Drugs online research references
J Auton Pharmacol. 1998 Oct;18(5):271-80.
Spectral analysis of intercycle heart fluctuations in the diethyl-ether-anaesthetized or pithed rat treated with prazosin, dl-propranolol, endothelin-1, alpha-r atriopeptin and ACE-inhibitors.
Bernardi M, Deslauriers R, Docherty J, Rossi C, Rossini L, Rossini P, Tonnini C.
I.M.O. - Institute of Experimental and Clinical Medicine, University of Ancona Medical School, Italy.
1. Frequency-domain spectral analysis of stationary ECG R-R intervals was made by fast Fourier transformation (FFT) in conditions of monitored arterial blood pressure and respiratory activity in diethyl-ether-anaesthetized and pithed adult rats. This technique yields a number of parameters which allow quantitative evaluation of the non-random distribution of the mean values obtained in time-domain studies. The frequency-analysis method enables the overall heart rate variability to be broken down into its various constituents, which are differently affected by physiological loading and capable of selective reactivity to pharmacological agents. 2. The low-frequency spectral component obtained by breaking down the total spectral density power, i.e. the appropriate variability signal (band width < 0.15 Hz) and a higher-frequency band corresponding to spontaneous (0.80-1.60 Hz) or artificially imposed (0.75 Hz) respiratory activity were estimated and their integrated areas evaluated as absolute powers or normalized fractional values. 3. The power of the high-frequency spectral component increased in all animal preparations under treatment with prazosin, dl-propranolol, endothelin-1 and the angiotensin converting enzyme (ACE) inhibitors captopril, lisinopril, quinapril and ramipril. The power of the low-frequency band increased under alpha-r atriopeptin and ACE inhibitors in the pithed preparations only, and decreased in the anaesthetized animals. 4. The new power spectrum features and trends detected indicate that these time-independent, model-dependent cardiovascular and respiratory markers are subject to some form of complex peptidergic control. 5. The relative roles of the various factors operating in the genesis of these short-term changes in spectral power in the low- and high-frequency bands cannot be interpreted as indicating a reciprocal push-pull relationship between sympathetic and parasympathetic control. 6. The study findings, however, can be interpreted as providing evidence of a different and to some extent alternative form of integrative cardiovascular control persisting in the pithed rats (i.e. in the 'peripheral', CNS-destroyed preparations). 7. New areas of theoretical and applied research are being developed in the (auto)classification of (iso)receptors and drug analogues through exploration of multiple physiological and pharmacokinetic parameters in the frequency-domain. Furthermore, model-independent frequency-domain methods not requiring stationary data will afford scope for even more significant developments by separating the overlapping dynamic processes from a whole series of correlated effects.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9831227&dopt=Abstract
Br J Pharmacol. 1997 Nov;122(6):1179-87.
Intravascular and interstitial degradation of bradykinin in isolated perfused rat heart.
Dendorfer A, Wolfrum S, Wellhoner P, Korsman K, Dominiak P.
Institute of Pharmacology, Medical University of Lubeck, Germany.
1. Bradykinin (BK) has been shown to exert cardioprotective effects which are potentiated by inhibitors of angiotensin I-converting enzyme (ACE). In order to clarify the significance of ACE within the whole spectrum of myocardial kininases we investigated BK degradation in the isolated rat heart. 2. Tritiated BK (3H-BK) or unlabelled BK was either repeatedly perfused through the heart, or applied as an intracoronary bolus allowing determination of its elution kinetics. BK metabolites were analysed by HPLC. Kininases were identified by ramiprilat, phosphoramidon, diprotin A and 2-mercaptoethanol or apstatin as specific inhibitors of ACE, neutral endopeptidase 24.11 (NEP), dipeptidylaminopeptidase IV and aminopeptidase P (APP), respectively. 3. In sequential perfusion passages, 3H-BK concentrations in the perfusate decreased by 39% during each passage. Ramiprilat reduced the rate of 3H-BK breakdown by 54% and nearly abolished [1-5]-BK generation. The ramiprilat-resistant kininase activity was for the most part inhibited by the selective APP inhibitor apstatin (IC50 0.9 microM). BK cleavage by APP yielded the intermediate product [2-9]-BK, which was rapidly metabolized to [4-9]-BK by dipeptidylaminopeptidase IV. 4. After bolus injection of 3H-BK, 10% of the applied radioactivity were protractedly eluted, indicating the distribution of this fraction into the myocardial interstitium. In samples of such interstitial perfusate fractions, 3H-BK was extensively (by 92%) degraded, essentially by ACE and APP. The ramiprilat- and mercaptoethanol-resistant fraction of interstitial kininase activity amounted to 14%, about half of which could be attributed to NEP. Only the product of NEP, [1-7]-BK, was continuously generated during the presence of 3H-BK in the interstitium. 5. ACE and APP are located at the endothelium and represent the predominant kininases of rat myocardium. Both enzymes form a metabolic barrier for the extravasated fraction of BK. Thus, only interstitial, but not intravascular concentrations of BK are increased by kininase inhibitors to the extent that a significant potentiation of BK effects could be explained. NEP contributes less than 5% to the total kininase activity, but is the only enzyme which is exclusively present in the interstitial space.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9401784&dopt=Abstract
Braz J Med Biol Res. 1996 Nov;29(11):1503-5.
Effect of intracerebroventricular injection of ramipril on the drinking response caused by injection of noradrenaline into the third ventricle.
Barros VM, Saad WA, Camargo LA, Renzi A, Saad WA, Menani JV.
Departamento de Ciencias Fisologicas, Faculdade de Odontologia, Universidade Estadual Paulista, Araraquara, SP, Brasil.
We studied the effect of ramipril injected into the third ventricle (3rdV) on the control of water intake induced by injection of noradrenaline into the 3rdV of adult male Holtzman rats (250-300 g) implanted with a chronic stainless steel cannula into the 3rdV. The injection volume was always 1 microliter and was injected over a period of 30-60 sec. Control animals were injected with 0.15 M NaCl. After the injection of isotonic saline (control, 0.15 M NaCl) into the 3rdV, water ingestion was 0.3 +/- 0.1 ml/h. Ramipril (1 mircogram/microliter) injected into the 3rdV prior to isotonic saline produced no changes in water ingestion (0.4 +/- 0.2 ml/h). The injection of noradrenaline (40 nmol/microliter) after isotonic saline induced an increase in water intake (3.0 +/- 1.1 ml/h). The prior injection of ramipril decreased this ingestion to 1.8 +/- 0.3 ml/h. These data show that the inhibition of converting enzyme in the brain reduces the water intake induced by catecholaminergic stimulation. We conclude that the brain is able to transform the prodrug ramipril into the active drug ramiprilat.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9196553&dopt=Abstract
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