Pieter A. van Zwieten

Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document.

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit

Postsynaptic α1- and α2-adrenoceptors in the circulatory system of the pithed rat: Selective stimulation of the α2-type by B-HT 933

The antagonism by yohimbine (1 mg/kg, i.v.) of vasopressor responses in pithed rats was most pronounced towards B-HT 933 (dose ratio 18.3) and moderate towards clonidine (dose ratio 3.7) and especially L-phenylephrine (dose ratio 2.5). Prazosin (0.1 mg/kg, i.v.) had no effect on the pressor responses to B-HT 933, moderately affected those to clonidine (dose ratio 3.9), but strongly diminished those to L-phenylephrine (dose ratio 53). Phentolamine (1 mg/kg, i.v.) was devoid of a differential antagonism. The results obtained suggest a subclassification of postsynaptic alpha-adrenoceptors into alpha 1- and alpha 2-subtypes mediating pressor effects. B-HT 933 is a selective agonist and yohimbine an antagonist of postsynaptic alpha 2-adrenoceptors. L-Phenylephrine preferably stimulates and prazosin preferentially occupies the alpha 1-adrenoceptors. Clonidine is a potent agonist of both types and phentolamine behaves as a non-selective antagonist.

Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document

Reappraisal of European guid elines on hypertension management: a European Society of Hypertension Task Force document Giuseppe Mancia, Stephane Laurent, Enrico Agabiti-Rosei, Ettore Ambrosioni, Michel Burnier, Mark J. Caulfield, Renata Cifkova, Denis Clement, Antonio Coca, Anna Dominiczak, Serap Erdine, Robert Fagard, Csaba Farsang, Guido Grassi, Hermann Haller, Anthony Heagerty, Sverre E. Kjeldsen, Wolfgang Kiowski, Jean Michel Mallion, Athanasios Manolis, Krzysztof Narkiewicz, Peter Nilsson, Michael H. Olsen, Karl Heinz Rahn, Josep Redon, Jose Rodicio, Luis Ruilope, Roland E. Schmieder, Harry A.J. Struijker-Boudier, Pieter A. van Zwieten, Margus Viigimaa and Alberto Zanchetti

VASCULAR SMOOTH-MUSCLE CONTRACTION INITIATED BY POSTSYNAPTIC ALPHA-2-ADRENOCEPTOR ACTIVATION IS INDUCED BY AN INFLUX OF EXTRACELLULAR CALCIUM

Vasoconstriction in pithed, normotensive rats elicited via stimulation of postsynaptic alpha 2-adrenoceptors by B-HT 920 was antagonized by EDTA and the calcium antagonists nifedipine, D 600 and verapamil, whereas pressor responses to the alpha 1-agonist methoxamine were unaffected. This indicates that vasoconstriction in vivo initiated via postsynaptic alpha 2-adrenoceptors requires an influx of extracellular calcium. Thus, the antihypertensive effect of calcium antagonists may be based upon a diminution of vascular tone maintained by postsynaptic alpha 2-adrenoceptors.

A lipophilic, selective α1 -adrenoceptor agonist: 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587)

Abstract A new compound (St 587) is described, which is a selective α 1 -adrenoceptor stimulating agent with lipophilic properties. This combination of characteristics is novel, since all α 1 -adrenoceptor agonists developed so far are hydrophilic. The α-adrenergic effects of 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), a derivative of clonidine, were examined in several animal models. St 587 (1–10,000 μg/kg, i.v.) induced vasoconstriction in pithed, normotensive rats. This peripheral pressor activity was strongly antagonized by prazosin (0.1 mg/kg), but not affected by yohimbine (1 mg/kg). In intact, pentobarbitone-anaesthetized normotensive rats, St 587 (1–3,000 μg/kg, i.v.) evoked transient pressor responses, but a secondary fall in blood pressure and cardiac frequency was not observed. In pitched rats, St 587 (1–1,000 μg/kg) failed to modify the increase in heart rate produced by electrical stimulation of the cardioaccelerator sympathetic nerve fibres. St 587 (300 and 1,000 μg/kg) did not display central hypotensive activity, when injected into the left vertebral artery of anaesthetized cats. In addition, no hypotensive effect was observed when St 587 was administered i.v. to anaesthetized normotensive rats and cats. In mice, St 587 (10–10,000 μg/kg, i.p.) lacked sedative properties, since it did not prolong the hexobarbitone (75 mg/kg, i.p.)-induced loss of the righting reflex. The overall lipophilicity (log P′) of St 587 in the octanol/buffer (pH=7.4) reference system at 37°C amounted to 1.54. The experimental data suggest that St 587 is a lipophillic compound with selective α 1 - agonistic activity. The inability of St 587 to cause hypotension and sedation provides further evidence for the view that α 1 -adrenoceptors in the brain are not involved in the central hypotensive action and the sedation, caused by clonidine and related drugs. These effects are solely mediated by homogenous populations of α 2 -adrenoceptors.

Involvement of the β3 adrenoceptor in nebivolol-induced vasorelaxation in the rat aorta

Nebivolol is a highly selective &bgr;1 adrenoceptor blocker with additional vasodilating properties. Although it has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) and cGMP dependent, the receptor that mediates these actions remains controversial, and serotonergic as well as &bgr;-adrenergic pathways may be involved. Therefore, functional experiments investigating the receptor involved in nebivolol-induced vasorelaxation were performed in the rat aorta. Isolated aortic rings were exposed to cumulative concentrations of nebivolol. Nebivolol concentrations of 3 &mgr;mol/L and higher caused vasorelaxation, which was inhibited by the presence of the NO synthase inhibitor l-NNA (100 &mgr;mol/L), or by mechanical removal of the endothelium. Exposure of the vessel rings to the selective 5-HT1A antagonist NAN-190 (1 &mgr;mol/L) or the 5-HT1/2 antagonist methysergide (1 &mgr;mol/L) did not influence nebivolol-induced vasorelaxation. Similarly, the incubation with the &bgr;2-adrenoceptor antagonist butoxamine (50 &mgr;mol/L) did not prevent vasorelaxation. The selective &bgr;3-adrenoceptor antagonist S-(−)-cyanopindolol (1 &mgr;mol/L), however, significantly counteracted the nebivolol-induced vasorelaxation. Furthermore, exposure of the aortic rings to cumulative concentrations of the &bgr;3 selective adrenoceptor agonist BRL37344 caused, like nebivolol, NO-dependent vasorelaxation that was antagonized by S-(−)-cyanopindolol. The results suggest that nebivolol-induced NO-dependent vasorelaxation is, at least in part, caused by a &bgr;3-adrenoceptor agonistic effect.

Antioxidant activity of nebivolol in the rat aorta.

The &bgr;-blocker nebivolol is a racemic mixture of d- and l- enantiomers that displays negative inotropic as well as direct vasorelaxant activity. In addition, it has been proposed that nebivolol exerts endothelium-protective effects caused by its antioxidant properties. In the present study we investigated the effect of d-, l-, and d/l-nebivolol on reactive oxygen species (ROS)-induced endothelial damage and compared it with carvedilol and metoprolol. Isolated rat aortic rings were exposed to ROS by electrolysis of the organ bath medium. Before and after electrolysis, endothelial function was measured by preconstricting the vessels with phenylephrine followed by the addition of methacholine. Carvedilol and nebivolol protected against ROS-induced endothelial damage, whereas metoprolol did not. The protective effect of nebivolol proved not to be stereoselective. Furthermore, we attempted to determine whether nebivolol acts a scavenger itself or whether another mechanism is involved. By means of HPLC measurements it was shown that nebivolol concentrations were decreased after exposure to electrolysis-induced ROS, thus indicating that nebivolol is degraded by its reaction with ROS. Functional experiments, in the rat aorta, demonstrated that exposure of nebivolol to ROS also affects its vasodilator activity. In conclusion, the present study demonstrates that nebivolol alleviates ROS-induced impairment of endothelium-dependent vasorelaxation. This protective effect is very likely the result of a direct ROS-scavenging action by the nebivolol molecule itself.

Comparison of the muscarinic receptors in the coronary artery, cerebral artery and atrium of the pig

SummaryThe affinity of various muscarinic antagonists for the muscarinic receptors mediating contraction (induced by acetyl-\-methylcholine) of the isolated pig coronary and basilar artery was determined in order to compare the muscarinic receptor subtype involved in the contractile response of these arteries. In order to identify the muscarinic receptor subtype(s) involved, the affinity of the antagonists for the M2 receptor present in the pig atria was also investigated. The following muscarinic antagonists were used: atropine, pirenzepine, AF-DX 116 (11-2{{2-{(diethyl-amino)methyl} -1- piperidinyl}acetyl} - 5, 11- dihydro - 6H - pyrido {2, 3 - b} {, 4}benzodiazepin - 6 - one), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide), HHSiD (hexahydrosiladifenidol), methoctramine (N, N′- bis{6 - {(2 - methoxybenzyl)amino} hexyl} -1, 8 - octane - diamine tetrahydrochloride) and ipratropium.The order of affinity of the antagonists with respect to the muscarinic receptor in the coronary artery was clearly different from that for the muscarinic receptor in the basilar artery. The order of affinity established on the basilar artery closely resembled that for the M2 receptor in the atria.It is concluded that the muscarinic receptors on smooth muscle of the coronary and basilar arteries are not identical. The muscarinic receptor involved in the contraction of the basilar artery adheres to the M2 receptor subtype. A comparison of the selectivity of the antagonists suggests that the muscarinic receptor involved in the contraction of the coronary artery belongs to the M3 (like in exocrine glands) or M4 (as found in ileal smooth muscle) receptor subtype.

Endothelium-dependent, nitric oxide-mediated inhibition of angiotensin II-induced contractions in rabbit aorta

The role of endothelium in angiotensin II-induced contractions of the rabbit aorta and the mechanism involved were investigated. Destruction of the endothelium significantly shifted the concentration-response curve for angiotensin II to the left in a non-parallel manner and enhanced the maximal response. The EC50 and Emax values obtained from the rings with and without functional endothelium were 2.44 +/- 0.13 x 10(-9) M, 4.50 +/- 0.45 g and 1.21 +/- 0.14 x 10(-9) M (n = 8, P < 0.05), 5.73 +/- 0.55 g (n = 8, P < 0.05), respectively. Indomethacin (10(-5) M) did not significantly alter the concentration-dependent response to angiotensin II in the presence of endothelium. Three inhibitors of nitric oxide synthase (NG-monomethyl-L-arginine; NG-nitro-L-arginine, and NG-nitro-L-arginine methyl ester) at 10(-4) M caused a similar endothelium-dependent potentiation of angiotensin II-induced contractions in the aortic rings with, but not in those without endothelium. These effects were reversed by L-arginine (3 x 10(-3) M) but not by D-arginine (3 x 10(-3) M). Angiotensin II in a concentration range of 10(-16) to 10(-6) M did not relax the endothelium-intact rings precontracted with phenylephrine (2 x 10(-7) M). In the presence of endothelium, the angiotensin II subtype 2 receptor antagonist, 1-[(4-amino-3-methylphenyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro- 1H- imidazol[4,5-C]pyridine-6-carboxylic acid (PD 123177), caused neither relaxation of the rings precontracted with phenylephrine nor alteration of the concentration-response curve for angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha1- and alpha2-adrenoceptor mediated vasoconstriction in the forearm of normotensive and hypertensive subjects

Summary: α1- And α2-adrenoceptor mediated vasoconstriction were studied in 13 patients with essential hypertension and 13 age-matched normotensive controls. This was done by comparing the changes in forearm blood flow induced by intra-arterial infusion of the selective α1- and α2-adrenoceptor agonists methoxamine and B-HT 933, the catecholamines adrenaline and noradrenaline, and the selective α2-adrenoceptor antagonist yohimbine in both study groups. The catecholamines were infused in the presence of propranolol in order to prevent β-adrenergic effects. Forearm blood flow was measured by plethysmography. All agonists produced a dose-dependent vasoconstriction which was more pronounced in the hypertensive patients, although the difference was significant only for the infusion of the catecholamines and for the combined effects of methoxamine and B-HT 933. No preference was found for either the α1- or α2-adrenoceptor mediated vasoconstriction in the greater response of the hypertensive patients. These results could well be explained by structural vascular changes, secondary to the elevated blood pressure. No evidence was found for increased α2-adrenoceptor mediated basal vascular tone in patients with essential hypertension, since yohimbine tended to induce a greater vasodilatation in the normotensive subjects.