Drugs online research references
Circulation. 1996 Oct 1;94(7):1713-8.
Phospholipase D plays a role in ischemic preconditioning in rabbit heart.
Cohen MV, Liu Y, Liu GS, Wang P, Weinbrenner C, Cordis GA, Das DK, Downey JM.
Department of Medicine, University of South Alabama College of Medicine, Mobile, USA.
BACKGROUND: Activation of protein kinase C (PKC) is thought to be a critical step in ischemic preconditioning. Many receptor agonists activate PKC via stimulation of phospholipase C (PLC), which degrades membrane phospholipids to diacylglycerol (DAG), an important PKC cofactor. However, adenosine receptors, critical components of the prototypical preconditioning pathway, are not thought to couple to PLC in the cardiomyocyte. We therefore tested whether ischemic preconditioning or adenosine might instead activate phospholipase D (PLD) to produce DAG. METHODS AND RESULTS: PLD activity was measured in isolated rabbit hearts. Ischemic injury was evaluated in either isolated rabbit hearts or dispersed myocytes. PLD activity doubled from a control level of 74.8 +/- 10.0 to 140.0 +/- 11.5 mumol.min-1.g-1 (P < .025) after two 5-minute periods of global ischemia separated by 5 minutes of reperfusion. A similar increase was noted after the heart had been exposed to (R)-N6-(2-phenylisopropyl)-adenosine [(R)-PIA] for 20 minutes. When sodium oleate, which activates PLD, was administered to isolated hearts before a 30-minute coronary occlusion, infarct size (15.6 +/- 2.0% of the risk zone) was significantly smaller than in untreated hearts (30.4 +/- 2.2%; P < .01). Exposure to sodium oleate significantly prolonged the rate of isolated myocyte survival during simulated ischemia. Propranolol 100 mumol/L, which blocks DAG production from metabolites produced by PLD catalysis, completely abolished the protective effects of both metabolic preconditioning and (R)-PIA exposure in myocytes. CONCLUSIONS: We conclude that PLD stimulation is involved in the protection of ischemic preconditioning in the rabbit heart.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8840865&dopt=Abstract
Br J Pharmacol. 1996 Aug;118(7):1653-8.
Direct positive chronotropic effects of angiotensin II and angiotensin III in pithed rats and in rat isolated atria.
Li Q, Zhang J, Pfaffendorf M, van Zwieten PA.
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
1. The direct positive chronotropic effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) were established in pithed rats and in rat spontaneously beating right atria. 2. In pithed rats, AII, AIII and AIV caused dose-dependent tachycardia with similar maximal responses (110 beats min-1). The beta-adrenoceptor antagonist propranolol (3.37 x 10(-6) mol kg-1) but not the alpha 1-adrenoceptor antagonist prazosin (2.38 x 10(-7) mol kg-1) significantly reduced these effects (P < 0.05; n = 7-8), but 20-25% of the responses could not be blocked by propranolol. 3. In isolated atria, AII, AIII and AIV caused concentration-dependent increases in beating rate with similar maximal responses to AII and AIII (34.3 +/- 0.4 and 34.7 +/- 0.4 beats min-1; n = 9-10), and a lower maximal response to AIV (26.8 +/- 0.6 beats min-1; P < 0.05; n = 8). AIII was about 9 times less potent than AII, whereas AIV proved approximately 3800 times less potent than AII. Neither propranolol (1 microM) nor prazosin (1 microM) could influence the effects of the angiotensin peptides. 4. In isolated atria, the selective AT1-receptor antagonist, losartan (10, 100 and 300 nM) caused parallel rightward shifts of the concentration-response curves for AII and AIII, whereas the selective AT2- receptor antagonist PD123177 (1 microM) did not influence the effects of AII and AIII. The aminopeptidase-A and -M inhibitor amastatin (10 microM), significantly steepened the slope of the AIII curves and increased the potency of AIII about 6 fold. Amastatin did not influence the responses to AII. 5. Our results indicate that both in vivo and in vitro, exogenous AII and AIII induced a direct dose-dependent chronotropic effect, which is independent of the adrenergic system. This chronotropic effect is mediated by AT1-subtype receptors.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8842428&dopt=Abstract
Br J Clin Pharmacol. 1984 Jan;17(1):31-6.
Central effects of single oral doses of propranolol in man.
Salem SA, McDevitt DG.
The central effects of propranolol, a lipophilic beta-adrenoceptor antagonist, were investigated in six healthy male volunteers using two flash fusion threshold (2FFT), simple reaction time (SRT), digital copying test (DCT), symbol digit modalities test (SDMT), Gibson spiral maze test (GSMT) and mood rating scales for tension, alertness, depression, detachment and anxiety. Compared to placebo, 2FFT was prolonged by propranolol 40, 80 and 160 mg at one or more times tested but not by propranolol 320 mg: the largest effect was seen at 3 h after 40 mg, and the effects of 40, 80 and 160 mg were significantly greater than 320 mg at 2 h. SRTs were significantly prolonged by all doses of propranolol at 2 and 3 h and by 40 and 80 mg doses at 5 h. DCT was lowered by 40 and 80 mg at 2 and 3 h by 80 mg at 5 h, and by 320 mg at 2 h, but the 160 mg dose had no effect. Propranolol impaired the expected retest gain of the SDMT with all doses except 320 mg and at 2 h after 40, 80 and 160 mg, performance was actually worsened. Mood rating scales showed increased detachment with 40 mg and decreased alertness with 80 and 320 mg. The results show that propranolol has central effects in man: the effects appeared to be greater with lower doses, 40 and 80 mg, than with higher doses, 160 and 320 mg.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6691887&dopt=Abstract
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