Biomedical subjects

R Tabrizchi

Publications and source records attributed to R Tabrizchi.

At least 19 recordsLinked to original sources

PubMed2006

Anomalous response to potassium in vascular smooth muscle cells of human saphenous vein.

1.--We have examined the relationship between the resting membrane potential (E(m)) and the concentration of the external ions, K(+), Cl(-) and Ca(2+), as well as the effects of K(+) on active force generation in human saphenous veins. 2.--As measured with sharp glass microelectrodes, the E(m) of vascular muscle cells was -76.0 +/- 7.0 mV (mean +/- SD; n = 328). Raising the concentration of external potassium ([K(+)](e)) from 4.2 to 20, 40, 80, 120 or 150 mm produced an incremental depolarization, revealing a maximal slope factor of 15 mV per 10-fold increase. 3.--Oubain (1.0 microm) did not have any effect on E(m) (-79.0 +/- 8.0 mV; n = 80). Replacement of external Cl(-) with propionate resulted in significant (P < 0.05) depolarization (E(m): -65.5 +/- 7.5 mV; n = 40). In Cl(-)-free buffer containing 80 mm K(+), E(m) depolarized to -52.0 +/- 6.7 mV (n = 45) compared with -64.7 +/- 6.5 mV (n = 55) (P < 0.05) measured in buffer containing 80 mm [K(+)](e) and Cl(-) 138.7 mm. Removal of Ca(2+) did not significantly modify the depolarizing response to K(+) 80 mm: E(m), -68.2 +/- 4.9 mV (n = 42) vs.-64.7 +/- 6.5 mV (n = 55) in the presence of Ca(2+). 4.--Despite their small size, changes in E(m) correlated closely with force generation in buffer containing high K(+), approximately 3.62 mN force being generated per mV of change in E(m). 5.--These data demonstrate that, in human saphenous smooth muscle cells, (i) the magnitude of depolarization induced by raising [K(+)](e) deviates considerably from the theoretical values predicted by the Goldman-Hodgkin-Katz equations, (ii) Cl(-) appears to contribute to the maintenance of E(m), and (iii) electromechanical coupling has a low threshold.

Aged↗

PubMed2006

Relaxant responses to calcium channel antagonists and potassium channel opener in human saphenous vein.

1.-- As shown in a parallel study the magnitude of depolarization induced in human saphenous vein by raising external potassium ([K(+)](e)) falls markedly below the theoretical values predicted by the Goldman-Hodgkin-Katz equations. This anomaly prompted us to re-examine the relaxant actions of L-type (nifedipine) and T-type (mibefradil) Ca(2+) channel antagonists, and relaxant and electrophysiological effects of the K(+) channel opener, pinacidil, on saphenous veins contracted by the elevation of [K(+)](e). 2.-- Nifedipine produced concentration-dependent relaxations in tissues contracted at various high [K(+)](e). In tissues contracted with 20 mm [K(+)](e), the pIC(50) for nifedipine was significantly (8.20 +/- 0.05; n = 6; mean +/- SEM; P < 0.05) greater than in tissues contracted with > or =40 mm [K(+)](e). 3.-- Tissues contracted with 20 mm [K(+)](e) also relaxed in response to mibefradil (pIC(50) = 6.1 +/- 0.14) and pinacidil (pIC(50) = 6.45 +/- 0.08), the latter being almost completely reversed (93.4 +/- 9.9%) by addition of glibenclamide (10 microm). 4.-- The resting E(m) of smooth muscle cells of saphenous vein was -77.0 +/- 0.7 mV (n = 52), and 20 mm [K(+)](e) produced a modest but significant depolarization to -73.0 +/- 0.7 mV (n = 52). Incubation with pinacidil plus 20 mm [K(+)](e) resulted in a significant hyperpolarization of the E(m) to -82 +/- 0.6 mV (n = 52). 5.-- N(omega)-nitro-L-arginine methyl ester did not impede the relaxant responses of nifedipine, mibefradil or pinacidil. 6.-- In conclusion, the relaxant effects of nifedipine and pinacidil (i) occurred at an E(m) distinctly below the presumed threshold for the opening of the classic (Ca(V)1.3alpha(1)) L-type Ca(2+) channels, and (ii) did not depend on generation of nitric oxide.

Calcium Channel Blockers↗

PubMed2001

The influence of tumour necrosis factor-alpha on the cardiovascular system of anaesthetized rats.

The effects of two vasoactive agents (adenosine A2A agonist, CGS 21680, and adrenoceptor agonist, noradrenaline) were examined on cardiac output (CO), heart rate (HR), blood pressure (BP), mean circulatory filling pressure (Pmcf), resistance to venous return, arterial resistance, dP/dt, plasma levels of NO2-/NO3-, and inducible nitric oxide synthase (iNOS) activity in lungs ex vivo, following treatment with tumour necrosis factor-alpha (TNF-alpha; 30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha produced significant reduction in CO (41+/-2%), dP/dt (26+/-3%), BP (26+/-2%) and Pmcf (27+/-4%; n=6; mean+/-SEM), but increased arterial resistance. There were no significant changes in the plasma levels of NO2-/NO3-levels over time following treatment with TNF-alpha, but there was a significant increase (approximately twofold) in the activity of the iNOS in the lungs of animals treated with TNF-alpha. Administration of CGS 21680 (1.0 microg/kg per min) significantly increased CO (44+/-6%), HR (12+/-2%), Pmcf (24+/-4%) and dP/dt (24+/-5%) in TNF-alpha-treated rats. CGS 21680 also significantly reduced arterial resistance (33+/-2%) without altering resistance to venous return in TNF-alpha-treated rats. While noradrenaline (1.0 microg/kg per min) infusion did not significantly increase CO, it did significantly increase HR (12+/-1%), BP (55+/-9%), Pmcf (47+/-5%), dP/dt (65+/-7%), resistance to venous return (64+/-20%), and arterial resistance (41+/-16%) in TNF-alpha-treated animals. The reduction in BP due to administration of TNF-alpha is the result of significant reduction in CO. Consequently, the decline in CO can be attributed to a combination of a negative inotropic effect as well as a reduction in Pmcf. It is evident that infusion with CGS 21680 could reverse the negative impact of TNF-alpha on CO by increasing dP/dt, Pmcf and HR as well as a reduction in arterial resistance. The fact that noradrenaline did not significantly increase CO in TNF-alpha-treated rats can be attributed to increased arterial resistance as well increase in resistance to venous return.

Adenosine↗

PubMed2001

Pharmacology of adenosine receptors in the vasculature.

Adenosine is widely distributed in mammals. One of the primary roles of adenosine within the cardiovascular system is to directly control the functions of both cardiac and vascular tissues. Recently, there has been considerable interest in the subclassification of adenosine receptors. Characterization of a heterogeneous population of receptors for adenosine could provide an opportunity for the development of novel compounds of therapeutic value. Adenosine is released from cells as a result of metabolism, and its release can be increased dramatically from cells that are metabolically stressed. This implies that adenosine can be released from a variety of cells throughout the body, as a result of increased metabolic rates, in concentrations that can have a profound impact on blood vessel function and, consequently, blood flow. It is recognized that the actions of this nucleoside on the vasculature are most prominent when oxygen demand is high and there is a reduction in oxygen tension at the site in question. Therefore, it is not surprising that adenosine has been shown to be an important regulator of blood vessel tone under hypoxic conditions. Furthermore, the activation of adenosine receptors on blood vessels can result in relaxation and/or contractions. The nature of the response subsequent to the activation of adenosine receptors is primarily dependent on the type of blood vessel involved and basal tone. This review will focus on the characterization of subtypes of adenosine receptors in blood vessels, as well as the effect of the stimulation of adenosine receptors on the peripheral circulation.

Adenosine↗

PubMed2001

The influence of phosphodiesterase inhibitor, rolipram, on hemodynamics in lipopolysaccharide-treated rats.

Administration of bacterial endotoxin (lipopolysaccharide, LPS) intravenously has been noted to produce a shock state, which is characterized by hypotension and multi-organ system failure. The aim of the present investigation was to (a) examine the influence of rolipram on hemodynamics, plasma levels of tumor necrosis factor-alpha (TNF-alpha) levels, and production of inducible nitric oxide synthase (iNOS) in the lungs, ex vivo, in LPS-treated rats, and (b) determine the cardiovascular effects of a selective alpha1-adrenoceptor agonist, methoxamine, in the absence or presence of rolipram in rats treated with LPS. Blood pressure, cardiac index, heart rate and arterial resistance were assessed in Long-Evans rats anesthetized with thiobutabarbital. Administration of LPS to animals resulted in a significant reduction in cardiac index over time. The administration of LPS to rats resulted in a substantial rise in the plasma levels of TNF-alpha. Furthermore, the injection of LPS resulted in a significant increase in the iNOS activity in the lungs. Pre-treatment with rolipram prevented the decline in cardiac index in animals that received LPS. Infusion of methoxamine into animals injected with rolipram and pre-treated with LPS did not result in significant changes in cardiac index. Pre-treatment with rolipram or dexamethasone in animals injected with LPS significantly prevented the rise in TNF-alpha when compared to the respective values in vehicle-treated animals. Our present observations support the view that the cardiac index can be maintained in animals treated with LPS independent of iNOS inhibition.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2001

Omapatrilat. Bristol-Myers Squibb.

Bristol-Myers Squibb (BMS) is developing the vasopeptidase inihibitor, omapatrilat, a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), for the potential treatment of cardiovascular diseases such as hypertension and heart failure [306287]. An NDA for the use of omapatrilat in hypertension was filed with the FDA and the regulatory authorities in the EU in December 1999 [351207], [353287]. In April 2000, BMS voluntarily withdrew the NDA in response to questions raised by the FDA regarding the comparative incidence and severity of an infrequent side effect (angioedema) reported within the NDA database. Prospective controlled clinical studies in patients with hypertension and heart failure were to continue. In May 2001, BMS reported that its blinded omapatrilat hypertension study was continuing and, pending supportive results from a data analysis anticipated in late summer/early autumn 2001, the company expected to refile an NDA with the FDA [409203]. In July 2000, BMS reported that it planned to conduct a multinational, 25,000 patient study (OCTAVE - Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) to compare the efficacy and safety of omapatrilat against enalapril in the treatment of hypertension [374909]. The OCTAVE trial was expected to generate data by mid-2001, which could allow for a launch by early 2002 [380280]. Phase III trials for hypertension had commenced by January 1998 [273646]. In January 2001, Merrill Lynch expected BMS to refile its NDA with the FDA in the second half of 2001 [395423]. In February 2001, Credit Suisse First Boston made a similar prediction, adding that it believed BMS would launch the drug in late 2002 or early 2003. The analysts also predicted peak sales for the drug of $585 million in 2005 [399484]. In May 2001, Merrill Lynch estimated sales of $1.8 billion in 2005 [411811].

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

The interrelationship between chloride ions and endothelium on alpha(1)-adrenoceptor-mediated contractions in aortic rings from Dahl normotensive and hypertensive rats.

OBJECTIVES: The effects of chloride-free buffer in the absence or presence of the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), or chloride channel antagonist, indanyloxyacetic acid 94 (IAA-94) on alpha(1)-adrenoceptor mediated contractions were investigated in aortic rings from Dahl salt-resistant normotensive (SRN) and salt-sensitive hypertensive (SSH) rats on a 4% salt diet. METHODS: Systolic and diastolic blood pressure were measured via intra-arterial catheters under halothane anesthesia. Subsequently, the aorta was removed and cirazoline-induced contractions were recorded in normal Krebs and chloride-free buffer using ring preparation. Guanosine 3',5'-cyclic monophosphate (cyclic GMP) content of aortic rings was also determined by scintillation proximity assay kits. RESULTS: Systolic and diastolic blood pressure of SSH (180/130+/-1/1, mean+/-S.E.; n=14) were significantly higher than those of SRN (101/76+/-1/1, mean+/-S.E.; n=14) 7 weeks after they were placed on a salt diet. While the presence of L-NAME failed to have any impact on cirazoline-induced contractions in aortic rings from SSH rats, it significantly accentuated the effects of cirazoline in tissues from SRN rats. On the other hand, IAA-94 was able to inhibit cirazoline-mediated contractions in aortic rings from both SRN and SSH rats. The removal of chloride ions potentiated contractions produced by cirazoline in tissues from SRN but not SSH rats. Moreover, cirazoline-evoked responses in tissues from SRN were not further accentuated by the inclusion of L-NAME in chloride-free buffer. Cirazoline-mediated contractions in tissues from SSH rats were not influenced by absence of chloride ions, and the presence of L-NAME. It was also apparent that the inclusion of IAA-94 in absence of chloride ions did not prevent the potentiation of responses to cirazoline. Removal of chloride ions did not significantly decrease basal cyclic GMP levels in aortic rings from either strain. CONCLUSIONS: Basal release of nitric oxide seems to make a greater contribution in the suppression of cirazoline-evoked contractions in vessels from SRN as opposed to SSH rats. Chloride channels appear to contribute to cirazoline-evoked contractions in normal Krebs but not in chloride-free buffer.

Adrenergic beta-Agonists↗

PubMed2000

Influence of T-type Ca2+ (mibefradil) and Cl- (indanyloxyacetic acid 94) channel antagonists on alpha1-adrenoceptor mediated contractions in rat aorta.

The effects of the T-type and L-type Ca2+ channel antagonists, mibefradil and nifedipine, respectively, and those of a Cl- channel antagonist, indanyloxyacetic acid 94, on mechanical responses elicited by selective activation of alpha1-adrenoceptors using cirazoline were examined in rat isolated aortic rings. The presence of mibefradil (300 nM), indanyloxyacetic acid, 94 (30 microM) and nifedipine (300 nM) alone inhibited mechanical responses elicited by cirazoline. The concentration-response curves to cirazoline were displaced to the right with significant increases in the EC50 and significant depressions of the maximal responses in the presence of the individual agents mibefradil, indanyloxyacetic acid 94, or nifedipine. A combination of mibefradil and indanyloxyacetic acid 94 further inhibited the mechanical activity produced by cirazoline. The further reduction in the maximal response to cirazoline, in the presence of mibefradil and nifedipine, was insignificant when compared with the effects of nifedipine alone. In addition, maximal mechanical responses produced by cirazoline were not significantly affected by a combination of nifedipine and indanyloxyacetic acid 94 when compared with either nifedipine alone or mibefradil and indanyloxyacetic acid 94 combined. Our current findings indicate that mibefradil, indanyloxyacetic acid 94, and nifedipine can inhibit cirazoline-induced contractions to a varying degree. Moreover, based on our present data it would be reasonable to suggest that the contribution of T-type versus L-type Ca2+ channels to contractile responses obtained with cirazoline are approximately 21% and 35%, respectively, of the Emax. It would appear that L-type Ca2+ channels play a greater role in processes that are involved in excitation-contraction coupling subsequent to stimulation of alpha1-adrenoceptors. In addition, Cl- channels also appear to be involved in the process of contraction following alpha1-adrenoceptor activation.

Adrenergic alpha-Agonists↗

PubMed2000

Edaravone Mitsubishi-Tokyo.

Mitsubishi-Tokyo (formerly Mitsubishi Chemical) is developing edaravone (norphenazone), a free radical scavenger, for the potential treatment of cardiovascular disease, cerebrovascular ischemia and cerebral edema. By February 2000, edaravone had been filed in Japan for the treatment of acute brain infarction, and was in phase III trials for subarachnoid hemorrhage [365460]. The compound blocks the action of the lipoperoxide, 15-HPETE, which normally increases with age and may be associated with neurodegeneration.

Antipyrine↗

PubMed1999

Influence of increase in osmotic pressure with sucrose on relaxation and cyclonucleotides levels in isolated rat aorta.

The influence of increases in osmolarity by addition of sucrose were investigated on relaxation and changes in adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) levels in isolated rat aortic rings. Isoprenaline-mediated relaxations were attenuated in hypertonic (341+/-0.4 mOsmol) (mean+/-S.E.M.) solution. The concentration-response curve to isoprenaline was displaced to the right. The EC(50) (0.16+/-0.05 vs. 1.14+/-0.5 microM) significantly (n=6; P<0.05) increased without any changes to the maximum response. Hypertonic solution also attenuated methacholine-mediated relaxations resulting in a significant increase in the EC(50) (0. 28+/-0.04 vs. 0.52+/-0.04 microM) and reduced the maximal response (73+/-5% vs. 51+/-8%). In contrast, an increase in tonicity did not have any influence on sodium nitroprusside, forskolin or pinacidil concentration-response curves. Hypertonic solution also did not affect either basal cyclic AMP or cyclic GMP production. In addition, an increase in osmolarity did not affect isoprenaline-stimulated increases in the levels of cyclic AMP. However, an increase in the tonicity of Krebs solution significantly inhibited methacholine-stimulated (58%-34%) accumulation of cyclic GMP. The present data indicated that an increase in the tonicity of Krebs solution impaired endothelium-dependent relaxation and the associated increase in cyclic GMP production without affecting basal levels of this nucleotide. The inhibitory effects of high osmolarity on beta-adrenoceptor-mediated relaxation did not appear to be due to a reduction in cyclic AMP generation, or the result of inhibition of pinacidil-sensitive K(ATP)(+) channels. Moreover, an increase in the tonicity of Krebs solution did not influence relaxation induced by direct activation of adenylate cyclase or guanylate cyclase by forskolin and sodium nitroprusside, respectively.

Adrenergic beta-Agonists↗

PubMed1999

Influence of chloride ions on alpha1-adrenoceptor mediated contraction and Ca2+ influx in rat caudal artery.

The objective of the present investigation was to compare and contrast the effects of 8-bromoguanosine 3':5'-cyclic monophosphate (8-Bromo-cyclic GMP), an analogue of guanosine 3':5'-cyclic monophosphate, felodipine, a dihydropyridine Ca2+ channel antagonist, and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), a putative chloride channel antagonist on alpha1-adrenoceptor mediated contraction and Ca2+ influx in rat caudal artery, in normal physiological salt solution and in chloride-free solution. Isometric contractions and 45Ca2+ influx were measured in isolated rat caudal arterial rings. Phenylephrine induced concentration-dependent contractions were inhibited by 8-Bromo-cyclic GMP (10 microM), felodipine (10 nM) and NPPB (3.0 microM). Removal of chloride ions also impaired phenylephrine-induced contractions. In chloride-free buffer, phenylephrine-induced contractions were partially inhibited by the presence of 8-Bromo-cGMP or felodipine, while NPPB had no effect. Phenylephrine induced 45Ca2+ influx was inhibited by the presence of 8-Bromo-cyclic GMP, felodipine and NPPB. Moreover, removal of chloride ions also inhibited phenylephrine-induced 45Ca2+ influx. The results of our study demonstrate that in the rat caudal artery the inhibitory effects of 8-Bromo-cyclic GMP, felodipine and NPPB, are mediated through a reduction of Ca2+ influx. In addition, chloride ions, in part, play a role in alpha1-adrenoceptor-mediated Ca2+ influx. However, the influence of removal of chloride ions on phenylephrine stimulated contraction is limited. Moreover, 8-Bromo-cyclic GMP and felodipine, but not NPBB, impair phenylephrine-induced contractions in the absence of chloride ions.

Animals↗

PubMed1998

Cardiovascular effects of noradrenaline in hypovolemic haemorrhage: role of inducible nitric oxide synthase.

Hypovolemia has been associated with the induction of nitric oxide synthase which is believed to result in an over-production of nitric oxide. In the present study, we have examined the effects of noradrenaline following haemorrhage on cardiac output, blood pressure, mean circulatory filling pressure and vascular resistance in anaesthetized rats after pre-treatment with nitric oxide synthase inhibitor, L-N6-(1-iminoethyl)lysine or dexamethasone. Hypovolemic haemorrhage resulted in induction of nitric oxide synthase, as measured in lungs, and both dexamethasone and L-N6-(1-iminoethyl)lysine inhibited the activity of the inducible form of nitric oxide synthase. An infusion of noradrenaline significantly increased cardiac output, blood pressure and mean circulatory filling pressure in animals pre-treated with L-N6-(1-iminoethyl)lysine and dexamethasone when compared with saline pre-treatment. In addition, the administration of noradrenaline significantly reduced venous resistance in animals pre-treated with L-N6-(1-iminoethyl)lysine when compared with saline pre-treatment. The results of this investigation indicated that the impact of noradrenaline on cardiac output, blood pressure and mean circulatory filling pressure was greater in hypovolemic rats treated with L-N6-(1-iminoethyl)lysine or dexamethasone. In addition, we found that in the hypovolemic state, the greater increase in cardiac output during the infusion of noradrenaline after inhibition of nitric oxide synthase was predominantly due to reduced resistance to venous return.

Animals↗

PubMed1998

Effects of CGS 21680, a selective A2A adenosine receptor agonist, on cardiac output and vascular resistance in acute heart failure in the anaesthetized rat.

1. The effects of CGS 21680, a selective A2A adenosine receptor agonist, on cardiac output, blood pressure, mean circulatory filling pressure (Pmcf), arterial and venous resistances, heart rate and left ventricular end-diastolic pressure were assessed in rats with acute heart failure by means of coronary artery occlusion. 2. Animals (n=6 in each group) were divided into five groups: group I, sham-operated vehicle-treated (0.9% saline; 0.018 mL min(-1)); groups II-V, subject to coronary artery occlusion and treated with vehicle (0.9% saline; 0.018 ml min(-1)) and CGS 21680 (0.1, 0.3 and 1.0 microg kg(-1) min(-1)), respectively. Haemodynamic measurements were taken one hour after completion of surgery, ninety minutes after coronary artery occlusion (except in group I), and fifteen minutes after infusion of saline or CGS 21680. 3. Baseline haemodynamic measurements before occlusion were found not to differ significantly between the different groups of animals. However, after occlusion, cardiac output, rate of rise in left ventricular pressure (+ dP/dt) and blood pressure were significantly reduced when compared to corresponding values in sham-operated animals. In addition, occlusion of the coronary artery resulted in a significant elevation in venous resistance, Pmcf and left ventricular end-diastolic pressure as compared to corresponding values in sham-operated animals. 4. Infusion with CGS 21680 at the highest dose significantly reduced blood pressure, arterial resistance and left ventricular end-diastolic pressure when compared to occluded vehicle-treated animals (group II). Administration of CGS 21680 at the highest dose also significantly increased cardiac output (28%) and heart rate (10%) in comparison to occluded vehicle-treated animals. In addition, the highest dose of CGS 21680 significantly reduced Pmcf (9%) and venous resistance (62%) in comparison to occluded vehicle-treated animals. Administration of CGS 21680 did not significantly affect +dP/dt when compared to occluded vehicle-treated animals. 5. The results from the present investigation indicate that occlusion of the coronary artery in rats results in a state of heart failure characterized by reduced arterial pressure and cardiac output, and increased venous resistance, Pmcf and left ventricular end-diastolic pressure. Administration of CGS 21680 to animals with acute heart failure resulted in increased cardiac output which was due to reduced venous resistance, as well as increased heart rate.

Acute Disease↗

PubMed1998

Haemodynamic effects of a selective adenosine A2A receptor agonist, CGS 21680, in chronic heart failure in anaesthetized rats.

1. Recently we demonstrated that the administration of an A2A adenosine receptor agonist, CGS 21680, to anaesthetized rats with acute heart failure (1 h post-coronary artery ligation) resulted in an increase in cardiac output. In the present investigation, the effects of CGS 21680 on cardiac output, vascular resistance, heart rate, blood pressure and mean circulatory filling pressure (Pmcf) were investigated in anaesthetized rats with chronic heart failure (8 weeks post-coronary artery ligation). 2. Experiments were conducted in five groups (n = 6) of animals: sham-operated vehicle-treated (0.9% NaCl; 0.037 mL kg(-1) min(-1)) animals in which the occluder was placed but not pulled to ligate the coronary artery; coronary artery-ligated vehicle-treated animals; and coronary artery-ligated CGS 21680-treated (0.1. 0.3 or 1.0 microg kg(-1) min(-1)) animals. 3. Baseline blood pressure, cardiac output and rate of rise in left ventricular pressure (+dP/dt) were significantly reduced in animals with coronary artery ligation when compared to sham-operated animals. Coronary artery ligation resulted in a significant increase in left ventricular end-diastolic pressure, Pmcf and venous resistance when compared to sham-operated animals. 4. Administration of CGS 21680 at 0.3 and 1.0 microg kg(-1) min(-1) significantly (n = 6; P<0.05) increased cardiac output by 19+/-4% and 39+/-5%, and heart rate by 14+/-2% and 15+/-1%, respectively, when compared to vehicle treatment in coronary artery-ligated animals. Administration of CGS 21680 also significantly reduced blood pressure and arterial resistance when compared to coronary artery-ligated vehicle-treated animals. Infusion of CGS 21680 also significantly reduced venous resistance when compared to vehicle-treated coronary artery-ligated animals. 5. The results show that heart failure is characterized by reduced cardiac output, and increased left ventricular end-diastolic pressure, venous resistance and Pmcf. Acute treatment with CGS 21680 in animals with chronic heart failure decreased left ventricular end-diastolic pressure and increased cardiac output. This increase in cardiac output was the result of reduced arterial and venous resistances and increased heart rate.

Adenosine↗

PubMed1997

Effects of niflumic acid on alpha1-adrenoceptor-induced vasoconstriction in mesenteric artery in vitro and in vivo in two-kidney one-clip hypertensive rats.

The influence of niflumic acid (3 and 10 microM), a Cl- channel antagonist, on cirazoline-induced vasoconstriction in isolated perfused mesenteric artery (5 ml/min) from two-kidney one-clip (2K1C) hypertensive and sham normotensive rats was examined. In addition, the effect of a single i.v. bolus injection of niflumic acid (3 mg/kg) on cirazoline-mediated reduction in vascular conductance in superior mesenteric artery was determined in pentobarbital-anaesthetized hypertensive and normotensive rats. Bolus injections of cirazoline induced a dose-dependent transient increase in the perfusion pressure in vitro. In the presence of niflumic acid, cirazoline-mediated vasoconstriction was significantly inhibited. Cirazoline-induced vasoconstriction in isolated mesenteric beds was also significantly inhibited following perfusion with Cl(-)-free buffer. Pre-perfusion of mesenteric blood vessels with Cl(-)-free buffer resulted in a significantly greater inhibition of cirazoline-mediated vasoconstriction in sham normotensive rats than in hypertensive rats. We found that in Cl(-)-free buffer, cirazoline-mediated vasoconstriction could be further inhibited by niflumic acid. Intravenous infusion of cumulative doses of cirazoline in vivo caused a dose-dependent decrease in superior mesenteric vascular conductance. Pretreatment with niflumic acid significantly impaired cirazoline-mediated decreases in vascular conductance. Our results indicate that chloride ions play an important role in alpha1-adrenoceptor-mediated vasoconstriction in mesenteric blood vessels. In addition, the contribution of chloride ions in alpha1-adrenoceptor-mediated vasoconstriction in blood vessels from hypertensive rats appears to be reduced.

Adrenergic alpha-Agonists↗

PubMed1997

Effects of adenosine and adenosine analogues on mean circulatory filling pressure and cardiac output in anesthetized rats.

The effects of adenosine and adenosine analogues, 2-[p-(2-[carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) and N6-2-(4-aminophenyl)-ethyladenosine (APNEA), on mean arterial pressure, cardiac output, mean circulatory filling pressure, arterial resistance, venous resistance and heart rate in untreated or treated (with ganglion-blockers mecamylamine and atropine) pentobarbital-anesthetized rats were examined. Infusion of adenosine (100, 300 and 900 microg/kg/min), CGS 21680 (0.1, 0.3 and 0.9 microg/kg/min) or APNEA (1.0, 3.0 and 9.0 microg/kg/min) reduced mean arterial pressure and arterial resistance in all groups. Adenosine and APNEA also reduced mean circulatory filling pressure, venous resistance and heart rate in untreated animals. Furthermore, APNEA but not adenosine reduced cardiac output. In contrast, CGS 21680 increased cardiac output and heart rate but did not have any effect on mean circulatory filling pressure or venous resistance. In ganglion-blocked rats, APNEA reduced cardiac output, mean circulatory filling pressure and heart rate, while adenosine did not have any effect on these parameters. In addition, APNEA and adenosine reduced arterial resistance but were unable to alter venous resistance while CGS 21680 reduced mean circulatory filling pressure and arterial resistance but did not further affect cardiac output, heart rate and venous resistance in ganglion-blocked animals. The results of the present study suggest that adenosine and APNEA dilate arterioles and vein, whereas CGS 21680 causes arterial dilatation but not venodilatation in untreated animals due to hypotension-induced sympathetic activation. A possible explanation for the present observations could be differences in the distribution of vascular A2 versus A3 adenosine receptors in the venous circulation.

Adenosine↗

PubMed1996

Regulation of intracellular Ca2+ by 8-bromoguanosine 3':5'-cyclic monophosphate, felodipine and ryanodine in rat caudal artery.

45Ca2+ efflux in isolated rat caudal artery was measured in the absence and presence of 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cGMP), felodipine or ryanodine after stimulation of alpha 1-adrenoceptors. The objectives of this study were to identify the mechanisms of action of 8-Br-cGMP, felodipine and ryanodine in a vascular resistance vessel. 8-Br-cGMP and ryanodine but not felodipine increased basal 45Ca2+ efflux. Phenylephrine-induced 45Ca2+ efflux was reduced by all three antagonists. The results of this study demonstrate that, (1) 8-Br-cGMP-mediated relaxation is affected in part by an increased extrusion of intracellular Ca2+ and/or inhibition of intracellular Ca2+ release, (2) the Ca(2+)-channel antagonist, felodipine, impairs intracellular Ca2+ release and (3) ryanodine reduced phenylephrine-induced Ca2+ efflux by depleting intracellular Ca2+ stores.

Animals↗

PubMed1996

Effects of adenosine A2A receptor agonist, CGS 21680, on blood pressure, cardiac index and arterial conductance in anaesthetized rats.

The effects of 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) on blood pressure, total peripheral resistance, cardiac index, heart rate and arterial conductance in different vascular beds in the presence and absence of hexamethonium (ganglionic blocker) and phenylephrine (alpha 1-adrenoceptor agonist) were investigated in pentobarbitone-anaesthetized rats using a radioactive microsphere technique. CGS 21680 (0.1, 0.3 and 1.0 microgram/kg/min) significantly decreased blood pressure and total peripheral resistance, and increased heart rate and cardiac index. In addition, after infusion with CGS 21680 (0.1, 0.3 and 1.0 microgram/kg/min) arterial conductance in coronary bed significantly increased. However, while CGS 21680 (0.3 and 1.0 microgram/kg/min) significantly increased conductance in skeletal muscle, it significantly decreased splenic arterial conductance. Moreover, CGS 21680 (1.0 microgram/kg/min) significantly increased conductance in cerebral arterial bed. Infusion with hexamethonium (200 micrograms/kg/min) resulted in significant reduction in blood pressure, heart rate and cardiac index whereas stroke volume and total peripheral resistance remained unchanged. In animals that were pretreated with hexamethonium (200 micrograms/kg/min), further administration of CGS 21680 (0.3 microgram/kg/min), compared to CGS 21680 alone, significantly reduced blood pressure, heart rate and cardiac index but did not affect total peripheral resistance or conductance in any vascular bed. Administration of phenylephrine (7 micrograms/kg/min) resulted in a significant increase in blood pressure and total peripheral resistance, and a significant reduction in cardiac index and heart rate. In animals infused with phenylephrine and CGS 21680 combined, in comparison to those animals that received CGS 21680 alone, no significant differences in blood pressure, heart rate, total peripheral resistance, cardiac index or conductance in any vascular beds were found. Our present findings suggest that CGS 21680 decreased blood pressure by decreasing total peripheral resistance, and increased cardiac index possibly through a reflex-mediated increase in heart rate. Moreover the coronary arterial bed is the most sensitive and cerebral arterial bed is the least sensitive to the effects of CGS 21680. In addition, the autonomic nervous system did not appear to play a major role in the actions of CGS 21680 on arterial conductance, and there was no difference in the action of this compound in the states of normal and raised vascular tone.

Adenosine↗