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PubMed1998

Possible modulation by endothelin-1, nitric oxide, prostaglandin I2 and thromboxane A2 of vasoconstriction induced by an alpha-agonist in mesenteric arterial bed from diabetic rats.

We hypothesized that in diabetes arterial reactivity to constrictors is attenuated by certain endothelium-derived substances. We examined the vasoconstriction induced by methoxamine (alpha1-agonist) in isolated mesenteric arterial beds from streptozotocin (STZ)-induced diabetic rats and age-matched control rats. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was impaired in mesenteric arterial beds from diabetic rats. The methoxamine vasoconstriction was reduced in endothelium-denuded preparations from controls rats, but increased in those from diabetic rats. Treatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine enhanced the vasoconstrictions induced by methoxamine in both control and diabetic rats. Indomethacin had no effect on the methoxamine vasoconstriction in control rats, but it shifted the dose-response curve to the left in diabetic rats. Whether given with or without indomethacin, BQ-123, (an ET(A)-receptor antagonist) plus BQ-788 (an ET(B)-receptor antagonist) shifted the dose-response curve for methoxamine to the right in control rats (while reducing the maximum response) but to the left in diabetic rats. The methoxamine-stimulated release of 6-keto-prostaglandin F1alpha from the mesenteric arterial bed in diabetic rats was approximately four times that seen in the control rats, while the methoxamine-induced release of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), was less in diabetic rats than in the control animals. These results suggest that an increased production of prostaglandin I2 (PGI2) and decreased formation of TXA2 could be responsible for the attenuation of the methoxamine-induced mesenteric vasoconstriction seen in diabetic rats, and these changes in the diabetic state could be partly responsible for the lower blood pressure seen in our diabetic rats.

Adrenergic alpha-Agonists↗
PubMed1998

Possible mechanism of the negative inotropic effect of alpha1-adrenoceptor agonists in rat isolated left atria after exposure to free radicals.

1. This study was designed to investigate the mechanism(s) of the negative inotropic effects of alpha1-adrenoceptor agonists observed in rat isolated left atria after exposure to free radicals. 2. Ouabain and calphostin C were used in contraction experiments to block the sodium pump and protein kinase C. Methoxamine-induced phospholipase C and Na+/K+ ATPase activities were measured. 3. Methoxamine (300 microM) increased contractile force by 1.6 +/- 0.2 mN in control atria but decreased contractile force in electrolysis-treated atria by 2.0 +/- 0.1 mN (P < 0.05), as determined 10 min after methoxamine addition. In contrast, the positive inotropic effects of endothelin-1 (30 nM) and isoprenaline (10 microM) were reduced from 2.6 +/- 0.3 to 1.3 +/- 0.1 mN and from 2.6 +/- 0.3 to 1.7 +/- 0.2 mN, respectively, by electrolysis treatment (P < 0.05), but not converted into a negative inotropic action. 4. In an inositol phosphate assay we observed that the stimulation of phospholipase C by methoxamine was attenuated by electrolysis when the (electrolyzed) medium from the organ bath was used, but the phospholipase C responses were restored by the use of fresh medium. However, fresh medium did not counteract the negative inotropic effect of methoxamine. Accordingly, the negative inotropic effect of methoxamine is not directly related to the impaired phospholipase C responses seen in atria subjected to electrolysis. 5. Ouabain (10 microM) and the protein kinase C inhibitor calphostin C (50 nM), completely prevented the negative inotropic effect of 300 microM methoxamine in electrolysis-treated atria. 6. Measurement of the Na+/K+ ATPase activity, revealed that in control atria, alpha1-adrenoceptor stimulation with 300 microM methoxamine, decreased the Na+/K+ ATPase activity by 14.4 +/- 7.7%. In contrast, methoxamine increased the Na+/K+ ATPase activity by 48.8 +/- 8.9% (P < 0.05) in electrolysis-treated atria. Interestingly, this increase in Na+/K+ ATPase activity was completely counteracted by calphostin C (1.4 +/- 0.1% over basal). 7. These results indicate that the negative inotropic effects of alpha1-adrenoceptor agonists, observed in rat isolated left atria exposed to free radicals, are likely to be caused by protein kinase C-mediated phosphorylation and subsequent activation of the Na+/K+ ATPase.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1997

Modulation of cardiac sodium current by alpha1-stimulation and volatile anesthetics.

BACKGROUND: Alpha1-adrenoceptor stimulation is known to produce electrophysiologic changes in cardiac tissues, which may involve modulations of the fast inward Na+ current (I(Na)). A direct prodysrhythmic alpha1-mediated interaction between catecholamines and halothane has been demonstrated, supporting the hypothesis that generation of halothane-epinephrine dysrhythmias may involve slowed conduction, leading to reentry. In this study, we examined the effects of a selective alpha1-adrenergic receptor agonist, methoxamine, on cardiac I(Na) in the absence and presence of equianesthetic concentrations of halothane and isoflurane in single ventricular myocytes from adult guinea pig hearts. METHODS: I(Na) was recorded using the standard whole-cell configuration of the patch-clamp technique. Voltage clamp protocols initiated from two different holding potentials (V(H)) were applied to examine state-dependent effects of methoxamine in the presence of anesthetics. Steady state activation and inactivation and recovery from inactivation were characterized using standard protocols. RESULTS: Methoxamine decreased I(Na) in a concentration- and voltage-dependent manner, being more potent at the depolarized V(H). Halothane and isoflurane interacted synergistically with methoxamine to suppress I(Na) near the physiologic cardiac resting potential of -80 mV. The effect of methoxamine with anesthetics appeared to be additive when using a V(H) of -110 mV, a potential where no Na+ channels are in the inactivated state. Methoxamine in the absence and presence of anesthetics significantly shifted the half maximal inactivation voltage in the hyperpolarizing direction but had no effect on steady-state activation. CONCLUSION: The present results show that methoxamine (alpha1-adrenergic stimulation) decreases cardiac Na+ current in a concentration- and voltage-dependent manner. Further, a form of synergistic interaction between methoxamine and inhalational anesthetics, halothane and isoflurane, was observed. This interaction appears to depend on the fraction of Na+ channels in the inactivated state. (Key words: Anesthetics, volatile: halothane; isoflurane; methoxamine. Patch clamp: whole-cell configuration; sodium current; ventricular guinea pig myocytes.)

Adrenergic alpha-Agonists↗
PubMed1997

Reduced response of the hypothalamo-pituitary-adrenal axis to alpha1-agonist stimulation during lactation.

To determine whether altered noradrenergic activation of the hypothalamo-pituitary-adrenal (HPA) axis contributes to the attenuated neuroendocrine response to stress observed during lactation, the effect of intracerebroventricular injection of the alpha1-agonist methoxamine (100 microg) was compared between virgin and lactating rats. Virgin rats showed significant increases in plasma corticosterone after methoxamine, reaching 317 +/- 44 ng/ml at 10 min and remaining significantly elevated for more than 120 min, but lactating rats showed no significant increase in corticosterone levels. Furthermore, methoxamine induced an increase in paraventricular nucleus (PVN) CRF messenger RNA expression in virgin, but not lactating, animals. Both groups of rats exhibited comparable elevations in plasma PRL after methoxamine treatment. Arginine vasopressin messenger RNA expression within the parvocellular PVN was greater in the lactating animals than in the virgin controls, but methoxamine injection was without further effect. Studies performed on ovariectomized virgin rats and ovariectomized rats receiving estradiol or progesterone replacement failed to reproduce the attenuated HPA responses seen after methoxamine treatment, although methoxamine-induced PRL levels were greatly increased by estradiol, probably arising from an effect on hormone synthesis. In vitro electrophysiological recordings of PVN neurons in hypothalamic slices from proestrous virgin and lactating rats showed that 45-52% of neurons in both groups exhibited excitatory responses to 10(-4) M methoxamine, but there was a differential response to 10(-5) M methoxamine, with PVN neurons from lactating animals failing to show a response. These data show a selective down-regulation of alpha1-mediated activation of the HPA axis in lactating animals. This may contribute to the attenuated stress-induced activation of the HPA axis during lactation.

Adrenergic alpha-Agonists↗
PubMedDate not supplied

Role of intracellular and extracellular calcium in alpha 1-adrenoceptor-mediated vasoconstriction in the rat perfused hindquarters.

The influence of the calcium channel antagonists, felodipine and cadmium, as well as of the putative phospholipase C inhibitor, 2-nitro-4-carboxyphenyl N,N-diphenylcarbamate (NCDC), on the vasoconstrictor actions of methoxamine in the rat perfused hindquarters was examined. Changes in perfusion pressure following bolus administration of methoxamine were monitored under constant flow. Methoxamine produced a dose-dependent increase in perfusion pressure of the hindquarters. Inclusion of cadmium (30 microM) in the physiological salt solution significantly reduced the maximum response, without significantly altering the ED50 or the Hill coefficient of the dose-response curve to methoxamine. Addition of felodipine (0.3 and 1 microM) in the physiological salt solution inhibited the vasoconstrictor actions of methoxamine. The dose-response curve to methoxamine was displaced to the right, with significant increases in ED50 and Hill coefficient, and the maximum response was significantly reduced. The vasoconstrictor action of methoxamine was also inhibited by NCDC (10 microM). The maximum response decreased and the Hill coefficient increased significantly, while the ED50 was not significantly altered. The presence of NCDC, together with either felodipine or cadmium, did not result in a further additive inhibition of the methoxamine-induced vasoconstriction. The inhibitory effects of felodipine and cadmium were partially reduced in the presence of NCDC. It is concluded that, in the rat perfused hindquarters, the vasoconstrictor actions of methoxamine depend on both intracellular and extracellular calcium ions. Calcium influx occurs, in part, via the felodipine-sensitive calcium channels. It is also apparent that NCDC interfered with the inhibitory actions of cadmium and felodipine.

Animals↗
PubMed1995

Modulation of the inwardly rectifying K+ channel in isolated human atrial myocytes by alpha 1-adrenergic stimulation.

We have examined the alpha 1-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) in isolated human atrial myocytes using the patch clamp technique. alpha 1-Adrenergic agonist methoxamine produced action potential prolongation and a depolarization of the resting membrane potential. Under whole-cell voltage-clamp conditions, bath application of methoxamine can inhibit macroscopic IK1. The methoxamine-induced inhibition was reversible and concentration dependent, with the concentration for half-maximal inhibition being 18 microM. The methoxamine-induced inhibition of IK1 was prevented by bath application of alpha 1-adrenergic blocker prazosin. The current was similarly inhibited by phorbol ester (PMA), an activator of protein kinase C (PKC). In contrast, methoxamine failed to inhibit the current in the presence of a specific PKC inhibitor H-9, suggesting that PKC is involved in the methoxamine-induced inhibition of IK1. In single channel recording from cell-attached patches, bath-applied methoxamine could suppress IK1 channels by decreasing the frequency and duration of bursting without affecting unitary amplitude. Direct application of purified PKC to excised inside-out patches inhibited channel activity similar to methoxamine in cell-attached patches. The PKC selective inhibitor, PKC19-36, prevented the PKC-induced inhibition of the channel. We conclude that human atrial IK1 can be inhibited by alpha 1-adrenergic stimulation via PKC-dependent pathways.

Adrenergic alpha-Agonists↗
PubMed1983

Alpha adrenergic stimulation modified prostaglandins release in vas deferens.

Methoxamine enhanced contractions of mouse vasa deferentia through alpha adrenoceptor stimulation. Additionally, the generation of PGF-like material by the tissue was increased by methoxamine, whereas that of PGE-like material was decreased. The effects of methoxamine on prostaglandin output (stimulation and depression) were antagonized by yohimbine and phenoxybenzamine. Moreover, the stimulating influence of methoxamine on the contractile activity of the preparations was attenuated by the prostaglandin synthesis inhibitors indomethacin and acetylsalicylic acid. The results suggest that methoxamine is able to modify prostaglandin synthesis and output in mouse vasa deferentia, probably through an alpha adrenergic mediated mechanism coupled to the prostaglandin synthesizing system. The fact that indomethacin and acetylsalicylic acid blocked alpha stimulatory responses to methoxamine, suggest a modulatory role for endogenous prostaglandins. Since methoxamine increased PGF levels, this prostaglandin might potentiate the contractile influence of methoxamine.

Animals↗
PubMed1987

Arrhythmogenic action of alpha 1-adrenoceptor stimulation in normoxic rat ventricular myocardium: influence of nisoldipine, reduced extracellular Ca2+ and ryanodine.

This study examines the arrhythmogenic action of alpha 1 and alpha 2-adrenoceptor stimulation in the isolated perfused rat heart. The alpha 1-agonist methoxamine in the presence of the beta 1-antagonist atenolol 10(-6) M decreased the ventricular fibrillation threshold in the normoxic rat ventricular myocardium: VFT values (mA): Control 11.2 +/- 0.5; methoxamine 10(-6) M 4.9 +/- 0.9 (P less than 0.01 vs control); methoxamine 10(-5) M 3.5 +/- 0.5 (P less than 0.01 vs control). The alpha 1-antagonist prazosin 10(-8) M prevented the methoxamine-induced fall in ventricular fibrillation threshold. The alpha 2-agonist BHT 933 (azepexole) in the presence of atenolol 10(-6) M produced no alteration in the ventricular fibrillation threshold. Methoxamine 10(-6) M to 10(-5) M had a positive inotropic effect with increased left ventricular pressure development, myocardial oxygen consumption and QT-interval; however, tissue levels of cyclic AMP remained unchanged. Methoxamine 10(-6) M did not alter heart rate, coronary flow rate or deplete tissue levels of adenosine triphosphate, phosphocreatine or glycogen. The enhanced vulnerability to ventricular fibrillation induced by methoxamine could be demonstrated only at supraphysiological extracellular calcium concentrations (2.5 mM) but not at physiological calcium concentrations (1.25 mM). The arrhythmogenic and inotropic effect of methoxamine 10(-6) M was prevented by inhibition of transsarcolemmal Ca2+ ion influx by nisoldipine 10(-8) M or by inhibition of release of Ca2+ from sarcoplasmic reticulum by ryanodine 10(-9) M to 10(-8) M. Thus in isolated normoxic rat heart preparations, activity of the alpha 1-receptor appears to mediate ventricular arrhythmogenesis but only in the setting of myocardial calcium overload. The arrhythmogenic effect of alpha 1-stimulation may be due to increased transsarcolemmal calcium influx and enhanced release of calcium from the sarcoplasmic reticulum; increased myocardial oxygen consumption secondary to greater left ventricular pressure development may contribute in part.

Adrenergic alpha-Agonists↗
PubMed1998

Porcine hepatic response to sepsis and its amplification by an adrenergic receptor alpha1 agonist and a beta2 antagonist.

1. We investigated the effect of adrenergic receptor stimulation or inhibition on the hepatic ultrastructural changes in a porcine faecal peritonitis model of multi-organ failure. We infused either the alpha1 adrenergic receptor agonist methoxamine or the beta2 adrenergic receptor antagonist ICI 118551 during 8 h of the study.2. Anaesthetized pigs (25-30 kg) were divided into four non-septic groups (control, non-septic, non-septic methoxamine and non-septic ICI 118551) and three septic groups (septic, septic methoxamine and septic ICI 118551).3. Changes in hepatic ultrastructure were measured by morphometric analysis. The septic group was significantly worse than all the non-septic groups. Septic methoxamine and septic ICI 118551 were significantly worse than the septic group.4. Septic methoxamine and septic ICI 118551 had a significantly increased perisinusoidal space; septic methoxamine had significant hepatocyte vacuolation.5. Hepatic ultrastructural changes were independent of hepatic blood flow.6. Septic methoxamine had significant myocardial depression.7. The alpha1 adrenergic receptor agonist methoxamine or the beta2 antagonist ICI 118551 both amplified the hepatic injury normally found during sepsis in our porcine model.8. These findings suggest that during sepsis a protective endogenous beta2 adrenergic receptor-mediated anti-inflammatory response is activated via cell membrane transduction to stimulate the trimeric G-protein complex Gs and activate the second cell messenger cAMP.9. In addition, it is likely that alpha1 adrenergic receptor agonists amplify the inflammatory response by stimulating the cell-surface receptor-linked trimeric G-protein complex to activate Gq and the second cell messenger phospholipase C.

Adrenergic alpha-Agonists↗
PubMed1994

Ontogeny of positive inotropic responses to sympathomimetic agents and of myocardial adrenoceptors in rats.

Positive inotropic efficacies (maximal increase in contractile force) and potencies of the alpha-adrenoceptor agonist methoxamine and beta-adrenoceptor agonist isoprenaline were determined on electrically driven (1 Hz) ventricular strips from rats aged 0.5, 1, 2, 3, 6, and 10 (adult) weeks. The inotropic response to methoxamine significantly decreased after 2 weeks of age. The inotropic potency of isoprenaline was slightly but significantly lower at all ages than at 0.5 weeks of age. Up to 2 weeks of age, the maximal inotropic effect of methoxamine was comparable with that of isoprenaline, thereafter it was but markedly less. Phenylephrine behaved like methoxamine, and noradrenaline like isoprenaline. The effect of methoxamine was antagonized by prazosin but not by propranolol; the reverse was true for isoprenaline. Injections at birth of triiodothyronine and dexamethasone exerted minimal effects on the inotropic responses to methoxamine and isoprenaline. Chemical sympathectomy with 6-hydroxydopamine caused supersensitivity to the inotropic effects of isoprenaline but produced subsensitivity to responses to methoxamine at 1 week; effects of methoxamine at 3 and 6 weeks of age were not altered by sympathectomy. No significant differences in alpha 1- or beta 1-adrenoceptor densities or affinities in ventricular membranes from 7-day-old and adult rats were found. It is concluded that the positive inotropic responses to sympathomimetic amines decline with age, the decline is most marked in the case of alpha 1-adrenoreceptor- mediated effects, and these changes do not appear to be due to a decrease in the number or affinity of alpha 1- and beta 1-adrenoceptors.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1976

On the relation between release of prostaglandins and contractility of rabbit splenic capsular strips.

Rabbit splenic capsular strips release prostaglandins E and F when contracted by noradrenaline or methoxamine. Contractions and prostaglandin release are dose-dependent. Cocaine increases significantly the effect of noradrenaline, but not that of methoxamine, on contraction of the strips and release of prostaglandin E. Release of prostaglandin F was increased by the addition of cocaine not only when noradrenaline was used as an agonist but also at two of three dose levels of methoxamine. When indometacin is added to the bath fluid, it inhibits prostaglandin release and at the same time potentiates the contractile effects of noradrenaline and methoxamine on the rabbit splenic capsular strips. The prostaglandin-synthetase blocker 5,8,11,14-eicosatetraynoic acid also potentiates the contractions induced by noradrenaline and methoxamine. Both the effects on prostaglandin synthesis and on contraction exerted by indometacin can be reversed, when indometacin is washed out. Exogenous prostaglandins E1, E2 and F2alpha in concentrations up to 150 ng/ml do not influence contractions of the strips induced by either noradrenaline or methoxamine. At higher concentrations prostaglandin E1 decreases, but prostaglandins E2 and F2alpha increase the contractions induced by both agonists. The potentiation of the effects of noradrenaline and methoxamine on rabbit splenic strips by indometacin and 5,8,11,14-eicosatetraynoic acid cannot be explained by inhibition of uptake1 or uptake2, release of endogenous noradrenaline or inhibition of metabolism of the agonists. It is suggested that the potentiation is caused by inhibition of synthesis of endogenous prostaglandins, although an undefined sensitizing effect of indometacin and 5,8,11,14-eicosatetraynoic acid cannot be completely exclused.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1995

alpha 1-Adrenoceptor stimulation inhibits the isoproterenol-induced effects on myocardial contractility and protein phosphorylation.

In the present study the influence of alpha 1-adrenoceptor stimulation on the beta-adrenoceptor agonist-induced increases in contractile parameters and protein phosphorylation was determined in isolated perfused hearts and isolated cardiac myocytes, respectively. Methoxamine inhibited the isoproterenol-induced increases in left ventricular pressure and heart rate dose dependently up to 90% and 75%, respectively; the EC50 of this antiadrenergic effect was 4.4 microM. The alpha 1-adrenoceptor antagonist, prazosin (1 microM), greatly diminished methoxamine's inhibitory action, confirming the alpha 1-adrenoceptor-mediated mechanism. The inotropic effect of glucagon was inhibited by methoxamine in a similar manner. Radioligand binding assays with [3H]dihydroalprenolol demonstrated that the antiadrenergic action of methoxamine is not due to an unspecific beta-adrenoceptor blocking property. In an additional experimental series the effects of methoxamine and isoproterenol on the protein phosphorylation pattern of isolated cardiac myocytes were investigated. Isoproterenol increased the phosphorylation state of five proteins (6-kDa, phospholamban; 15-kDa; 28-kDa, troponin I; 97-kDa; 140-kDa) while in the experiments with methoxamine the 15-kDa protein was the only phosphorylated substrate. In the presence of methoxamine the isoproterenol-induced phosphorylation of phospholamban, troponin I and the 97-kDa and 140-kDa protein was markedly inhibited while the phosphorylation state of the 15-kDa protein remained unaltered. The present study clearly demonstrated that alpha 1-adrenoceptor stimulation potently inhibits the beta-adrenoceptor-mediated changes in contractile force and phosphorylation of key regulatory proteins, most likely through modulation of cAMP metabolism.

Adrenergic alpha-Antagonists↗
PubMed1996

Effect of terlipressin on in vitro vascular hyporeactivity of portal hypertensive rats.

BACKGROUND/AIMS: Isolated vessels of portal hypertensive rats exhibit decreased responsiveness to vasoconstrictors. The vasopressin analogue terlipressin is used in the treatment of portal hypertension since it is known to reduce portal pressure, an effect that is thought to arise from splanchnic vasoconstriction via stimulation of vasoconstrictor V1 receptors. This study assessed the effect of terlipressin on the in vitro vascular reactivity of portal hypertensive rats to the alpha-adrenoceptor agonist methoxamine. METHODS: Portal hypertension was produced by portal vein ligation. Sham-operated rats served as controls. In isolated perfused mesenteric arteries of portal vein ligated and sham-operated rats pressor responses to methoxamine (3 nmol-3 mumol) were determined in the absence and presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), terlipressin or the selective V2 receptor agonist desmopressin (each 0.5 microM). In addition, the direct pressor properties of terlipressin (3 pmol-100 nmol) were compared to arginine vasopressin (3 pmol-1 nmol) in vessels of normal rats. RESULTS: Mesenteric vessels of portal vein ligated rats were markedly hyporeactive to methoxamine, even in the presence of L-NAME. Terlipressin alone reduced and in combination with L-NAME abolished the difference in reactivity to methoxamine between the portal vein ligated and sham-operated groups, while desmopressin was ineffective. Arginine vasopressin potently contracted vessels of normal rats with a threshold dose of 10 pmol and was maximally effective at 300 pmol. In contrast, terlipressin failed to produce pressor responses up to 100 nmol. CONCLUSIONS: Hyporeactivity of mesenteric vessels of portal vein ligated rats to methoxamine is predominantly independent of nitric oxide. Terlipressin alone ameliorates and in combination with L-NAME abolishes the hyporesponsiveness to methoxamine presumably by inhibiting the nitric oxide-independent mechanism that underlies the reduced responsiveness to methoxamine in portal hypertension. This effect of terlipressin appears to be independent of stimulation of V2 as well as vasoconstrictor V1 receptors.

Acetylcholine↗
PubMed1989

Positive inotropic effects mediated by alpha 1 adrenoceptors in intact human subjects.

The role of alpha 1-adrenergic receptors (adrenoceptors) on cardiac contractility was investigated in human subjects. The effect of methoxamine, a selective alpha-adrenoceptor agonist, and angiotensin II, on cardiac contractility was determined by means of noninvasive assessment of the slope of the end-systolic pressure (ESP)/end-systolic dimension (ESD) relationship. The slope (m) of this ratio was significantly higher with methoxamine (17.0; SD = 9.0 mm Hg/mm) than with angiotensin II (4.8; SD = 1.9 mm Hg/mm) (p less than 0.05). Slopes with methoxamine were higher when heart rates (HRs) were reflexly reduced, and were significantly diminished when reflex bradycardia was prevented by atropine (p less than 0.05) or atrial pacing (p less than 0.01). Previous treatment with propranolol did not modify m values with methoxamine (m = 15.5; SD = 4.4 mm Hg/mm). Phentolamine, given at peak methoxamine effect, did not consistently modify m values, resulting in an average slope not significantly different from that obtained with methoxamine alone. However, the addition of phentolamine did not cause an increase in ESDs at each level of ESP with respect to methoxamine. In the same subjects, infusion of phentolamine after angiotensin did not modify ESDs at comparable ESP levels. These findings suggest the existence of a positive inotropic effect mediated by alpha 1 adrenoceptors in the intact human heart.

Adult↗
PubMed1989

The effect of relaxants working through different transduction mechanisms on the tonic contraction produced in rat aorta by 4 beta-phorbol dibutyrate.

1. We have examined the effects of a range of smooth muscle relaxants on the maintained contractions produced in rat aortic rings by the protein kinase C activator, 4 beta-phorbol dibutyrate; these effects were compared with those on the contraction induced by the selective alpha 1-adrenoceptor agonist, methoxamine. The phorbol ester, at 0.3 microM, gave a sustained contraction which was, on average, of approximately the same magnitude as the maximum contraction produced by methoxamine, 10 microM. 2. The beta-adrenoceptor agonist, isoprenaline (0.01-1 microM) caused a dose-related relaxation of the methoxamine-induced contraction but had no effect on the contraction induced by the phorbol ester. 3. An activator of adenylate cyclase, forskolin (0.01-1 microM) produced a dose-related relaxation of the methoxamine-induced contraction and at 0.01-10 microM caused relaxation of the contraction induced by the phorbol ester. Similar results were obtained with the potassium channel activator, cromakalim (0.001-10 microM). 4. An activator of guanylate cyclase, sodium nitroprusside (0.001-100 microM) caused a dose-related relaxation of both the methoxamine-induced and the phorbol ester-induced contraction, being more effective on the former than on the latter. Similar results were obtained with enprofylline (1-1000 microM). 5. Methoxamine (10 nM-100 microM), given cumulatively, caused a dose-related contractile response. Pretreatment with isoprenaline (1 microM), enprofylline (10 microM) and nicorandil (1 microM) resulted in partial decrease of the subsequent response to methoxamine, while nicorandil (10 microM), forskolin (1 microM), sodium nitroprusside (10 microM) and cromakalim (1 microM) totally abolished it. 6. The phorbol ester, given cumulatively, caused increasing contraction in the concentration range 30 nM-10 microM. Pretreatment with forskolin (1 microM), sodium nitroprusside (10 microM), isoprenaline (1 microM), enprofylline (10 microM), nicorandil (1 microM or 10 microM), or cromakalin (1 microM or 10 microM), resulted in partial decrease of the subsequent response to 4 beta-phorbol dibutyrate. 7. These results are discussed in the light of the suggestion that protein kinase C may have a role in the 'latch-bridge' phase of smooth muscle contraction, and that inappropriate activation of protein kinase C may contribute to the pathogenesis of hypertension and other conditions involving vasospasm.

Animals↗
PubMed1989

EDRF-mediated dilatation in the rat isolated perfused kidney: a microangiographic study.

1. X-ray microangiographic techniques were used to study the influence of endothelium-derived relaxing factor (EDRF) on vasomotion in the isolated, intact, buffer-perfused kidney of the rat. The main renal (R0), segmental (R1) and interlobar (R2) arteries (control diameters ca. 600, 400 and 300 microns respectively) were studied quantitatively. 2. Inhibition of basal EDRF activity by haemoglobin (1 microM) did not elevate perfusion pressure or constrict R0, R1 and R2 in control preparations, implying a low level of spontaneous myogenic tone. In preparations preconstricted by 0.3 microM methoxamine, haemoglobin caused a further rise in perfusion pressure and amplified constrictor responses in R1 and R2 while also inducing 'paradoxical' dilatation of R0. 3. A spatially heterogeneous pattern of diameter responses (constriction of R2 and R1 with minimal dilatation of R0) was observed with two concentrations of methoxamine (0.3 microM and 3 microM). The magnitude of these responses was, however, smaller with 3 microM than 0.3 microM methoxamine, even though it increased perfusion pressure to a greater extent (88 mmHg cf. 24 mmHg). This 'paradoxical' behaviour indicates more pronounced constriction of distal arteries (which could not be resolved quantitatively) with 3 microM methoxamine. 4. In contrast to the heterogeneity of constrictor responses induced by methoxamine, the dilator action of acetylcholine was spatially homogeneous: log IC50 values calculated from the diameter changes induced in R0, R1 and R2 were similar and, moreover, equivalent to that calculated from the corresponding alterations in perfusion pressure. The fall in perfusion pressure induced by an approximately median effective concentration of acetylcholine (0.3 microM) was completely reversed by haemoglobin, consistent with the involvement of EDRF, although, reversal of the acetylcholine-induced dilatation of R0, R1 and R2 was not observed. 5. The results are consistent with the idea that constriction of distal vessels can attenuate and even directionally reverse intrinsic constrictor responses in the proximal R0, RI and R2 'feed' arteries by producing an overriding increase in 'upstream' pressure. This effect explains the paradoxical dilatation of Ro induced by haemoglobin in the presence of 0.3 microM methoxamine, the smaller magnitude of the diameter changes induced in R0, RI and R2 by 3 microM as compared to 0.3 microM methoxamine, and the failure of haemoglobin to reverse the acetylcholine-induced dilatation of R0, R1 and R2.

Acetylcholine↗
PubMed2003

Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2001

Hypoxia alters the sensitivity of the L-type Ca(2+) channel to alpha-adrenergic receptor stimulation in the presence of beta-adrenergic receptor stimulation.

The effects of alpha-adrenergic receptor (alpha-AR) stimulation alone and the effects in the presence of beta-adrenergic receptor (beta-AR) stimulation were examined on L-type Ca(2+) currents (I(Ca-L)) in the absence and presence of hypoxia. The alpha-AR agonist methoxamine either had no effect or had a slight inhibitory effect on basal I(Ca-L) in the absence and presence of hypoxia. Hypoxia significantly decreased the K(0.5) for activation of I(Ca-L) by norepinephrine from 79.8+/-6.6 to 13.3+/-0.7 nmol/L. To determine whether hypoxia specifically altered the sensitivity of the channel to alpha-AR stimulation, cells were exposed to increasing concentrations of methoxamine in the presence of 100 nmol/L isoproterenol (Iso). In the absence of hypoxia, methoxamine inhibited the Iso-activated I(Ca-L) in a concentration-dependent manner with an EC(50) of 86.9+/-9.9 micromol/L. However, in the presence of hypoxia, the EC(50) for inhibition of I(Ca-L) by methoxamine was significantly increased to 266.7+/-10.8 micromol/L. Methoxamine had little effect on I(Ca-L) activated by forskolin or histamine in the absence or presence of hypoxia. In addition, inhibition of protein kinase C by bisindolylmaleimide 1 or protein kinase C beta peptide inhibitor had no effect on the methoxamine-induced antagonism of I(Ca-L) in the absence or presence of hypoxia. The tyrosine kinase inhibitor genistein attenuated the methoxamine response in nonhypoxic cells only. However, during hypoxia it was attenuated with the phospholipase A(2) inhibitors mepacrine and indomethacin. These findings represent a novel regulation of the L-type Ca(2+) channel by the phospholipase A(2) pathway and illustrate the complexity of regulation of the channel under hypoxic conditions.

Adrenergic alpha-Agonists↗