Alpha-adrenoceptor Responsiveness Research Articles

Hypersensitivity of vascular alpha-adrenoceptor responsiveness: a possible inducer of pain in neuropathic states.

Hypersensitivity of vascular alpha-adrenoceptor responsiveness: a possible inducer of pain in neuropathic states.

The influence of 17-beta-oestradiol and the natural oestrous cycle on alpha-adrenoceptor-mediated responses of the cardiovascular system in the rat.

The effect of 17 beta-oestradiol pretreatment and the natural oestrous cycle on responses of rat cardiac and vascular alpha-adrenoceptors was investigated. It was found that treatment with the oestrogen had no effect on cardiac adrenoceptor sensitivity, while pretreatment with the hormone caused a significant increase in vascular alpha 2-, but not vascular alpha 1-adrenoceptor responsiveness. Pressor responses of pithed rats to selective alpha 1- or alpha 2-adrenoceptor agonists did not alter, however, during the natural oestrous cycle. These findings suggest that changes in oestrogen levels are capable of altering alpha-adrenoceptor-mediated vascular responses but that the relatively small changes in oestrogen which may occur throughout the natural oestrous cycle do not appear to alter the responses of these vascular alpha-adrenoceptors.

Alpha-adrenergic responsiveness in rat isolated perfused heart after abdominal aortic coarctation.

Chronic isoproterenol pre-treatment, a well-known model of compensatory hypertrophy associated with cardiac beta-adrenoceptor desensitization, enhances the inotropic response to phenylephrine in rat isolated perfused hearts, supporting the hypothesis that myocardial alpha-adrenoceptor stimulation contributes to the maintenance of myocardial performance in situations in which cardiac beta-adrenoceptor function is compromised. To further corroborate this hypothesis, the effects of abdominal aortic coarctation on cardiac alpha-adrenergic responsiveness were investigated in Langendorff heart preparations. Abdominal aortic coarctation causes cardiac hypertrophy (21%) as shown by a significant increase in the ratio of ventricular dry weight to bodyweight. In preparations from hypertrophied rats, both maximum increases in left ventricular systolic pressure and heart rate elicited by isoproterenol (10(-12) to 10(-4) M) were significantly reduced (the isoproterenol concentration producing 50% of the maximum positive inotropic and chronotropic responses was enhanced almost 21- and 2-fold, respectively). However, the positive inotropic response to phenylephrine (10(-12) to 10(-4) M) remained unaffected following abdominal aortic coarctation, when compared with sham-operated rats. In preparations from both groups, phenylephrine infusion did not induce significant changes in heart rate. These results show that although abdominal aortic stenosis induced desensitization of cardiac beta-adrenoceptors, it did not enhance cardiac alpha-adrenoceptor responsiveness. This suggests that such an enhancement depends on the experimental model used to induce cardiac hypertrophy associated with desensitization of cardiac beta-adrenoceptors.

Lateral Hypothalamic-Induced Alpha-Adrenoceptor Modulation Occurs in a Model of Inflammatory Pain in Rats

Previous work from our lab showed that stimulation of the lateral hypothalamus (LH) produces analgesia (antinociception) in a model of thermal nociceptive pain. This antinociceptive effect is mediated by alpha2-adrenoceptors in the spinal cord dorsal horn. However, a concomitant, opposing hyperalgesic (pro-nociceptive) response also occurs, which is mediated by alpha1-adrenoceptors in the dorsal horn. Antinociception predominates but is attenuated by the pronociceptive response. To determine whether such an effect occurs in a model of inflammatory pain, we applied mustard oil (allyl isothiocyanate; 20 microl) to the left ankle of female Sprague-Dawley rats. We then stimulated the LH using carbamylcholine chloride (carbachol; 125 nmol). The foot withdrawal latencies were measured. Some rats received intrathecal alpha-adrenoceptor antagonists to determine whether the opposing alpha-adrenoceptor response was present. Mustard oil application produced hyperalgesia in the affected paw, while the LH stimulation increased the foot withdrawal latencies for the mustard oil paw as compared to the control group. Following carbachol microinjection in the LH, WB4101, an alpha1-adrenoceptor antagonist, produced significantly longer foot withdrawal latencies compared to saline controls, while yohimbine, an alpha2-antagonist, decreased the foot withdrawal latencies from 10 min postinjection (p < .05). These findings support the hypothesis that the LH-induced nociceptive modulation is mediated through an alpha-adrenoceptor opposing response in a model of inflammatory pain.

Graded sympatholytic effect of exogenous ATP on postjunctional α‐adrenergic vasoconstriction in the human forearm: implications for vascular control in contracting muscle

Recent evidence suggests that adenosine triphosphate (ATP) can inhibit vasoconstrictor responses to endogenous noradrenaline release via tyramine in the skeletal muscle circulation, similar to what is observed in contracting muscle. Whether this involves direct modulation of postjunctional alpha-adrenoceptor responsiveness, or is selective for alpha(1)- or alpha(2)-receptors remains unclear. Therefore, in Protocol 1, we tested the hypothesis that exogenous ATP can blunt direct postjunctional alpha-adrenergic vasoconstriction in humans. We measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses to local intra-arterial infusions of phenylephrine (alpha(1)-agonist) and dexmedetomidine (alpha(2)-agonist) during moderate rhythmic handgrip exercise (15% maximum voluntary contraction), during a control non-exercise vasodilator condition (adenosine), and during ATP infusion in eight young adults. Forearm hyperaemia was matched across all conditions. Forearm vasoconstrictor responses to direct alpha(1)-receptor stimulation were blunted during exercise versus adenosine (DeltaFVC = -11 +/- 3% versus -39 +/- 5%; P< 0.05), and were abolished during ATP infusion (-3 +/- 2%). Similarly, vasoconstrictor responses to alpha(2)-receptor stimulation were blunted during exercise versus adenosine (-13 +/- 4% versus -40 +/- 8%; P< 0.05), and were abolished during ATP infusion (-4 +/- 4%). In Prototol 2 (n = 10), we tested the hypothesis that graded increases in ATP would reduce alpha(1)-mediated vasoconstriction in a dose-dependent manner compared with vasodilatation evoked via adenosine. Forearm vasoconstrictor responses during low dose adenosine (-38 +/- 3%) and ATP (-33 +/- 2%) were not significantly different from rest (-40 +/- 3%; P> 0.05). In contrast, vasoconstrictor responses during moderate (-22 +/- 6%) and high dose ATP (-8 +/- 5%) were significantly blunted compared with rest, whereas the responses during adenosine became progressively greater (moderate = -48 +/- 4%, P = 0.10; high = -53 +/- 6%, P< 0.05). We conclude that exogenous ATP is capable of blunting direct postjunctional alpha-adrenergic vasoconstriction, that this involves both alpha(1)- and alpha(2)-receptor subtypes, and that this is graded with ATP concentrations. Collectively, these data are consistent with the conceptual framework regarding how muscle blood flow and vascular tone are regulated in contracting muscles of humans.

Neuroendocrine and other studies of the mechanism of antidepressant action of desipramine.

It is not known whether in depressed patients antidepressant treatment increases or reduces monoaminergic neurotransmission. Clinical studies are therefore reviewed that investigate adaptive changes at adrenoceptors in depressed patients treated with desipramine, and the net effect of these changes upon neurotransmission. Although in animals chronic desipramine treatment enhances the responsiveness of alpha 1-adrenoceptors to phenylephrine, no such effect could be demonstrated in patients upon the responsiveness of pupil diameter to phenylephrine. However, in keeping with animal studies, clinical evidence of altered responsiveness of alpha 2-adrenoceptors could be demonstrated after chronic desipramine treatment. The alpha 2-mediated growth hormone response to clonidine was increased after one week's treatment with desipramine and then reduced during the second and third weeks of treatment. No clinical measure of the responsiveness of central beta-adrenoceptors is available. However, the secretion of melatonin is a measure of neurotransmission at noradrenergic terminals in the pineal with alpha 1-, alpha 2- and beta 1-adrenoceptors. In normal volunteers the secretion of melatonin was increased by the noradrenaline uptake inhibitors desipramine and (+)-oxaprotiline; (-)-oxaprotiline had no effect. In depressed patients melatonin secretion was increased after three weeks' treatment with desipramine. These and other clinical studies suggest that antidepressant treatments increase noradrenergic neurotransmission in depressed patients.

Adrenergic and serotonergic receptor responsiveness in depression.

Preliminary results are presented from a series of studies designed to characterize the regulation of release/metabolism and receptor responsiveness in the noradrenergic and serotonergic systems in acutely depressed patients and depressed patients in remission. Abnormal regulation of noradrenaline release/metabolism might be expected to be associated with the acute state of depression, while abnormalities of adrenoceptor responsiveness were hypothesized to persist in remission. Growth hormone responses to clonidine were measured as indices partially reflecting alpha 2-adrenoceptor responsiveness. Blunted responses to clonidine were found in both acutely depressed patients and patients in remission. The possible implications of these findings for the pathophysiology of the noradrenergic system in depression are discussed. Prolactin responses to the serotonergic agonist and serotonin-releasing agent fenfluramine were evaluated in acutely depressed patients, patients in remission and controls. A subset of the depressed patients appeared to have blunted prolactin responses to fenfluramine. However, very preliminary results do not show any difference in this response between patients who were acutely ill and those in remission, although the variability in both groups was great. These and related findings are discussed in terms of a possible contributory role of the serotonergic system in depression.

Ageing and leg postjunctional α‐adrenergic vasoconstrictor responsiveness in healthy men

Muscle sympathetic vasoconstrictor nerve activity increases with advancing age, but does not result in elevated forearm vasoconstrictor tone because of a selective reduction in alpha1-adrenoceptor responsiveness. In contrast, the leg circulation of older adults is under greater tonic sympathetic vasoconstriction, but it is unclear whether alpha-adrenoceptor responsiveness is altered with age. In the present study, we tested the hypothesis that postjunctional alpha-adrenergic vasoconstrictor responsiveness is reduced in the leg circulation with age. We measured femoral blood flow (Doppler ultrasound) and calculated the femoral vascular conductance (FVC) responses to alpha-adrenoceptor stimulation during local blockade of beta-adrenoceptors in 12 young (24 +/- 1 year) and seven healthy older men (62 +/- 2 year). Whole-leg vasoconstrictor responses to local intrafemoral artery infusions of tyramine (evokes noradrenaline (NA) release), phenylephrine (alpha1-agonist) and dexmedetomidine (alpha2-agonist) were assessed. Consistent with previous data, resting femoral blood flow and FVC were approximately 30% lower in older compared with young men (P < 0.05). Maximal vasoconstrictor responses to tyramine (-30 +/- 3 versus -41 +/- 3%), phenylephrine (-25 +/- 4 versus -45 +/- 5%), and dexmedetomidine (-22 +/- 4 versus -44 +/- 3%) were all significantly lower in older compared with young men (all P < 0.05). Our results indicate that human ageing is associated with a reduction in leg postjunctional alpha-adrenoceptor responsiveness to endogenous NA release, and this reduction is evident for both alpha1- and alpha2-adrenoceptors. However, given that basal leg vascular conductance is reduced with age and is primarily mediated by sympathetic vasoconstriction, impaired alpha-adrenoceptor responsiveness does not negate the ability of the sympathetic nervous system to evoke greater tonic vasoconstriction in the leg vasculature of older men.

Long-term administration of citalopram reduces basal and stress-induced extracellular noradrenaline levels in rat brain

Panic disorders are commonly treated with selective serotonin reuptake inhibitors (SSRIs). However, the effect of SSRIs on noradrenaline systems in the brain has not been fully elucidated at the present time. The effects of long-term administration of citalopram, an SSRI, on basal as well as stress-induced extracellular noradrenaline levels in the basolateral nucleus of the amygdala (BLA) and the locus coeruleus (LC) were determined. In addition, the responsiveness of noradrenaline transporters and alpha2-adrenoceptors were determined after long-term administration of citalopram. Brain microdialysis was used to assess the extracellular levels of noradrenaline in conscious rats. Desipramine and clonidine were used to functionally evaluate the noradrenaline transporter and alpha2-adrenoreceptor, respectively. In rats treated daily for 14 days with citalopram (10 mg kg(-1) day(-1) s.c.), dialysate noradrenaline levels showed remarkable decreases in both the BLA and the LC to about 25 and 45% of controls, respectively. The stress-induced increase of noradrenaline was almost completely abolished in the BLA, but was relatively stable in the LC. The effect of local application of desipramine tended to be suppressed only in the LC. The effect of local application of clonidine was enhanced only in the BLA. The present results indicate that chronic administration of citalopram strongly decreases the extracellular levels of noradrenaline in the brain. The anti-panic effect of citalopram might be due to sensitization of the alpha2-adrenoceptors leading to suppression of the stress response through noradrenergic activity. This mechanism is specific for the BLA.

Impaired α1‐adrenergic responses in aged rat hearts

To determine age-related changes in the cardiac effect of alpha1-adrenergic stimulation, both cardiomyocyte Ca2+-transient and cardiac protein kinase C (PKC) activity were measured in 3-month- (3MO) and 24-month- (24MO) old Wistar rats. Ca2+ transients obtained under 1 Hz pacing by microfluorimetry of cardiomyocyte loaded with indo-1 (405/480 nm fluorescence ratio) were compared in control conditions (Kreb's solution alone) and after alpha1-adrenergic stimulation (phenylephrine or cirazoline, an alpha1-specific agonist). PKC activity and PKC translocation index (particulate/total activity) were also assayed before and after alpha1-adrenergic stimulation. In 3MO, cirazoline induced a significant increase in Ca2+ transient for a 10(-9) M concentration which returned to control values for larger concentrations. In contrast, in 24MO, we observed a constant negative effect of cirazoline on the Ca2+ transient with a significant decrease at 10(-6) M compared with both baseline and Kreb's solution. Preliminary experiments showed that, in a dose-response curve to phenylephrine, the response of Ca2+ transient was maximal at 10(-7) M. This concentration induced a significant increase in Ca2+ transient in 3MO and a significant decrease in 24MO. The same concentration was chosen to perform PKC activity measurements under alpha1-adrenergic stimulation. In the basal state, PKC particulate activity was higher in 24MO than that in 3MO but was not different in cytosolic fractions; so that the translocation index was higher in 24MO (P < 0.01). After phenylephrine, a translocation of PKC toward the particulate fraction was observed in 3MO but not in 24MO. In conclusion, cardiac alpha1-adrenoceptor response was found to be impaired in aged hearts. The negative effect of alpha1-adrenergic stimulation on Ca2+ transient in cardiomyocytes obtained from old rats can be related to an absence of alpha1-adrenergic-induced PKC translocation.

Developmental changes in the alpha-adrenergic responses of rat periaqueductal grey neurons.

The postnatal changes in alpha-adrenoceptor mediated postsynaptic actions in neurons of the rat midbrain periaqueductal grey (PAG) were examined using whole cell patch clamping techniques. Noradrenaline produced an alpha1-adrenoceptor-mediated inward current which was less in younger (P9-12) than in older rats (P21-30). The alpha1-adrenoceptor response increased between postnatal days 13 and 16. In contrast, alpha2-adrenoceptor, GABA-B and mu-opioid receptor-mediated outward currents remained unchanged between P7 and P30. These observations suggest that alpha1-adrenoceptor responses in the PAG undergo significant postnatal developmental upregulation. Thus, catecholaminergic modulation of the autonomic and nociceptive functions of the PAG are likely to undergo significant postnatal alterations.

Changes in vascular alpha 1- and alpha 2-adrenoceptor responsiveness by selegiline treatment.

Pharmacoepidemiological studies have reported an excess of mortality with selegiline, a MAO B inhibitor used in the treatment of Parkinson's disease. The mechanism of this putative adverse effect remains unknown but an interaction with the sympathetic nervous system was suggested. The aim of the present study was to investigate the influence of selegiline (10 mg/daily, orally during one week) on vascular alpha1- and alpha2-adrenoceptor responsiveness in conscious unrestrained dogs. Selegiline significantly increased resting values of both systolic and diastolic blood pressures and noradrenaline plasma levels (HPLC) without changing heart rate. Moreover, spectral analysis of systolic blood pressure (Fast Fourier Transformation) showed that selegiline increased the relative energy of a low frequency band without modifying the total spectrum. ED 50 calculated from dose-pressor response curves with phenylephrine (after beta-blockade by propranolol), an index of alpha1-adrenoceptor response or with noradrenaline (after alpha1- and beta blockade by prazosin plus propranolol), an index of alpha2-adrenoceptor response, were significantly higher after selegiline. Selegiline failed to modify the number of platelet alpha2-adrenoceptors measured by [(3)H] RX 821002 binding. Yohimbine-induced increase in noradrenaline release was significantly more marked after selegiline. These results support the evidence that selegiline induces a vascular alpha1- and alpha2-adrenoceptor-hyposensitivity that can be explained by the increase in noradrenaline release elicited by the drug.

Arrhythmogenesis in isolated rat hearts with enhanced alpha-adrenoceptor-mediated responsiveness.

1. It has been postulated that stimulation of myocardial alpha-adrenoceptors is one of the primary mediators of the dysrhythmias which occur during periods of myocardial ischaemia and reperfusion. This study examines arrhythmogenesis during coronary artery occlusion and reperfusion in isolated perfused rat hearts from control animals and from rats with enhanced myocardial alpha-adrenoceptor responsiveness. 2. Rats were administered propylthiouracil (PTU) in their drinking water for 8 weeks. This treatment resulted in an enhanced responsiveness of isolated left atria to the alpha-adrenoceptor agonist phenylephrine compared with atria from control animals. 3. In Langendorff-perfused isolated hearts, the spontaneous rate of contraction was significantly lower in the PTU-pretreated group than in either age-matched or weight-matched controls. Occlusion of the left anterior descending artery (LAD) for 25 min resulted in ventricular tachycardia (VT) of similar incidence and duration in all groups and ventricular fibrillation (VF) in both control groups but not the PTU-pretreated group. 4. Following the 25-min ischaemic period the myocardium was reperfused for 10 min. The incidence and duration of VT and VF during this period was similar in all groups except that the duration of VF in the PTU-pretreated group was significantly lower than in controls. 5. In perfused hearts paced at 4 Hz, the incidence and duration of dysrhythmias during ischaemia and reperfusion was again similar in all groups, only the duration of VF being affected (reduced) by PTU-pretreatment. 6. In conclusion, this study does not lend support to the hypothesis that myocardial alpha-adrenoceptors have a primary role in arrhythmogenesis, but the data would support a role for these receptors in myocardial protection.

Effect of neuropeptide Y on the sympathetic contraction of the rabbit central ear artery during cooling.

In order to analyse the effect of neuropeptide Y (NPY) on the cutaneous vascular response to sympathetic nerve stimulation during cooling, the isometric response of isolated 2-mm segments of the rabbit central ear (cutaneous) artery was recorded at 37 degrees C and during cooling (30 degrees C). Electrical field stimulation (4-16 Hz) at 37 degrees C produced a frequency-dependent contraction, which was reduced during cooling (45% for 16 Hz) and potentiated by NPY (10(-8), 3x10(-8) and 10(-7) M), this potentiation being greater at 30 degrees C than at 37 degrees C. The NPY-induced potentiation of the contraction elicited by electrical field stimulation (8 Hz) was abolished by an antagonist of Y1 subtype NPY receptors, BIBP3226 (10(-6) M), at 37 degrees C and 30 degrees C, reduced by phentolamine (10(-6) M) at 30 degrees C but not at 37 degrees C, was not modified by the purinoceptor antagonist PPADS (3x10(-5) M) and was reduced by application of both phentolamine and PPADS at both temperatures. Both NiCl2 (10(-3) M) and verapamil (10(-5) M) abolished the potentiating effect of NPY at 37 degrees C and reduced it at 30 degrees C. Neither application of an inhibitor of nitric oxide synthesis, L-Nomega-nitro-arginine (L-NOARG, 10(-4) M), nor endothelium removal modified the potentiating effect of NPY at 37 degrees C or 30 degrees C. NPY (10(-8), 3x10(-8) and 10(-7) M) potentiated in a concentration-dependent way the arterial contraction in response to exogenous noradrenaline (10(-8)-10(-4) M) at 30 degrees C but not at 37 degrees C, and it increased the response to ATP (10(-4)-10(-2) M) at both temperatures. Therefore, in cutaneous (ear) arteries: (1) NPY potentiates the sympathetic response at 37 degrees C and at 30 degrees C, (2) this potentiating effect of NPY was more marked at 30 degrees C than at 37 degrees C, probably because of greater potentiation of the alpha-adrenoceptor response during cooling, and (3) the potentiating effect of NPY at both temperatures is mediated by NPY receptors of the Y1 subtype, is dependent of Ca2+ channels and is independent of the release of endothelial nitric oxide.

Effects of the menopause, gender, and estrogen replacement therapy on vascular nitric oxide activity.

Changes in vascular nitric oxide (NO) activity may contribute to cardiovascular risk. We determined the effect of the menopause, gender, and estrogen replacement therapy on arterial vascular NO activity. Vascular NO activity and sensitivity were determined in 15 healthy premenopausal women (mean age, 48 yr), 12 postmenopausal women (51 yr), and 14 men (51 yr). The effects of 14 days of estrogen replacement therapy (625 microg conjugated estrogens) were studied in 20 healthy postmenopausal women (60 yr). Forearm blood flow responses to brachial arterial infusions of L-NG-monomethyl-arginine (L-NMMA), norepinephrine, glyceryl trinitrate (GTN), and serotonin were determined using venous occlusion plethysmography. Constrictor responses to L-NMMA were reduced in postmenopausal women (82 +/- 14, summary response, mean +/- SEM) and men (89 + 6) compared to premenopausal women (118 + 10; P < 0.05). Constrictor responses to norepinephrine were increased in males (125 +/- 13) compared to premenopausal (81 +/- 8) and postmenopausal (88 +/- 16) women (P < 0.05). No differences were observed in GTN or serotonin responsiveness. Constrictor responses to L-NMMA increased after estrogen replacement (132 +/- 7 vs. 89 +/- 14; P < 0.05), with no change in norepinephrine, GTN, or serotonin responses. The menopause and male gender were associated with reduced arterial NO activity. Two weeks of estrogen replacement therapy restored vascular NO activity to premenopausal levels. Changes in vascular NO activity may contribute to changes in cardiovascular risk associated with male gender, postmenopausal status, and estrogen replacement therapy. Increased alpha-adrenoceptor responsiveness may contribute to increased cardiovascular risk in males.

Heterogeneity of vascular smooth muscle alpha-adrenoceptors in canine blood vessels.

1. For the past decade, using radioligand binding, contractility and immunohistochemical techniques, we have been characterizing vascular smooth muscle (VSM) adrenoceptors in four functionally different canine blood vessels, namely the dog aorta (DAO), dog mesenteric artery (DMA), dog mesenteric vein (DMV) and dog saphenous vein (DSV). 2. This communication briefly reviews our findings (with a special emphasis on alpha-adrenoceptor subtypes), which showed that none of the four canine vessels showed the same complement of alpha-adrenoceptor subtypes. 3. All four vessels elicited alpha 1-adrenoceptor contractile responses (antagonized by prazosin), but alpha 2-adrenoceptor responses (sensitive to rauwolscine), were found only in DMV and DSV. 4. Pharmacological characterization using alpha 1-adrenoceptor subtype-selective antagonists showed that DAO contains mainly alpha 1B-adrenoceptors (some alpha 1D-adrenoceptors) and DMA has primarily alpha 1A/1L-adrenoceptors, alpha 1-Adrenoceptors in DMV are primarily of the alpha 1D subtype, but either a new or unusual alpha 1-adrenoceptor subtype was revealed in the DSV.

Pathophysiology of Autonomic Dysreflexia: Long-Term Treatment With Terazosin in Adult and Paediatric Spinal Cord Injury Patients Manifesting Recurrent Dysreflexic Episodes

Introduction Spinal cord injury (SCI) results in disruption of synaptic influences on the sympathetic preganglionic neurones. Remodelling of spinal cord circuits takes place in spinal neurones caudal to cord injury. There is an increased vascular alpha-adrenoceptor responsiveness, and peripheral afferent (bladder) stimulation in SCI subjects induces a marked noradrenaline spillover below the level of spinal lesion. These neurophysiological changes possibly contribute to the development of autonomic dysreflexia, a condition of sympathetic hyper-excitability that develops after cervical, or upper dorsal cord injury with resultant paroxysmal rise in arterial pressure, and provide the scientific basis for the use of terazosin, a once-a-day, selective alpha-one adrenergic blocking drug. Objectives The use of terazosin, a long-acting, alpha 1-selective blocking agent was investigated in SCI patients who developed recurrent symptoms of autonomic dysreflexia, eg headache, sweating flushing of the face together with an increase in the arterial pressure. Design An open, prospective study of the efficacy of terazosin in controlling recurrent autonomic dysreflexia in traumatic tetraplegic/paraplegic patients manifesting clinical features of dysreflexia in the absence of an acute precipitating cause such as a blocked catheter. Setting The initial assessment and treatment were carried out in the Spinal Injuries Centre. Subsequently, the patients were followed-up in the community. They were monitored by telephonic interviews, follow-up visits by the patients to the hospital, and home-visits by the staff of the spinal unit. Subjects Eighteen adults with tetraplegia (female: 1; male: 17), three children with ventilator-dependent tetraplegia and three adult male patients with paraplegia who exhibited recurrent features of autonomic dysreflexia in the absence of an acute predisposing factor for dysreflexia eg performance of an invasive procedure such as cystoscopy, digital evacuation of bowels, or acute urinary retention, were enrolled in this study. Intervention After discussion with the patients and their carers, terazosin was prescribed with a starting dose of 1 mg in an adult and 0.5 mg in a child administered nocte. The patients were observed for (1) drug-induced hypotension; (2) clinical symptoms due to side effects of terazosin; and (3) continued occurrence of dysreflexic symptoms. Step-wise increments of the dose of terazosin (1 mg in case of adults, and 0.5 mg in a child) was carried out at intervals of 3-4 days, if a patient continued to develop dysreflexia but did not manifest any serious side effect. Outcome measures Complete subsidence of dysreflexic symptoms, or development of an adverse event necessitating termination of the terazosin therapy was the clinical end point. Results The dysreflexic symptoms subsided completely with the terazosin therapy in all the patients. The twenty-one adult patients required a dose varying from 1-10 mg, whereas the paediatric patients required only 1-2 mg of terazosin. The side effects of postural hypotension and drowsiness were transient, and mild. One tetraplegic patient developed persistent dizziness and therefore, the drug therapy was discontinued. Conclusion In 21 adult and three paediatric spinal cord injury patients manifesting recurrent episodes of autonomic dysreflexia in the absence of an acute predisposing cause, the use of terazosin, a once-a-day, specific alpha-one blocker resulted in complete subsidence of the dysreflexic symptoms. However, one tetraplegic patient required termination of terazosin therapy because of persistent dizziness.

Modelling the changes due to the endothelium and hypertension in the alpha-adrenoreceptor-mediated responses of rat aorta.

The present study focuses on the role of endothelium on alpha1-adrenoceptor-mediated vasoconstriction in aorta from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). To define and quantify changes in the parameters governing agonism at alpha1-adrenoceptor by hypertension and/or endothelium, the operational model of analysis was used. In either endothelium intact or denuded aorta, the sensitivity (P < 0.001) and the maximum contraction (P < 0.05) to phenylephrine were smaller in SHR than in WKY. However, in each strain of rats, removal of endothelium increased the sensitivity (P < 0.001) to phenylephrine but reduced (P < 0.05) KCl-evoked vasoconstriction, suggesting a modulation of these responses by the endothelium. The observed differences in sensitivity and maximum contraction are interpreted in terms of the operational parameters: Em, the maximum possible effect; pK(A), the agonist affinity; alpha, the agonist efficacy and n, the slope for the function relating receptor occupancy to pharmacological effect. The estimated parameters reflected differences, between strains, in the signal transduction processes linked to alpha1-adrenoceptor stimulation ascribed to the presence of the endothelium. N(G)-nitro-L-arginine methyl ester (L-NAME), enhanced to a similar extend in both rat strains the sensitivity (P < 0.001) and the maximum contraction to phenylephrine. Indomethacin reduced the maximum contraction to phenylephrine by 56.85% in SHR and by 11.80% in WKY suggesting that contracting prostanoids play a more major role in this response in SHR than in WKY. Nevertheless, these inhibitors were without effect on denuded vessels from both strains suggesting that NO and cyclooxygenase products from the media or the adventitia do not play a role on the phenylephrine-mediated responses. The studied endothelial factors partially explain the observed differences in modulation of alpha1-adrenoceptor responses by the endothelium but suggest the participation of other compounds released by the endothelium.

THE EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ERECTILE DYSFUNCTION

Published studies on the epidemiology of erectile dysfunction and the physiology/ pathophysiology of erectile function are reviewed. A literature search of more than 400 studies of the epidemiology and pathophysiology of impotence and erectile dysfunction published during the last 3 decades was conducted and the most pertinent articles are discussed. It has been estimated that the prevalence of erectile dysfunction of all degrees is 52% in men 40 to 70 years old, with higher rates in those older than 70 years. Erectile dysfunction has a significant negative impact on quality of life. Risk factors for erectile dysfunction include aging, chronic illnesses, various medications and cigarette smoking. A nitric oxide/cyclic guanosine monophosphate mechanism has an important role in mediating the corporal smooth muscle relaxation necessary for erectile function. Other mechanisms involving neuropeptides, gap junctions and ion channels also may modulate corporal smooth muscle tone. Erectile dysfunction can be due to vasculogenic, neurogenic, hormonal and/or psychogenic factors as well as alterations in the nitric oxide/cyclic guanosine monophosphate pathway or other regulatory mechanisms, resulting in an imbalance in corporal smooth muscle contraction and relaxation. Erectile dysfunction is a common condition associated with aging, chronic illnesses and various modifiable risk factors. Normal penile erection is a hemodynamic process that is dependent on corporal smooth muscle relaxation mediated by parasympathetic neurotransmission, nitric oxide, and possibly other regulatory factors and electrophysiological events. As more knowledge is gained of the physiology and regulatory factors that mediate normal erectile function, the mechanisms involved in the pathophysiology of erectile dysfunction should be further elucidated.

Alpha2-adrenoceptor-mediated contractions of the porcine isolated ear artery: evidence for a cyclic AMP-dependent and a cyclic AMP-independent mechanism.

1. The aim of this study was to determine the conditions under which the alpha2-adrenoceptor agonist UK14304 produces vasoconstriction in the porcine isolated ear artery. 2. UK14304 (0.3 microM) produced a small contraction of porcine isolated ear arteries which was 7.8+/-3.3% of the response to 60 mM KCl. Similar sized contractions were obtained after precontraction with either 30 nM angiotensin II, or 0.1 microM U46619 (8.2+/-1.8% and 10.2+/-2.6% of 60 mM KCl response, respectively). However, an enhanced alpha2-adrenoceptor response was uncovered if the tissue was precontracted with U46619, and relaxed back to baseline with 1-2 microM forskolin before the addition of UK14304 (46.9+/-9.6% of 60 mM KCl response). 3. The enhanced responses to UK14304 in the presence of U46619 and forskolin were not inhibited by the alpha1-adrenoceptor antagonist prazosin (0.1 microM), but were inhibited by the alpha2-adrenoceptor antagonist rauwolscine (1 microM), indicating that the enhanced responses were mediated via postjunctional alpha2-adrenoceptors. 4. In the presence of 0.1 microM U46619 and 1 mM isobutylmethylxanthine (IBMX), 1 microM forskolin produced an increase in [3H]-cyclic AMP levels in porcine isolated ear arteries. Addition of 0.3 microM UK14304 prevented this increase. 5. The enhanced UK14304 response was dependent upon the agent used to relax the tissue. After relaxation of ear arteries precontracted with 10 nM U46619 and relaxed with forskolin the UK14304 response was 46.9+/-9.6% of the 60 mM KCl response, and after relaxation with sodium nitroprusside (SNP) the response was 24.8+3.3%. However, after relaxation of the tissue with levcromakalim the UK14304 response was only 8.2+/-1.7%, which was not different from the control response in the same tissues (12.2+/-5.6%). An enhanced contraction was also obtained after relaxation of the tissue with the cyclic AMP analogue dibutyryl cyclic AMP (23.2+/-1.3%) indicating that at least part of the enhanced response to UK14304 is independent of the ability of the agonist to inhibit cyclic AMP production. 6. Relaxation of U46619 contracted ear arteries with SNP could be inhibited by the NO-sensitive guanylyl-cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) indicating that production of cyclic GMP is necessary for the relaxant effect of SNP. However, ODQ had no effect on the relaxation of tissue by forskolin, suggesting that this compound does not act via production of cyclic GMP. Biochemical studies showed that while forskolin increases the levels of cyclic AMP in the tissues, SNP had no effect on the levels of this cyclic nucleotide. 7. In conclusion, enhanced contractions to the alpha2-adrenoceptor agonist UK14304 can be uncovered in porcine isolated ear arteries by precontracting the tissue with U46619, followed by relaxation back to baseline with forskolin, SNP or dibutyryl cyclic AMP before addition of UK14304. There was a greater contractile response to UK14304 after relaxation with forskolin than with SNP or dibutyryl cyclic AMP, suggesting that cyclic AMP-dependent and- independent mechanisms are involved in the enhancement of the UK14304 response.