摘要:

AbstractThis article presents the new concept that surface‐bound drugs can remove coagulation promoters from the bloodstream and thus produce much needed improvement in the surface thromboresistance of polymeric devices such as catheters, vascular grafts, and artificial organs. For example, calcium plays a central role in promoting coagulation, which suggests that surface thromboresistance could be improved by bonding a polymer to a calcium chelator which removes calcium from circulation. This technique has been tried and found successful in animal tests using hydroxyproline as the calcium chelator (Wilson and Jones:Biomater. Artif. Organs17:437–445, 1989. An alternative design for a thromboristance polymer is proposed: Chemically bond a commercial polymer to a suitable drug containing cationic groups capable of complexing blood coagulation factors and rendering them inactive. The feasibility of this approach is based on two lines of evidence: (1) Several blood coagulation factors are routinely isolated by complexation on ion exchange resins containg cationic groups (tertiary amines). (2) A number of polymers containing cationic groups (tertiary amines) have been patented on the basis of their thromboresistance. In this article an ion exchange equilibrium is postulated between each anionic coagulation factor adsorbed on the polymer and dissolved in the liquid phase, with the surface affinity of each anionic factor being greater the more cationic (basic) the polymer surface. Data on the competitive adsorption of proteins on cationic polymers have been analyzed mathematically. The results suggest more attention should be given to cation/anion interactions in studies of polymeric thromboresistance and protein adsorpti

ISSN:0272-4391    

DOI:10.1002/ddr.430210202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractMedorinone (5‐methyl‐1, 6‐naphthyridin‐2(1H)‐one) is a structurally novel cardiotonic/vasodilator agent. The purpose of the present study was to evaluate the effects of medorinone on subcellular systems involved in the contractile‐relaxation processes of cardiac and vascular smooth muscle (VSM); cyclic nucleotide phosphodiesterase (PDE), Ca2+‐regulated contractile proteins, and sarcolemmal Na+‐K+ATPase. Medorinone produces concentration‐related inhibition (IC50values between 0.38 and 1.3 μ) of the cGMP‐inhibitable, low‐KmcAMP PDE (peak III PDE from a DEAE‐cellulose column) present in guinea pig and canine cardiac and vascular smooth muscle. The potency of medorinone is similar to that of milrinone and papaverine, less than CI‐930, and greater than imazodan, piroximone, and amrinone. Medorinone is approximately 300–400 × less potent an inhibitor of the low‐KmcAMP PDE. Medorinone appears to be a non‐linear mixed inhibitor of the low‐KmcAMP PDE having a Kivalue of approximately 0.3 μM. Medorinone is also an equipotent inhibitor (IC50values between 0.23 and 0.35 μM) of the low‐mcAMP PDE present in soluble and particulate fractions obtained from normal and myopathic human hearts, with no differences in potency observed between normal and myopathics. Medorinone (10 and 100 μM) does not affect VSM myosin light chain phosphorylation or VSM actomyosin superprecipitation. Moreover, medorinone does not affect cardiac myofibrillar ATPase activity or cardiac sarcolemmal Na+‐K+ATPase activity. In summary, these data are consistent with the hypothesis that inhibition of the low‐KmcAMP PDE isozyme by medorinone in cardiac and vascular smooth muscle is a mechanism by which this agent produce both

ISSN:0272-4391    

DOI:10.1002/ddr.430210203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractMedorinone is a structurally novel positive inotropic/vasodilator agent that selectively inhibits cardiovascular low Km cAMP phosphodiesterase (PDE). As inhibitors of this PDE isozyme would be expected to activate the cAMP system, the objectives of the present study were to quantitate changes in cAMP content, activation of cAMP protein kinase (cAPK), and positive inotropy in isolated guinea pig papillary muscles or vasorelaxation in aortic smooth muscle by medorinone. In papillary muscles, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.92;P<0.01) or cAPK activity ratio, an index of activation of cAPK (r = 0.78,P<0.05) for concentrations of medorinone from 1 to 300 μM. Similar correlations were evident in aortic smooth muscles frozen during medorinone‐mediated relaxation of phenylephrine contractions (r = 0.89,P<0.05). These correlations and lines of regression were similar to those obtained for milrinone, papaverine, and isoproterenol; the correlation was similar for forskolin while the slope of the regression line was less. The temporal sequence of these events was also quantitated for a concentration of medorinone (100 μM) that produced approximately a 100% increase in papillary muscle isometric force and 90% vasorelaxation. Significant increases in either cAMP content or cAPK activity ratio paralleled increases in force development (papillary muscle) or vasorelaxation (aortic smooth muscle). In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with modulation of cardiac or vascular force by medorinone and thus support the hypothesis that inhibition of the low Km cAMP PDE is a mechanism by which medorinone effects positive inotropy and vasodilat

ISSN:0272-4391    

DOI:10.1002/ddr.430210204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe hemodynamic effects of the low KmcAMP peak III PDE inhibitor medorinone (0.01–0.3 mg/kg, i. v. ) were evaluated in anesthetized dogs in the presence and absence of β‐adrenoreceptor blocked. Medorinone increased the peak derivative of left ventricular pressure (+ dP/dt) in non‐blocked (all doses) and β‐blocked dogs (≥0.03 mg/kg) (2,766±259 and 1,403±262 mm Hg/sec, respectice max. changes). Heart rate (HR) was increased by medorinone in non‐blocked (≥0.1 mg/kg) and β‐blocked dogs (≥0.03 mg/kg) (77.4±8.9 and 25.5±4.3 beats/min, respective max. changes). In non‐blocked dogs only, medorinone (all doses) decreased left ventricular end‐diastolic pressure (LVEDP) (7.7±1.7 mm Hg, max. change). Mean arterial pressure (MAP) was similarly decreased by medorinone (<0.03 mg/kg) in β‐blocked and non‐blocked dogs (max. approx. −27 mm Hg). Medorinone did not affect cardiac output or renal blood flow. The hemodynamics of medorinone and milrinone (another peak III PDE inhibitor) in non‐blocked dogs were similar, except meddorinone was less potent in increasing +dP/dt (2,766±259 vs. 3,747±388, max. changes) and more potent in reducing LVEDP (−7.7±1.7 vs. −1.8±1.2 mm Hg, max. changes). In conclusion, medorinone similarly reduced MAP, but more effectively decreased preload, increased inotropy and chronotropy in non‐blocked than β‐blocked anesthetized dogs. Medorinone is more potent in reducing preload, but less potent in enhancing inotr

ISSN:0272-4391    

DOI:10.1002/ddr.430210205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractA series of new catechol ether imidazolidinones incorporating structural features of rolipram and Ro 20‐1724 were synthesized as inhibitors of the calcium‐independent phosphodiesterase (IPDE) from rat cerebral cortex. Several compounds were found to be more potent than rolipram as IPDE inhibitors; all of the compounds studied were more potent than Ro 20‐1724. The new imidazolidinones also showed affinity for the [3H]rolipram binding site in mouse brain membranes and reversed reserpine‐induced hypothermia in mice at relatively low doses. In vitro, the potency of these compounds as IPDE inhibitors did not correlate with their affinity for the [3H]rolipram binding site. Reversal of reserpine hypothermia by the imidazolidinones (“antidepressant effect”) could not be linked definitively to either in vit

ISSN:0272-4391    

DOI:10.1002/ddr.430210206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractAlthough optimal blood pressure control is important for managing stroke patients, the use of antihypertensives in stroke patients often causes cerebral blood flow reduction leading sometimes to deterioration of symptoms. Effects of arotinolol, a β‐blocker with a moderate α‐blocking action, on the regional cerebral blood flow (rCBF) were investigated in 10 hypertensive patients with a history of stroke by using a noninvasive133Xe inhalation method. The rCBF was measured before and after administration of 15 mg/day arotinolol (three times a day) for 2–3 weeks. After the administration, the blood pressure was reduced in all the patients showing a change in average values of from 176/105 mmHg to 152/90 mmHg. The rCBF in the infarcted and healthy hemispheres was 44.3 ± 4.4 and 44.6 ± 5.0 ml/100 g/min before arotinolol and 44.9 ± 6.4 and 45.3 ± 6.5 ml/100 g/min after arotinolol, respectively. No significant rCBF change was observed after arotinolol in both hemispheres. During the administration, none of the patients suffered from dizziness or other ischemic symptoms. The above results suggest that arotinolol exerts little influence on the cerebral circulation and may be useful for the management of hypertension in stro

ISSN:0272-4391    

DOI:10.1002/ddr.430210207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

ISSN:0272-4391    

DOI:10.1002/ddr.430210201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY