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PubMed2002

Restored capillary density in spared myocardium of infarcted rats improves ischemic tolerance.

Myocardial infarction (MI)-induced hypertrophy is associated with a decreased capillary density, which may negatively affect ischemic tolerance of the spared myocardium. The current study investigated the effects of moxonidine, a centrally acting sympatholytic, on left ventricular (LV) hypertrophy and capillary density in relation to sensitivity to ischemia in infarcted hearts. Infarcted rats were randomized to receive 3 or 6 mg/kg/d of moxonidine from 1 to 21 days after MI. LV hypertrophy after MI was indicated by increased ventricular to body weight ratio and was significantly inhibited by moxonidine. Histologic analysis revealed that MI-induced concentric hypertrophy of the spared myocardium, as indicated by almost double cross-sectional area of Gomori-stained myocytes, was completely prevented by 6 mg/kg/d of moxonidine. This effect was accompanied by a a restored number of lectin-stained capillaries per tissue area. However, capillary-to-myocyte ratio was similar in all groups. LV dysfunction after MI, measured in isolated perfused hearts, was confirmed by decreased LV systolic pressure and +dP/dtmax and was not affected by moxonidine. Low-flow ischemia, induced by lowering perfusion pressure from 85 to 15 mm Hg for 30 min, resulted in a further reduction of cardiac perfusion compared with sham rats, which was normalized with 6 mg/kg/d of moxonidine. Ischemic sensitivity in MI hearts, as reflected by increased maximal coronary flow during reperfusion, was reduced with moxonidine. This was further supported by substantially lower purines and lactate concentrations in the coronary effluent during ischemia. These results indicate that moxonidine-induced prevention of hypertrophy may preserve capillary density without affecting capillary number, thereby improving ischemic tolerance of the spared myocardium.

Animals↗
PubMed1992

Anesthetic considerations for electroconvulsive therapy.

Electrically induced seizures have been used widely to treat psychiatric disease since their introduction in 1938. Seizure activity is the therapeutic aspect of this form of treatment, but it is accompanied by untoward physiologic consequences. Cardiovascular responses consist of generalized autonomic nervous system stimulation with initial parasympathetic outflow, followed immediately by a sympathetic response. In certain patients the sequence described may result in an initial bradycardia or even asystole, followed by tachycardia, dysrhythmia, and hypertension. The cerebrovascular system responds with a marked increase in cerebral blood flow in response to increased cerebral oxygen consumption, and dramatic elevation of intracranial pressure. General anesthesia for electroconvulsive therapy (ECT) must be administered only in locations equipped for support of the unconscious patient and treatment of complications. Intravenous access is mandatory in all patients, as is monitoring of blood pressure, and ECG, as well as pulse oximetry. Appropriate oxygen supplementation and ventilatory support are essential as they are during any procedure necessitating general anesthesia. Methohexital, 0.75 to 1.0 mg/kg intravenously, is the most frequently used agent for induction of anesthesia for ECT; muscle relaxation usually is accomplished with succinylcholine, 0.5 to 1.0 mg/kg. In patients at risk for ill effects from the tachycardia and hypertension that may accompany sympathetic nervous system response to ECT, nitroglycerin, propranolol, hydralazine, or other sympatholytic agents should be used to attenuate the potentially harmful sequelae of ECT. The efficacy of ECT requires a knowledge of anesthetic precepts, an understanding of the interaction between anesthetic drugs and seizure activity, and an awareness of the physiologic effects of ECT as well as the treatment of those effects.

Anesthesia↗
PubMed1996

The Pharmacology of Alcohol Withdrawal Syndrome Treatment Reviewed: Efficacy, Cost, and Safety.

Alcohol continues to be one of the most common drugs of abuse. The morbidity and mortality associated with alcohol withdrawal has decreased significantly with the advent of pharmacologic intervention. However, the best method for the treatment of alcohol withdrawal syndrome remains controversial. With chronic use, alcohol can disturb the function and balance of several neurotransmitter systems such as excitatory amino acids, GABA, serotonin, and acetylcholine. Compensatory mechanisms in these pathways appear to predominate during chronic use but may become pathologic during withdrawal. As the understanding of alcohol-induced cellular changes increases, treatment of chronic abuse and withdrawal can be refined. Several groups of drugs are efficacious as either primary or adjunct agents in the treatment of alcohol withdrawal. This review describes the current theories on the etiology and treatment of alcohol withdrawal syndrome with emphasis on efficacy, cost, pharmacokinetic parameters, and safety considerations. A proposed withdrawal regimen is also described. Benzodiazepines appear to be the safest and most efficacious choice. With a wide variety of pharmacokinetic parameters and low cost of treatment, they remain the drugs of choice for withdrawal. Ethanol, barbiturates, antiseizure medications, and sympatholytic and sympathomimetic drugs are also reviewed. Newer agents that may have a future role in withdrawal are discussed as well.

Journal Article↗
PubMed2002

Postictal asystole during ECT.

BACKGROUND: Asystole is an uncommon but potentially fatal complication of electroconvulsive therapy (ECT). Several risks for poststimulus asystole have been described, but risks for asystole at other times have not. METHOD: Two instances of ECT postictal asystole in healthy adult males are reported. Features in common are identified. RESULTS: features shared differ from risk factors for poststimulus asystole. In common were adult but not geriatric age, male sex, good physical and cardiac health, mesomorphic habitus, anticholinergic pretreatment, vigorous ECT seizure, and low resting heart rate. Both patients showed postictal bradyarrhythmia at the previous ECT. CONCLUSIONS: Postictal asystole has apparent similarities to postexertional asystole in athletes. The combination of higher pretreatment doses of an atropinic agent, a sympatholytic agent, and close monitoring of postictal cardiac rhythm should be considered with patients similar to ours, especially after occurrence of postictal bradyarrhythmia.

Adult↗
PubMed2004

Sympathetic hyperactivity in chronic renal failure: a wake-up call.

Sympathetic hyperactivity plays an important and distinct role in hypertension associated with chronic renal failure (CRF). Renal ischemia, elevated angiotensin II, and suppressed brain nitric oxide (NO) all stimulate sympathetic activity. Evidence is accumulating for a role of sympathetic hyperactivity in renal and cardiac damage in patients with CRF. Decreased NO availability and increased oxidative stress, characteristic in CRF patients, seem to sensitize target organs for damaging actions of sympathetic hyperactivity. Fortunately, sympatholytic agents can slow down progression of renal and cardiac dysfunction. Angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists suppress sympathetic activity, but complete elimination of the effect of sympathetic hyperactivity can be obtained only with specific adrenergic blockers. However, this important therapeutic option is grossly neglected, painfully illustrated by the unwillingness to treat CRF patients with beta-blockers, even if they have had a myocardial infarction. After discussion of mechanisms and effects of the sympathetic hyperactivity, a case is made for increased application of specific adrenergic blockers in patients with CRF.

Heart↗
PubMedDate not supplied

Acupuncture in the treatment of heart failure.

Few clinical studies evaluating the efficacy of acupuncture in heart failure have been performed. These studies have focused on the acupoint Neiguan (P6) in patients experiencing heart failure and have variably reported either an acute increase in ventricular contractility and/or relaxation or no effect on ventricular contractility and/or relaxation. To date, clinical studies have been hampered by small enrollment, inadequate controls, and unblinded design. Recent scientific studies of animal models of acupuncture support the concept that acupuncture produces release of endogenous opioids in the central nervous system, which in turn could inhibit central sympathetic outflow. Patients experiencing heart failure have markedly elevated sympathetic activity, and those with the greatest sympathetic activation have the worst survival. Preliminary data from our laboratory suggests that acupuncture could be sympatholytic in heart failure. We found that sympathetic activation during acute mental stress was virtually eliminated after acupuncture. More studies defining the efficacy of acupuncture, and its mechanisms, in the treatment of heart failure are warranted.

Acupuncture Therapy↗
PubMed2006

Insulin resistance and sympathetic overactivity in women.

Insulin sensitivity decreases for the first time in females at the time of menarche. A much more profound decrease in insulin sensitivity is observed at the end of pregnancy. This physiological insulin resistance is not accompanied by a rise in overall sympathetic activity as reflected in plasma noradrenaline levels, but there is evidence of moderate sympathetic overactivity in muscle and the heart. Pre-eclampsia is characterized by increased insulin resistance, sympathetic overactivity and a particular lipid profile. Thus it is the first manifestation of metabolic syndrome. Women with a history of pre-eclampsia have persistent insulin resistance after pregnancy associated with increased sympathetic activity of the cardiovascular system, and coronary artery disease later in life. Aging is accompanied by a greater increase in sympathetic traffic in women than in men, and inflammation (measured via C-reactive protein) seems to be more strongly related to metabolic syndrome in women than in men. The clinical relevance of these observations remains to be shown. As the key factors of metabolic syndrome, such as insulin resistance and sympathetic overactivity, are closely inter-related, treatment should be aimed at cutting the vicious circle at many points: lifestyle modification (diet, increasing exercise) as a basis of therapy, use of insulin sensitizers (e.g. metformin) to decrease insulin resistance, central sympatholytics (e.g. moxonidine), and AT-receptor blockers or angiotensin-converting enzyme (ACE) inhibitors to overcome sympathetic overactivity, hypertension and inflammation.

Adult↗
PubMed2005

Alpha-2B adrenoceptor polymorphism and peripheral vasoconstriction.

OBJECTIVES: Alpha-2B adrenoceptors (AR) mediate vasoconstriction in the mice. A human alpha-2B AR deletion (D) variant has been associated with loss of short-term agonist-promoted receptor desensitization, which may lead to increased vasoconstriction upon alpha-2 AR activation. This study tested the hypothesis that alpha-2 AR activation will induce enhanced vasoconstriction in carriers of the alpha-2B AR DD genotype, compared to carriers of the II or the DI genotypes. METHODS: We administered 1 microg/kg dexmedetomidine (an alpha-2 agonist) intravenously to 80 surgical patients in whom sympatholytic effects of the drug were attenuated by general anesthesia. Measurements were made of finger blood volume (an indicator of vasoconstriction) by photoplethysmographic determination of light transmission through a finger (LTF) and of hemodynamic variables. RESULTS: Dexmedetomidine increased LTF (vasoconstriction), induced an initial increase in systolic blood pressure and decreased heart rate in all genotype groups (P<0.0001 for all). Three min after the start of dexmedetomidine infusion, the increase in LTF was more pronounced (P=0.014) in the DD group compared to the DI and II groups. There were no significant differences in LTF values between the groups at the end of or 5 min after dexmedetomidine infusion. There were no differences in systolic blood pressure or heart rate values between the groups during or after the dexmedetomidine infusion. CONCLUSIONS: The results of this study confirm that the alpha-2 agonist dexmedetomidine induced marked peripheral vasoconstriction. Subjects with the alpha 2B DD genotype had an enhanced vasoconstrictive response at the beginning of dexmedetomidine infusion. However, this enhanced vasoconstrictive response was not sustained throughout or after the 15-min dexmedetomidine infusion.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1980

Pharmacology of centrally acting hypotensive drugs.

1. A survey is given of the various aspects of centrally acting hypotensive drugs. The majority of centrally acting hypotensive agents act by way of central alpha-adrenoceptors, probably located in the pontomedullary region of the brain. These central receptors are stimulated by clonidine, guanfacine and various related compounds, and also by alpha-methylnoradrenaline, generated in vivo upon biotransformation of alpha-methyldopa within the brain. The stimulation of the alpha-adrenoceptors induces a decrease in peripheral sympathetic tone and thus a fall in arterial blood pressure and bradycardia. 2. The possibility that presynaptic alpha-adrenoceptors in the brain are involved in the central hypotensive action of clonidine, guanfacine and related compounds is discussed. Also, the possible involvement of central histaminergic and cholinergic receptors in central hypotensive effects is reviewed. 3. Various experimental compounds with a central hypotensive effect different from that of clonidine and related drugs are mentioned. 4. Finally, it is pointed out that the hypotensive effects of various beta-sympatholytic drugs and of prazosin are probably not of central origin.

Adrenergic alpha-Antagonists↗
PubMed1993

Effects of physiological and pharmacological variation of sympathetic nervous system activity on plasma non-esterified fatty acid concentrations in man.

1. The consequence of the sympatholytic effect of clonidine (alpha 2-adrenoceptor agonist) was compared with the effect of a physiological inhibition of sympathetic nervous system activity (change from upright to supine position) on plasma catecholamine and non-esterified fatty acid (NEFA) concentrations in overnight fasting healthy men. 2. Clonidine (150 micrograms orally) administered in upright position induced a significant reduction of plasma noradrenaline and NEFA concentrations. A change from upright to supine position which provoked a more marked decrease in plasma noradrenaline concentrations induced a weak increase in plasma NEFA concentrations. 3. The modification of plasma NEFA and catecholamine concentrations brought about by standing up was studied after placebo or yohimbine (alpha 2-adrenoceptor antagonist) administration. With placebo, standing up promotes a 100% increase in plasma noradrenaline concentrations (measured 5 and 15 min after rising) and a weak transient decrease in plasma NEFA concentrations (5 min after rising). In the supine position, yohimbine increased plasma noradrenaline and NEFA concentrations by about 100% and 55% respectively. Standing after yohimbine administration promoted large increases in plasma noradrenaline and NEFA concentrations. 4. These results indicate that a reduction of sympathetic nervous activity is not associated with a decrease of plasma NEFA concentrations and argue for a role of alpha 2-adrenoceptors in the NEFA mobilization from adipose tissue after sympathetic nervous system activation in man.

Adult↗
PubMed1979

Contractile behaviour of rat epididymis after sympathectomy produced by the administration of guanethidine.

The effect of guanethidine (a sympatholytic agent) on epididymal contractions was studied in rats, in order to contribute new data on the role of both the adrenergic and cholinergic nerves in the spontaneous motility of the epididymis and also during ejaculation. The first type of activity was increased when adrenergic innervation was damaged, but the amplitude and frequency of contractions reached normal values approximately 3 hours after beginning the records. Since spermatozoa were eliminated after electroejaculation, the second type of contractions was not affected either. As the epididymis and vas deferens were congested with spermatozoa, it is possible to assume that guanethidine caused a functional obstruction in a distal segment of the genital tract. The increase of spontaneous activity could be the response of the epididymal muscle to overcome this obstruction and, therefore, to cause the elimination of spermatozoa into the urethra, which normally occurs in absence of ejaculations. Finally, no pregnancies occurred among female rats mated with treated males, at least up to 150 days after ending treatment.

Adrenergic Fibers↗
PubMedDate not supplied

Cardiovascular effects of prazosin in normotensive and genetically hypertensive rats.

1. The cardiovascular effects of prazosin, a new antihypertensive drug, were studied in normotensive and genetically hypertensive rats. 2. Prazosin, infused intra-arterially, lowered vascular resistance in the blood-perfused rat hind limb. This effect was dependent on the presence of intact sympathetic innervation to the limb; no direct vasodilatation was demonstrated. In this preparation prazosin infusion reduced vasoconstrictor responses to noradrenaline. 3. In the saline-perfused rat mesenteric artery preparation prazosin reduced responses to noradrenaline and sympathetic nerve stimulation but not those to serotonin and vasopressin. Prazosin was more potent than phentolamine, on a molar basis, in reducing the vasoconstrictor effects of noradrenaline. 4. A comparison of the effects of prazosin injected intravenously and into a lateral cerebral ventricle failed to show any central action of the drug on blood pressure. Experiments using the donor blood-perfused, vascularly isolated rat hind limb preparation confirmed that the sympatholytic effect of prazosin occurred within the limb itself.

Animals↗
PubMed1994

The influence of captopril and naloxone on the Valsalva manoeuvre and systolic time intervals in healthy volunteers.

1. The aim of the study was to ascertain whether the inhibition of the sympathetic nervous system by angiotensin-converting enzyme (ACE) inhibitors is mediated by endogenous opioids. Naloxone was used to evaluate the effects of the latter on systolic time intervals (STI) and Valsalva manoeuvre-induced blood pressure and heart rate changes. 2. Baseline recordings were done in 12 healthy male volunteers and repeated 2 h after oral administration of 75 mg of captopril and again after naloxone 0.4 mg/kg was administered intravenously over 10 min. 3. After captopril there was a significant reduction in systolic (P < 0.02) and mean blood pressure (P < 0.04) without any changes in heart rate. Furthermore, captopril increased the Valsalva ratio (P < 0.06) but did not influence inotropism as indicated by STI. Naloxone did not influence any of these findings. 4. The changes in the Valsalva ratio after captopril were mediated by an increase in the maximum bradycardia in nine of the 12 subjects. 5. The results indicate that endogenous opioids do not play a role in the putative sympatholytic effect of ACE inhibition.

Adult↗
PubMed1995

omega-Conotoxin GVIA and prazosin, but not felodipine, cause postural hypotension in rabbits.

1. The aim was to compare the effect of N-type calcium channel blockade by omega-conotoxin GVIA (omega-CTX) with alpha 1-adrenoceptor or L-type calcium channel blockade on postural adaptation in conscious rabbits. 2. Orthostatic responses were assessed by rapidly tilting the rabbits through 90 degrees for 1 min. Tilts were performed before, 30 and 60 min after i.v. bolus administration of vehicle (propylene glycol 0.17 mL/kg; n = 8), prazosin (0.5 mg/kg; n = 8), felodipine (30 micrograms/kg; n = 8) or omega-CTX (3 & 7 micrograms/kg; n = 9). 3. Prazosin, felodipine or omega-CTX caused significant falls in mean arterial pressure (MAP) with corresponding increases in heart rate (HR). Vehicle administration had no effect on MAP but caused a small fall in HR. 4. Before drug or vehicle administration, a small rise in MAP and HR occurred in response to tilt in all rabbits. In the vehicle treatment group, similar responses were observed to tilt at 30 and 60 min. Postural hypotension was observed in the prazosin treatment group, but not following administration of felodipine. Tilts 30 and 60 min after omega-CTX (3 micrograms/kg) caused an increase in HR but no change in MAP, different to the small pressor response observed following vehicle administration. However, following administration of omega-CTX 7 micrograms/kg (total dose, 10 micrograms/kg), significant falls in MAP with tachycardia were observed in response to tilt. 5. In conclusion, orthostatic hypotension was observed following acute alpha 1-adrenoceptor or N-type calcium channel blockade in the conscious rabbit. These findings are compatible with the expectation that agents which are directly sympatholytic interfere with postural adaptation. In contrast, L-type calcium channel antagonism with felodipine did not elicit postural hypotension.

Adrenergic alpha-Antagonists↗
PubMed1999

Sympathetic activation and the role of beta-blockers in chronic heart failure.

Chronic heart failure (CHF) is associated with activation of the sympathetic nervous system. This activation provides short term haemodynamic support to the failing myocardium, but may be deleterious over longer periods as chronic catecholamine excess appears to contribute to disease progression and increased mortality in this condition. Therefore, blockade of sympathetic activation represents a logical, if somewhat counter-intuitive, approach to the management of the patient with systolic CHF. Pharmacological approaches to blockade of this system include inhibition of central sympathetic outflow (using central sympatholytics, e.g. rilmenidine, moxonidine), blockade of the catecholamine biosynthetic pathway (dopamine beta hydroxylase antagonists) and blockade of the cardiac effects of sympathetic activation (beta-adrenoceptor blocking agents). Beta-blockers have now been extensively studied in patients with symptomatic CHF of the New York Heart Association (NYHA) Class II and III severity. Provided beta-blocker therapy is carefully up-titrated from sub-therapeutic doses and given for at least three to four months, these agents have been associated with favourable long term haemodynamic, functional and mortality outcomes. Furthermore, beta-blockers delay disease progression in CHF by reversing the pathological myocardial remodelling process that accompanies the disease. Non-selective beta-adrenoceptor blocking drugs appear to be of particular benefit in CHF therapy. Myocardial beta2 receptors are down-regulated to a lesser extent than beta1 receptors in CHF, therefore blockade of the beta2 receptor sub-type may assume greater importance in inhibiting the deleterious effects of sympathetic activation on the myocardium in this disease. Newer agents that possess additional vasodilator properties (carvedilol, bucindolol, nebivolol) may be useful in overcoming the initial negative inotropy of the beta-blocking component of the drug, however, it is unlikely that vasodilation contributes greatly to long term clinical benefits. Drugs such as carvedilol are also anti-oxidant, anti-proliferative and have anti-endothelin actions; the clinical significance of these properties is yet to be determined. Unanswered questions remain regarding the use of beta-blockers in heart failure. Ongoing studies are further examining mechanisms underlying the clinical benefits of these agents as well as their therapeutic potential in NYHA Class IV patients, heart failure post-myocardial infarction and patients with asymptomatic left ventricular dysfunction.

Adrenergic beta-Antagonists↗
PubMed2005

Use of intravenous midazolam and clonidine in cyclical vomiting syndrome: a case report.

We report a case of a teenage boy with cyclical vomiting syndrome (CVS) who was referred to the anesthesia-run postoperative pain service for symptom management. His symptoms were uncontrolled by oral pizotifen prophylaxis and acute therapy with intravenous (IV) hydration and ondansetron. A continuous low dose IV midazolam infusion was added to his treatment regimen (as is instituted for recalcitrant postoperative nausea and vomiting) with benefit, but not total symptom resolution. Recent literature review suggested links between migraine, CVS and adrenergic autonomic dysfunction. Consequently, IV clonidine was administered, in addition, with recovery. This combination was reinstituted successfully on subsequent admissions and emergency department presentations with shortened episode durations from 4-5 days to 16-48 h. It is uncertain if clonidine's sympatholytic effects were significantly beneficial or if associated sedation or natural resolution were contributors. Many agents have been used in CVS therapy but no trials have been done. Neither midazolam nor clonidine has been reported previously as used in the treatment of CVS. The apparent success of this combination raises possibilities both for future trials and research into the pathogenesis of CVS.

Adrenergic alpha-Agonists↗
PubMed1991

Clonidine but not propranolol decreases plasma neuropeptide Y (NPY) levels.

The effects of acute administration of two antihypertensive drugs, clonidine and propranolol, on plasma NPY and catecholamine levels were compared in sinoaortic denervated (a model associated with a marked increase in sympathetic tone and a rise in blood pressure) and normal conscious dogs. Clonidine decreased plasma noradrenaline and NPY concentrations in both groups of animals. Propranolol failed to change plasma noradrenaline and NPY levels in sinoaortic denervated dogs but elicited a decrease in plasma noradrenaline with no change in NPY levels in normotensive animals. The present experiments show that changes in plasma noradrenaline and NPY concentrations are not always simultaneous. The decrease in plasma NPY concentrations could contribute to the sympatholytic effect of clonidine.

Animals↗
PubMed1996

alpha-Adrenergic regulation of human renal function.

Pharmacological and molecular cloning techniques have identified six human subtypes of alpha-adrenoceptors which are designated alpha 1A, alpha 1D, alpha 2A, and alpha 2C. At the protein level human kidney expresses predominantly alpha 2A-adrenoceptors while other alpha 2-adrenoceptor subtypes or alpha 1-adrenoceptors have not been detected consistently in radioligand binding studies. However, the presynaptic receptors, which inhibit noradrenaline release in the human kidney, appear to belong to the alpha 2C-subtype. Intrarenal infusion of the nonselective alpha-adrenoceptor antagonist, phentolamine, and of the selective alpha 2-adrenoceptor antagonist, yohimbine, but not of the selective alpha 1-adrenoceptor antagonist, doxazosin, increase renal blood flow and renin release in hypertensive patients undergoing diagnostic renal angiography. Thus, alpha 2- but not alpha 1-adrenoceptors appear to mediate a tonic renal vasoconstriction and inhibition of renin release. Effects of systemically given alpha 1-adrenoceptor agonists and antagonists are difficult to interpret on a mechanistic level since direct effects in the kidney and indirect effects due to baroreflex activation and peripheral presynaptic and central sympatholytic actions may at least partially offset each other. Moreover, some of these drugs may additionally act independent of alpha-adrenoceptors, for example, via imidazoline recognition sits. The net result in a given subject may depend on the endogenous sympatho-adrenal tone. Thus, for each target population of interest, effects have to be described empirically for each drug.

Adrenergic alpha-Agonists↗