Higher Concentrations Of Phenylephrine Research Articles

A comparative study on the effect of dopamine vs phenylephrine in improving the cutaneous analgesic effect of mexiletine in rats

BackgroundThe present study aimed to compare the effects of the combined administration of two adjuvants, dopamine and phenylephrine, on the cutaneous analgesic effect and duration of mexiletine in rats.MethodsNociceptive blockage was evaluated by the inhibition of response to skin pinpricks in rats via the cutaneous trunci muscle reflex (CTMR). After subcutaneous injection, the analgesic activities of mexiletine in the absence and presence of either dopamine or phenylephrine were assessed. Each injection was standardized into 0.6 ml with a mixture of drugs and saline.ResultsSubcutaneous injections of mexiletine successfully induced dose-dependent cutaneous analgesia in rats. The results revealed that rats injected with 1.8 μmol mexiletine exhibited 43.75% blockage (%MPE), while rats injected with 6.0 μmol mexiletine showed 100% blockage. Co-application of mexiletine (1.8 or 6.0 μmol) with dopamine (0.06, 0.60, or 6.00 μmol) elicited full sensory block (%MPE). Sensory blockage ranged from 81.25% to 95.83% in rats injected with mexiletine (1.8 μmol) and phenylephrine (0.0059 or 0.0295 μmol), and complete subcutaneous analgesia was observed in rats injected with mexiletine (1.8 μmol) and a higher concentration of phenylephrine (0.1473 μmol). Furthermore, mexiletine at 6.0 μmol completely blocked nociception when combined with any concentration of phenylephrine, while 0.1473 μmol phenylephrine alone exhibited 35.417% subcutaneous analgesia. The combined application of dopamine (0.06/0.6/6 μmol) and mexiletine (1.8/6 μmol) resulted in increased %MPE, complete block time, full recovery time, and AUCs compared to the combined application of phenylephrine (0.0059 and 0.1473 μmol) and mexiletine (1.8/6 μmol) (p < 0.001).ConclusionDopamine is superior to phenylephrine in improving sensory blockage and enhancing the duration of nociceptive blockage by mexiletine.

Halothane, Isoflurane and Enflurane Potentiate the Effect of Noradrenaline on Ventricular Automaticity in the Rat Heart: Evidence of the Involvement of Both α- and β-Adrenoceptors

Direct evidence has been sought as to what extent the sensitization of heart to the arrhythmogenic action of sympathomimetic drugs in the presence of the inhalatory anaesthetics, halothane, isoflurane and enflurane, is mediated by either alpha- or beta-adrenoceptors. For this purpose, the effects of isoprenaline, noradrenaline and phenylephrine on ventricular automaticity induced by local injury have been studied in the isolated right ventricle of the rat. Isoprenaline was more potent in increasing ventricular automaticity than either phenylephrine or noradrenaline. The anaesthetic potentiated the effects of noradrenaline, as well as that of higher concentrations of phenylephrine, but not those of isoprenaline. These results support the contention that increases in ventricular automaticity induced by sympathomimetic drugs are mainly mediated by adrenoceptors of the beta-type. However, the simultaneous activation of both alpha- and beta-adrenoceptors seems to be necessary for the effect of the anaesthetics in sensitizing the heart to sympathomimetic drugs.

α- and β-adrenergic receptor mechanisms in spontaneous contractile activity of rat ileal longitudinal smooth muscle

Gastrointestinal motility is influenced by adrenergic modulation. Our aim was to identify specific subtypes of adrenergic receptors involved in inhibitory mechanisms that modulate gut smooth muscle contractile activity. Muscle strips of rat ileal longitudinal muscle were evaluated for spontaneous contractile activity and for equimolar dose-responses (10(-7) to 3 x 10(-5) M) to the adrenergic agents norepinephrine (nonselective agonist), phenylephrine (alpha(1)-agonist), clonidine (alpha(2)-agonist), prenalterol (beta(1)-agonist), ritodrine (beta(2)-agonist), and ZD7114 (beta(3)-agonist) in the presence and absence of tetrodotoxin (nonselective nerve blocker). Norepinephrine (3 x 10(-5) M) inhibited 65 +/- 6% (mean +/- SEM) of spontaneous contractile activity. The same molar dose of ritodrine, phenylephrine, or ZD7114 resulted in less inhibition (46 +/- 7%, 31 +/- 5%, and 39 +/- 3%, respectively; P < 0.05). The calculated molar concentration of ZD7114 needed to induce 50% inhibition was similar to that of norepinephrine, whereas higher concentrations of phenylephrine or ritodrine were required. Clonidine and prenalterol had no effect on contractile activity. Blockade of intramural neural transmission by tetrodotoxin affected the responses to ritodrine and phenylephrine (but not to norepinephrine or ZD7114), suggesting that these agents exert part of their effects via neurally mediated enteric pathways. Our results suggest that adrenergic modulation of contractile activity in the rat ileum is mediated primarily by muscular beta(3)-, beta(2)-, and alpha(1)-receptor mechanisms; the latter two also involve neural pathways.

Recruitment of smooth muscle cells and arterial vasomotion.

Investigating the recruitment and synchronization of smooth muscle cells (SMCs) is the key to understanding the physical mechanisms leading to contraction and spontaneous diameter oscillations of arteries, called vasomotion. We improved a method that allows the correlation of calcium oscillations (flashing) of individual SMCs with mean calcium variations and arterial contraction using confocal microscopy. Endothelium-stripped rat mesenteric arteries were cut open, loaded with dual calcium fluorescence probes, and stimulated by increasing concentrations of the vasoconstrictors phenylephrine (PE) and KCl. We found that the number and synchronization of flashing cells depends on vasoconstrictor concentration. At low vasoconstrictor concentration, few cells flash asynchronously and no local contraction is detected. At medium concentration, recruitment of cells is complete and synchronous, leading to strip contraction after KCl stimulation and to vasomotion after PE stimulation. High concentration of PE leads to synchronous calcium oscillations and fully contracted vessels, whereas high concentration of KCl leads to a sustained nonoscillating increase of calcium and to fully contracted vessels. We conclude that the number of simultaneously recruited cells is an important factor in controlling rat mesenteric artery contraction and vasomotion.

Topical phenylephrine increases anal sphincter resting pressure.

Phenylephrine is an alpha1-adrenergic agonist which causes contraction of human internal anal sphincter muscle in vitro. Its intra-arterial administration in animals has been shown to increase resting sphincter pressure in vivo. In this study the effect of topical application of phenylephrine on resting anal pressure in healthy human volunteers was investigated. Twelve healthy volunteers had measurements of maximum resting sphincter pressure (MRP) and anodermal blood flow taken before and after topical application of increasing concentrations of phenylephrine gel to the anus. To determine the duration of effect of the agent, readings were taken throughout the day after a single application. There was a dose-dependent rise in the resting anal sphincter pressure, with a small 8 per cent rise after 5 per cent phenylephrine (P = 0.012) and a larger 33 per cent rise with 10 per cent phenylephrine (mean(s.d.) MRP 85(12) cmH2O before versus 127(12) cmH2O after treatment, P < 0.0001). Thereafter no additional response was noted with higher concentrations of phenylephrine. The median duration of action of a single application of 10 per cent phenylephrine was 7 (range from 6 to more than 8) h. Topical application of 10 per cent phenylephrine gel to the anus produces a significant rise in the resting anal sphincter pressure in healthy human volunteers. This represents a potential novel therapeutic approach to the treatment of passive faecal incontinence associated with a low resting anal sphincter pressure.

Biphasic Action of Phenylephrine on the Ca2+-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 Ca²⁺-activated K⁺ channel (K_Ca channel) of human prostatic smooth muscle cells in phenylephrine-induced contraction. Using the patch-clamp technique, the K_Ca 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 K_Ca channel which was activated by 10 µM A23187, a calcium ionophore. Similar inhibition was obtained with 1 µM 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 K_Ca channel. In this study, a physiological concentration of phenylephrine induced activation of the K_Ca channel of human prostatic smooth muscle cells, which brought about membrane hyperpolarization and relaxation of human prostatic smooth muscle cells. The regulation of the K_Ca channel by phenylephrine may explain the need of a high concentration of phenylephrine for the contraction of prostatic tissue.

Possible Mechanism of High Calcium–Induced Relaxation of Rabbit Thoracic Aorta

1. The present study examined the effects of various agents on high calcium–induced relaxation of the rabbit thoracic aorta precontracted by phenylephrine (0.1 μM) or KCl (30 mM). 2. The vascular smooth muscle relaxation caused by high calcium was not changed in the presence of endothelium, glibenclamide (3 μM), TEA (5 mM), verapamil (1 μM), lidocaine (0.1 mM) and vanadate (0.1 mM). 3. In the presence of ouabain (0.1 mM) or potassium-free medium, high calcium–induced relaxation was completely abolished. 4. When rings were precontracted by high concentrations of phenylephrine (1 μM, 10 μM) and KCl (30 mM, 45 mM, 60 mM), calcium-induced relaxation was gradually decreased. 5. A low concentration of calcium ionophore A-23187 (0.1 μM) did not change calcium-induced relaxation, but A-23187 at a high concentration (1 μM) depressed this relaxation. 6. These results suggest that Na-K-ATPase activation could be responsible for high calcium–induced relaxation.

Botulinolysin, a thiol-activated hemolysin produced by Clostridium botulinum, inhibits endothelium-dependent relaxation of rat aortic ring

The effects of botulinolysin (Blyn), a thiol-activated hemolysin produced by Clostridium botulinum, on contractility of rat aortic ring were studied in order to clarify an underlying mechanism of vasoconstriction by the toxin observed previously as an increase in perfusion pressure in isolated rat organs. Blyn (30 hemolytic units/ml; HU/ml) itself did not elicit any apparent change in resting tension of the ring. Contractile tension elicited by a high concentration of phenylephrine in endothelium-intact rings increased significantly after treatment with Blyn (30 HU/ml), while phenylephrine-induced contraction of endothelium-denuded rings was not influenced by toxin treatment. In rings with intact endothelium, acetylcholine (ACh)-induced relaxation was significantly inhibited after treatment with Blyn (30, 10, 1 HU/ml). In contrast, relaxation of denuded rings by sodium nitroprusside was not affected by toxin treatment (30 HU/ml). Arginine (10 −4 M) partly reversed the inhibition of ACh-induced relaxation by the toxin (1 HU/ml). Endothelium-dependent relaxation by histamine or adenosine triphosphate was also inhibited by Blyn (1 HU/ml), but the relaxation elicited by calcium ionophore A23187 was not influenced by the toxin. The results indicate that Blyn acts on endothelium and inhibits agonist-induced endothelium-dependent relaxation of blood vessels.

Effects of a calcium antagonist and of the adrenergic system on spontaneous vasomotion and mean arteriolar diameter in the hamster cheek pouch: influence of buflomedil.

Intravital microscopy of the hamster cheek pouch microvasculature was used for in vivo studies of the effects of diltiazem (calcium antagonist, group I), prazosin (alpha 1-adrenergic receptor antagonist, group III), rauwolscine (alpha 2-adrenergic receptor antagonist, group V), phenylephrine (alpha-adrenergic receptor agonist, group VII) and isoproterenol (beta-adrenergic receptor agonist, group IX) in a concentration range of 10(-9)-10(-5) M and their combination with 10(-7) M of buflomedil (groups II, IV, VI, VIII and X) on mean arteriolar internal diameter and spontaneous vasomotion. All drugs were applied topically. Vasomotor activity was studied in 270 arterioles (internal diameter range 20.0-75.0 microns) of 60 preparations. Diltiazem dose dependently increased the microvascular diameter and reduced and ultimately abolished the vasomotion frequency and amplitude. Addition of buflomedil did not significantly change the vasodilation evoked by diltiazem and potentiated its depressive effect on vasomotion frequency and amplitude. Prazosin dose-dependently increased the arteriolar diameter and reduced the vasomotion frequency and amplitude. Addition of buflomedil potentiated both the vasodilation elicited by prazosin and the reduction in vasomotion frequency and amplitude. Rauwolscine tended to elicit vasoconstriction at lower concentrations (10(-9) and 10(-8) M) and vasodilation at higher concentrations (10(-5) M) and significantly reduced the vasomotion frequency and amplitude. Addition of buflomedil potentiated both the vasodilation and the reduction in vasomotion frequency, but tended to increase the vasomotion amplitude. Phenylephrine significantly decreased the mean arteriolar internal diameter, moderately decreased the vasomotion frequency and did not significantly change the vasomotion amplitude. Addition of buflomedil totally blocked the vasoconstriction elicited by phenylephrine, potentiated the reduction in vasomotion frequency and amplitude when combined with lower concentrations of phenylephrine (10(-9)-10(-7) M) and restored the vasomotion frequency and amplitude when combined with higher concentrations of phenylephrine (10(-6) and 10(-5) M). Isoproterenol significantly increased the mean arteriolar diameter and reduced the vasomotion frequency and amplitude. Addition of buflomedil did not significantly change either the vasodilation or the reduction in vasomotion frequency and amplitude. The effects observed with buflomedil on the hamster cheek pouch microcirculation further support its properties as a competitive inhibitor of alpha-adrenergic receptors, not selective for either the alpha 1- or alpha 2-adrenergic receptor subtype, and as a weak calcium antagonist.

Phenylephrine contracts rat tail artery by one electromechanical and three pharmacomechanical mechanisms

There are at least four mechanisms hypothesized to account for excitation-contraction coupling in arterial smooth muscle. 1) Contractile agonists and changes in extracellular [K+] ([K+]o) induce contraction by depolarization, which increases Ca2+ influx; this is the only mechanism involving a change in membrane potential (Em). 2) Contractile agonists release Ca2+ from the intracellular Ca2+ store. 3) Contractile agonists increase Ca2+ influx without changing Em either by activating voltage-dependent L-type Ca2+ channels or by opening other Ca(2+)-permeable channels. 4) Contractile agonists increase intracellular Ca2+ ([Ca2+]i) sensitivity of force; this is the only mechanism that does not involve changes in [Ca2+]i. Each of these mechanisms has been demonstrated in intact, skinned, or dissociated smooth muscle preparations. However, these four mechanisms have not been compared in the same preparation. The goal of this study was to determine which of these four contractile mechanisms are physiologically relevant in the intact rat tail artery. We stimulated deendothelialized rat tail artery with phenylephrine and high [K+]o. We then measured Em with microelectrodes, [Ca2+]i with fura 2, and isometric force with a strain gauge transducer. We find that all four mechanisms contributed to phenylephrine-induced rat tail artery contraction. The majority of phenylephrine-induced contraction was caused by depolarization and by increases in the [Ca2+]i sensitivity of force. Low concentrations of phenylephrine also increased [Ca2+] independent of changes in Em, potentially by increases in Ca2+ influx. Release of Ca2+ from intracellular stores was only observed with high concentrations of phenylephrine. Smooth muscle appears to invoke multiple mechanisms for excitation-contraction coupling.

Comparative studies on intracellular calcium and nadh fluorescence of the rabbit corpus cavernosum

Erectile function (erection and detumescence) involves the complex interaction of direct neuronal stimulation of corporal smooth muscle, neurohumoral release of specific endothelial contractile and relaxant factors, and secondary modulation by a variety of putative neuropeptides and vasoactive modulators. Using surface spectrofluorometry, we have correlated spontaneous contractile activity and the contractile response to field and pharmacological agents with intracellular calcium and NADH metabolism. The results demonstrate that the corpus cavernosal tissue has very unusual properties. Spontaneous contractile activity is correlated with a phasic increase in intracellular calcium. However, spontaneous contractile activity is most often correlated with a bi-phasic effect on the ratio of NADH/NAD. At the start of the spontaneous contraction, there is a sharp phasic increase in NADH/NAD; peak contractile force occurs simultaneous with a phasic decrease in this ratio showing that at peak force generation, there is a decrease in the level of intracellular energy. Phenylephrine stimulation results in an increase in intracellular calcium in proportion to the increase in tension; however, phenylephrine stimulation at low concentrations results in a net increase in the NADH/NAD ratio whereas high concentrations of phenylephrine result in a net decrease in the NADH/NAD ratio. In general, field stimulation results in a decrease in tension at low frequencies, a biphasic response at midfrequencies, and a contraction at high frequencies. These contractile responses are directly directly related to alterations in the intracellular concentration of calcium. That is, a decrease in tension is preceded by a decrease in intracellular calcium while an increase in tension is preceded by an increase in intracellular free calcium. Field stimulation results in a rapid and phasic alteration in the NADH/NAD ratio; however, the NADH/NAD response can be either an increase, decrease, or biphasic response. There does not appear to be a consistent relationship between the contractile/relaxant response to field stimulation and altered NADH/NAD ratio. Finally, ATP, bethanechol, and nitroprusside induce a decrease in the basal tension of the corpus cavernosal strips which corresponds with a decrease in the NADH/NAD ratio. However, whereas nitroprusside relaxation is correlated with a decreased intracellular calcium level, both ATP and bethanechol stimulate an increase in intracellular free calcium. These studies indicate that the response of the corpus cavernosal tissue to both field stimulation and pharmacological agents is complex and may involve both direct and indirect actions of a variety of cellular mediators on the corporal smooth muscle.

Endocardial endothelium mediates positive inotropic response to alpha1-adrenoceptor agonist in mammalian heart

Although the positive inotropic response to alpha 1-agonists has been well documented, the mechanism is incompletely understood. In isolated papillary muscle of cat and rabbit, low physiological concentrations of phenylephrine (PE) (10(-9)-10(-7) M; 35 degrees C) under beta-blockade (propranolol 10(-6) M) and in physiological [Ca2+]o (1.25 mM), significantly increased peak twitch tension (TT) with typical unchanged or slightly prolonged twitch contraction duration. This typical response necessitated the presence of an intact endocardial endothelium (EE) since no inotropic response was observed at or below 10(-7) M PE in muscles where the EE had been damaged by 1 s exposure to 1% Triton X-100 prior to the first PE addition. After Triton-induced EE damage prior to the first PE addition, a direct myocardial inotropic response could be demonstrated, but this response required higher concentrations of PE (10(-6)-10(-3) M) and was significantly less pronounced than in muscles with intact EE. At elevated (2.5 mM) or high (7.5 mM) Ca2+, a concentration dependent inotropic response to PE could be induced at the higher concentrations of PE (10(-6) M or higher), but the inotropic response to low concentrations of PE (10(-7) M or below) was absent even in the presence of an intact EE. In papillary muscles with intact EE at physiological [Ca2+]o of 1.25 mM, the higher concentrations of PE (10(-6) M or higher) destroyed the EE. Indeed, after washing with fresh bathing solution following prolonged exposure to these high concentrations of PE, the baseline twitches resembled twitches in muscles where the EE had been experimentally damaged. Selective destruction of the EE by PE in these conditions with no morphological damage to the subjacent myocardium was confirmed on electron microscopy. A second concentration-response curve to PE was significantly depressed, shifted to the right and with no response at or below 10(-7) M PE. Subsequent successive curves were not significantly different from the second one. At the higher Ca2+ (2.5 mM or 7.5 mM), neither functional nor morphological evidence of damage to the EE was observed regardless of the PE concentration and exposure time; in some muscles EE damage did occur at high Ca2+, however, but only after multiple exposures to high PE each followed by abundant wash. At all concentrations of PE, the alpha 1-antagonist prazosin (10(-5) M) blocked the inotropic response regardless of [Ca2+]o and prevented morphological endothelial damage at 1.25 mM Ca2+.

Enhancement by neuropeptide Y (NPY) of the dihydropyridine‐sensitive component of the response to α1‐adrenoceptor stimulation in rat isolated mesenteric arterioles

1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to noradrenaline (pD2 decreased from 6.2 +/- 0.06 to 5.7 +/- 0.03) and phenylephrine (pD2 decreased from 5.6 +/- 0.03 to 5.3 +/- 0.03). Diltiazem (10(-5) M) also shifted to the right the concentration-response curve to phenylephrine (pD2 decreased from 6.0 +/- 0.06 to 5.5 +/- 0.04). In addition, the maximal response to phenylephrine was significantly decreased in the presence of either nitrendipine or diltiazem. 3. In the absence of a calcium channel blocking agent, NPY (100 nM) produced a leftward shift of the concentration-response curves to noradrenaline (pD2 increased from 6.2 +/- 0.06 to 6.5 +/- 0.05) and phenylephrine (pD2 increased from 5.6 +/- 0.03 to 6.0 +/- 0.06 and from 6.0 +/- 0.06 to 6.3 +/- 0.11). In the presence of either nitrendipine (10(-6) M) or diltiazem (10(-5) M), NPY (100 nM) did not alter the concentration-response curves to either noradrenaline or phenylephrine. 4. NPY was added to arterioles brought to the same level of tension (40% of the maximal contraction) either by phenylephrine alone (1.5 x 10(-6) M) or by a higher concentration of phenylephrine (3 x 10(-6) M) followed by the addition of prazosin (1.3 x 10(-9) M; a concentration at which it partially blocks alpha 1-adrenoceptors). In these conditions, the response to phenylephrine was completely abolished by nitrendipine (10-6 M) or by diltiazem (10-5M). Furthermore, NPY (10-1" to 10-7M) increased the arteriolar tension up to the maximal contractile capacity of the vessels with pD2 values of 8.6 + 0.02 and 8.7 + 0.01, in the absence and presence of prazosin, respectively. 5. Prazosin was replaced in the above protocol by other vasodilator agents acting through different mechanisms. Whether in the presence of 2 x 10-7M forskolin, 6 x 10-7M sodium nitroprusside (which stimulate adenylate cyclase or guanylate cyclase, respectively) or 2 x 10- 7M diltiazem (a concentration at which calcium entry is partially blocked), NPY enhanced phenylephrine-induced contraction to the maximum level with an identical potency (pD2 values of the peptide ranged from 8.3 to 8.7). 6. The results show that, in rat mesenteric arterioles, NPY potentiates only the calcium entry blockersensitive component of contraction induced by stimulation of alpha,-adrenoceptors. In addition, they provide evidence that the peptide counteracts with an equal potency the inhibitory effect of partial block of alpha,-adrenoceptors and of relaxing agents acting through different mechanisms. It is suggested that NPY enhances calcium entry induced by stimulation of alpha l-adrenoceptors in this tissue.

α1-Adrenoceptor activity in arterial smooth muscle following congestive heart failure

The interactions between yohimbine (selective alpha 2-antagonist) with noradrenaline (mixed agonist) and phenylephrine (selective alpha 1-agonist) were studied in the canine dorsal pedal artery in an attempt to characterize the peripheral vascular response to adrenergic agents before and after the development of congestive heart failure in the dog. The contractile responses of the dorsal pedal artery to potassium chloride were also examined. Both noradrenaline and phenylephrine contracted the dorsal pedal artery in a concentration-dependent manner before and at peak heart failure, the responses to the agonists being enhanced at heart failure. The responses of the artery to potassium were not modified by congestive heart failure. Yohimbine caused concentration-dependent antagonism of noradrenaline, without altering the magnitude of the maximum response, providing pA2 values ranging from 8.26 to 7.06 against low and high concentrations of noradrenaline, respectively, before heart failure development. Following heart failure, the pA2 values for yohimbine against noradrenaline remained unchanged, but slopes from the Arunlakshana-Schild plots were significantly different from unity, implying a noncompetitive antagonism. The pA2 values of yohimbine against phenylephrine were at least 10 orders of magnitude lower than those against noradrenaline. After congestive heart failure, yohimbine was even less effective against high concentrations of phenylephrine. These findings suggest that enhanced vasoconstriction during heart failure results, in part, from increased alpha 1-adrenoceptor mechanisms in peripheral arterial smooth muscle.

Desensitization of alpha-1 adrenergic receptor mediated smooth muscle contraction in aorta from endotoxic rats

Desensitization of vascular smooth muscles in endotoxemia was studied using the aorta from intraperitoneally endotoxin-injected rats. The KCl- and phenylephrine-induced contractions were significantly decreased in the endotoxic aorta compared to the control. In the endotoxic aorta the phenylephrine-induced contracture showed a gradual tension decrease after reaching a plateau and was attenuated by prior exposure to high concentration of phenylephrine, while KCl produced a sustained contraction and it was not affected by prior exposure to phenylephrine. The phenylephrine- and KCl-induced contractures of the control aorta showed stable plateaus and were not affected by prior exposure to phenylephrine. Neither diminished contractile force nor in vitro desensitization of phenylephrine contracture of isolated aorta was prevented by pretreatment of endotoxic rats with an alpha-adrenergic antagonist, phentolamine. These findings suggest that the contractile response to phenylephrine is easily desensitized in the endotoxic aorta compared to the control and neither this in vitro desensitization nor the diminution of contractile force is caused by in vivo exposure of aorta to a high concentration of catecholamines during endotoxemia.

Vasorelaxant effects of and receptors for atrial natriuretic peptides in the mesenteric artery and aorta of the rat.

Vasorelaxant effects of different atrial natriuretic peptides (ANP) were measured on rat aortic strips and mesenteric artery rings. These results were compared with the potency of the same peptides to displace 125I-labelled ANP (101-126) on membrane preparations of aorta and of mesenteric vascular bed. In aortic strips and mesenteric artery rings precontracted with phenylephrine (3 X 10(-8) and 10(-6) M, respectively), the order of potency of ANP was as follows: ANP (99-126) greater than ANP (101-126) greater than ANP (103-126) = ANP (103-125) much greater than ANP (103-123). In the displacement binding assays, the order of potency of ANP peptides was similar to that of the relaxation experiments: ANP (99-126) = ANP (101-126) greater than ANP (103-126) = ANP (103-125) much greater than ANP (103-123). When the vessels were precontracted by a smaller concentration of phenylephrine (10(-7) M in mesenteric artery and 10(-8) M in aorta), the IC50 of ANP (101-126) was significantly lower than when the higher concentration of phenylephrine was used. These results show that ANP receptors in the mesenteric artery and in the aorta have similar structural requirements, according to the order of potency of different length ANP, both for binding and myotropic responses.

Pharmacological comparison of isolated monkey and dog cerebral arteries.

Pharmacological differences between canine and monkey basilar arteries were studied in vitro. The constrictor response of canine basilar artery to either norepinephrine or an alpha 1-adrenoceptor agonist phenylephrine was partly inhibited by an alpha 2-adrenoceptor antagonist yohimbine but not by an alpha 1-adrenoceptor antagonist prazosin. The contraction elicited by an alpha 2-adrenoceptor agonist clonidine was inhibited by neither prazosin nor yohimbine. These results suggest that the receptors in canine basilar artery which mediate norepinephrine-induced contraction are different from classical alpha 1 or alpha 2-adrenoceptors, although they more closely resemble the alpha 2- rather than the alpha 1-subtype. Using monkey basilar artery, phenylephrine produced the same amplitude of maximum contractile response as norepinephrine, though a much higher concentration of phenylephrine than norepinephrine was needed in order to elicit that maximum response. Clonidine did not elicit contractions. The contraction induced by norepinephrine was markedly suppressed by both prazosin and yohimbine in a noncompetitive fashion. The constrictor response of monkey basilar artery to norepinephrine, therefore, appears to be mediated by alpha 1-like adrenoceptors. Comparison of ED50 values for thromboxane A2 revealed that the monkey basilar artery was more sensitive to thromboxane A2 than that of the canine. Prostaglandin F2 alpha produced a larger maximum contraction in monkey basilar arteries than in canine basilar arteries, although the ED50 values for monkey basilar arteries were larger than those for canine basilar arteries. The ED50 values for serotonin in canine basilar arteries were a little less than those for monkey basilar arteries, although both arteries produced nearly identical maximum contractions.

Nitroglycerine and catecholamine actions on smooth muscle cells of the canine coronary artery.

1. The membrane potential of smooth muscle cells of the canine coronary artery was - 52 mV, and cells were electrically quiescent. The length and time constant of the membrane were 0.83 mm and 410 msec, respectively. 2. TEA (> 10(-3) M) depolarized the membrane, increased the membrane resistance and suppressed the rectifying property of the membrane. In 10(-2) M-TEA, an outward current pulse evoked a small active response in the canine coronary artery and a large response in the porcine coronary artery. 3. In the canine coronary artery, the minimum [K]o required for contraction was 11.8 mM (-48 mV), and the maximum amplitude of the contraction was evoked in 89 mM-[K]o (-13 mV). The maximum depolarization produced by a tenfold increase in [K]o was 49 mV. 4. In the canine coronary artery, isoprenaline and a low concentration of phenylephrine reduced the resting tension, and a high concentration of phenylephrine (> 5 x 10(-5) M) produced a contraction without affecting the membrane properties. 5. Nitroglycerine reduced resting tension, suppressed the amplitude and raised the threshold of contraction evoked by excess [K]o, electrical depolarization or phenylephrine. In the canine coronary artery, the minimum concentration of nitroglycerine required to suppress K-induced contraction (17.7 mM) was 2.8 x 10(-12) M nitroglycerine. However, resting membrane properties were not affected by 2.8 x 10(-5) M nitroglycerine. TEA induced electrical response was only a little depressed by 2.8 x 10(-5) M nitroglycerine in the porcine coronary artery, while the mechanical response was markedly suppressed. 6. In the canine coronary artery, adenosine (> 10(-5) M) relaxed the tissue in the presence of 17.7 M-[K]o without affecting the membrane property. ACh (> 5 x 10(-5) M) had much the same effects as those observed by treatment with adenosine.

Alpha-Sympathomimetic amines and calcium-mediated action potentials in guinea-pig ventricular muscle.

1 The ability of amines, having alpha- or alpha- and beta-adrenoceptor stimulating activity, to restore excitability and contractility in heart preparations partially depolarized by potassium, was investigated in guinea-pig ventricular muscle in order to elucidate the mechanism of the positive inotropic effect mediated via alpha-adrenoceptors. 2 In preparations in which fast sodium channels were inactivated by K+-rich medium (22 mM) slow electrical responses as well as contractions were consistently induced by high concentrations of phenylephrine (10(-4) to 3 X 10(-4) M) and synephrine (3 X 10(-4) M). 3 The restorative effective effects of both phenylephrine and synephrine were unaffected by phentolamine (10(-5) M) but were readily abolished by practolol (10(-5) M) or sotalol (10(-5) M). 4 Methoxamine induced a dose-dependent positive inotropic effect in ventricular strips paced at 0.5 Hz in normal Tyrode solution; the maximum increase in contractile tension was obtained with methoxamine 10(-4) M. However, at the same concentration, the amine did not induce slow electrical responses in potassium-depolarized preparations. 5 It is concluded that the induction of slow responses by phenylephrine and synephrine is due to beta-adrenoceptor stimulation, and that the increase in cardiac contractility caused by alpha-adrenoceptor stimulation does not involve an increase in slow inward calcium current.

Interaction between phenylephrine and prostaglandins E 1 and F 1α on the contractile responses of vascular muscle

Prostaglandins (PGs) E 1 or F 1α (1.4−8.4 × 10 −8 M) contracted strips of rabbit aorta and increased the contractions produced by 1−6 × 10 −7 M phenylephrine (PE). The addition of the PGs simultaneously with PE or after a low concentration of PE (2 × 10 −7 M) significantly increased the PE-induced contractions. However, when the PGs were added after a higher concentration of PE (6 × 10 −7 M) an additional increase in the PE-induced contraction was produced with PGF 1α but not with PGE 1. Isobolic plots of the data obtained from the simultaneous addition of PE and the PGs indicate that both PGs interact with PE in a synergistic or potentiative manner, suggesting that their effects are mediated through different receptor mechanisms. Addition of the PGs after a high dose of PE indicates that there may also be either qualitative or quantitative differences between PGE 1 and PGF 1α.