W. Loots

Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo.

Ketoconazole inhibits in vitro (IC50:2.6 X 10(-5) M) the formation of 5-HETE and LTB4 by isolated, carrageenin-elicited rat peritoneal PMN leukocytes, challenged with the Ca2+-ionophore A23187 in the presence of [14C]-arachidonic acid ([14C]-AA). The relative potency of various compounds tested in this respect is NDGA greater than nafazatrom greater than phenidone greater than ketoconazole greater than BW 755C. In contrast to the other compounds studies, ketoconazole in vitro, up to 1 X 10(-4) M, has no effect on the fatty acid cyclo-oxygenase or the 12-lipoxygenase-mediated metabolism of [14C]-AA by isolated human platelets; however, it stimulates the 15-lipoxygenase activity in phenylhydrazine-induced rabbit reticulocytes. After oral administration (10-40 mg/kg, -2 hr), ketoconazole inhibits in a dose-dependent way, the leukotriene-mediated anaphylactic bronchoconstriction in guinea pigs. This study demonstrates that ketoconazole is a comparatively specific and orally active inhibitor of the 5-lipoxygenase activity bearing on the production of leukotrienes derived from arachidonic acid.

5-Hydroxytryptamine and arachidonic acid metabolites modulate extensive platelet activation induced by collagen in cats in vivo.

1 The pathways contributing to the platelet adhesion/aggregation reaction elicited by collagen microfibrils, administered to cats in vivo, were analysed. 2 The intra‐aortic infusion of collagen (100 μg kg−1 in 1 min) caused an extensive activation of platelets, as evidenced by the time‐dependent drop of free platelet numbers in whole blood, and the increases of 5‐hydroxyindoles (5‐HI), 5‐hydroxytryptamine (5‐HT) and thromboxane B2 (TXB2) levels in plasma, prepared from effluent venous blood sampled from the inferior caval vein. 3 5‐HT2 receptor blockade with ketanserin (0.63 mg kg−1 i.v., 10 min) and cyclo‐oxygenase inhibition with aspirin (10 mg kg−1 i.v., 10 min) slightly attenuated the peak reduction of free platelets in whole blood in response to collagen without affecting changes in plasma 5‐HI. Aspirin, but not ketanserin, reduced the collagen‐induced changes in plasma TXB2, prostaglandin E2 (PGE2) and 6K‐PGF1α. 4 Dual TXA2 synthetase inhibition/TXA2‐prostaglandin endoperoxide receptor antagonism with ridogrel (5 mg kg−1 i.v., 10 min) halved the drop in free platelets, reduced the release of platelet 5‐HI, inhibited the increase in plasma TXB2 and elevated that of 6K‐PGF1α and PGE2 in response to collagen. 5 Combined treatment with ketanserin and aspirin reduced the collagen‐induced drop of free platelets and the release of platelet 5‐HI to a similar extent as ridogrel alone; plasma prostanoids were affected as with aspirin alone. 6 Combined administration of ketanserin and ridogrel virtually eliminated the collagen‐induced platelet adhesion/aggregation response and release of 5‐HI; prostanoids were affected as with ridogrel alone. 7 The results indicate that the interplay between 5‐HT and arachidonic acid metabolites is causally involved in the platelet reaction to activation induced by collagen in cats in vivo.

A cardiac arrest model in rats for evaluating the antihypoxic action of flunarizine

Abstract Ventricular fibrillation was used to produce hypoxia in unanaesthetized rats. Flunarizine was given as hypoxia protectant in doses of 1 mg/kg i.v. just before fibrillation, which was induced with a small bipolar electrode catheter placed in the right ventricle. Aortic blood pressure (AoP), electrocardiogram (ECG) and the respiratory amplitude were recorded continuously. A significant lethality in the control group and the significantly enhanced recovery of ECG, AoP and respiration in the flunarizine groups make the model suitable to indicate antihypoxic actions of a drug.

Differential effects of nebivolol on adrenoceptors in the heart and in resistance arterioles in the rat. Quantitative intravital microscopic analysis

Abstract The effects of adrenoceptor antagonists on heart rate and on arteriolar reactions to epinephrine, terbutaline, vasopressin, angiotensin II or dopamine in the rat cremaster muscle were compared using ECG analysis and quantitative intravital microscopy. Phentolamine (0.5 mg/kg i.v.) significantly reduced the vasoconstriction of arterioles elicited by topically applied epinephrine (10−8 to 3.3 × 10−6 M) while propranolol (0.63 mg/kg i.v.) significantly attenuated the arteriolar vasodilatation elicited by topically applied terbutaline (10−6 to 10−4 M). Nebivolol (0.63 mg/kg i.v.) at a dose producing a reduction of resting heart rate equivalent to that caused by propranolol modified neither the epinephrine-induced constriction nor the terbutaline-induced vasodilatation of arterioles. The arteriolar vasoconstriction induced by topically applied vasopressin (9.3 × 10−9 M), angiotensin II (9.4 × 10−7 M) or dopamine (5.2 × 10−5 M) was not modified by nebivolol either. While propranolol reduced the tachycardia and hypotension induced by isoprenaline (0.025, 0.1 μg/kg i.v.), nebivolol reduced the cardiac rhythm increase but not the blood pressure drop in response to the catecholamine (0.025, 0.1, 0.4 μg/kg i.v.). The present intravital microscopic study in the rat demonstrated that, at a dose exerting cardiac β1-adrenoceptor blockade, nebivolol is devoid of significant activity on α1-, α2-, β-2-adrenoceptors and on receptors for vasopressin, angiotensin II or dopamine in resistance arterioles.

Differential Effects of Nebivolol on Adrenoceptors in the Heart and in Resistance Arterioles in the Rat

The effects of adrenoceptor antagonists on heart rate and on arteriolar reactions to epinephrine, terbutaline, vasopressin, angiotensin II or dopamine in the rat cremaster muscle were compared using ECG analysis and quantitative intravital microscopy. Phentolamine (0.5 mg/kg i.v.) significantly reduced the vasoconstriction of arterioles elicited by topically applied epinephrine (10(-8) to 3.3 x 10(-6) M) while propranolol (0.63 mg/kg i.v.) significantly attenuated the arteriolar vasodilatation elicited by topically applied terbutaline (10(-6) to 10(-4) M). Nebivolol (0.63 mg/kg i.v.) at a dose producing a reduction of resting heart rate equivalent to that caused by propranolol modified neither the epinephrine-induced constriction nor the terbutaline-induced vasodilatation of arterioles. The arteriolar vasoconstriction induced by topically applied vasopressin (9.3 x 10(-9) M), angiotensin II (9.4 x 10(-7) M) or dopamine (5.2 x 10(-5) M) was not modified by nebivolol either. While propranolol reduced the tachycardia and hypotension induced by isoprenaline (0.025, 0.1 microgram/kg i.v.), nebivolol reduced the cardiac rhythm increase but not the blood pressure drop in response to the catecholamine (0.025, 0.1, 0.4 micrograms/kg i.v.). The present intravital microscopic study in the rat demonstrated that, at a dose exerting cardiac beta 1-adrenoceptor blockade, nebivolol is devoid of significant activity on alpha 1-, alpha 2-, beta-2-adrenoceptors and on receptors for vasopressin, angiotensin II or dopamine in resistance arterioles.

Differential Effects of Nebivolol, Atenolol and Propranolol on Heart Rate and Bronchoconstrictor Responses to Histamine in the Guinea-Pig

Changes in heart rate and in bronchomotor reactions to histamine as parameters for beta 1- and beta 2-adrenergic receptor blockade, respectively, were analyzed in anaesthetized, ventilated guinea-pigs after administration of propranolol, atenolol and nebivolol. Propranolol (0.04 to 0.63 mg/kg i.v., -15 min) produces a significant reduction of the resting heart rate (80.4 +/- 4.25 to 74.9 +/- 4.17% of premedication values; n = 8; p less than 0.05) and, at the same dose levels, a significant enhancement of the bronchoconstrictor responses to histamine (3 micrograms/kg i.v.) (129.1 +/- 6.3 to 167.7 +/- 11.2% of premedication values; n = 8; p less than 0.05). Atenolol (0.02 to 1.25 mg/kg i.v., -15 min) significantly reduces heart rates from 0.04 mg/kg on (79.4 +/- 2.6 to 69.3 +/- 3.2% of premedication value at 1.25 mg/kg; n = 8; p less than 0.05) and significantly enhances the pulmonary reaction to histamine from 0.63 mg/kg on (139.1 +/- 6.3% to 137 +/- 11.6% of premedication values at 1.25 mg/kg; n = 8; p less than 0.05), yielding a dissociation factor of 16 between the lowest cardiac active dose and the pulmonary active one. Nebivolol (0.08 to 2.5 mg/kg i.v., -15 min) significantly reduces heart rates from 0.125 mg/kg on (78 +/- 3.2% to 65.4 +/- 3.9% of premedication value at 2.5 mg/kg; n = 8; p less than 0.05) without significantly increasing pulmonary reactivity (132.2 +/- 5.4% of premedication values at 2.5 mg/kg; n = 8; p greater than 0.05), thus yielding a dissociation factor greater than 20 between cardiac-pulmonary active doses. The study demonstrates a substantial dissociation between the cardiac (beta 1-adrenoceptors) and pulmonary (beta 2-adrenoceptors) active doses of nebivolol and atenolol in comparison with propranolol in vivo.