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PubMed1975

Studies on the positive inotropic effect of phenylephrine: a comparison with isoprenaline.

1. The effects of phenylephrine and isoprenaline on the isometric contraction of guinea-pig ventricle were compared over the whole range of their respective dose-response curves. 2. In preparations driven at 2.5 Hz the increase in contractile force induced by either isoprenaline of phenylephrine was linearly correlated to an increase in maximum velocity of force development. The relaxation time was shortened by isoprenaline but not by phenylephrine. 3. The negative inotropic effect induced by delta [N-(3,4-dimethoxyphenethyl)-N-methyl-amino]-alpha-(3,4,5-trimethoxyphenyl)alpha-isopropylvaleronitrile hydrochloride (D(600)) was reversed by isoprenaline, but little influenced by phenylephrine. 4. The study of the interval-force relationship shows that the increase in contractile force induced by phenylephrine (3 X 10(-5) M) was relatively greater at low frequencies of stimulation, and that the maximum effect was reached at the frequency of 1 Hz. 5. The positive inotropic effect of phenylephrine (10-4 M) was significantly higher at a frequency of 1 Hz than at 2.5 Hz; the effect of isoprenaline (3 x 10-8 M) was not significantly different at the two driving frequencies. 6. In preparations driven at 1 Hz the inotropic effect of the lower concentrations of phenylephrine was due to an increase in the time to peak tension without any change of the maximum velocity of force development; however an increase of this parameter became evident only after higher concentrations of the amine (10-5 M or more), associated with a progressive shortening of the time to peak. 7. A correlation between mechanical and electrophysiological effects of phenylephrine is attempted; the suggestion is advanced that the prolongation of the action potential and of the active state duration may be an important factor in the inotropic effect of phenylephrine.

Action Potentials↗

PubMed1984

Effects of alpha-adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart.

The mechanism of the cyclic AMP-independent positive inotropic effect of cardiac alpha-adrenoceptor stimulation was studied by analyzing the effects of phenylephrine on force of contraction, calcium-dependent slow action potentials and the slow inward current (Isi) in bovine ventricular trabeculae. The preparations were electrically driven at 0.3 Hz in the presence of propranolol 1 mumol 1(-1). Phenylephrine increased the force of contraction in a concentration-dependent manner (maximum about 200% of control at 30 mumol 1(-1). The effect was surmountably antagonized by phentolamine. The positive inotropic effect of phenylephrine was accompanied by a concentration-dependent increase in time to peak force and occurred without any detectable increase in cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels. The positive inotropic effect of phenylephrine was accompanied by an increase in action potential duration both at 20% and 90% repolarization. Calcium-dependent slow action potentials were also prolonged by phenylephrine and there was a distinct increase in the maximal rate of depolarization (dV/dtmax) of these slow potentials. These effects were also completely reversible on washing and surmountably blocked by phentolamine. However, the increase in dV/dtmax was smaller than that of isoprenaline in concentrations producing similar inotropic effects. Voltage-clamp experiments with the single sucrose-gap method showed that the phenylephrine-induced increase in force of contraction was associated not only with an increase in peak slow calcium inward current, Isi max, but also with a delay in the inactivation of Isi. Outward currents were not detectably altered by phenylephrine. It is concluded that the alpha-adrenoceptor mediated, cyclic AMP-independent positive inotropic effects of phenylephrine in bovine cardiac muscle are associated with an increase in slow inward current. Additionally, the amount of calcium influx during excitation is probably increased by a delay in the inactivation of Isi. Both effects can explain the phenylephrine-produced prolongation of the action potential, and probably contribute to the positive inotropic effect of alpha-adrenoceptor stimulation. However, as the effect on dV/dtmax is smaller than that of isoprenaline, other (still unknown) mechanisms may also be involved.

Action Potentials↗

PubMed1995

Effect of swimming on vascular reactivity to phenylephrine and KC1 in male rats.

1. The present study aimed to examine whether there is any change in vascular responsiveness to phenylephrine and KC1 during exercise, and whether the vascular endothelium plays a role in these changes. 2. Adult male rats were subjected to a swimming schedule every day for 5-6 weeks. Studies were performed in vitro on thoracic aortae. 3. Maximum contractile response to phenylephrine of endothelium-intact thoracic aortic rings (passive tension 1.0 g) obtained from swimming rats (1.2 +/- 0.2 g, n = 8) was lower than of sedentary control rats (2.1 +/- 0.2 g, n = 8). When the endothelium was removed, however, the dose-response curves of both groups of rats were shifted to the left with an increase in maximum responses and they were no longer significantly different (max. tension, swimming rats: 3.2 +/- 0.3 g, n = 6, control rats: 3.4 +/- 0.4 g, n = 5). 4. Indomethacin did not significantly alter the dose-response curves. A similar effect to that obtained by removal of the endothelium was observed when methylene blue and indomethacin were both added. 5. Passive tension in the range of 2.5-3.0 g, caused a significant increase in active tension developed to phenylephrine (1 microM for endothelium-intact and 0.1 microM for endothelium-denuded) of thoracic aortic rings of both swimming and sedentary control rats compared to their corresponding groups when using passive tension of 1.0-1.5 g. 6. The reduction in responses to phenylephrine of endothelium-intact thoracic aortic rings of swimming rats persisted with the use of a passive tension of 3.0 g. The presence of 300 microM N0-nitro-L-arginine (LNOARG)caused a significant leftward shift of the curve with an increase in maximum responses when a passive tension of either 1.0 or 3.0 g was applied to the rings. However, for the rings with a passive tension of 1.0 g, L-NOARG caused a smaller increase in maximal contractile responses to phenylephrine of the rings of sedentary controls than those of swimming rats.7. There was no difference in the dose-response curves to depolarizing concentrations of KCl (20, 40, 80 and 120 mM) of endothelium-intact thoracic aortic rings from swimming and sedentary control rats.When the endothelium was removed, however, the dose-response curves of both groups of animals were shifted to the left with an increase in maximum responses. Moreover, the responses to KCl of endothelium-denuded thoracic aortic rings of swimming rats were greater than those of sedentary control rats.8. These results suggest that there were changes in vascular responsiveness to phenylephrine and KCl during exercise. The fall in sensitivity to phenylephrine with no change in KCl responses, and the increase in maximum responses to phenylephrine in the presence of L-NOARG in endothelium-intact aortae (passive tension 1.0 g) from swimming rats, were due to an increase in spontaneous release and upregulation of phenylephrine-stimulated release of EDRF/NO, and may not be a consequence of an increase in prostaglandins or a decrease in the production of endothelial constrictors by vascular endothelium. EDRF/NO may play an important role in modulating local vasodilatation.

Analysis of Variance↗

PubMed1995

Effects of 8-bromoguanosine 3':5'-cyclic monophosphate on phenylephrine-induced phosphatidylinositol hydrolysis and contraction in rat caudal artery.

1. The effects of 8-bromoguanosine 3':5'-cyclic monophosphate (8-bromo-cyclic GMP) on phenylephrine-induced contractions and phosphatidylinositol (PI) hydrolysis were investigated in rat isolated caudal artery. The effects of the nucleotide were compared to those of felodipine, a dihydropyridine Ca2+ channel antagonist and ryanodine, a putative depletor of intracellular Ca2+ stores. The purpose of this investigation was to examine the regulatory effects of cyclic GMP on receptor-mediated signal transduction in vascular smooth muscle. 2. Phenylephrine induced a concentration-dependent increase in PI hydrolysis that reached a maximum at 10 microM phenylephrine. Pre-incubation with felodipine (10 nM) significantly reduced PI turnover, but did not affect basal hydrolysis. Similarly, removal of extracellular Ca2+ (2 mM ethylene glycol-bis(beta-amino-ethyl ether) N, N, N', N'-tetraacetic acid (EGTA)) blocked phenylephrine-induced PI hydrolysis, but did not affect basal turnover. In contrast, 8-bromo-cyclic GMP (10 microM) did not affect phenylephrine-induced PI hydrolysis, nor did it affect basal turnover. 3. Phenylephrine induced concentration-dependent contractions that were inhibited by each of 8-bromo-cyclic GMP (10 microM), felodipine (1 nM and 10 nM) and ryanodine (3 microM and 10 microM). In addition, removal of Ca2+ from the physiological salt solution (2 mM EGTA) completely abolished contractions elicited by phenylephrine. 4. Phenylephrine-induced contractions were not further affected by felodipine and 8-bromo-cyclic GMP applied concomitantly than by equivalent concentrations of felodipine alone. However, ryanodine and 8-bromo-cyclic GMP applied together significantly inhibited phenylephrine-induced contractions in comparison to ryanodine alone. 5 These results suggest that phospholipase C-activated PI hydrolysis in the rat caudal artery is dependent on extracellular Ca2+, mediated, in part, through dihydropyridine-sensitive Ca2+ channels.Inhibition of contraction by felodipine may be brought about through indirect inhibition of IP3 production and subsequent attenuation of intracellular Ca2+ release. 8-Bromo-cyclic GMP does not inhibit PI hydrolysis; it may regulate vascular smooth muscle contraction by inhibition of Ca2+ release from IP3-mediated intracellular stores, but it is unlikely that 8-bromo-cyclic GMP affects ryanodine-sensitive stores.

Animals↗

PubMed1992

Phenylephrine-induced translocation of protein kinase C and shortening of two types of vascular cells of the ferret.

1. The relationship between phenylephrine-induced smooth muscle contraction and the subcellular distribution of protein kinase C (PKC) was investigated. 2. Cell shortening induced by phenylephrine (10(-5) M) was measured in single vascular cells freshly isolated from ferret portal vein and aorta. 3. At various time points during phenylephrine activation, single cells were fixed with paraformaldehyde and the distribution of PKC was imaged in cells labelled with the fluorescent PKC probe 12-(1,3,5,7-tetramethylBODIPY-2-propionyl)phorbol-13-acetate. 4. The PKC probe located to a perinuclear region, the cytosol and surface membrane. The amplitude and time course of the phenylephrine-induced changes in the surface membrane/cytosol fluorescence ratio were measured and compared with the amplitude and time course of phenylephrine-induced cell shortening. 5. In portal vein cells incubated in 1 mM-external Ca2+, phenylephrine caused significant shortening and time-dependent translocation of the PKC probe to the surface membrane, but cell shortening preceded PKC translocation. In Ca2+free solution both cell shortening and translocation of the probe were completely inhibited. 6. Verapamil (3 x 10(-7) M) partially, but significantly, inhibited the magnitude of cell shortening and delayed the onset and time to peak shortening. Translocation of PKC in verapamil preceded or coincided with cell shortening. 7. In aorta cells incubated in 1 mM-extracellular Ca2+, phenylephrine induced significant shortening and time-dependent translocation of the PKC probe. Cell shortening preceded PKC translocation. In Ca(2+)-free solution, shortening was only partially, but significantly, inhibited and PKC translocation preceded the fraction of the shortening response that remained. 8. These data are consistent with a role for PKC in the maintenance of the phenylephrine-induced contraction in both portal vein and aorta. The data also suggest that phenylephrine-induced contraction may involve activation of a Ca(2+)-dependent PKC isoform in ferret portal vein but a Ca(2+)-independent isoform in ferret aorta.

Animals↗

PubMed2005

Chronic ethanol consumption enhances phenylephrine-induced contraction in the isolated rat aorta.

Changes in reactivity to phenylephrine in aortas isolated from 2-, 6-, and 10-week ethanol-treated rats and their age-matched control and isocaloric rats were investigated. Chronic ethanol consumption enhances the contractile response of endothelium-intact and -denuded rat aortic rings to phenylephrine, a response that is time-independent. Pretreatment with indomethacin reduced E(max) for phenylephrine in denuded aortas from ethanol-treated rats but not control or isocaloric rats. After indomethacin treatment, no differences in E(max) from phenylephrine were observed among the groups. SQ29548 ([1S-[1alpha-2alpha(Z)3alpha,4alpha]]-7-[3-[[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid), an antagonist of prostaglandin H(2)/thromboxane A(2) (TXA(2)) receptors, did not alter phenylephrine-induced contraction in control or isocaloric aortas. However, in ethanol-treated aortas, E(max) was reduced to control level. Moreover, phenylephrine-stimulated release of thromboxane B(2), a stable metabolite of TXA(2), was higher in tissues from ethanol-treated rats. Simultaneous measurement of the changes in [Ca(2+)](i) and contraction induced by phenylephrine showed that both parameters are higher in the rat aorta from ethanol-treated rats. CaCl(2)-induced contraction in free Ca(2+) solution containing phenylephrine was increased in ethanol-treated aortas. Additionally, the enhancement in CaCl(2)-induced contraction was prevented by SQ29548. The major contribution of the present study is that it demonstrates a detailed description of the mechanisms involved in the enhancement of phenylephrine-induced contraction in rat aorta from ethanol-treated rats. We provided evidence that this response was not different among the three periods of treatment employed in this study and that it is maintained by two mechanisms: an increased release of vascular smooth muscle-derived vasoconstrictor prostanoids (probably TXA(2)) and an enhanced extracellular Ca(2+) influx.

Animals↗

PubMed1998

Biphasic action of phenylephrine on the Ca(2+)-activated K+ channel of human prostatic smooth muscle cells.

The elevation of cytosolic Ca2+ ([Ca2+]i) is known to regulate smooth muscle contractility. A physiological concentration of phenylephrine induced the elevation in [Ca2+]i of human prostatic smooth muscle cells; however, contraction of prostatic tissues in vitro needs a higher concentration of phenylephrine than the physiological level. To investigate this discrepancy, we investigated the functional importance of the Ca(2+)-activated K+ channel (KCa channel) of human prostatic smooth muscle cells in phenylephrine-induced contraction. Using the patch-clamp technique, the KCa channel of human prostatic smooth muscle cells was activated by phenylephrine at a physiological concentration (10(-7)-10(-5) M) but was inhibited at a higher concentration (10(-4)-10(-3) M). Phenylephrine (10(-3) M) also inhibited the KCa channel which was activated by 10 microM A23187, a calcium ionophore. Similar inhibition was obtained with 1 microM phorbol 12-myristate 13-acetate, an activator of protein kinase C (C-kinase). Both inhibitions were reversed by subsequent application of 1 nM staurosporine, a protein kinase inhibitor. These results suggested that C-kinase mediated the phenylephrine-induced inhibition of the KCa channel. In this study, a physiological concentration of phenylephrine induced activation of the KCa channel of human prostatic smooth muscle cells, which brought about membrane hyperpolarization and relaxation of human prostatic smooth muscle cells. The regulation of the KCa channel by phenylephrine may explain the need of a high concentration of phenylephrine for the contraction of prostatic tissue.

Adrenergic alpha-Agonists↗

PubMed1999

Differences between the vasorelaxant activity of adenosine-receptor agonists on guinea-pig isolated aorta precontracted with noradrenaline or phenylephrine.

The relaxant effect of adenosine and 5'-(N-ethylcarboxamido)adenosine (NECA) against alpha-adrenoceptor-mediated contractile tone in guinea-pig isolated aortic rings has been examined to determine if this A2B-receptor-mediated relaxation was dependent upon the contracting agent, and whether the contractions were dependent upon intracellular or extracellular calcium. Relaxation responses were consistently greater for aortic rings pre-contracted with phenylephrine (3x10(-6) M) than for rings pre-contracted with noradrenaline (3x10(-6) M). Maximum inhibition by NECA was significantly greater for phenylephrine-contracted aortae than for noradrenaline-contracted (81.9+/-2.8% compared with 25.0+/-1.5%). These differences persisted in the presence of beta- and alpha2-adrenoceptor blockade and could not, therefore, be attributed to stimulation of these receptors by noradrenaline. The ratio of the contractions obtained before and in the presence of adenosine or NECA was compared with the control ratio obtained before and after vehicle. Experiments were performed both in the presence of normal calcium levels and under calcium-free conditions. In normal-calcium medium, NECA inhibited phenylephrine-induced contractions (test ratio, 76.7+/-3.9%; control ratio, 133.1+/-9.8%) to a greater extent than noradrenaline-induced contractions (108.4+/-4.1 and 123.4+/-4.9%); adenosine similarly inhibited phenylephrine-induced contractions more than those induced by noradrenaline. Under calcium-free conditions, adenosine (36.7+/-11.9 and 110.7+/-26.6%) and NECA (55.2+/-9.1 and 87.1+/-14.9%) were only effective against phenylephrine-induced contractions. This suggests that activation of the A2B-receptor by these agonists inhibited intracellular mobilization of calcium for phenylephrine-induced contractions only. The effects on extracellular calcium influx were examined for phenylephrine- and noradrenaline-induced contractions in normal-calcium medium but in the presence of ryanodine to prevent intracellular calcium mobilization. NECA inhibited phenylephrine-induced contractions (77.3+/-12.4 and 111.4+/-9.3%), presumably by interfering with influx of calcium through receptor-operated calcium channels. In contrast, NECA failed to reduce noradrenaline-induced contractions (121.5+/-10.7 and 122.4+/-11.6%), suggesting that the effect on noradrenaline is predominantly via interaction with intracellular calcium. Adenosine was consistently a more effective relaxant than NECA, possibly because of an additional intracellular component of the response. We conclude that adenosine receptor agonists inhibit phenylephrine-induced contractions of guinea-pig aorta more selectively than noradrenaline-induced contractions. A2B-receptor stimulation might reveal a fundamental difference between the modes of contraction elicited by these two alpha-adrenoceptor agonists.

Adenosine↗

PubMed2004

Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery.

UNLABELLED: In a randomized, double-blinded, controlled trial, we investigated the prophylactic infusion of IV phenylephrine for the prevention of hypotension during spinal anesthesia for cesarean delivery. Immediately after intrathecal injection, phenylephrine was infused at 100 microg/min (n = 26) for 3 min. From that point until delivery, phenylephrine was infused at 100 microg/min whenever systolic arterial blood pressure (SAP), measured each minute, was less than baseline. A control group (n = 24) received IV bolus phenylephrine 100 microg after each measurement of SAP <80% of baseline. Phenylephrine infusion decreased the incidence (6 [23%] of 26 versus 21 [88%] of 24; P < 0.0001), frequency, and magnitude (median minimum SAP, 106 mm Hg; interquartile range, 95-111 mm Hg; versus median, 80 mm Hg; range, 73-93 mm Hg; P < 0.0001) of hypotension compared with control. Heart rate was significantly slower over time in the infusion group compared with the control group (P < 0.0001). Despite a large total dose of phenylephrine administered to the infusion group compared with the control group (median, 1260 microg; interquartile range, 1010-1640 microg; versus median, 450 microg; interquartile range, 300-750 microg; P < 0.0001), umbilical cord blood gases and Apgar scores were similar. One patient in each group had umbilical arterial pH <7.2. Prophylactic phenylephrine infusion is a simple, safe, and effective method of maintaining arterial blood pressure during spinal anesthesia for cesarean delivery. IMPLICATIONS: In patients receiving spinal anesthesia for elective cesarean delivery, a prophylactic infusion of phenylephrine 100 microg/min decreased the incidence, frequency, and magnitude of hypotension with equivalent neonatal outcome compared with a control group receiving IV bolus phenylephrine.

Acid-Base Equilibrium↗

PubMed2006

Effect of D-004, a lipid extract from the Cuban royal palm fruit, on atypical prostate hyperplasia induced by phenylephrine in rats.

BACKGROUND AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that results in obstructive lower urinary tract symptoms. Saw palmetto (Serenoa repens), the dwarf American palm (Arecaceae family), is commonly used to treat BPH. The Cuban royal palm (Roystonea regia) also belongs to the Arecaceae family, and 200-400mg of D-004, a lipid extract from its fruits, administered orally for 14 days has been shown to prevent testosterone- but not dihydrotestosterone-induced prostatic hyperplasia in rats. D-004 (125-250 microg/mL) added to preparations of rat vas deferens caused a marked, dose-dependent and significant inhibition of noradrenaline-induced smooth muscle contraction, a response mediated through alpha(1)-adrenoceptors, and was more effective in these respects than Saw palmetto. However, the in vivo effects of D-004 and Saw palmetto on the hypertensive response induced by noradrenaline were modest (albeit significant), and neither treatment affected resting blood pressure or heart rate in rats. The differential effects of D-004 in in vitro and in vivo models could be related to a differential affinity for adrenoceptor subtypes or to different bioavailabilities in vascular and urogenital targets. Phenylephrine injected into rodents induces prostatic hyperplasia with all the characteristic morphological changes of the condition but does not result in enlargement of the prostate. Therefore, this phenylephrine-induced change in rat prostate tissue is called atypical prostatic hyperplasia. It serves as an in vivo model of prostatic hyperplasia induced by stimulation of alpha(1)-adrenoceptors. The objective of this study was to determine whether D-004 can inhibit induction of atypical prostatic hyperplasia by phenylephrine in rats. METHODS: Rats were randomly distributed into five groups (ten rats/group). One group was a negative control and received oral vehicle only. The other four groups were injected subcutaneously with phenylephrine (2 mg/kg): of these groups, one was a positive control receiving the vehicle, and the other three groups were treated with D-004 or Saw palmetto (both 400 mg/kg) or tamsulosin 0.4 mg/kg. All active treatments were given orally for 28 days. After completion of treatment, rats were placed unrestrained in metabolic cages and micturition studies were performed. The rats were later killed and their prostates removed and weighed. Prostate samples were processed for histological study, with histological changes being assessed according to a scoring system. Bodyweight was measured at baseline and at weekly intervals. RESULTS: Histological examination of positive control rats revealed features of atypical prostatic hyperplasia, with piling-up, papillary and cribiform patterns and budding-out of epithelial cells. Micturition assessment revealed that phenylephrine significantly lowered both the total volume of urine in 1 hour and the volume per micturition; the latter was considered the main efficacy variable. D-004 and Saw palmetto extracts significantly prevented this reduction in volume per micturition by 70.5% and 68.6%, respectively, while tamsulosin totally abolished the reduction in micturition induced by phenylephrine (100% inhibition). Tamsulosin, D-004 and Saw palmetto significantly reduced the histological changes of atypical prostatic hyperplasia induced by phenylephrine by 73.1%, 61.2% and 50.0%, respectively. CONCLUSIONS: Administration of D-004 resulted in marked and significant prevention of phenylephrine-induced impairment of micturition and histological changes in rat prostate. These findings indicate that, in vivo, D-004 effectively opposes these responses to phenylephrine, which are mediated through urogenital alpha(1)-adrenoceptors. In this respect, D-004 was moderately more effective than Saw palmetto, a phytotherapeutic standard used to treat BPH, but less effective than tamsulosin, a selective alpha(1A)-adrenoceptor antagonist.

Animals↗

PubMed1978

The effects of phenylephrine in various ionic environments on the circular muscle of mid-pregnant rat myometrium.

In 12-15-day pregnant rat myometrium, spikes of the longitudinal muscle were discharged spontaneously in burst, while the circular muscle had predominantly a plateau potential. In the longitudinal muscle, phenylephrine (10(-7) g/ml) slightly decreased the duration of the burst discharge and suppressed the contraction by beta-adrenoreceptor stimulation. In the circular muscle, phenylephrine (10(-7) g/ml) prolonged the duration of the plateau potential leading to an increase in tension without changing the amplitude of plateau, membrane potential and membrane conductance by alpha-adrenoreceptor stimulation. The effects of phenylephrine on the circular muscle in various ionic environments were observed. In K-free solution, spike generation ceased but phenylephrine depolarized the membrane, generated the prepotential with spikes and prolonged plateau duration. In low-Ca solution, spontaneous spike generation ceased and electrically evoked spikes showed short plateau duration. Phenylephrine restored the membrane activity and prolonged the plateau duration. Excess Ca showed either prolonged (less than 5mM) or reduced (greater than 8mM) the plateau duration, but phenylephrine consistently prolonged plateau duration. When Cl was replaced with either Br or benzene sulphonate, the former prolonged plateau duration and increased the excitability, whereas the latter reduced plateau duration and suppressed the spontaneous activity. Phenylephrine prolonged plateau duration in both Cl-deficient solutions. When NaCl was replaced by choline-Cl, leaving 15.7 mM Na remaining in NaHCO3 buffer, phenylephrine action completely ceased. The ionic mechanism involved in phenylephrine action is discussed.

Action Potentials↗

PubMed1994

Dissociation of the positive inotropic effect of methoxamine from the hydrolysis of phosphoinositide in rabbit ventricular myocardium: a comparison with the effects of phenylephrine and the subtype of the alpha-1 adrenoceptor involved.

The effects of methoxamine on the contractile force and the hydrolysis of phosphoinositide (PI) were examined and compared with those of phenylephrine in the rabbit ventricular myocardium. Methoxamine, as well as phenylephrine, caused the concentration-dependent accumulation of [3H]inositol monophosphate in rabbit ventricular slices. The maximal responses of the two drugs were equivalent, but methoxamine was approximately 10 times less potent than phenylephrine. The extents and time courses of accumulation of [3H]inositol phosphates induced by 10(-4) M methoxamine and 10(-5) M phenylephrine were very similar, whereas the positive inotropic effect (PIE) of methoxamine developed much more slowly and its extent was much smaller than that of phenylephrine. The maximal inotropic response achieved with 10(-4) M methoxamine was one third of that achieved with phenylephrine. The PIE of methoxamine induced by a single administration was markedly attenuated when the same dose was given by cumulative administration. The concentration-response curve for the PIE of phenylephrine was shifted to the right and downward in the presence of methoxamine in a concentration-dependent manner. These results indicate that methoxamine accelerates the hydrolysis of PI as effectively as does phenylephrine, but it has a smaller PIE because of its depressant effect on the process subsequent to acceleration of the hydrolysis of PI induced by alpha-1 adrenoceptors. The accumulation of [3H]inositol 1,4,5-trisphosphate induced either by methoxamine or by phenylephrine was abolished by 10(-5) M chlorethylclonidine, whereas the maximal inhibition induced by WB 4101 was 60%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1977

Role of neuronal and extraneuronal uptake in responses of rabbit iris dilator muscle to levarterenol and phenylephrine.

The roles of neuronal and extraneuronal uptake mechanisms in the response of iris dilator muscles of rabbit to levarterenol (norepinephrine) and phenylephrine were investigated. Chemical denervation with 6-hydroxydopamine was used to eliminate neuronal uptake. Exposure to corticosterone prior to and during exposure to levarterenol or phenylephrine was used to assess the importance of extraneuronal uptake. Dose-response curves and ED50 values for levarterenol or phenylephrine in control and 6-hydroxydopamine-denervated tissues, both in the presence and absence of corticosterone, are shown. Curves illustrating the decay of tension on washout of levarterenol or phenylephrine from treated tissues were analyzed. 6-Hydroxydopamine denervation affected the response to levarterenol more than that to phenylephrine. Washout of both agonists was slower after 6-hydroxydopamine pretreatment, and washout of phenylephrine was more rapid when corticosterone was present. These data indicate that extraneuronal uptake in iris dilator muscles was more important in determining the response to phenylephrine than to levarterenol and that neuronal uptake was more important in determining tissue responsiveness to levarterenol than to phenylephrine.

Animals↗

PubMed1982

Selective additive effect of phenylephrine to the inotropic action of isoproterenol on rabbit left atria.

The chronotropic and inotropic effects of isoproterenol, adrenaline and phenylephrine were examined in isolated right and left rabbit atria. 1. Spontaneous right atrial rate (RAR) and left atrial contractile force (LACF) (electrically stimulated at 2 Hz) were monitored during separate concentration-response curves to all 3 agonists. The order of potency for both parameters was isoproterenol greater than adrenaline greater than phenylephrine. 2. At maximum agonist effect, adrenaline produced the greatest LACF increase, followed in order by isoproterenol and phenylephrine. 3. When phenylephrine (6.0 x 10(-5) M) was added to the left atria maximally stimulated with isoproterenol, an additional 32% increase in LACF was recorded, but an additive effect was not noted when phenylephrine was added to atria maximally stimulated with adrenaline. The LACF achieved by a combination of isoproterenol and phenylephrine approximated the maximum LACF induced by adrenaline alone. 4. At maximum agonist effect, isoproterenol and adrenaline produced a greater RAR increase than phenylephrine. Further, phenylephrine did not increase the maximum RAR effect of isoproterenol or adrenaline. 5. Adrenergically mediated chronotropic increases appear to be mediated by a beta adrenoceptor and the maximum response to agonists of full intrinsic activity can not be further increased by agonist combinations. However inotropic increases appear to be mediated by 2 adrenoceptor types which may be simultaneously stimulated to produce additive effects. The two adrenoceptors mediating inotropic change are probably alpha and beta.

Animals↗

PubMed1993

The role of endothelium in phenylephrine- and potassium-induced contractions of the rat aorta during pregnancy.

The involvement of endothelium in the contractile responses of rat aortic rings to phenylephrine and potassium chloride in pregnancy was examined. Contractions in response to both agents were significantly greater in rings from non-pregnant rats than in rings from pregnant rats, and they were unaltered by treatment of the rings with indomethacin. De-endothelialization potentiated the contractions of rings from pregnant rats in response to phenylephrine, but had no significant effect on similar rings contracted with potassium chloride. Whereas de-endothelialization had no significant effect on the contractions to phenylephrine in rings from non-pregnant rats, it decreased those of rings from the same type of rats, contracted with potassium chloride. Pregnancy significantly inhibited contractions in response to calcium chloride of rings treated with phenylephrine or potassium chloride. The effect of endothelium removal on contractions to calcium chloride in rings from pregnant and non-pregnant rats treated with phenylephrine or potassium chloride was similar to that observed for phenylephrine-induced and potassium chloride-induced contractions, respectively. Contractions of intact aortic rings from pregnant and non-pregnant rats to phenylephrine in calcium-free medium were similar. Results of the study suggest that the effect of pregnancy on the contractions of the rat aorta in response to phenylephrine and potassium chloride is at least partly mediated by the endothelium and is independent of prostaglandin synthesis. The endothelial factor involved in this effect appears to modulate contractions by interfering with calcium influx through the receptor-operated calcium channels and the voltage-operated calcium channels.

Animals↗

PubMed1995

Effect of phenylephrine and prazosin on the somatostatinergic system in the rat frontoparietal cortex.

Somatostatin (SS) and noradrenaline (NA) are distributed in the rat cerebral cortex, and seizure activity is one of the aspects of behavior affected by both neurotransmitters. Due to the possible interaction between both neurotransmitter systems, we studied whether phenylphrine, an alpha 1-adrenoceptor agonist, and prazosin, an alpha 1-adrenoceptor antagonist, can modulate SS-like immunoreactivity (SS-LI) levels, binding of [125I][Tyr11]SS to its specific receptors, the ability of SS to inhibit adenylate cyclase (AC) activity, and the guanine nucleotide binding regulatory protein G, and G., in the Sprague-Dawley rat frontoparietal cortex. An IP dose of 2 or 4 mg/kg of phenylephrine injected 7 h before decapitation decreased the number of SS receptors and increased the apparent affinity in frontoparietal cortex membranes. An IP dose of 20 or 25 mg/kg of prazosin administered 8 h before decapitation increased the number of SS receptors and decreased their apparent affinity. The administration of prazosin before the phenylephrine injection prevented the phenylephrine-induced changes in SS binding. The addition of phenylephrine and/or prazosin 10(-5) M to the incubation medium changed neither the number nor the affinity of the SS receptors in the frontoparietal cortex membranes. Phenylephrine or prazosin affected neither SS-LI content nor the basal or forskolin (FK)-stimulated AC activities in the frontoparietal cortex. In addition, SS caused an equal inhibition of AC activity in frontoparietal cortex membranes of phenylephrine-and prazosintreated rats compared with the respective control group. Finally, phenylephrine and prazosin did not vary the pertussis toxin (PTX)-catalyzed ADP ribosylation of Gi- and/or Go-proteins. These results suggest that the above-mentioned changes are related to the phenylephrine activation of alpha 1-adrenoceptors or to the blocking of these receptors by prazosin. In addition, these data provide further support for a functional interrelationship between the alpha 1-adrenergic and somatostatinergic systems in the rat frontoparietal cortex.

Adenosine Diphosphate Ribose↗

PubMed1997

Thapsigargin does not affect phenylephrine-induced contractions in the anococcygeus muscle of rats.

1. The aims of the present study were to investigate the contribution of intracellular calcium and to evaluate the effect of the antagonists of the intracellular calcium stores, thapsigargin and [8-(Diethylamino)-octyl-3,4,5-trimethoxybenzoate, HC1] TMB-8, on phenylephrine-stimulated contractions of rat anococcygeus smooth muscle, using functional studies. 2. Phenylephrine induced concentration-related contractions in both 2.5 mM Ca2(+)-free EGTA media. 3. In Ca2(+)-free media phenylephrine stimulated successive contractions, and the contractile response was abolished only after approximately 26 stimulations. 4. In Ca2(+)-free media, after incubation with 10 microM TMB-8 for 30 min, phenylephrine induced concentration-response curves that shifted to the right. The EC50 values were not changed, and the maximum contractile response was reduced by 39.2 +/- 7.6% in relation to phenylephrine-stimulated responses in absence of TMB-8. 5. Thapsigargin (1 microM) did not alter phenylephrine-stimulated contractions in Ca2(+)-free media. 6. These results indicate that intracellular Ca2+ plays an important role on phenylephrine-stimulated contractions on rat anococcygeus muscle and that the phenylephrine-sensitive intracellular Ca2+ store is not sensitive to thapsigargin.

Animals↗

PubMed1995

Phenylephrine and pilocarpine in the treatment of post-operative irido-corneal adhesion.

Following cataract surgery, entrapment of the iris within the surgical wound is often managed by intensive use of miotics. As the radial fibres stretch, only a small amount of fraction is exerted upon the entrapped iris. Application of a combination of phenylephrine and pilocarpine drops causes simultaneous contraction of the pupil sphincter and the radial muscle fibres. This study investigated the relative magnitude of forces induced in the iris periphery by pilocarpine and phenylephrine and the effectiveness of adding g. phenylephrine 10% to g. pilocarpine 4% drops in the treatment of postoperative irido-corneal adhesions. The investigation was divided into two parts. First, the forces induced in the iris periphery upon exposure to pilocarpine and phenylephrine were measured in 6 cadaver irises. The mean force was 27.5 +/- 5.7 x 10(-3) N for pilocarpine and 23.3 +/- 4.0 x 10(-3) N for phenylephrine. The combination of the two drugs produced a force of 54.2 +/- 6.6 x 10(-3) N (p < 0.05). In the second part of the study intensive pilocarpine 4% drops were administered to 17 patients who had iris-wound entrapment on the first post-operative day. Patients with persistent adhesion were commenced on intensive g. phenylephrine 10% and assessed after 90 minutes. Of the 17 patients, 6 responded to pilocarpine drops alone; in a further 7 the irido-corneal adhesion was released only by the addition of phenylephrine drops, and in 4 patients drops were ineffective in relieving the adhesion. This study indicates that addition of phenylephrine 10% to pilocarpine 4% drops enhances the effectiveness of pharmacological treatment of post-operative irido-corneal adhesion.

Cataract Extraction↗