazosentan is a selective ETA receptor antagonist that provides for the first time clinical proof that ET-1 is involved in the pathogenesis of cerebral vasospasm. The aim of the present investigation was, therefore, to define the pharmacological properties of clazosentan that affect ETA receptor—mediated contraction in the cerebrovasculature. Methods. Isometric force measurements were performed in rat basilar artery (BA) ring segments with (E+) and without (E−) endothelial function. Concentration effect curves (CECs) were constructed by cumulative application of ET-1 or big ET-1 in the absence or presence of clazosentan (10−9, 10−8, and 10−7 M). The inhibitory potency of clazosentan was determined by the value of the affinity constant (pA2). The CECs for contraction induced by ET-1 and big ET-1 were shifted to the right in the presence of clazosentan in a parallel dose-dependent manner, which indicates competitive antagonism. The pA2 values for ET-1 were 7.8 (E+) and 8.6 (E−) and the corresponding values for big ET-1 were 8.6 (E+) and 8.3 (E−). Conclusions. The present data characterize clazosentan as a potent competitive antagonist of ETA receptor—mediated constriction of the cerebrovasculature by ET-1 and its precursor big ET-1. These functional data may also be used to define an in vitro profile of an ET receptor antagonist with a high probability of clinical efficacy.

Comparative Effects of Bupivacaine and Ropivacaine on Intracellular Calcium Transients and Tension in Ferret Ventricular Muscle

2004 ◽  
Vol 101 (4) ◽  
pp. 888-894 ◽  
Author(s):  
Yasushi Mio ◽  
Norio Fukuda ◽  
Yoichiro Kusakari ◽  
Yoshikiyo Amaki ◽  
Yasumasa Tanifuji ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Bay K 8644 ◽  
Clinical Settings ◽  
Ca Channel ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Intracellular Ca ◽  
Slope Difference ◽  
The Relationship

Background Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. Methods Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. Results Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. Conclusion The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.

Effects of extracellular ATP on ICa, [Ca2+]i, and contraction in isolated ferret ventricular myocytes

1993 ◽  
Vol 264 (3) ◽  
pp. C702-C708 ◽  
Author(s):  
Y. Qu ◽  
H. M. Himmel ◽  
D. L. Campbell ◽  
H. C. Strauss
Keyword(s):  
Action Potential ◽  
Ventricular Myocytes ◽  
Ventricular Myocardium ◽  
Inhibitory Effect ◽  
Extracellular Atp ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
The Right

The effects of extracellular ATP on the voltage-activated "L-type" Ca current (ICa), action potential, resting and transient intracellular Ca2+ levels, and cell contraction were examined in enzymatically isolated myocytes from the right ventricles of ferrets. With the use of the whole cell patch-clamp technique, extracellular ATP (10(-7) to 10(-3) M) inhibited ICa in a time- and concentration-dependent manner. ATP decreased the peak amplitude of ICa without altering the residual current at the end of 500-ms clamp steps. The concentration-response relationship for ATP inhibition of ICa was well described by a conventional Michaelis-Menten relationship with a half-maximal inhibitory concentration of 1 microM and a maximal effect of 50%. Consistent with its inhibitory effect on ICa, ATP hyperpolarized the plateau phase and shortened the action potential duration. In fura-2-loaded myocytes, extracellular ATP did not change the resting myoplasmic Ca2+ levels; however, when current was elicited under voltage-clamp conditions, ATP both decreased the myoplasmic intracellular Ca2+ transient and inhibited the degree of cell shortening. Our results suggest that ATP could be a genuine and potent extracellular modulator of cardiac function in ferret ventricular myocardium.

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)

Pressor responses of rats to vasopressin: effect of sodium, angiotensin, and catecholamines

1983 ◽  
Vol 244 (2) ◽  
pp. H253-H258 ◽  
Author(s):  
M. Burnier ◽  
H. R. Brunner
Keyword(s):  
Angiotensin Ii ◽  
Sodium Intake ◽  
Pressor Response ◽  
Response Curves ◽  
Ether Anesthesia ◽  
Spontaneously Hypertensive ◽  
Lysine Vasopressin ◽  
Pressor Responses ◽  
Wistar Kyoto ◽  
The Right

The pressor response to lysine vasopressin was tested in groups of male Wistar, Brattleboro, Wistar-Kyoto, and spontaneously hypertensive rats. Moreover, the influence of sodium intake, angiotensin II, saralasin, captopril, norepinephrine, and isoproterenol on vasopressin pressor responses was evaluated. The right iliac artery and one or both femoral veins of the animals were catheterized under light ether anesthesia. The experiments were carried out following a 2-h stabilization period with the rats awake and semirestrained. Pressor responsiveness was evaluated acutely on the basis of dose-response curves (0.5-4 mU). In the Wistar rats, angiotensin II (10 and 30 ng/min) and isoproterenol (10 ng/min) markedly decreased the response to vasopressin, whereas variations in sodium intake and blood pressure per se did not seem to exert any influence. Norepinephrine (250 ng/min) slightly enhanced the pressor responsiveness to the smaller doses of lysine-vasopressin. Brattleboro rats with congenital diabetes insipidus were less sensitive to vasopressin than the other animals, and neither angiotensin II nor isoproterenol induced any change. In conclusion, the pressor responsiveness to vasopressin can vary considerably depending on several factors. These must be taken into account when evaluating the possible pressor role of vasopressin in experimental and clinical settings.

scholarly journals Estrogen replacement attenuates stress-induced pressor responses through vasorelaxation via β2-adrenoceptors in peripheral arteries of ovariectomized rats

2018 ◽  
Vol 314 (2) ◽  
pp. H213-H223 ◽  
Author(s):  
Shoko Tazumi ◽  
Sayo Omoto ◽  
Yu Nagatomo ◽  
Mariko Kawahara ◽  
Naoko Yokota-Nakagi ◽  
...  
Keyword(s):  
Mesenteric Artery ◽  
Pressor Response ◽  
Mrna Level ◽  
Treated Group ◽  
Inhibitory Effect ◽  
Ovariectomized Rats ◽  
Peripheral Arteries ◽  
Estrogen Replacement ◽  
Depressor Response ◽  
Pressor Responses

We examined whether chronic estrogen replacement has an inhibitory effect on stress-induced pressor responses via activation of β2-adrenoceptor (AR) in peripheral arteries of ovariectomized rats. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, pellets containing either 17β-estradiol (E2) or placebo (Pla) were subcutaneously implanted into the rats. After 4 wk of treatment, rats underwent cage-switch stress, and, in a separate experiment, a subset received an infusion of isoproterenol (ISO) with or without pretreatment with the β1-AR blocker atenolol or the β2-AR blocker butoxamine. In addition, the isolated mesenteric artery was used to assess the concentration-related relaxing responses to ISO and the β1- or β2-AR mRNA level. The cage-switch stress-induced pressor response was significantly attenuated in the E2-treated group compared with the Pla-treated group. Pretreatment with atenolol reduced blood pressure responses in both groups. However, butoxamine enhanced the pressor response only in the E2-treated group, resulting in no difference between the two groups. In addition, the intravenous ISO-induced depressor response was significantly enhanced in the E2-treated group compared with the Pla-treated group. Furthermore, the difference in the depressor response was abolished by pretreatment with butoxamine but not by atenolol. In the isolated mesenteric artery, butoxamine caused a rightward shift in ISO-induced concentration-related relaxation in the E2-treated group. The β2-AR mRNA level in the mesenteric artery was higher in the E2-treated group than in the Pla-treated group. These results suggest that estrogen replacement attenuated the stress-induced pressor response probably by suppressing vasoconstriction via activation of β2-ARs in peripheral arteries of ovariectomized rats. NEW & NOTEWORTHY In this study, we show, for the first time, that estrogen replacement has an inhibitory effect on the psychological stress-induced pressor response through vasorelaxation via β2-adrenoceptors, probably due to overexpression of β2-adrenoceptor mRNA, in peripheral arteries of ovariectomized rats.

scholarly journals Inhibitory effect of Sphagnum palustre extract and its bioactive compounds on aromatase activity

2016 ◽  
Vol 11 (3) ◽  
pp. 661
Author(s):  
Hee Jeong Eom ◽  
Yong Joo Park ◽  
Hee Rae Kang ◽  
Ha Ryong Kim ◽  
In Jae Bang ◽  
...  
Keyword(s):  
Video Clip ◽  
Inhibitory Effect ◽  
The Other ◽  
Aromatase Activity ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Aromatase Inhibition ◽  
Concentration Dependent Manner ◽  
Cardiac Pain ◽  
Sphagnum Palustre

<p><em>Sphagnum palustre</em> (a moss) has been traditionally used in Korea for the cure of several diseases such as cardiac pain and stroke. In this research, the inhibitory effect of <em>S. palustre</em> on aromatase (cytochrome P<sub>450</sub> 19, CYP19) activity was studied. [1β-<sup>3</sup>H] androstenedione was used as a substrate and incubated with <em>S. palustre</em> extract and recombinant human CYP19 in the presence of NADPH. <em>S. palustre</em> extract inhibited aromatase in a concentration-dependent manner (IC<sub>50</sub> value: 36.4 ± 8.1 µg/mL). To elucidate the major compounds responsible for the aromatase inhibitory effects of <em>S. palustre</em> extract, nine compounds were isolated from the extract and tested for their inhibition of aromatase activity. Compounds <strong>1</strong>, <strong>6</strong>, and <strong>7</strong> displayed aromatase inhibition, while the inhibition by the other compounds was negligible.</p><p><strong>Video Clip</strong></p><p><a href="https://youtube.com/v/n6xeo3RXJVY">Aromatase enzyme activity:</a> 4 min 16 sec  </p>

scholarly journals Effects of an Atypical Antipsychotic, Zotepine, on Astroglial L-Glutamate Release through Hemichannels: Exploring the Mechanism of Mood-Stabilising Antipsychotic Actions and Antipsychotic-Induced Convulsion

2021 ◽  
Vol 14 (11) ◽  
pp. 1116
Author(s):  
Kouji Fukuyama ◽  
Motohiro Okada
Keyword(s):  
Plasma Membrane ◽  
Atypical Antipsychotic ◽  
Plasma Membranes ◽  
Glutamate Release ◽  
Chronic Administration ◽  
Antipsychotic Agent ◽  
Acute Administration ◽  
Dependent Manner ◽  
Akt Inhibitor ◽  
Cx43 Expression

Accumulating neuropsychopharmacological evidence has suggested that functional abnormalities of astroglial transmission and protein kinase B (Akt) contribute to the pathophysiology and/or pathomechanisms of several neuropsychiatric disorders, such as epilepsy, schizophrenia, affective disorders and antipsychotic-induced convulsions. Therefore, to explore the pathophysiology of mood-stabilising antipsychotics and the proconvulsive actions of atypical antipsychotics, the present study determined the effects of a mood-stabilising, atypical, antipsychotic agent, zotepine (ZTP), on astroglial L-glutamate release and the expression of connexin43 (Cx43) protein in cortical, primary, cultured astrocytes using ultra-high-pressure liquid chromatography and capillary immunoblotting systems. Both acute and subchronic administrations of therapeutically relevant concentrations of ZTP did not affect astroglial L-glutamate release or Cx43 expression in plasma membranes; however, chronic administration of a therapeutically relevant concentration of ZTP increased astroglial L-glutamate release and Cx43 expression in the plasma membrane. Subchronic administrations of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release and Cx43 expression in the plasma membrane, whereas acute administration of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release without affecting Cx43 expression. These stimulatory effects of ZTP on astroglial L-glutamate release through activated hemichannels and Cx43 trafficking to the astroglial plasma membrane were suppressed by the Akt inhibitor. These results suggest that ZTP enhances astroglial L-glutamate release in a concentration-dependent and time-dependent manner due to the enhanced function of astroglial hemichannels, probably via activation of Akt signalling. Therefore, the enhanced astroglial L-glutamatergic transmission induced by ZTP is, at least partially, involved in the mood-stabilising antipsychotic and proconvulsive actions of ZTP.

A Comparative Study of the Effects of Adrenoceptor Antagonists on Platelet Aggregation and Thromboxane Generation

1985 ◽  
Vol 54 (02) ◽  
pp. 480-484 ◽  
Author(s):  
I A Greer ◽  
J J Walker ◽  
M McLaren ◽  
A A Calder ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Vascular Disease ◽  
Platelet Rich Plasma ◽  
Thromboxane A2 ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Wide Range ◽  
The Right

SummaryPlatelet aggregation and thromboxane A2 have been implicated in the pathogenesis of several forms of vascular disease. The aim of this study was to determine the effect of a wide range of adrenoceptor antagonists on platelet aggregation, and thromboxane A2 production, from normal human platelet rich plasma in vitro. Labetalol, pindolol and propranolol inhibited platelet aggregation to collagen in a dose dependent manner. Increasing the concentration of collagen “shifted” the dose response curve to the right. These 3 drugs also significantly inhibited thromboxane A2 generation in response to collagen but not to arachidonic acid. This effect was independent of any inhibitory effect of these drugs on platelet aggregation, and occurred at a drug concentration close to that obtained in vivo. Atenolol, metoprolol, prazosin and timolol were similarly assessed but had no effect on either platelet aggregation or thromboxane A2 generation. This ability of labetalol, pindolol, and propranolol to inhibit platelet aggregation and thromboxane generation, may be of clinical benefit in view of the increasing evidence implicating thromboxane A2 in the pathogenesis of vascular disease.

Pre- and postjunctional effects of some prostanoids in human isolated vas deferens

1991 ◽  
Vol 260 (4) ◽  
pp. R792-R797 ◽  
Author(s):  
F. Holmquist ◽  
H. Hedlund ◽  
K. E. Andersson
Keyword(s):  
Vas Deferens ◽  
Thromboxane A2 ◽  
Electrical Field Stimulation ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Thromboxane A2 Receptor ◽  
Thromboxane Receptor ◽  
Thromboxane A2 Analogue

The effects of prostaglandin (PG) E1, PGE2, the thromboxane A2 analogue U-44069, and the prostacyclin derivative iloprost were studied on isometric contractions induced by norepinephrine (NE) and by electrical field stimulation of nerves in isolated preparations of the human vas deferens. The effects of these agents on the electrically induced release of 3H from preparations preincubated with [3H]NE were also investigated. PGE1 and PGE2 inhibited the electrically induced contractions concentration dependently. U-44069 augmented the contractions without affecting baseline tension, and in preparations where the contractions had been inhibited by PGE1 or PGE2, U-44069 restored the contractions almost to starting levels. The thromboxane A2-receptor antagonist BM 13505, having no effect or inhibitory effects on electrically induced contractions, abolished the stimulatory effect of U-44069. Contractions induced by exogenous NE were augmented by U-44069, whereas PGE1 and BM 13505 were without effects. The electrically induced release of 3H was inhibited by PGE1 and PGE2 in a concentration-dependent manner, whereas U-44069 and BM 13505 increased the release of 3H. Furthermore, the inhibitory effect of PGE1 on 3H release was partly counteracted by U-44069. Iloprost had no significant effect on electrically induced contractions or on 3H release. These results suggest that, in the human vas deferens, thromboxane A2 augments contractions predominantly through a postjunctional site of action, whereas PGs of the E type have a prejunctional inhibitory effect. In addition, the pre- and post-junctional effect profiles of U-44069 and BM 13505 suggest that there may be more than one thromboxane receptor.

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