Drugs online research references
Hypertens Res. 2000 Sep;23(5):491-6.
Possible involvement of endothelin-1 in cardioprotective effects of benidipine.
Ikeda K, Tojo K, Tokudome G, Akashi T, Hosoya T, Harada M, Nakagawa O, Nakao K.
Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
Benidipine hydrochloride has been developed as an antagonist for the L-type calcium channel and is used as an anti-hypertensive drug. But recent studies have reported that benidipine exerts not only antihypertensive actions but also anti-hypertrophic actions on cardiac muscles. Endothelin-1 (ET-1), one of the endogenous pathological humoral factors of cardiovascular diseases such as hypertension and heart failure, has a strong vasoconstrictive action and could induce hypertension and cardiac hypertrophy. So, it is a matter of great interest whether or not calcium antagonists can decrease cardiac hypertrophy induced by the pathological vasoactive substances such as ET-1. Thus, the present study was designed to elucidate the effects of benidipine on cardiac hypertrophy, and particularly on the interaction with ET-1, using neonatal rat cardiac myocytes (MCs) and cardiac non-myocytes (NMCs) culture systems. Cells were cultured with or without ET-1, benidipine, and nifedipine and the effects of calcium antagonists on cardiac hypertrophy were evaluated by incorporations of [3H]-leucine and [3H]-thymidine into MCs and/or NMCs. Benidipine significantly decreased the ET-1-induced increase of [3H]-leucine and [3H]-thymidine uptake into cardiac MCs and NMCs, whereas no significant effects of nifedipine were observed. Furthermore, benidipine (10(-8)M) attenuated ET-1 secretions from NMCs. In summary, benidipine at least partially decreased the cardiac hypertrophy induced by paracrine mechanisms through its attenuation of ET-1 secretions from NMCs. Benidipine could thus be a useful tool for preventing cardiac hypertrophy due to hypertension.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11016804&dopt=Abstract
Am J Physiol. 1991 Jun;260(6 Pt 1):L434-43.
Mechanisms of action of endothelin 1 in maturing rabbit airway smooth muscle.
Grunstein MM, Rosenberg SM, Schramm CM, Pawlowski NA.
Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania 19104.
Maturational differences in the effects and mechanisms of action of endothelin 1 (ET-1) on airway contractility were investigated in tracheal smooth muscle (TSM) segments isolated from 2-wk-old and adult rabbits. In TSM under passive tension, ET-1 elicited dose-dependent contractions, with a potency of action that was significantly greater (P less than 0.001) in the 2-wk-old vs. adult tissues (i.e., mean +/- SE - log 50% of maximal response values: 8.59 +/- 0.17 vs. 7.79 +/- 0.15 - log M, respectively). In TSM half-maximally contracted with acetylcholine (ACh), however, ET-1 elicited dual and opposing dose-dependent effects. At lower doses (less than or equal to 10(-9) M), ET-1 induced TSM relaxation that was significantly greater in the adult vs. 2-wk-old TSM segments (i.e., approximately 100 vs. 26.5% decrease in active tension, respectively). The relaxant responses were associated with significantly enhanced (P less than 0.001) ET-1-induced release of prostaglandins E2 and I2 in the adult tissues. At higher doses (greater than 10(-9) M), ET-1 induced TSM contractions that were 1) attenuated to a relatively greater extent by the Ca2+ channel blocker, nifedipine (10(-5) M) in the 2-wk-old tissues and 2) associated with significantly (P less than 0.001) enhanced ET-1-stimulated accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in the immature TSM. Moreover, the TSM contractions were inhibited by the protein kinase C (PKC) antagonist, H-7, and the latter effect was more potent in the immature TSM. Collectively, these findings demonstrate that ET-1 exerts a potent duality of action in rabbit TSM which varies significantly with maturation, wherein 1) age-dependent differences in airway relaxation are associated with changes in the evoked release of bronchodilatory prostaglandins and 2) maturational differences in airway contraction are associated with changes in Ins(1,4,5)P3 accumulation and extracellular Ca2+ mobilization, coupled to differences in PKC activation.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2058688&dopt=Abstract
Microcirc Endothelium Lymphatics. 1990 Aug-Oct;6(4-5):355-68.
Effect of nifedipine on endothelin induced contractions of skeletal muscle arterioles of spontaneously hypertensive rats.
Lougee L, Hinojosa-Laborde C, Harder DR, Lombard JH.
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226.
Endothelin is a potent vasoactive polypeptide isolated from cultured endothelial cells. However, there are relatively few studies of the action of endothelin on microvessels in vivo. To determine the effects of this compound on arterioles of normotensive and hypertensive rats, endothelin (1 x 10(-12) M to 1 x 10(-8) M) was dissolved in physiological salt solution and superfused over the cremaster muscle of 12-15 week old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. Endothelin caused about a 55% constriction of second order arterioles and complete closure of most third order arterioles and all fourth order arterioles studied. SHR arterioles tended to be more sensitive to endothelin than those of WKY, although this difference was significant for only the third order arterioles. Endothelin induced contractions were significantly inhibited by 10(-6) M nifedipine in both WKY and SHR. These studies demonstrate that endothelin is a potent constrictor of skeletal muscle arterioles, and suggest that activator Ca2+ for endothelin induced contractions of these vessels enters the vascular smooth muscle cells through dihydropyridine sensitive calcium channels.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2280745&dopt=Abstract
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