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PubMed2006

Effects of estradiol on phenylephrine contractility associated with intracellular calcium release in rat aorta.

The ability of estradiol to affect phenylephrine-induced contraction and the subsequent increase in resting tone, associated with capacitative Ca(2+) entry across the plasma membrane, was evaluated in rat aortic rings incubated in Ca(2+)-free solution. The incubation with estradiol (1-100 nM, 5 min) inhibited both the phenylephrine-induced contraction and the IRT. Neither cycloheximide (1 microM; inhibitor of protein synthesis) nor tamoxifen (1 microM; blocker of estrogenic receptors) modified the effects of estradiol. Estradiol (100 microM) also blocked the contractile response to serotonin (10 microM) but not to caffeine (10 mM). In addition, estradiol (100 microM) inhibited the contractile responses to cyclopiazonic acid (1 microM; selective Ca(2+)-ATPase inhibitor) associated with capacitative Ca(2+) influx through non-L-type Ca(2+) channels. Finally, estradiol inhibited the Ca(2+)-induced increases in intracellular free Ca(2+) (after pretreatment with phenylephrine) in cultured rat aorta smooth muscle cells incubated in Ca(2+)-free solution. In conclusion, estradiol interfered in a concentration-dependent manner with Ca(2+)-dependent contractile effects mediated by the stimuli of alpha(1)-adrenergic and serotonergic receptors and inhibited the capacitative Ca(2+) influx through both L-type and non-L-type Ca(2+) channels. Such effects are in essence nongenomic and not mediated by the intracellular estrogenic receptor.

Animals↗

PubMed1988

Effects of phenylephrine on calcium current and contractility of feline ventricular myocytes.

Previous studies on numerous cardiac preparations have shown that stimulation of alpha 1-receptors produces a positive inotropic effect. The cellular basis for this effect is not well understood. Isolated feline ventricular myocytes were used in the present study to examine the idea that the increase in contractility induced by stimulation of alpha 1-receptors is produced by an increase in inward Ca2+ current and that this event is caused by the stimulation of protein kinase C (PKC). These experiments showed that phenylephrine (10(-4) M) increased Ca2+ current from 0.56 +/- 0.02 (control) to 1.12 +/- 0.25 nA and increased contractile magnitude by 201 +/- 28%. The effect on Ca2+ current was completely blocked by propranolol (10(-7)M), whereas after beta-receptor blockade, contractile state was still 130 +/- 8% of control levels. alpha 1-Receptor blockade by prazosin eliminated this residual inotropic component of phenylephrine. Lower concentrations of phenylephrine (10(-7)M) were without effect on Ca2+ current and contractility as was stimulation of PCK with 150 nM of a phorbol ester. These results suggest that the positive inotropic effect of alpha 1-receptor stimulation in adult feline ventricular myocytes is not produced by increasing inward Ca2+ current and that this response is also not associated with stimulation of PKC.

Animals↗

PubMed1994

WB4101- and CEC-sensitive positive inotropic actions of phenylephrine in rat cardiac muscle.

This study was designed to determine the role of the alpha 1-adrenergic receptor (AR) subtypes in the positive inotropic action of alpha 1-adrenergic agonists in rat myocardium. Isolated left atrial and papillary muscle were suspended in oxygenated Krebs-Henseleit buffer (37 degrees C) containing 3 microM nadolol and paced at 3.3 Hz. Isometric tension was continuously monitored. Cumulative concentration-response curves for phenylephrine (3 x 10(-7) to 3 x 10(-4) M) were obtained in the presence and absence of WB4101 (4 and 10 nM) and with and without treatment with chloroethylclonidine (CEC; 10, 100, and 300 microM). WB4101 antagonized the effect of phenylephrine in both tissues, increasing half-maximal effective concentration (EC50) values in a concentration-dependent manner. CEC pretreatment also increased EC50 values in both tissues, and 300 microM CEC reduced the maximal positive inotropic effect of phenylephrine by approximately 48 and 38% in left atrial and papillary muscle, respectively. CEC alone elicited significant increases in contractile force that were not readily reversible. These data suggest that the positive inotropic effect of alpha 1-adrenergic agonists in rat atrial and ventricular myocardium results from stimulation of both WB4101- and CEC-sensitive alpha 1-ARs.

Adrenergic alpha-Antagonists↗

PubMed2005

Vascular sensitivity to phenylephrine in rats submitted to anaerobic training and nandrolone treatment.

The effect of anaerobic physical training and nandrolone treatment on the sensitivity to phenylephrine in thoracic aorta and lipoprotein plasma levels of rats was studied. Sedentary and trained male Wistar rats were treated with vehicle or nandrolone (5 mg/kg IM; twice per week) for 6 weeks. Training was performed by jumping into water (4 sets, 10 repetitions, 30-second rest, 50% to 70% body weight load, 5 days/week, 6 weeks). Two days after the last training session, the animals were killed and blood samples for lipoprotein dosage were obtained. Thoracic aorta was isolated and concentration-effect curves of phenylephrine were performed in intact endothelium and endothelium-denuded aortic rings in the absence or presence of NG-L-arginine-methyl ester. No changes were observed in endothelium-denuded aortic rings. However, in endothelium-intact thoracic aorta, anaerobic physical training induced subsensitivity to phenylephrine (pD2=7.11+/-0.07) compared with sedentary group (7.55+/-1.74), and this effect was canceled by the inhibition of nitric oxide synthesis. No difference was observed between trained (7.22+/-0.07) and sedentary (7.28+/-0.09) groups treated with nandrolone. Anaerobic training induced an increase in high-density lipoprotein levels in vehicle-treated rats, but there were no changes in nandrolone-treated groups. Training associated with nandrolone induced an increase in low-density lipoprotein levels but no change in the other groups. If altering endothelium-dependent vasodilatation is considered to be a beneficial adaptation to anaerobic physical training, it is concluded that nandrolone treatment worsens animals' endothelial function, and this effect may be related to lipoprotein blood levels.

Anabolic Agents↗

PubMed1995

Effect of angiotensin II blockade on the fibroproliferative response to phenylephrine in the rat heart.

In this study we infused phenylephrine into adult Wistar rats and used losartan to test for a possible role of angiotensin II in the phenylephrine-induced fibrosis. Phenylephrine, given by Alzet minipumps at a rate of 25 mg.kg-1.d-1, produced a rapid and striking fibrotic response that was obvious after 1 day and progressed throughout a 3-day infusion period. Northern and Western blot analyses showed large increases in cardiac fibronectin expression and atrial natriuretic peptide mRNA, corresponding to fibroblast proliferation and myocyte hypertrophy, respectively. Cardiac fibrosis, fibronectin mRNA, and atrial natriuretic peptide mRNA were blocked by prazosin (7 mg.kg-1.d-1). Administration of losartan (10 mg.kg-1.d-1) resulted in a threefold decrease in interstitial and perivascular fibroblast proliferation, as measured by proliferating cell nuclear antigen immunoreactivity (p < .05), a marked reduction of fibronectin mRNA in the heart, and a moderate reduction of cardiac atrial natriuretic peptide mRNA. The data suggest that effects mediated by a1-adrenergic and angiotensin type 1 receptors may promote cardiac fibrosis.

Angiotensin II↗

PubMed2003

NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro.

Biomechanical stress on the heart results in activation of numerous signaling cascades, leading to cardiomyocyte hypertrophy, apoptosis, and ultimately, heart failure. The Ca2+-dependent phosphatase calcineurin is an essential mediator of cardiac hypertrophy, and in most but not all studies, calcineurin inhibition attenuated cardiac hypertrophy in vivo. However, calcineurin inhibition has been reported to have adverse effects on cardiac remodeling and cardiomyocyte apoptosis. Calcineurin regulates the activity of a number of downstream targets, including the transcription factors NFAT, MEF2, and NF-kappaB, and the apoptotic factor Bad. To evaluate the contribution of NFAT activation by calcineurin to cardiomyocyte responses to hypertrophic stimulation, we used adenovirus to express VIVIT, a selective peptide inhibitor of calcineurin-mediated NFAT activation. We found that selective NFAT inhibition during phenylephrine stimulation inhibited hypertrophy but resulted in increased cardiomyocyte apoptosis. In contrast, nonselective inhibition of calcineurin by cyclosporin A did not cause cardiomyocyte apoptosis after phenylephrine stimulation. Cyclosporin A suppressed the effect of VIVIT on cardiomyocyte apoptosis. These results demonstrate that during phenylephrine stimulation calcineurin activates both pro- and antiapoptotic pathways in cardiomyocytes, and that NFAT activity is a critical component of the antiapoptotic pathway that regulates whether the outcome of calcineurin activation is cardiomyocyte apoptosis or survival.

Amino Acid Sequence↗

PubMed1990

High-dose phenylephrine infusion in the hemodynamic support of septic shock.

A 75-year-old man with hyperdynamic septic shock and vasodilation was successfully supported hemodynamically for 88.5 hours through the use of a continuous infusion of phenylephrine at dosages up to 360 micrograms/min. The only other vasoactive compound administered was dopamine at a dosage of 3.4 micrograms/kg/min. Hemodynamic evaluation indicated improvements in mean arterial pressure, cardiac output, and oxygen transport parameters during the period of hemodynamic support, which did not indicate a detrimental effect on perfusion of vital organs and tissues despite the use of this vasoconstrictor. Phenylephrine's pharmacologic properties may represent an advantage for its use as a vasoconstrictor over catecholamines such as norepinephrine and dopamine, particularly in patients who develop tachyarrhythmias with these agents. The pharmacology, dosage, and appropriate monitoring of therapy with phenylephrine in patients with septic shock are discussed.

Acute Kidney Injury↗

PubMed2004

The effect of diabetes on the interrelationship between jugular venous oxygen saturation responsiveness to phenylephrine infusion and cerebrovascular carbon dioxide reactivity.

In this study, we examined whether cerebrovascular carbon dioxide (CO(2)) reactivity was related to the response of jugular venous oxygen saturation (SjvO(2)) to phenylephrine infusion in diabetic patients during cardiopulmonary bypass. Forty diabetic patients scheduled for coronary artery bypass graft surgery were studied, and 40 age-matched nondiabetic cardiopulmonary bypass patients served as controls. Cerebrovascular CO(2) reactivity was measured continuously using transcranial Doppler. Mean arterial blood pressure (MAP) was increased by repeated phenylephrine infusion until reaching 100% of baseline values. There was a significant difference in absolute CO(2) reactivity between the diabetic and control groups (controls, 2.8 +/- 0.7 cm. s(-1). mm Hg(-1); diabetics, 2.2 +/- 1.1 cm. s(-1). mm Hg(-1); P = 0.02). Among the diabetics, absolute CO(2) reactivity in insulin-dependent patients was less than that in noninsulin-dependent patients (diet therapy group, 3.2 +/- 0.7; glibenclamide group, 2.6 +/- 0.7; insulin-dependent group, 1.0 +/- 0.7; P < 0.01). There was a correlation between absolute CO(2) reactivity and the mean slope of SjvO(2) versus MAP for increasing MAP (r = 0.54; P < 0.0001). In conclusion, we found that the interrelationship between SjvO(2) responsiveness to phenylephrine infusion and cerebrovascular CO(2) reactivity, as well as impaired cerebrovascular autoregulation, were associated with previous hyperglycemia.

Aged↗

PubMed1989

Effect of hetastarch, mannitol, and phenylephrine on spinal cord blood flow following experimental spinal injury.

Anesthetized lambs were subjected to epidural cord compression at T13 by means of an epidural balloon distended to 200 mmHg for 80 minutes. Determinations of spinal cord blood flow (SCBF) were made by labelled microspheres prior to and during compression, and then 1/2, 1 1/2, and 2 1/2 hours after compression. Twelve control animals received saline (80 ml/h). Nine animals received hetastarch (a 20 ml/kg bolus followed by an 80 ml/h infusion) and 8 animals received mannitol (a 1 g/kg bolus followed by 1 g/kg/hr). An additional 10 animals received phenylephrine to raise mean arterial pressure by 20 to 40%. Somatosensory evoked potentials (SEPs) were recorded following each determination of SCBF. Animals were killed following determination of the 2 1/2 hour postcompressive flow. The animals treated with either hetastarch or phenylephrine had a postcompressive mean arterial pressure that was significantly greater than that of the controls (P less than 0.01). During treatment, cardiac output in the hetastarch and mannitol animals was significantly greater and hematocrit significantly less than in the controls (P less than 0.05). In spite of these changes, postcompressive SCBF was significantly increased only in those animals treated with phenylephrine (P less than 0.05). Statistical analysis of the relationship between mean arterial pressure and postcompressive SCBF revealed that autoregulation is indeed lost with this experimental model of spinal cord injury. Histological examination of the injured site failed to demonstrate any difference in the area of hemorrhagic necrosis among the four groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Different mode of action between norepinephrine and phenylephrine on prostaglandin synthesis by dog renal inner medullary slices.

The dog renal inner medullary slices synthesized and released prostaglandin (PG) E2, PGF2 alpha, PGI2 (measured as 6-keto-PGF1 alpha) and thromboxane (TX) A2 (measured as TXB2). When incubated in the presence of norepinephrine, the synthesis of these arachidonic acid metabolites were stimulated about 2-fold. The norepinephrine effect could be antagonized by the addition of an alpha-adrenoceptor blocking agent, phenoxybenzamine, but not by a beta-adrenoceptor blocking drug, propranolol. Phenoxybenzamine at concentrations that block norepinephrine stimulation of prostaglandin biosynthesis did not suppress the increase in prostaglandins synthesized by exogenous arachidonic acid. By contrast, phenylephrine caused only PGI2 production without producing other prostaglandins and thromboxane. This phenylephrine effect could not be antagonized by either alpha- or beta-adrenoceptor blocking agents, but it was abolished by the specific PGI2 synthetase inhibitors 15-hydroperoxy arachidonic acid and tranylcypromine. These results suggest that norepinephrine-induced prostaglandin synthesis is mediated via an alpha-adrenergic receptor mechanism, whereas phenylephrine stimulation is primarily occurring at the step which follows the cyclooxygenase reaction in the metabolism of arachidonic acid.

Animals↗

PubMed1992

The role of endothelium in the phenylephrine-induced oscillatory responses of rabbit mesenteric arteries.

Phenylephrine-induced oscillatory contractions in rabbit mesenteric arteries were investigated in vitro. Adrenergic, cholinergic, or histamine antagonists as well as cyclooxygenase and lipoxygenase inhibitors had no effect on this phenylephrine-induced oscillation. The removal of extracellular calcium ions or treatment with a calcium antagonist reduced the amplitude and frequency of the oscillation. Removal of the endothelium or treatment with inhibitors of the synthesis or the target enzyme of endothelium-derived relaxing factor (EDRF) also reduced the amplitude and frequency of the oscillation. In a perfusion bioassay, the perfusate from an endothelium-intact arterial segment induced oscillation of an endothelium-denuded arterial ring recipient. These results suggest that phenylephrine-induced oscillation is mediated by an endothelium-derived factor such as EDRF and depends on the influx of extracellular calcium ions.

Animals↗

PubMed2004

Differential inotropic effects of endothelin-1, angiotensin II, and phenylephrine induced by crosstalk with cAMP-mediated signaling process in dog ventricular myocardium.

Endothelin-1 (ET-1), angiotensin II (Ang II), and phenylephrine, an alpha1-adrenoceptor agonist, share the common signaling process, resulting in activation of Gq protein-coupled receptor (GqPCR) to activate the hydrolysis of phosphoinositide (PI). They do not elicit any inotropic effect in isolated dog ventricular muscle. In the presence of forskolin or IBMX (3-isobutyl-1-methylxanthine), ET-1 produced a dual effect, that is, a positive inotropic effect (PIE) and/or a negative inotropic effect (NIE) depending on concentrations of forskolin or IBMX present simultaneously with ET-1. Phenylephrine produced a definite PIE and Ang II induced a small and transient PIE in the presence of forskolin or IBMX, but they did not elicit a NIE. Facilitation of Ca2+ influx via L-type Ca2+ channel may play a crucial role in the crosstalk because GqPCR agonists produced, likewise a PIE in the presence of Bay k 8644. GqPCR agonists failed to induce a PIE in the presence of dihydroouabain or elevated [Ca2+]o. These findings indicate that the accumulation of cAMP or activation of L-type Ca2+ channels markedly modulates the inotropic response to GqPCR agonists in a manner that leads to a PIE in dog ventricular myocardium. In addition, ET-1, but not Ang II or phenylephrine, activates the signal transduction process that results in a NIE.

Angiotensin II↗

PubMed2004

alpha1A-adrenergic receptor mediated pressor response to phenylephrine in anesthetized rat.

To determine which subtype of alpha1-adrenergic receptors plays a role in the regulation of blood pressure, with alpha1A-adrenergic receptor-mediated vasoconstriction in perfused hindlimb as a control, we compared the inhibitory effects of various alpha1-adrenergic receptor selective antagonists on the vasopressure responses to phenylephrine between the mean arterial pressure and hindlimb perfusion pressure in anesthetized rats. In Normotensive Wistar rats, the results showed that the inhibitory effects (dose ratios of ED50, Dr) of alpha1-adrenoceptor selective antagonist (prazosin, Dr 13.5+/-3.6 vs.15.1+/-4.3, n = 11), alpha1A-adrenoceptor selective antagonist (5-methyl-urapidil, Dr 2.4+/-0.9 vs. 3.7+/-2.3, n = 12; RS-17053, Dr 3.2+/-1.6 vs. 4.4+/-3.3, n =12) and alpha1D-adrenoceptor selective antagonist (BMY7378, Dr 1.9+/-0.9 vs. 2.2+/-0.8, n=8) on phenylephrine- induced increases of perfusion pressure in the autoperfused femoral beds were the same as that in the mean arterial blood pressure in normotensive Wistar rats. The inhibitory effects of antagonists (RS-17053, Dr 3.4+/-0.6 vs. 4.3+/-0.9, n = 5; BMY7378, Dr 1.7+/-0.5 vs. 1.7+/-0.5, n = 8) in spontaneous hypertensive rats were similar with the Wistar rats. These results suggest that the mean arterial pressure induced by phenylephrine was mainly mediated by alpha1A-adrenergic receptor in both the anesthetized Wistar rats and spontaneous hypertensive rats.

Adrenergic alpha-Agonists↗

PubMed1980

Double-blind comparison of metaproterenol and isoetharine-phenylephrine solutions in intermittent positive pressure breathing in bronchospastic conditions.

A 5 percent solution of metaproterenol sulfate (Alupent) and a fixed-combination solution of isoetharine and phenylephrine were compared in a single-dose double-blind study in a total of 27 patients with reversible bronchospastic disease. The patients were assigned to parallel groups for treatment and received the usual dose of 0.3 ml of metaproterenol and 0.5 ml of the isoetharine-phenylephrine solution via equipment for intermittent positive-pressure breathing. Tests of pulmonary function, blood pressure, and pulse rate were performed before the treatment and at intervals of 30 minutes to six hours after administration. The duration of effect (defined as an increase over baseline in the forced expiratory volume in one second [FEV1] of at least 15 percent) of metaproterenol averaged four hours, as compared with one hour for the reference solution. The overall response of FEV1 to metaproterenol was significantly (P = 0.01) superior to the response to the isoetharine-phenylephrine solution. Metaproterenol also surpassed the reference drug in terms of increases in the mean forced expiratory flow during the middle half of the forced vital capacity (FEF-25-75%) to a degree approaching statistical significance. Changes in blood pressure and pulse rate were clinically insignificant with both drugs, and the total number of adverse experiences was substantially the same with both solutions.

Adult↗

PubMed2000

The effects of the initial arterial tone on the pressure responses to phenylephrine.

The effect of the elevated arterial tone on pressure responses to stimulation of arterial alpha-adrenoreceptors by phenylephrine hydrochloride was studied in anesthetized Wistar rats. Different levels of the arterial tone and, hence of the mean arterial pressure, were established by means of angiotensin II infusion in the range from 101 to 160 mmHg. An elevation of the arterial tone led to a significant reduction of the arterial pressure and peripheral resistance rise produced by phenylephrine. The degree of relative reduction of the increase in the diastolic pressure exceeded 1.3 times that in the systolic pressure. The shifts of cardiac outputs remained unchanged. After cessation of angiotensin II infusion the restoration of the arterial pressure took place almost till the initial level. At this time the pressure effects of phenylephrine were tended to recovery. It is suggested that the elevated arterial tone attenuates the systemic pressure response to stimulation of arterial alpha-adrenoreceptors by a vascular mechanism based on a transmural pressure changes evoked by the constriction of the arterial vessels.

Adrenergic alpha-Agonists↗

PubMed1992

Vascular responsiveness to angiotensin II and phenylephrine, the tubular function and the prostaglandin, renin-angiotensin system in a patient with Bartter's syndrome.

In a 39-yr-old female patient with Bartter's syndrome, vascular responsiveness to angiotensin II and phenylephrine was studied. Pressor responses to angiotensin II and to phenylephrine were markedly decreased prior to treatment and were improved by administration of indomethacin, dextran, KCl, captopril, propranolol or pindolol. Moreover, the responses of total peripheral vascular resistance to angiotensin II and phenylephrine were markedly decreased before treatment and were improved by the treatment. A relatively low fractional distal chloride reabsorption was found, and that was not changed after the administration of KCl or indomethacin. The results of this patient were compatible with the primary cause of Bartter's syndrome, defective chloride reabsorption at the loop of Henle, but the possibility of an abnormality in the vascular wall could not be denied.

Adult↗

PubMed1986

Additive effects of isoproterenol-phenylephrine aerosol following ipratropium bromide on airway obstruction in older patients with intrinsic asthma and chronic bronchitis.

The additive bronchodilating effect of isoproterenol-phenylephrine aerosol following ipratropium bromide was examined in seven intrinsic asthmatic patients and seven chronic bronchitic patients. FVC, FEV1 and Zrs were measured before and 30 min. after inhalation of ipratropium, 40 micrograms. Then inhalation of isoproterenol, 600 micrograms and phenylephrine, 570 micrograms was added and the pulmonary functions were measured 30 min. later. The age, baseline values of FVC and FEV1, and the increases in FEV1 and 1/Zrs with ipratropium did not differ between the two. Isoproterenol-phenylephrine aerosol following ipratropium produced further increases in FEV1 and 1/Zrs in asthmatic patients but no additive increases in bronchitic patients. These findings indicate that the role of autonomic nervous system, especially adrenergic system, on airway obstruction may be different between asthmatic and bronchitic patients and the method applied in this study may be helpful in differentiating these airway disorders.

Aerosols↗

PubMed1993

Phenylephrine-induced rhythmic activity in the rabbit ear artery.

Isolated rabbit ear arteries displayed rhythmic contractions when stimulated with alpha 1 agonist phenylephrine. These rhythmic responses were greatly attenuated by endothelium removal. However, contractions were sufficiently rhythmic in the arteries treated with NG-monomethyl-L-arginine, NG-nitro-L-arginine and indomethacin, synthetic inhibitors of endothelium-derived nitric oxide and prostanoids. Phenylephrine-induced rhythmic contractions were converted to tonic contractions by the blockade both of the voltage-dependent Ca2+ channel and the Ca(2+)-activated K+ channel by nifedipine and charybdotoxin, respectively. In contrast, glibenclamide, an ATP-sensitive K+ channel antagonist, did not alter the rhythmic contractions. These results suggest that endothelium may in part regulate the phenylephrine-induced rhythmic contractions in the rabbit ear artery, although endothelium-derived nitric oxide or prostanoids may not be involved in these responses. These endothelium-involved rhythmic responses may be attributed to the activation of the voltage-dependent Ca2+ channel and the Ca(2+)-activated K+ channel.

Animals↗