Effects of idarubicin and idarubicinol on rat coronary resistance and vasoconstrictor responsiveness of isolated aorta and mesentery.

It has been hypothesized that coronary vasoconstriction is involved in the cardiotoxic action of anthracyclines. The purpose of this study was to determine whether an increase in coronary resistance induced by idarubicin (IDA) or its primary circulating metabolite idarubicinol (IDOL) is correlated with a decrease in vascular sensitivity to vasoconstrictor agonists. Coronary vasoconstriction was studied in single-pass perfused rat hearts after a 10-min infusion of 0.5 mg IDA or IDOL. In the endothelium-intact rat thoracic aorta and mesentery we measured the inhibition of phenylephrine (PE)- and KCl-induced contraction in the presence of IDA and IDOL, respectively. The increase in coronary vascular resistance evoked by IDOL (121%) exceeded that of IDA (75%). IDA (10-100 micromol/l) concentration-dependently diminished vascular sensitivity to PE and KCl due to a reduction in maximal contractile response (Emax), i.e. the antagonism by IDA of PE- or KCl-induced vasoconstriction was non-competitive, indicating a post-receptor cellular mechanism. These reductions of PE or KCl efficacy elicited by IDOL were significantly larger than those elicited by the corresponding doses of IDA. The decrease in efficacy of PE in the presence of IDA and IDOL was characterized by IC50 estimates of 44.3 and 30.7 mumol/l, respectively. With a 10-fold lower IC50, IDA inhibited the reactivity of small mesenteric arteries to noradrenaline with 10-fold higher potency. The correlation between the increase in coronary resistance and the decrease in vasoconstrictor responsiveness may suggest that these anthracyclines act through a common cellular mechanism.

The indirect negative inotropic effect of carbachol in beta1-adrenoceptor antagonist-treated human right atria.

To find out whether indirect negative inotropic effects of carbachol (i.e. decreases in force of contraction that had been stimulated by cyclic AMP-increasing agents) might differ dependent on the agonist employed to increase contractile force in isolated human right atrium, we studied effects of carbachol on atria prestimulated with noradrenaline, terbutaline, histamine and serotonin. All four agonists increased right atrial adenylyl cyclase activity and contractile force, whereby increases for terbutaline, histamine and serotonin, but not for noradrenaline, were significantly larger in right atria from beta(1)-adrenoceptor antagonist-treated vs. non-beta(1)-adrenoceptor antagonist-treated patients. Carbachol (10(-8)-10(-3) M) concentration-dependently decreased agonist-stimulated contractile force: maximum decrease was not significantly different within the four agonists. pD(2) values for carbachol, however, were higher in atria from non-beta(1)-adrenoceptor antagonist-treated vs. beta(1)-adrenoceptor antagonist-treated patients.We conclude that, in isolated human right atria, carbachol-induced indirect negative inotropic effect is not dependent from the agonist employed to increase (via cyclic AMP accumulation) contractile force. However, in atria from beta(1)-adrenoceptor antagonist-treated patients, carbachol-induced indirect negative inotropic effect is attenuated.

Age-dependent changes of cardiac neuronal noradrenaline reuptake transporter (uptake1) in the 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.

Noradrenaline-induced contraction of human saphenous vein and human internal mammary artery: involvement of different alpha-adrenoceptor subtypes.

Although saphenous veins and internal mammary arteries are commonly used for coronary artery bypass grafting, only a very few comparative studies are available on alpha-adrenoceptor-mediated vasoconstriction in these vessels. Thus, we determined, in isolated rings from human saphenous vein and human internal mammary artery, contractile responses to noradrenaline (10(-8)-10(-4) M) in the absence and presence of the alpha-adrenoceptor antagonists yohimbine (alpha(2)-adrenoceptor antagonist, 10(-8)-10(-6) M), prazosin (alpha(1)-adrenoceptor antagonist, 10(-9)-10(-7) M), 5-methyl-urapidil (5-MU, alpha(1A)-adrenoceptor antagonist, 10(-8)-10(-6) M), BMY 7378 (alpha(1D)-adrenoceptor antagonist, 10(-7)-10(-6) M), and chloroethylclonidine (CEC, irreversible alpha(1B)-adrenoceptor antagonist, 3x10(-5) M for 30 min). All experiments were carried out in the presence of 10(-7) M propranolol and 10(-5) M cocaine. In both vessel types noradrenaline evoked concentration-dependent contractions. In saphenous veins yohimbine was a potent antagonist (pA(2)-value 8.32) while prazosin, 5-MU and BMY exhibited only marginal antagonistic effects. CEC, however, significantly decreased noradrenaline-induced contractions. In contrast, in internal mammary arteries prazosin (pA(2)-value 9.65) and 5-MU (pK(B)-values 7.2-7.5) were potent antagonists, while yohimbine and BMY exhibited only weak antagonistic effects. CEC, however, significantly decreased noradrenaline-induced contractions. We conclude that in saphenous vein the contractile response to noradrenaline is mediated predominantly by alpha(2)-adrenoceptors, while in internal mammary artery it is mediated (to a major part) by alpha(1B)- and (to a minor part) by alpha(1A)-adrenoceptors.

Changes in alpha(1)-adrenergic vascular reactivity in monocrotaline-treated rats.

In rats, injection of monocrotaline (MCT) causes pulmonary hypertension that leads to right ventricular failure. The aim of the present study was to characterize the responses of various vessels (the pulmonary artery, the thoracic aorta and small mesenteric arteries) to noradrenaline (NA; 10(-10)-10(-5) M) and carbachol (10 microM) in MCT-treated rats. For this purpose 6-week-old male Wistar rats ( n=13) were treated with 60 mg/kg MCT i.p. After 4-6 weeks the rats were killed and the heart, lungs and vessels removed and compared with those from age-matched saline-treated control rats ( n=47). First, the alpha(1)-adrenoceptor subtype(s) involved in the vascular NA-responses were characterized in normal rats using the alpha(1)-adrenoceptor subtype-selective antagonists 5-methylurapidil (5-MU; competitive alpha(1A)-adrenoceptor antagonist; 10(-8)-10(-6) M), BMY 7378 (competitive alpha(1D)-adrenoceptor antagonist; 10(-7)-10(-6) M) and chloroethylclonidine (CEC; irreversible alpha(1B)-adrenoceptor antagonist; 30 microM). In the pulmonary artery the pA(2) for BMY 7378 was 7.93, while that for 5-MU could not be calculated. CEC suppressed the NA-induced contraction significantly. In the thoracic aorta, the pA(2) for BMY 7378 was 8.06, while 5-MU was less effective (pA(2) 7.31). CEC again suppressed the NA-induced contraction significantly. In mesenteric arteries, CEC was ineffective whereas 5-MU induced a significant, rightwards shift of the concentration/response curve for NA (pA(2) 8.05). BMY 7378 had a lower pA(2) (6.6). MCT-treated rats developed an increased right ventricular pressure, obliteration of pulmonary vessels and inflammatory lung infiltration. In the pulmonary artery, but not in the thoracic aorta or mesenteric artery of MCT-treated rats NA-induced contraction was attenuated. In addition, carbachol-induced relaxation was reduced in the pulmonary and mesenteric arteries. In conclusion, NA-induced contraction is mediated predominantly by alpha(1A)-adrenoceptors in small mesenteric arteries, by alpha(1D)-adrenoceptors in the thoracic aorta (with a contribution from alpha(1A)- and alpha(1B)-adrenoceptors) and by alpha(1D)- and alpha(1B)-adrenoceptors in pulmonary arteries. MCT leads to reduced NA-responsiveness exclusively in the pulmonary artery that does not, however, account for the development of pulmonary hypertension, and to a more generalized endothelial dysfunction which may contribute to the pathogenesis of pulmonary hypertension in this model.