Drugs online research references
Pharmacology. 1993 Nov;47(5):295-9.
Lipophilic beta-blockers inhibit rat skeletal muscle mitochondrial respiration.
Dreisbach AW, Greif RL, Lorenzo BJ, Reidenberg MM.
Department of Pharmacology and Medicine, Cornell University Medical College, New York, NY 10021.
Propranolol, metoprolol, acebutolol, nadolol and atenolol were incubated with isolated rat skeletal muscle mitochondria at 30 degrees C, and the rate of oxygen consumption was measured with an oxygen microelectrode. The potency of these drugs to inhibit state III respiration was correlated with lipid solubility as measured by the octanol/water partition coefficient. The most lipid-soluble beta-blocker, propranolol, had an ED50 of 0.6 mmol/l. The most water-soluble one, atenolol, showed no inhibition at concentrations up to 16 mmol/l. Inhibition of respiratory control ratio, state IV respiration and ADP/O ratio occurred at 2 mmol/l for propranolol, 16 mmol/l for metoprolol and was not consistently observed for the other beta-blockers at the concentrations tested. The inhibition of state III respiration of skeletal muscle mitochondria by lipid-soluble beta-blockers may be one of the causes of the fatigue observed in some patients receiving these drugs.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7903463&dopt=Abstract
Circulation. 1993 Oct;88(4 Pt 1):1885-92.
Propranolol and lidocaine inhibit neural norepinephrine release in hearts with increased extracellular potassium and ischemia.
Du XJ, Riemersma RA, Fox KA, Dart AM.
Baker Medical Research Institute, Melbourne, Australia.
BACKGROUND. Propranolol and lidocaine are effective antiarrhythmic drugs in myocardial ischemia and infarction. As sympathetic nerve activation and norepinephrine release in ischemic hearts are arrhythmogenic, we tested the possibility that both agents inhibit neural norepinephrine release following sympathetic activation in the ischemic environment. METHODS AND RESULTS. The model used was an in situ perfused innervated rat heart. Norepinephrine release was induced by electrical stimulation of the left cervicothoracic stellate ganglion and analyzed using radioenzymatic assay or high-performance liquid chromatography. In normoxically perfused hearts, evoked norepinephrine release was not affected by either of the two agents at doses of 1 to 10 mumol/L when extracellular K+ concentration was 4 mmol/L but dose-dependently reduced at 10 mmol/L K+ (D,L-propranolol: -53 +/- 4% at 1 mumol/L and -64 +/- 6% at 10 mumol/L K+, lidocaine: -37 +/- 11% at 0.1 mumol/L, -67 +/- 5% at 1 mumol/L, and -75 +/- 6% at 10 mumol/L). At 10 mmol/L K+, norepinephrine release was not affected by timolol or atenolol (both 10 mumol/L but was equally inhibited by D- or L-propranolol at 10 mumol/L (-56 +/- 5% and -53 +/- 9%, respectively), indicating a beta-blocking-independent mechanism. In hearts with metabolic acidosis (pH 6.85) at K+ of 4 mmol/L, neural norepinephrine release was also reduced by propranolol at 10 mumol/L (-37%). Finally, in hearts perfused with 4 mmol/L K+ and subjected to 6-minute periods of ischemia, neural norepinephrine release was similarly suppressed by D,L-propranolol (-38 +/- 6% at 0.1 mumol/L, -44 +/- 5% at 1 mumol/L, and -78 +/- 3% at 10 mumol/L) or lidocaine (-39 +/- 7% at 0.1 mumol/L, -58 +/- 9% at 1 mumol/L, and -91 +/- 3% at 10 mumol/L). CONCLUSIONS. These data indicate that propranolol and lidocaine inhibit neural norepinephrine release via a Na+ channel-blocking mechanism that is synergistic with changes induced by ischemia, primarily raised extracellular K+. This mechanism may contribute to the anti-ischemic and antiarrhythmic properties of both agents in acute myocardial ischemia, which induces increased extracellular K+ and sympathetic activation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8403334&dopt=Abstract
J Mol Cell Cardiol. 1990 Jun;22(6):687-95.
Oxygen radical-mediated injury of myocytes-protection by propranolol.
Mak IT, Kramer JH, Freedman AM, Tse SY, Weglicki WB.
Department of Medicine, George Washington University Medical Center, Washington, DC 20037.
UIe effects of propranolol and atenolol on free radical mediated injury in myocytes were examined. Freshly isolated adult canine myocytes were incubated with a superoxide generating (from dihydroxyfumarate) and Fe-catalyzed free radical system. Exposure of the myocytes to free radicals for 20 min resulted in more than a 5-fold increase in thiobarbituric acid reactant (peroxide) formation and elevated levels of lactate dehydrogenase (LDH) activity released into the media compared to controls. Ultrastructurally, severe sarcolemmal damage, mitochondrial and myofibril derangements were evident. At 40 min, cellular viability (trypan blue exclusion) in the samples exposed to free radicals decreased to about one-third of controls; concomitantly, major losses in total cellular phospholipids occurred. When the cells were pretreated with 200 microM propranolol before the addition of free radicals, both peroxide formation and increased LDH release were inhibited; in agreement, complete ultrastructural preservation was observed. In addition, the subsequent losses in cellular viability and phospholipids were prevented. For comparison, the more water soluble beta-blocker, atenolol at 200 microM was shown ineffective in providing significant protection against the induced injury. The results suggest that propranolol may provide antiperoxidative protection to myocytes when elevated levels of free radicals are present.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2231736&dopt=Abstract
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