SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Pharmacotherapy of human hypertension is effective, safe and well-tolerated. Antihypertensive drugs are of three broad classes: diuretics, sympatholytics and vasodilators. The use of each class is discussed and a summary of therapeutic considerations offered for representative agents. Recent trends in antihypertensive therapy are identified.
A new behavioral test is described in which quantitation is independent of the observer and is sensitive to all classes of analgesics. A computer-assisted device measures the period during which a rat hind paw fails to touch the surface of a rotating cylinder for 1 min (paw elevation time). Intra-articular injection of carrageenin induces a progressive and dose-dependent incapacitation of the limb. The maximum paw elevation time is attained 3-4 h after carrageenin challenge. The model showed dose-dependent sensitivity to (a) a central acting opiate (morphine, ID50 = 1.5 mg/kg, i.p.), (b) cyclooxygenase inhibitors (indomethacin, ID50 = 0.8 mg/kg, i.p.; diclofenac, ID50 = 0.22 mg/kg, i.p.), and (c) peripheral analgesics which directly antagonize nociceptor hypersensitivity: dipyrone (ID50 = 21 mg/kg, i.p.), N-methyl-nalorphine (ID50 = 14 mg/kg, i.p.) and BW443C (ID50 = 17.5 mg/kg, i.p.). The knee-joint carrageenin incapacitation was also blocked by the sympatholytics, propranolol and guanethidine. After the blockade by either indomethacin or guanethidine, intra-articular injections of prostaglandin E2 or dopamine, respective, reversed carrageenin-induced incapacitation. These results suggest that during inflammatory articular incapacitation cyclooxygenase and sympathomimetic mediators are involved, as has been suggested for the rat paw carrageenin hyperalgesia test and formalin test.
BACKGROUND: Enhanced central hypercapnic chemosensitivity is known to mediate excessive exercise ventilation and to indicate a poor prognosis in patients with chronic heart failure. The present study was designed to elucidate the role of central sympathetic activity in the enhancement of hypercapnic chemosensitivity. METHODS: Central hypercapnic chemosensitivity and plasma norepinephrine were measured in 99 patients with chronic heart failure. In 40 patients, the alpha index was derived from simultaneous analysis of R-R interval and systolic blood pressure variability. The effects of a central sympatholytic agent, guanfacine (0.25 mg/day), on hypercapnic chemosensitivity and exercise ventilatory response were studied in 20 of these patients. RESULTS: Hypercapnic chemosensitivity was enhanced in 76% of the patients and correlated significantly with plasma norepinephrine levels (r = 0.49, P < .01) at rest. There was a significant inverse relationship between central chemosensitivity and the alpha index (r = -0.41, P < .01). Guanfacine significantly reduced plasma norepinephrine levels by 29% (P < .01) and chemosensitivity by 31% (P < .01). The beneficial effect of central sympathoinhibition with guanfacine was observed specifically in patients who had enhanced chemosensitivity prior to drug administration. Similarly, the patients with excessive exercise ventilation showed a greater reduction in exercise ventilation with this agent. CONCLUSIONS: The present findings suggest that central sympathoexcitation could play an important role in the pathogenesis of enhanced hypercapnic chemosensitivity and a resultant increase in exercise ventilation in chronic heart failure.
Patients with essential hypertension often show alterations of the autonomic nervous system. We evaluated the sympathetic and parasympathetic drive to the heart in 12 mildly hypertensive patients and 9 healthy subjects by power spectral analysis of heart rate variability. All subjects underwent measurements of RR interval, low (LF) and high frequency (HF) components of heart rate variability, LF/HF ratio and blood pressure in the resting and sitting positions, both before and after oral clonidine (300 microg), a central sympatholytic agent. In the supine position before clonidine, hypertensive patients had higher blood pressure and lower HF values than healthy subjects. Clonidine induced increases in RR interval and HF in both groups, while LF and LF/HF ratio decreased in healthy subjects, but not in hypertensive patients. On assuming the sitting position, both groups showed reductions in RR and HF and increments in LF and LF/HF. In healthy subjects, the response to the postural challenge was unaffected by clonidine. In contrast, hypertensive patients showed no changes in LF and LF/HF ratio, and a significantly lower decrease in HF. These differences were probably due to the existence of two subsets of patients, one exhibiting similar responses to clonidine as healthy subjects, and the other showing no appreciable response to the drug. These results suggest that hypertensive patients have an altered sympatho-vagal balance to the heart, which can be unmasked by clonidine. This phenomenon should be taken into account to achieve a better control of the overall cardiovascular risk of hypertensive patients.
Activation of the sympathetic nervous system is associated with increased mortality in congestive heart failure (CHF), and inhibition of the sympathetic nervous system by centrally acting sympatholytic agents has been shown to have beneficial effects on hemodynamics in these patients. However, the effect of sympathetic inhibition on survival in CHF is not clear. In the present study, the effect of sympathetic inhibition with clonidine on survival was examined in a rat model of heart failure. Myocardial infarction and heart failure was induced in rats by ligation of the left coronary artery and sham-operated rats served as the control. Two weeks after surgery, the ligated rats were randomly assigned to the clonidine (100 microg kg(-1) d(-1), n=30) group or the placebo (vehicle, n=31) group. All rats were followed daily for a 1-year period or until spontaneous death. Compared with placebo therapy, clonidine treatment reduced systolic blood pressure and heart rate throughout the experimental period. The plasma norepinephrine level determined at the end of the experiment was also reduced. Long-term sympathetic inhibition with clonidine treatment improved 1-year survival (50% vs. 22.6%, P<0.05) after surgery in this rat model of CHF.
The target article discusses various aspects of the relationship between the sympathetic system and pain. To this end, the patients under study are divided into three groups. In the first group, called "reflex sympathetic dystrophy" (RSD), the syndrome can be characterized by a triad of autonomic, motor, and sensory symptoms, which occur in a distally generalized distribution. The pain is typically felt deeply and diffusely, has an orthostatic component, and is suppressed by the ischemia test. Under those circumstances, the pain is likely to respond to sympatholytic interventions. In a second group, called "sympathetically maintained pain" (SMP) syndrome, the principal symptoms are spontaneous pain, which is felt superficially and has no orthostatic component, and allodynia. These symptoms, typically confined to the zone of a lesioned nerve, may also be relieved by sympathetic blocks. Since the characteristics of the pain differ between RSD and SMP, the underlying kind of sympathetic-sensory coupling may also vary between these cases. A very small third group of patients exhibits symptoms of both RSD and SMP. The dependence or independence of pain on sympathetic function reported in most published studies seems to be questionable because the degree of technical success of the block remains uncertain. Therefore, pain should not be reported as sympathetic function independent until the criteria for a complete sympathetic block have been established and satisfied.
The cardiovascular and sympatholytic effects of combination therapy with guanabenz were examined in 26 patients (48 +/- 13 years old [mean +/- SD]) with stage 2 and 3 hypertension. Included in the study were patients under treatment with conventional antihypertensive drugs whose systolic and diastolic blood pressure was above 140 and 90 mmHg, respectively. Blood pressure, heart rate, and sympathetic parameters such as plasma concentration of norepinephrine and muscle sympathetic nerve activity at rest as well as during ambulatory conditions, 24-hour urinary excretion of norepinephrine, and low frequency (LF: 0.04-0.15 Hz)/high frequency (HF: 0.15-0.4 Hz) power ratio as a marker of cardiac sympathetic activity during 24 hours were examined before and after guanabenz (4-8 mg/d) combination therapy with first-line antihypertensive drugs such as diuretics. Left ventricular mass index (LVMI) was also calculated by conventional echocardiography. After 32 weeks of guanabenz combination therapy, systolic and diastolic blood pressure, heart rate, plasma and urinary excretion of norepinephrine, muscle sympathetic nerve activity, and LF/HF power ratio were significantly decreased, while neither LF nor HF power was changed. LVMI was also significantly decreased (270 +/- 81 vs. 236 +/- 83 g/m2, p < 0.005). These results indicate that guanabenz combination therapy inhibits sympathetic nerve activity under resting conditions as well as during ambulatory conditions and may accelerate regression of left ventricular hypertrophy in patients with moderate to severe hypertension.
We have studied (i) the contribution of specific adrenergic receptors to the proinflammatory effects of the sympathetic nervous system in experimental arthritis and (ii) the phases of the disease during which the sympathetic nervous system influences joint injury. Severity of joint injury was measured radiographically 28 days after induction of adjuvant arthritis in control rats and in rats treated with a variety of sympatholytic agents at various times during the course of the disease. Rats treated with a nonspecific catecholamine depletor (reserpine) or a beta-adrenergic receptor antagonist (propranolol) had a delayed onset and significantly less severe joint injury than saline-treated controls when treatment began prior to injection of the adjuvant and continued to day 28 after the injection. When administered over the same treatment period, neither nonselective (phenoxybenzamine) nor selective [prazosin (alpha 1) and yohimbine (alpha 2)] alpha-adrenergic receptor antagonists affected the onset or severity of joint injury. Metoprolol, a beta 1 antagonist, was also without effect. In contrast, two beta 2 antagonists (butoxamine and ICI 118,551) significantly retarded disease onset and reduced the severity of joint injury. When reserpine or butoxamine treatment was initiated after the onset of clinically apparent arthritis, it was still possible to favorably influence the course of the disease. These data indicate an important contribution of the beta 2-adrenergic receptor to joint injury in experimental arthritis.
UNLABELLED: In this prospective study, we evaluated whether high thoracic epidural anesthesia (TEA) or i.v. clonidine, in addition to general anesthesia, affects the cardiopulmonary bypass- and surgery-associated stress response and incidence of myocardial ischemia by their sympatholytic properties. Seventy patients scheduled for elective coronary artery bypass graft (CABG) received general anesthesia with sufentanil and propofol. TEA was randomly induced before general anesthesia and continued during the study period in 25 (anesthetized dermatomes C6-T10). Another 24 patients received i.v. clonidine as a bolus of 4 microg/kg before the induction of general anesthesia. Clonidine was then infused at a rate of 1 microg x kg(-1) x h(-1) during surgery and at 0.2-0.5 microg x kg(-1) x h(-1) postoperatively. The remaining 21 patients underwent general anesthesia as performed routinely (control). Hemodynamics, plasma epinephrine and norepinephrine, cortisol, the myocardial-specific contractile protein troponin T, and other cardiac enzymes were measured pre- and postoperatively. During the preoperative night and a follow-up of 48 h after surgery, five-lead electrocardiogram monitoring was used for ischemia detection. Both TEA and clonidine reduced the postoperative heart rate compared with the control group without jeopardizing cardiac output or perfusion pressure. Plasma epinephrine increased perioperatively in all groups but was significantly lower in the TEA group. Neither TEA nor clonidine affected the increase in plasma cortisol. The release of troponin T was attenuated by TEA. New ST elevations > or = 0.2 mV or new ST depression > or = 0.1 mV occurred in > 70% of the control patients but only in 40% of the clonidine group and in 50% of the TEA group. We conclude that TEA (but not i.v. clonidine) combined with general anesthesia for CABG demonstrates a beneficial effect on the perioperative stress response and postoperative myocardial ischemia. IMPLICATIONS: Thoracic epidural anesthesia combined with general anesthesia attenuates the myocardial sympathetic response to cardiopulmonary bypass and cardiac surgery. This is associated with decreased myocardial ischemia as determined by less release of troponin T. These findings may have an impact on the anesthetic management for coronary artery bypass grafting.
OBJECTIVE: There is growing controversy on the value of blocking the sympathetic nervous system for the treatment of complex regional pain syndromes (CRPS). The authors sought to evaluate the efficacy of sympathetic blockade with local anesthetic in these syndromes. In addition, they performed a comprehensive review of the pathophysiology and other treatments for CRPS. DESIGN: Systematic review of the literature was performed. MEDLINE was searched from 1966 through 1999. The authors identified only three randomized controlled trials (RCTs) that evaluated sympathetic blockade with local anesthetic, but because of differences in study design they were unable to pool the study data. The authors therefore included nonrandomized studies and case series. INTERVENTIONS: Studies were included if local anesthetic sympathetic blockade was used in at least 10 patients. Studies were excluded if continuous infusion techniques, somatic nerve blocks, or combined sympatholytic therapies were evaluated. OUTCOME MEASURES: Pain relief was classified as full, partial, or absent. The lack of a comparison group in the studies allowed only the calculation of distribution of the response categories, and the sum of the pooled rates does not equal 100%. RESULTS: Twenty-nine studies were included that evaluated 1,144 patients. Nineteen studies were retrospective, 5 prospective case series, 3 RCTs, and 2 nonrandomized controlled studies. The quality of the publications was generally poor. Twenty-nine percent of patients had full response, 41% had partial response, and 32% had absent response. It was not possible to estimate the duration of pain relief. CONCLUSIONS: This review raises questions as to the efficacy of local anesthetic sympathetic blockade as treatment of CRPS. Its efficacy is based mainly on case series. Less than one third of patients obtained full pain relief. The absence of control groups in case series leads to an overestimation of the treatment response that can explain the findings.
Diuretics, when used for antihypertensive therapy, may also affect lipoprotein metabolism. The following observations were made after 1-12 months of treatment. Various thiazide-type diuretics significantly increased the potentially atherogenic serum low-density lipoprotein cholesterol (LDL-C) and/or very-LDL-C (V-LDL-C) fractions, while the antiatherogenic high-density lipoprotein cholesterol (HDL-C) level was largely unchanged. Certain loop diuretics also increased the LDL-C/HDL-C ratio. Both types of diuretics elevated serum triglyceride (Tg) levels in some, but not all, studies. Levels of LDL-C were increased in diuretic-treated men and in chlorthalidone-treated postmenopausal women, but not in chlorthalidone-treated premenopausal women. Only two diuretics evaluated, indapamide and spironolactone, had no apparent influence on lipoproteins. A tendency for increased Tg levels and lower HDL-C concentrations was apparent during combined thiazide-type diuretic-beta-blocker treatment; these changes resembled those observed during beta-blocker monotherapy. Diuretic-induced increases in LDL-C were prevented or reversed by concomitant beta-blockade, but not by combination treatment with sympatholytics such as reserpine, methyldopa, and clonidine. Prospective studies are needed to clarify the long-term course and the pathogenic and prognostic relevance of lipoprotein changes induced by various diuretics. In the meantime, it is of clinical interest that premenopausal women may be protected from thiazide-induced increases in LDL-C, certain diuretic agents have no significant effect on serum lipoproteins, and beta-blockers may prevent or reverse increases in LDL-C in men and postmenopausal women during diuretic treatment.
There have been many changes in the treatment of hypertension over the past few decades. The Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC) has published four reports since 1977. The first three highlighted diuretic therapy as the main ingredient of stepped care for hypertensive patients. In the fourth report, this position has been revised to a patient-oriented, or individualized, approach. The shift reflects the results of many studies on hypertensive patients treated with a variety of approaches and drugs, including diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, sympatholytics, and calcium channel blockers. After analyzing the patient's history, physical, and laboratory findings, the report recommends making choices from the various agents, based on patient demographics, sequelae, concomitant diseases, and other risk factors such as cholesterol levels.
The purpose of this study was to investigate the effects of some alpha and beta sympathomimetic and sympatholytic drugs on respiratory impedance in healthy conscious calves. Ten Friesian calves were investigated in this study. The forced oscillation technique was used to measure the resistance (Rrs) and the reactance (Xrs) of the respiratory system at frequencies ranging from 4 to 26 Hz. Isoprenaline (1 microgram/kg i.v.), propranolol (3 micrograms/kg i.v.), noradrenaline (2 micrograms/kg i.v.), xylazine (20 micrograms/kg i.v.) and yohimbine (0.25 mg/kg i.v.) were were administered. Isoprenaline induced a significant decrease of Rrs. An increase of Rrs after administration of propranolol was observed but without any change of the frequency dependence of Rrs. A small increase in the resonant frequency was also recorded. A decrease of Rrs was recorded after yohimbine injection. Noradrenaline and xylazine administration increased the resistances and the resonant frequency and induced a negative frequency dependence of Rrs. These results suggest that (1) the major effects of beta adrenergic drugs are on the central airways, (2) the alpha adrenergic system may play a role on the regulation of bronchomotor tone in calves, (3) the effects of alpha adrenergic drugs are on both central and peripheral airways and (4) the forced oscillation technique allows the differentiation of calibre changes occurring in small and large airways.
This report reviews various management options for treatment-induced neuropathic pain in breast cancer. First-line options include tricyclic antidepressants and anticonvulsant drugs. Opioids should be prescribed according to published guidelines. Second-line treatments include lignocaine, mexiletine and ketamine. Sympatholytic therapies are available to patients with features of chronic regional pain syndrome. Anti-inflammatory agents are used for neurogenic inflammation. Surgical interventions are considered for refractory neuropathic pain. Interdisciplinary management is appropriate when persisting pain causes physical and psychosocial disabilities.
The aim of this study was to investigate: 1) the effects of treadmill exercise on plasma catecholamines and endothelin-1 (ET-1, a potent vasoconstrictor) levels in hypertensive patients; and 2) the impact of 1-month therapy with losartan as compared with moxonidine on catecholamine and ET-1 changes during exercise. Twenty-eight patients with essential hypertension were randomized in two groups: group A received losartan and group B received moxonidine for 1 month. Plasma catecholamines exhibited an almost 10-fold increase during exercise (p<0.00001) before treatment. Moxonidine significantly decreased catecholamine levels (p<0.05), while losartan reduction was nonsignificant (p<0.36). Plasma ET-1 increased significantly during exercise before treatment (p<0.00005). Moxonidine therapy did not affect ET-1 levels (p<0.88), while losartan resulted in a significant decrease of ET-1 levels both at baseline and during exercise (p<0.007). These findings suggest a mechanism for the reduced cardiovascular mortality noted with an angiotensin receptor blocker as compared with a sympatholytic agent.
Results of a retrospective study of 22 dogs with signs of dysuria and/or stranguria in which a diagnosis of idiopathic detrusor-urethral dyssynergia was made are presented. The diagnosis was based on the exclusion of detectable pathological conditions which could also cause urine outflow obstruction. The affected cases were 22 middle-aged male dogs (mean age 4.9 years) of large and giant breeds (mean bodyweight 36.7 kg). Nine dogs had had periodic clinical signs for longer than one year, one for seven months and eight for two to five weeks, while in four dogs signs had begun four to five days before referral. All dogs received the alpha-sympatholytic agent prazosin as an initial treatment and in 11 it remained the only therapy. There was a good effect in seven and a moderate response in the other four dogs. In one dog, prazosin was ineffective and was replaced by diazepam, which markedly reduced the signs. Three other dogs required frequent catheterisation and antibiotics were administered. These dogs responded favourably. Another three dogs with evidence of impaired bladder contractility were also treated with the parasympathomimetic agent carbachol. One did not improve and was euthanased. Four dogs developed bladder paralysis and severe infectious cystitis. Only one of these could be managed satisfactorily by long-term administration of prazosin, carbachol and antibiotics, and the others had to be euthanased.
Most of the classic functions of the renin-angiotensin system are mediated by type 1 (AT1) angiotensin receptors, of which two subtypes, AT1A and AT1B, have been identified. However, distinct functions for these two AT1 receptors have been difficult to separate. We examined the pressor effects of angiotensin II in Agtr1A -/- mice, which lack AT1A receptors. In enalapril-pretreated Agtr1A -/- mice, angiotensin II caused significant and dose-proportional increases in mean arterial pressure. This pressor response was not blocked by pretreatment with sympatholytic agents but was completely inhibited by the AT1-receptor antagonists, losartan and candesartan, suggesting that it is directly mediated by AT1B receptors. Chronic treatment of Agtr1A -/- mice with losartan reduced systolic blood pressure from 80 +/- 5 to 72 +/- 4 mmHg (P < 0.04), suggesting a role for AT1B receptors in chronic blood pressure regulation. These studies provide the first demonstration of in vivo pressor effects mediated by AT1B receptors and demonstrate that, when AT1A receptors are absent, the AT1B receptor contributes to the regulation of resting blood pressure.
Patients with chronic kidney disease and patients undergoing hemodialysis treatment show a sustained overactivity of the sympathetic nervous system, which originates from signals arising in the failing kidneys and traveling via afferent renal nerves to cardiovascular centers in the brainstem. Additional important factors are increased levels of angiotensin II and asymmetrical dimethylarginine. The sympathetic overactivity contributes to hypertension and cardiovascular morbidity and mortality in that patient population. Sympathetic overactivity can be reduced by adrenergic receptor blockers, centrally acting sympathicolytic drugs such as moxonidine and rilmenidine, angiotensin-converting enzyme inhibition, and angiotensin II type 1 receptor antagonists. Daily short hemodialysis and long nocturnal hemodialysis may reduce the elevated sympathetic activity, possibly because of an increased clearance of asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor. Prospective trials examining the potential impact of both beta-blockers and centrally acting sympatholytic drugs on cardiovascular mortality in chronic kidney disease and hemodialysis patients are very much needed.