Peripherally applied candesartan inhibits central responses to angiotensin II in conscious rats.

In the brain, angiotensin II (Ang II) induces various effects such as blood pressure increase, the release of arginine vasopressin (AVP) and drinking behaviour. In the present study, we investigated the ability of the angiotensin II type-I (AT(1)) receptor antagonist, candesartan, administered peripherally, to block the central effects of Ang II. Experiments were performed in conscious rats instrumented with an intracerebroventricular (i.c.v.) cannula or a guide cannula into the paraventricular nucleus (PVN) and arterial and femoral catheters. Candesartan was administered intravenously (i.v.) at doses of 0.01, 0.1, 1 or 10 mg/kg. Controls received vehicle (0.05 N Na(2)CO(3)). The drinking response ( n=10-11 per group), the pressor response ( n=7-8) and the release of AVP into the circulation ( n=10-11) following i.c.v. Ang II (100 ng) were measured 0.5, 2, 4 and 24 h following i.v. drug application. Candesartan inhibited the central responses to i.c.v. injected Ang II dose- and time-dependently. At the highest dose (10 mg/kg), the drinking and pressor responses and the release of AVP in response to i.c.v. Ang II were completely blocked at 4 h and still markedly inhibited 24 h after the antagonist application (by 85%, 48% and 86%, respectively). The lowest dose of the antagonist was without effect. In a further experiment, the release of AVP induced by microinjection of Ang II (100 ng) into the PVN was determined before and 4 h after administration of vehicle or candesartan (1 mg/kg, i.v.). Candesartan completely blocked the AVP release into the circulation induced by Ang II microinjection into the PVN. Our results demonstrate that candesartan administered peripherally effectively inhibits responses mediated by AT(1) receptors localised in periventricular brain regions as well as inside the blood-brain-barrier.

Candesartan cilexetil: development and preclinical studies.

The nonpeptide AT(1) receptor antagonist candesartan is generated from the prodrug candesartan cilexetil during gastrointestinal absorption. In vitro studies have shown that candesartan acts as an insurmountable, tightly bound antagonist at the AT(1) receptor, producing a dose-dependent reduction in the maximal responses to angiotensin II (AII) and virtually an elimination of the AT(1) receptor-mediated effects of AII at high concentrations. The binding of candesartan to the AT(1) receptor is highly selective, and the drug dissociates slowly from the receptor. Candesartan cilexetil produces the expected changes in the parameters of the renin-angiotensin system. Plasma renin activity and plasma AII concentrations were increased and aldosterone levels decreased following drug application. As a consequence, stimulation of AT(2) receptor-mediated actions of AII, such as growth inhibition and vasodilation, may contribute to the overall effects of the AT(1) antagonist, since the AT(2) receptors are left unopposed by candesartan. The antihypertensive efficacy of candesartan cilexetil has been demonstrated in different animal models of hypertension including 2 kidney-1 clip and 1 kidney-1 clip hypertensive rats and spontaneously hypertensive rats (SHR). Candesartan cilexetil produced a slow onset, long-lasting antihypertensive action at a dose range of 0.1-10 mg/kg with no rebound effect upon drug withdrawal. A growing number of studies indicate that candesartan cilexetil can produce end organ protection in addition to lowering blood pressure. In preclinical studies, candesartan cilexetil caused prevention and regression of left ventricular hypertrophy and cardiac fibrosis, protected the heart against ischemia-reperfusion injury and reduced myocardial damage during myocarditis. In different animal models of renal dysfunction, candesartan cilexetil reduced proteinuria and albuminuria, inhibited histopathological renal changes and controlled the renal expression of TGF-beta1 and collagen types I and III. Finally, in stroke prone SHR, candesartan cilexetil markedly attenuated the incidence of stroke even at low doses, with minimal blood pressure lowering effects, and fully protected against stroke at higher doses.

Computerized analysis of the in vitro activation of the plasmatic clotting system.

We analyzed the kinetics of the clotting system by a chromogenic substrate method in plasma with isolated factor deficiency. The sigmoidal extinction curve obtained was mathematically described by an equation with four constants K(i) relating to the activity of clotting factors and to the concentration of fibrinogen. The analysis of constants obtained from dilution series of factor-deficient plasma revealed a distribution pattern differing from one factor to another both for the extrinsic and the intrinsic system. The observations indicated that isolated factor deficiency may be identified through the analysis of 2 of the 4 constants, K(1) being the time value of the point of inflection of the extinction curve and K(2) a measure for the slope of the curve at the point of inflection. The observation was confirmed by a reclassification through nearest-neighbor discriminant analysis of K(1) and K(2) which revealed a correct classification in the pathological range for all factor deficiencies investigated with the exception of factors VIII and IX, the distribution patterns of which were superposed within the limits of distribution.