Schwieler J

Circulatory effects and pharmacology of clevidipine, a novel ultra short acting and vascular selective calcium antagonist, in hypertensive humans.

The pharmacokinetics of clevidipine, a potent short-acting vascular-selective calcium antagonist, was investigated during steady state and the postinfusion period in patients with mild to moderate hypertension. Furthermore, the dose-effect and blood concentration-effect relations and the tolerability of the drug were studied. Twenty patients were randomized to clevidipine intravenously at target dose rates of 0.18, 0.91, 2.74, and 5.48 microg/kg/min, respectively, or placebo. Each patient received in random order three infusion rates of clevidipine or placebo during three separate study days. Dose-dependent reduction in blood pressure and a modest increase in heart rate were noted. The extremely high clearance value and the small volume of distribution resulted in short half-lives of clevidipine, 2.2 and 16.8 min, respectively. The blood concentration and dose rate producing half the maximal effect (i.e. EC50 and ED50) were approximately 25 nM and 1.5 microg/kg/min, respectively. There was a linear relation between blood concentration and dose rate in the range studied. Clevidipine was safe and generally well tolerated; one patient was excluded because of adverse events at 2.74 microg/kg/min. In conclusion, clevidipine is a high-clearance calcium antagonist that may become a valuable contribution to the drugs used in conditions in which precise and rapid control of blood pressure is needed.

Influence of Angiotensin-converting Enzyme Inhibition on Sympathetic Neurotransmission: Possible Roles of Bradykinin and Prostaglandins

Effects of angiotensin-converting enzyme (ACE) inhibitors on sympathetic neurotransmission have generally been ascribed to their ability to block angiotensin II (Ang II) formation, but they also inhibit the degradation of vasoactive kinins, such as bradykinin. The latter may, in turn, lead to enhanced prostaglandin formation. Prostaglandins have been reported to influence sympathetic neurotransmission at different sites; much less is known about the influence of bradykinin due to the lack (until recently) of specific and effective bradykinin receptor antagonists, and difficulties with measurements of true plasma or tissue levels of bradykinin. Bradykinin may modulate sympathetic activity via a central stimulatory action and via activation of sensory input to the central nervous system; however, the importance of bradykinin for central effects of ACE inhibition remain to be established. At the sympathetic neuro-effector junction, results are more conflicting. Thus, bradykinin has been reported to enhance or reduce peripheral noradrenergic transmission or even lack any effect. Possible explanations for the differing results obtained include species and/or tissue differences in the responses to bradykinin. Also, the effects of bradykinin may be influenced by enhanced formation of prostaglandins and/or endothelium-derived relaxing factor (EDRF), which may contribute to the confusion. As most studies have been performed under in vitro conditions and with high doses of bradykinin, the physiological relevance of the data may be questioned. Hence, the importance of bradykinin-related mechanisms must be confirmed with physiologically sound experiments and by the use of specific bradykinin receptor antagonists, which will establish whether or not the endogenous levels of bradykinin under basal conditions or during ACE inhibition are of importance for interactions with sympathetic neurotransmission. In canine skeletal muscle in situ we have shown that reduced Ang II production, enhanced bradykinin accumulation, and augmented formation of prostaglandins all seem to contribute to the effect of ACE inhibition on sympathetic vascular neuro-effector mechanisms.

Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages.

Noradrenaline release evoked by a physiological irregular sympathetic discharge pattern is modulated by prejunctional α‐ and β‐adrenoceptors in vivo

1 Sympathetic nerve stimulation‐evoked overflow of endogenous noradrenaline (NA) and vasoconstriction were studied in canine blood‐perfused gracilis muscle in situ. Nerves were stimulated at an average frequency of 2 Hz (240 pulses, 120 s) with impulses derived from a recording of the normal irregular sympathetic discharge to human skeletal muscle, with regular bursts of impulses, or with the conventional continuous stimulus mode. 2 Variations in impulse activity were closely paralleled by changes in vascular tone. However, all stimulation patterns evoked the same integrated NA overflow and the same degree of vasoconstriction. 3 Blockade of β‐adrenoceptors by propranolol (0.5mgkg−1 i.v.) significantly reduced NA overflow and vasoconstriction evoked both by continuous and irregular nerve stimulation, by approximately 15–20%. 4 The enhancement of NA overflow following α‐adrenoceptor blockade by phenoxybenzamine (0.5mgkg−1 local i.a.) was significantly greater when evoked by continuous than by irregular nerve discharge (24 vs 14 fold). Effects were similar with irregular and regular burst activity. Half of this enhancement has been shown to be due to blockade of neuronal uptake of NA by phenoxybenzamine. Vasoconstrictor responses to all stimulation patterns were similarly reduced, but not abolished, by phenoxybenzamine. 5 The normal irregular sympathetic discharge seems to evoke a similar integrated NA release and equally pronounced vasoconstriction as stimulation with regular bursts or at constant frequency. We provide additional evidence for a physiological prejunctional α‐adrenoceptor‐mediated inhibition of NA release. This mechanism may be influenced by the discharge pattern. Also prejunctional β‐adrenoceptors seem to modulate NA release under physiological conditions. However, the α‐adrenoceptor‐mediated mechanism is quantitatively more important.

Cryothermal vs. radiofrequency ablation as atrial flutter therapy: a randomized comparison.

AIMS Radiofrequency (RF) ablation of the cavotricuspid isthmus (CTI) is an effective treatment for atrial flutter (AFL). However, RF may injure cardiac structures such as the atrio-ventricular node or the right coronary artery and is usually painful. This prospective, randomized study compares cryoablation (Cryo) with RF ablation regarding efficacy, safety, and perceived pain. METHODS AND RESULTS One-hundred and fifty-three patients (78 Cryo; 75 RF) with CTI-dependent AFL--median age 65 years (range 34-82), 140 men (91%)--were randomized to Cryo or RF. Primary endpoint was demonstration of long-term efficacy defined as no symptomatic recurrence of AFL at the 6-month follow-up. Radiofrequency ablation was performed with a 3.5 mm open-irrigated-tip catheter and Cryo with a 9 F, 8 mm tip catheter. Ablation endpoint was bidirectional CTI block. Pain was evaluated with a visual analogue scale (VAS; 0-10). The acute success rate was 92% for Cryo and 95% for RF (P = 0.58). Procedural time was longer in the Cryo group (152 ± 54 min) than the RF group (116 ± 41 min) (P < 0.001). Cryoablation was considerably less painful compared with RF (mean VAS-Cryo 0.7 ± 1.2 vs. VAS-RF 4.6 ± 2.0; P < 0.001). Success rate at 6-month follow-up was 93% (73 of 78) for Cryo and 97% (73 of 75) for RF (P = 0.86). No major adverse events occurred in any group. CONCLUSION Cryoablation of isthmus-dependent AFL is not inferior to RF but with significantly less procedure-related pain.

D-myo-inositol-1,2,6-triphosphate (PP56) antagonizes nonadrenergic sympathetic vasoconstriction: possible involvement of neuropeptide Y.

The possibility that D-myo-inositol-1,2,6-triphosphate (PP56), which has shown some specificity for antagonism of neuropeptide Y (NPY) in vitro, may antagonize responses to sympathetic nerve stimulation was investigated in canine blood-perfused gracilis muscle in situ after pretreatment with irreversible α-adrenocep-tor blockade by phenoxybenzamine and β-adrenoceptor blockade by propranolol. Sympathetic nerve stimulation (10 Hz, 2 min) increased muscle perfusion pressure and evoked overflow of norepinephrine (NE) from the tissue. PP56 at 50 and 500 μM (calculated local arterial plasma concentrations) did not influence NE overflow but attenuated the late phase of the vasoconstrictor response to nerve stimulation and reduced the increase in perfusion pressure evoked by exogenous NPY. PP56 also induced vasodilatation per se, but had no effect on the vascular response to exogenous angiotensin II (AH) or the remaining vasoconstrictor response to exogenous NE. PP56 antagonizes late components in the nonadrenergic sympathetic vasoconstriction and vasoconstriction evoked by exogenous NPY, without influencing transmitter release. Because previous results with this and other models propose a role for NPY in mediating nonadrenergic vasoconstriction, we suggest that PP56 may antagonize effects of neuronally released NPY at the postjunctional level.

Influence of the renin-angiotensin system on sympathetic neurotransmission in canine skeletal muscle in vivo

SummaryThe physiological importance of interactions between angiotensin II and sympathetic neurotransmission was studied in an in vivo model with constant flow blood perfused gracilis muscle in situ in dogs pretreated with desipramine and atropine. Sympathetic nerve stimulation- (2 and 8 Hz, 480 pulses) evoked overflow of endogenous noradrenaline and vasoconstriction, and vasoconstrictor responses to exogenous noradrenaline (0.5 nmol, locally i. a.) were evaluated.Angiotensin converting enzyme inhibition by benazeprilat (10 mg i. v.; n = 8) reduced arterial angiotensin II levels from 26 ± 8 to 2 +- 1 pM and reduced mean arterial and basal muscle perfusion pressures. Subsequent resubstitution of angiotensin II (3, 30 and 90 ng kg−1 min−1 i.v.) elevated arterial angiotensin II dose-dependently (to 67 ± 14, 622 ± 63 and 1940 ± 251 pM, respectively), as well as mean arterial and muscle perfusion pressures. Nerve stimulation-evoked noradrenaline overflow was unchanged following benazeprilat (−4 ± 4 and + 1 ± 8% at 2 and 8 Hz, respectively) and during subsequent infusions of angiotensin II. Vasoconstrictor responses to nerve stimulation and exogenous noradrenaline were also uninfluenced by these treatments. Thus, angiotensin II did not enhance sympathetic neurotransmission at the postjunctional level.Another group of animals was pretreated with noncompetitive α-adrenoceptor blockade locally by phenoxybenzamine and benextramine (0.5 mg kg−1 i. a. of each; n = 7), which abolished vasoconstrictor responses to nerve stimulation. The effects of benazeprilat and subsequent angiotensin II infusions (3 and 30 ng kg−1 min−1 i.v.) on circulating angiotensin II levels, mean arterial and muscle perfusion pressures were similar in this group. Following α-adrenoceptor blockade, however, inhibition of angiotensin converting enzyme reduced sympathetic nerve stimulation-evoked noradrenaline overflow by 23 ± 4 and 21 ± 5% at 2 and 8 Hz, respectively (P < 0.01 for both). Angiotensin II infusions failed to enhance evoked noradrenaline overflow (−5 ± 10 and −18 ± 10% at 2 Hz; +6 ± 13% and −3 ± 14% at 8 Hz) also under these conditions.It is concluded that circulating angiotensin II does not influence sympathetic vascular control in canine skeletal muscle even at very high levels in arterial plasma. Angiotensin converting enzyme inhibition reduces nerve stimulation-evoked noradrenaline overflow only in the presence of α-adrenoceptor blockade, suggesting that prejunctional α-adrenoceptors have an overriding importance over prejunctional angiotensin II-receptors in the modulation of noradrenaline release in this model. The effect of converting enzyme inhibition may be related to merely local changes in angiotensin II concentration or — unrelated to the renin-angiotensin system — to other consequences of the blockade of this unspecific enzyme.

Involvement of neuropeptide Y in sympathetic vascular control of skeletal muscle in vivo.

The possibility that neuropeptide Y, a vasoconstrictor peptide co-stored with noradrenaline in sympathetic nerves, participates in neurogenic vascular control was investigated in canine gracilis muscle in situ. Sympathetic nerve stimulation with recordings of the normal irregular sympathetic discharge to human skeletal muscle elicited frequency-dependent overflows of neuropeptide Y-like immunoreactivity and noradrenaline, and vasoconstriction. The overflow of neuropeptide Y-like immunoreactivity was more markedly enhanced with increasing frequency. Exogenous neuropeptide Y reduced nerve stimulation-evoked noradrenaline overflow, possibly through a prejunctional mechanism, and caused dose-dependent vasoconstriction. Nerve stimulation elicited significant vasoconstrictor responses following α- and β-adrenoceptor blockade with phenoxybenzamine and propranolol, which abolished the vasoconstriction to exogenous noradrenaline. Nerve stimulation-evoked overflows of neuropeptide Y-like immunoreactivity and noradrenaline were enhanced, consistent with prejunctional α-adrenoceptor-mediated inhibition of the release. Thus, neuropeptide Y is likely to be involved in the non-adrenergic component of vasoconstriction, and may participate in the physiological control of vascular tone at moderate to high impulse frequencies.

Inhibition of the renin-angiotensin system does not reduce platelet activity at rest or during stress in hypertension.

Objectives: We investigated the influence of angiotensin receptor blockade and angiotensin-converting enzyme inhibition on stress-induced platelet activation in hypertensive patients. Secondary aims were effects on inflammation, coagulation, and endothelial function. Methods: Following a 4-week placebo period, 25 hypertensive patients entered a double-blind, crossover study comparing enalapril (20 mg once daily) and losartan (100 mg once daily) treatment (each for 8 weeks). Patients were studied at rest and after a standardized exercise test. Results: Mean arterial pressure was reduced from 119 ± 2 to 104 ± 2 (enalapril) and 106 ± 2 (losartan) mmHg (both P <0.001). Plasma angiotensin II decreased from 2.4 ± 0.4 to 0.5 ± 0.1 pmol/l with enalapril, and increased to 7.2 ± 1.3 pmol/l with losartan (both P <0.001). Exercise-evoked platelet activation, as evidenced by increased numbers of P-selectin-positive platelets (P <0.01), elevated circulating platelet-platelet aggregates (P <0.01) and soluble P-selectin levels (P <0.001), and increased platelet responsiveness to adenosine diphosphate and thrombin (both P <0.05). Neither drug influenced these markers of platelet activation at rest or following exercise. Markers of inflammation (high-sensitivity C reactive protein, interleukin-6, tissue necrosis factor-&agr;), coagulation (tissue plasminogen activator antigen, prothrombin fragment F1+2), and endothelial function (von Willebrand factor, soluble vascular cellular adhesion molecule-1, and intercellular adhesion molecule-1) were also uninfluenced by treatment. Conclusion: Enalapril and losartan failed to reduce platelet activity both at rest and during exercise in hypertensive patients. Markers of inflammation, coagulation, and endothelial function were similarly unaffected. Inhibition of the renin–angiotensin system promotes its beneficial effects in hypertension through mechanisms other than platelet inhibition.

Nerve stimulation augments angiotensin II overflow from canine gracilis muscle in vivo.

The overflow of endogenous angiotensin-(1-8)octapeptide (angiotensin II) from blood-perfused canine gracilis muscle vasculature in situ was studied. A positive veno-arterial concentration difference for angiotensin II over the gracilis muscle was found, indicating a net generation of angiotensin II under basal conditions. Angiotensin II levels in the venous effluent were elevated during 2 Hz (4-min) nerve stimulation, suggesting enhanced local angiotensin II generation both in the presence and absence of alpha-adrenoceptor blockade. Thus, our results in this in vivo model demonstrate a local overflow of angiotensin II from the skeletal muscle vasculature which can be enhanced by nerve stimulation. Whether this overflow of angiotensin II is due to conversion of circulating angiotensin I to angiotensin II or local de novo synthesis of angiotensin II remains to be established.