Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0038454 (stroke)
147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pharmacology of central alpha-adrenoceptor-stimulating agents is discussed, with particular reference to clonidine (Catapres; Boehringer Ingelheim) and guanfacine (Estulic; Sandoz), and their haemodynamic effects are compared and contrasted. The main differences between the effects of clonidine and guanfacine on hypertension are: guanfacine activates presynaptic alpha-adrenoceptors 10 times more selectively than clonidine; guanfacine has an alpha 2/alpha 1-selectivity ration 25 times higher than clonidine; clonidine decreases cardiac output and guanfacine decreases peripheral resistance, clonidine has no effect on stroke volume but guanfacine increases it; and when the clonidine withdrawal syndrome in the spontaneously hypertensive rat is compared with cessation of guanfacine treatment at an equipotent antihypertensive dose, the withdrawal syndrome after guanfacine appears later and is much less severe. Guanfacine may be preferable to clonidine as a central alpha-adrenoceptor stimulant in the treatment of hypertension.
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PMID:Clonidine and guanfacine--comparison of their effects on haemodynamics in hypertension. 388 93

Clonidine produces hemodynamic effects that are mediated through both the heart and the peripheral vascular system. The cardiac effects (decrease in heart rate and stroke volume) appear to predominate early in treatment, but peripheral vascular resistance is usually reduced. In some studies, the reduction in peripheral resistance was found to persist beyond the initial period of therapy. The sympathetic tone in various parts of the cardiovascular system probably determines whether the drug preferentially affects the heart or the resistance vessels. The clonidine-induced reduction in blood pressure and heart rate decreases the cardiac workload. The drug is also beneficial in patients with coronary artery disease, and appears to have a coronary vasodilating effect. Clinically, the drug is useful when given alone or in combination with either a peripheral vasodilator or a diuretic. Although clonidine reduces the heart rate, severe bradycardia is uncommon. The drug should be used with caution in patients with AV conduction disease.
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PMID:Hemodynamic and cardiac effects of clonidine. 615 35

These studies were undertaken to clarify the role of the central and peripheral sympathetic nervous system and the renin-aldosterone system on the onset and maintenance of high blood pressure in essential hypertension (EH), and the following examinations were performed: 1) Urinary free norepinephrine and epinephrine excretion (UNEf and UEf), urinary conjugated norepinephrine and epinephrine excretion (UNEconj and UEconj), plasma norepinephrine and epinephrine concentration (PNE and PE), plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 52 patients with EH, who were divided into two groups (borderline EH: b-EH, and sustained EH: s-EH), and fifteen normals (N). 2) Cardiac index (CI), total peripheral resistance index (TPRI), appearance time, mean transit time and stroke index (SI) were determined by the dye-dilution method in eight patients with b-EH, ten patients with s-EH and ten N. 3) Clonidine was administered orally in a single dose of 150 micrograms to seven patients with s-EH and three patients with b-EH, and PNE, PE and growth hormone (GH) were measured before and after the administration. 4) Isoproterenol was infused intravenously in a dose of 0.02 microgram/kg/min for 30 min to 18 patients with s-EH and six N, then plasma cyclic AMP (c-AMP) and PRA were determined before, during and after the infusion. 5) Methacholine was injected intramuscularly in a dose of 10 mg to seven N, and PNE, PE and PRA were measured before and after the injection. There were no significant differences of PNE, PE, UNEf and UEf among the three groups (b-EH, s-EH and N), but UNEconj in both b-EH and s-EH was higher than in N (b-EH: p less than 0.1, s-EH: p less than 0.05). PRA in s-EH was slightly lower not only in N but also in b-EH. PAC in b-EH and s-EH was slightly lower than in N. The difference of PAC between b-EH and s-EH was not found. CI and SI were higher than in N (p less than 0.05), but TPRI was normal. In s-EH, TPRI was slightly elevated as compared with b-EH (p less than 0.1). In s-EH, clonidine caused a significant lowering of both blood pressure and PNE with a simultaneously marked increment of GH; on the other hand, in b-EH blood pressure and PNE did not change significantly in spite of the distinct rise of GH. After the isoproterenol infusion, PRA and c-AMP increased, and there was a significant correlation between the initial level of PRA and the maximal increment of PRA after the infusion in both s-EH and N.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Studies on the role of the central and peripheral sympathetic nervous system and the renin-aldosterone system on the onset and maintenance of high blood pressure in essential hypertension]. 632 58

Daily doses of 0.3 mg clonidine and 3 mg guanfacine were equiactive in decreasing blood pressure and heart rate in 17 subjects with essential hypertension. Clonidine decreased cardiac output and guanfacine decreased total peripheral resistance, while clonidine had no effect on stroke volume but guanfacine increased it. Both clonidine and guanfacine decreased plasma renin activity. Naloxone, 0.4 mg iv, reversed the antihypertensive effect of clonidine but was ineffective even at higher doses (1.6 mg iv) when subjects were treated with placebo or guanfacine. It is suggested that the hemodynamic differences between the two centrally acting alpha 2-adrenoceptor agonist antihypertensive drugs may at least in part result from the involvement of opioid mechanisms only in the action of clonidine.
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PMID:Effects of clonidine and guanfacine in essential hypertension. 638 75

We have evaluated left ventricular function in anaesthetized (morphine, pentobarbital), artificially ventilated, normotensive beagle dogs immediately (0 to 30 min) after i.v. bolus injection of clonidine (1, 3, 5, 7, 10 and 15 micrograms/kg of b.w.) using computer assisted catheterization technique. Clonidine decreased heart rate and prolonged pre-ejection, ejection and diastolic periods significantly. Cardiac output, mean systolic ejection rate, left ventricular (LV) dP/dtmax and Vmax decreased (p less than 0.05 to 0.01). LV peak pressure and aortic pressures decreased but the decrease was preceded by an initial rise at doses 5 to 10 micrograms/kg. At dose 15 micrograms/kg the rise persisted through the whole period. LV filling and end-diastolic pressures increased while end-diastolic and stroke volumes decreased. These changes indicate negative chronotropic and inotropic effects and increment in preload with the latter being a situation met in the case of proper LV filling. Tension time index and mean outflow resistance, however, indicate reduction in LV oxygen consumption at doses less than 10 micrograms/kg. It is suggested that enhancement of parasympathetic tone would account for these changes.
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PMID:Left ventricular responses to intravenous administration of clonidine in anaesthetized dogs. 659 61

To assess the hemodynamic effects of Clonidine in hypertensive patients (pts) with an acute myocardial infarction (AMI), we administered the drug to 12 such patients either in a single bolus (75--150 micrograms in 5 min - 8 pts) or by continuous infusion (0.4--5 micrograms/min - 4 pts). Hemodynamic measurements were obtained by means of a Swan-Ganz thermodilution catheter, before and 60 min after the administration of the drug. Clonidine did not significantly affected Heart Rate (from 80.5 +/- 3.9 to 78.4 +/- 5.9 beats/min), Mean Pulmonary Arterial Pressure (from 18.6 +/- 1.7 to 15.1 +/- 1 mmHg), Mean Pulmonary Wedge Pressure (from 12.5 +/- 1.1 to 10.6 +/- 0.7 mmHg), central Venous Pressure (from 4 +/- 0.8 to 3 +/- 0.9 mmHg), Cardiac Index (from 2.6 +/- 0.07 to 2.6 +/- 0.7 L/min/m2), Stroke Volume (from 65.2 +/- 2.8 to 68.5 +/- 5.5 ml/b). Conversely Mean Arterial Pressure fell significantly from 127 +/- 3.1 to 96.2 +/- 7.2 mmHg (P less than 0.001). Left Ventricular Systolic Work Index was reduced from 62.3 +/- 3.3 to 50.4 +/- 4.4 gm/beats/m2 (P less than 0.025), Total Systemic Resistances from 1888 +/- 50 to 1412 +/- 117 dyne sec cm-5 (P less than 0.005) and Tension Time Index from 3536 +/- 495 to 2389 +/- 385 x 10(3) mmHg x sec/min (p less than 0.05). Clonidine is a safe and useful drug to obtain a fall of high blood pressure often complicating AMI, without depressing left ventricular performance, as suggested by no significant changes of CI, WP and LVSWI. The reduction of TTI suggests a beneficial effect on the balance between myocardial oxygen delivery and demand. Clonidine is a hypotensive drug which can be safely used in patients with AMI, without depressing the left ventricular performance.
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PMID:[Hemodynamic effects of intravenous clonidine in patients with acute myocardial infarction]. 676 71

After intravenous bolus injections of clonidine HCl (150 micrograms) to 12 patients with congestive heart failure, peak effects appeared in 5 to 20 min. Clonidine reduced heart rate from 94 +/- 14 to 82 +/- 14 bpm (mean +/- SD, P less than 0.05), left ventricular filling pressure from 31 +/- 5 to 23 +/- 5 mm Hg (P less than 0.001), mean systemic arterial pressure from 98 +/- 13 to 82 +/- 13 mm Hg (P less than 0.001), mean pulmonary artery pressure from 46 +/- 6 to 38 +/- 6 mm Hg (P less than 0.001), and right atrial pressure from 14 +/- 5 to 11 +/- 5 mm Hg (P less than 0.05). Cardiac index increased from 1.6 +/- 0.4 to 1.8 +/- 0.6 l/min/m2 (P less than 0.05) and stroke volume from 32 +/- 10 to 43+/- 12 ml/beat (P less than 0.05). Systemic vascular resistance decreased from 2,342 +/- 800 to 1,795 +/- 345 dynes sec cm-5 (P less than 0.05) and pulmonary vascular resistance from 365 +/- 158 to 263 +/- 114 dynes sec cm-5 (P less than 0.05). We conclude that clonidine decreases heart rate and left ventricular preload and afterload in congestive heart failure.
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PMID:Short-term effects of intravenous clonidine in congestive heart failure. 730 22

Clonidine-displacing substance (CDS) is a novel endogenous ligand for clonidine receptors previously detected in bovine brain and human serum. We examined for the first time whether CDS can be detected and measured in human cerebrospinal fluid (CSF). Using the [3H]clonidine displacement assay, we found that CDS could be identified and quantified in each of the CSF samples obtained from 81 patients with various neurological disorders. Mean level of CDS in CSF was 4.66 units/ml. Exceedingly high levels were observed in the CSF of patients with neoplastic meningitis (mean, 36.75 units/ml) and stroke (mean, 19.5 units/ml) (P < 0.0001). No correlation was found between CDS levels in CSF and age, gender, CSF protein or number of cells. CDS levels in CSF were higher than those in the serum (P < 0.01). We conclude that CDS is present and can be measured in human CSF. High CDS levels in CSF from patients with leptomeningeal metastases may serve as a tumor marker for malignant infiltration of the meninges. Additional studies in stroke patients will determine whether this endogenous ligand plays a role in the pathogenesis of cerebral ischemia.
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PMID:Detection and measurement of an endogenous clonidine-displacing substance in human cerebrospinal fluid. 843 81

We reported previously that genetic polymorphisms of the alpha 2-adrenergic receptor are associated with hyperinsulinemia, diabetes mellitus, and hypertension in blacks. The evolutionary driving force for maintaining such deleterious mutations in the black population is unknown. Recognizing that vascular alpha 2-adrenergic receptors mediate cold-induced vasoconstriction and that temperature maintenance is a primary thrust of cellular metabolism, we postulated that vascular alpha 2-adrenergic receptors contribute significantly to metabolic heat generation in homeotherms such as humans. Using aerobic lactate production as an indicator of thermogenesis, we measured metabolic heat production in HT29 cells that expressed the gene encoding human vascular alpha 2-adrenergic receptors. Epinephrine, an alpha 2-adrenergic receptor agonist, increased net lactate efflux from 226 +/- 20 to 280 +/- 20 nmol/min (mean +/- SE) (P = .06). Clonidine, a more specific alpha 2-adrenergic agonist, increased lactate efflux from 110 +/- 6 to 156 +/- 8 nmol/min (P < .01). Similarly, in the presence of physiological concentrations of glucose (5.5 mmol/L), insulin increased lactate production from 123 +/- 6 to 175 +/- 10 nmol/min (P < .01). Because differences in aerobic glycolysis may also explain the heat intolerance and abnormal fuel homeostasis found in genetically hypertensive rats, we also measured lactate production in cultured vascular smooth muscle cells isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive control Wistar-Kyoto rats (WKY). Vascular smooth muscle cells from SHRSP had significantly greater lactate efflux compared with cells from normotensive WKY (296 +/- 4 versus 172 +/- 2 nmol/min, P < .001). These differences were not due to abnormalities in glucose uptake, as lactate efflux was greater in SHRSP cells compared with WKY cells when dextrose was replaced with equimolar concentrations of fructose (230 +/- 6 versus 138 +/- 2 nmol/min, P < .001). alpha 2-Adrenergic agonists increase lactate efflux in HT29 cells, and abnormalities in vascular smooth muscle lactate metabolism in genetically hypertensive rats is independent of altered glucose uptake. These data provide support for our hypothesis that balanced polymorphisms of the alpha 2-adrenergic receptor could offer protection against cold stress by increasing the thermogenic response associated with aerobic lactate production.
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PMID:Alpha 2-adrenergic agonists increase cellular lactate efflux. 862 Dec 3

Our previous studies have shown that ethanol selectively counteracts centrally mediated hypotensive responses. This study investigated the role of cardiac output and peripheral resistance in the antagonistic interaction between ethanol and antihypertensive drugs. Changes in blood pressure, heart rate, cardiac index, stroke volume, and peripheral resistance elicited by clonidine and subsequent ethanol or saline administration were evaluated in conscious rats. The aortic barodenervated rat was employed because it exhibits greater hypotensive responses to clonidine compared with the intact rat. Aortic barodenervation elicited acute rises in blood pressure, heart rate, and peripheral resistance, whereas cardiac index and stroke volume were not altered. The blood pressure of conscious aortic barodenervated rats returned to sham-operated levels by 48 hours due to concomitant reductions in cardiac index and stroke volume; the peripheral resistance, however, remained significantly elevated. Clonidine (30 microg/kg, I.V.) elicited greater decreases in blood pressure in aortic barodenervated compared with sham-operated rats. The hypotension was caused by decreases in cardiac index and stroke volume because peripheral resistance did not change. Ethanol (1 g/kg, I.V.) counteracted the hypotensive effect of clonidine and raised blood pressure to levels higher than preclonidine values. Significant (P<.05) increases in cardiac index and stroke volume and decreases in peripheral resistance accompanied the pressor effect of ethanol. Additional control groups were included in the study to determine the selectivity of the interaction. A dose of hydralazine (0.5 mg/kg, I.V.) was used that produced similar hypotension to that evoked by clonidine in aortic barodenervated rats. Hydralazine-evoked hypotension was similar in denervated and control rats and resulted from significant reductions in peripheral resistance. Reflex increases in heart rate and stroke volume and hence cardiac output were observed. Ethanol given after hydralazine produced a short-lived pressor effect (<5 minutes versus 40 minutes in the case of clonidine) and counteracted the sympathetically mediated increases in cardiac output, stroke volume, and heart rate. These findings support our hypothesis that ethanol selectively counteracts hypotensive responses of central origin by reversing the reduction in cardiac output elicited by clonidine.
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PMID:Role of cardiac output in ethanol-evoked attenuation of centrally mediated hypotension in conscious rats. 926 Sep 94


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