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From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors.These experimental findings in different models of LVH characterise ACE inhibitors as remarkable antihypertrophic and antifibrotic substances. [ABSTRACT FROM AUTHOR]

The inhibitors of the Na/H-exchange (NHE1) system Hoe 694 and Hoe 642 possess cardioprotective effects in ischaemia/reperfusion. It is assumed that these effects are due to the prevention of intracellular sodium (Na) and calcium (Ca) overload. The purpose of the present study was to investigate the effects of Hoe 642 on intracellular pH, Naand Ca(pH, Naand Ca) in isolated rat ventricular myocytes under anoxic conditions or in cells in which oxidative phosphorylation had been inhibited by 1.5 mmol/l cyanide. In cells which were dually loaded with the fluorescent dyes 2,7-biscarboxyethyl-5,6-carboxyfluorescein (BCECF) and Fura-2, anoxia caused acidification of the cells (from pH7.2 to pH6.8) and an increase in Cafrom about 50 nmol/l to about 1 μmol/l. The decrease in pHbegan before the cells underwent hypoxic (rigor) contracture, whereas Caonly began to rise after rigor shortening had taken place. After reoxygenation, pHreturned to its control value and Caoscillated and then declined to resting levels. It was during this phase that the cells rounded up (hypercontracture). When 10 μmol/l Hoe 642 was present from the beginning of the experiment, pHand Cawere not significantly different from control experiments. At reoxygenation, pHdid not recover, but Caoscillated and returned to its resting level. To monitor Na, the cells were loaded with the dye SBFI. After adding 1.5 mmol/l cyanide or 100 μmol/l ouabain, Naincreased from the initial 8 mmol/l to approximately 16 mmol/l. Hoe 642 or Hoe 694 (10 μmol/l) did not prevent the increase in Na. In contrast, the blocker of the persistent Nacurrent R56865 (10 μmol/l) attenuated the CN-induced rise in Na. The substance ethylisopropylamiloride was not used because it augmented considerably the intensity of the 380 nm wavelength of the cell's autofluorescence. In conclusion, the specific NHE1 inhibitor Hoe 642 did not attenuate anoxia-induced Caoverload, nor CN-induced Naand Caoverload. Hoe 642 prevented the recovery of pHfrom anoxic acidification. This low pHmaintained after reoxygenation may be cardioprotective. Other possible mechanisms of NHE1 inhibitors, such as prevention of Caoverload in mitochondria, cannot be ruled out. The increase in Naduring anoxia is possibly due to an influx of Navia persistent Nachannels. [ABSTRACT FROM AUTHOR]

The present study examined whether alterations of endothelium-dependent vasorelaxation in spontaneously hypertensive rats (SHR) in response to the endothelium-dependent vasodilators acetylcholine and bradykinin ran parallel. We tried to find out the age at which endothelium-dependent vasorelaxation in response to each agonist became impaired and compared three different groups of SHR aged 7, 21 and 51 weeks. To be able to separate hypertension-induced alterations from age-dependent changes age-matched normotensive Wistar rats were included. Endothelium-dependent vasorelaxation was studied in the mesenteric vascular bed precontracted with noradrenaline, a typical resistance vessel, which showed relaxation to both acetylcholine and bradykinin, and the precontracted thoracic aorta, which only responded to acetylcholine. There were major differences in the agonist-dependent vasorelaxation between bradykinin and acetylcholine in SHR as a function of age. A surprising finding was that acetylcholine-induced relaxation was preserved, even slightly improved not only in young SHR (7 weeks) with developing hypertension but also in adult SHR (21 weeks) with established hypertension, which can be interpreted as a compensatory mechanism. As expected, in old SHR (51 weeks) acetylcholine induced vasorelaxation was impaired as a consequence of the detrimental effects of long-term hypertension on endothelium. The parallel changes observed with acetylcholine in the mesenteric vascular bed and thoracic aorta provided mutual confirmation. In clear contrast to acetylcholine bradykinin-induced vasorelaxation was already impaired in young SHR with developing hypertension suggesting that bradykinin-induced vasorelaxation is either much more sensitive to detrimental effects of (even slightly) increased blood pressure or, more likely, that there is a basic deficiency in the action of bradykinin in SHR. Thus, our study allows to conclude that impairment of acetylcholine-induced endothelium-dependent vasorelaxation in the mesenteric vascular bed of SHR is a secondary phenomenon developing as a consequence of long-term hypertension while the impaired bradykinin-induced vasorelaxation seems to be a primary phenomenon that could be closely related to the development of hypertension. [ABSTRACT FROM AUTHOR]

The pharmacological and binding properties of the novel enantiomerically pure benzothiazinone (R)-(+)-3, 4-dihydro-2-isopropyl-4-methyl-2-[2-[4-[4-[2-(3,4,5-trimethoxyphenyl)-ethyl]-piperazinyl]-butoxyl-phenyl]-2H-1, 4-benzothiazine-3-one dihydrochloride (HOE 166), are described. HOE 166 stereoselectively inhibited KCl but not noradrenaline-induced contractions of guinea-pig pulmonary arteries, rabbit aorta, rat mesenteric artery preparations and k-strophantin-induced enhancement of guinea-pig papillary muscle contraction in a dose-dependent manner. KCl-induced smooth muscle contraction was inhibited by HOE 166 with IC-values of ∼ 70 nM (5-11 times less potent than nifedipine, 2-16 times more potent than verapamil), the respective S-(−)-enantiomer being ∼ 10-fold less potent. HOE 166 decreased the upstroke velocity of the slow action potential in partially depolarized guinea-pig papillary muscle at similar concentrations than nifedipine. To investigate possible interactions with the calcium channel, HOE 166 and its S-(−)-enantiomer were characterized by radioligand binding studies in heart, brain and skeletal muscle transverse-tubule membranes. HOE 166 was a 4-15 times more potent inhibitor of reversible (+)-[H]PN200-110, (−)-[H]desmethoxyverapamil and d-cis [H]diltiazem binding compared to its pharmacologically less active (S)-(−)-enantiomer, with IC values in the low nanomolar range. Extensive equilibrium and kinetic studies suggest that HOE 166 exerts its Ca-antagonistic effect by binding to a Ca-channel-associated drug receptor which is distinct from the 1,4-dihydropyridine, phenylalkylamine or benzothiazepine-selective domain. This HOE 166-selective site is, however, allosterically linked to the other sites of the Ca antagonist receptor complex. We conclude that HOE 166 is a novel calcium antagonist. [ABSTRACT FROM AUTHOR]

Objective: The aim was to characterise the new compound HOE642 as a selective and cardioprotective Na+/H+ exchange inhibitor in various models. Methods: The effect of HOE642 was tested in the osmotically activated Na+/H+ exchange of rabbit erythrocytes and in propionate induced swelling of human thrombocytes. Recovery of pH after an NH4Cl prepulse and effects on other ion transport systems by patch clamp technique were investigated in rat cardiomyocytes, NHE subtype specifity of the compound was determined by 22Na+ uptake inhibition in a fibroblast cell line separately expressing subtype isoforms 1–3. Protective effects of HOE642 in cardiac ischaemia and reperfusion by ligation of coronary artery were investigated in isolated working rat hearts and in anaesthetised rats. Results: HOE642 concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets induced by intracellular acidification, and delayed pH recovery in rat cardiomyocytes. In the isolated working rat heart subjected to ischaemia and reperfusion HOE642 dose dependently reduced the the incidence and the duration of reperfusion arrhythmias. It also reduced the the release of lactate dehydrogenase and creatine kinase, and preserved the tissue content of glycogen, ATP, and creatine phosphate. In anaesthetised rats undergoing coronary artery ligation intravenous and oral pretreatment with HOE642 caused a dose dependent reduction or a complete prevention of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation. The compound was well tolerated and neutral to circulatory variables. Other cardiovascular agents tested in this model were not, or were only partly, effective at doses showing marked cardiodepressive effects. Conclusions: HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprotective and antiarrhythmic effects in ischaemic and reperfused hearts. Further development of well tolerated compounds like HOE642 could lead to a new therapeutic approach in clinical indications related to cardiac ischaemia and reperfusion. [ABSTRACT FROM PUBLISHER]