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Objectives: We sought to identify soluble vasoconstrictor substances that are released during stent implantation into saphenous vein aortocoronary bypass grafts., Background: Atherosclerotic saphenous vein aortocoronary bypass grafts are particularly vulnerable to plaque rupture. Protection devices prevent particulate debris from being embolized. Additional soluble vasoconstrictor substances possibly also contribute to impaired microvascular perfusion., Methods: Peripheral venous blood (VB) and aspirate (AS) were obtained from 14 patients with a significant stenosis in a saphenous vein graft during stent implantation under protection with a distal balloon occlusion device. In five additional patients, arterial blood (AB) was also taken distal to the stented lesion before intervention. Vasomotor substances in VB, AB, and AS plasma were identified in a bioassay of rat mesenteric arteries with intact (+E) and denuded endothelium (-E). Vasoconstriction was normalized to that induced by potassium chloride depolarization (100%)., Results: Venous blood, AB, and AS plasma induced maximum vasoconstriction within six minutes. The AS plasma induced a vasoconstriction of 138 +/- 13% (-E) and 87 +/- 14% (+E); VB, of 70 +/- 14% (-E) and 23 +/- 4% (+E); and AB plasma obtained before intervention, of 49 +/- 9% (-E) and 36 +/- 8% (+E). The vasoconstrictor potency of AS plasma in endothelium-denuded vessels was related to the severity of anginal symptoms, angiographic stenosis severity, plaque volume, and plaque burden as determined by intravascular ultrasound. The AS plasma-induced vasoconstriction was largely attenuated by combined serotonin/5-hydroxytryptamine (5-HT)(2A/2C)- and 5-HT(1A/1B)-receptor blockade and eliminated by additional thromboxane A2 thromboxane-prostanoid (TP)-receptor blockade., Conclusions: Stent implantation releases, apart from and in addition to particulate debris, soluble vasoconstrictor substances that possibly contribute to impaired microvascular perfusion.

Objectives: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent., Background: In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling., Methods: We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed., Results: With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects., Conclusions: Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment.

Objectives: We sought to find out whether G-protein-coupled receptor kinase (GRK) activity is also increased in the aging human heart., Background: In the aging and failing human heart, cardiac beta-adrenoceptors (beta-AR) are desensitized. In heart failure (HF), an increase in cardiac GRK activity considerably contributes to this beta-AR desensitization., Methods: We assessed GRK activity (by in vitro rhodopsin phosphorylation) in the right atria (RA) from 16 children (mean age 9 +/- 2 years) and 17 elderly patients (mean age 67 +/- 2 years) without apparent HF and in the RA from four patients with end-stage HF.Cytosolic and membranous GRK activities in the RA from children were not significantly different from those in elderly patients; in contrast, cytosolic and membranous GRK activities in the RA from patients with end-stage HF were significantly increased., Conclusions: In contrast to the failing human heart, in the aging human heart, GRK activity is not increased. Thus, GRK activity appears to not play an important role in beta-AR desensitization in the aging human heart.

Objectives: The purpose of this study was to elucidate whether the neuronal noradrenaline reuptake transporter (uptake1) undergoes age-dependent regulation in the human heart., Background: Aging is associated with various alterations in cardiovascular function., Methods: We determined uptake1 density (by [3H]-nisoxetine binding to membranes) and activity (by accumulation of [3H]-noradrenaline into tissue slices) in the right atria (RA) of 42 patients (age range 3 months to 76 years) undergoing open-heart surgery without apparent heart failure. Moreover, the effects of 1 micromol/l desipramine on the noradrenaline-induced positive inotropic effect were assessed in the isolated, electrically driven RA trabeculae of these patients., Results: There was a significant negative correlation between RA uptake1 density and age; moreover, RA uptake1 activity was significantly reduced in elderly patients. Desipramine (1 micromol/l) significantly shifted noradrenaline concentration-response curves to the left; this shift was significantly more pronounced in younger patients than in older patients., Conclusions: With increasing age, human myocardial uptake1 activity decreases, possibly because of age-dependent downregulation of uptake1 density.