Vasorelaxant actions of enoximone, dobutamine, and the combination on human arterial coronary bypass grafts.

Enoximone (a type III-selective phosphodiesterase inhibitor) and dobutamine (a beta-receptor agonist) are positive inotropic drugs frequently used in the postoperative management of coronary bypass surgery. The purpose of this study was to characterize their relaxant effects on the human internal mammary artery (IMA) and the gastroepiploic artery (GEA) and to test the hypothesis that their combination may have greater than additive relaxant effects. In organ baths, the relaxant effects of enoximone and dobutamine were tested on rings of IMA (n = 86) precontracted with U46619 (a thromboxane A2 mimetic), norepinephrine (NE), or KCl. The relaxant effects of dobutamine and enoximone also were tested on rings of GEA (n = 42) precontracted with U46619 and NE. The effect of the combination of enoximone and dobutamine were tested on rings of IMA (n = 24) precontracted with U46619 or NE. With respect to maximal relaxations induced by papaverine (10(-4) M), enoximone (< or =10(-3) M) caused full relaxations of IMA precontracted with NE, U46619, or KCI. Dobutamine (< or =10(-3) M) caused full relaxations of IMA precontracted with NE or KCI but only 46% (95% CI, 27-65) relaxation in the rings precontracted with U46619. Similar patterns of relaxation were observed in GEA rings, with dobutamine inducing partial relaxation in GEA precontracted with U46619. The pD2 values of enoximone and dobutamine were both significantly lower in segments precontracted with U46619. The in vitro threshold relaxant concentrations were in the upper limits or over the range of therapeutic plasma concentrations. The relaxant effect of the combination was significantly more important than the theoretic additive effect in IMA contracted with U46619 or NE. Enoximone and dobutamine are potent in vitro vasodilators but exert weak relaxant effects in IMA and GEA at concentrations in the therapeutic range. There is, however, a greater than additive vasorelaxant effect of the combination, suggesting that the vasorelaxant effect of the combination, in addition to the additive inotropic effect, may be beneficial to patients undergoing coronary bypass grafting.     

Critical analysis of the response to antihypertensive therapy. Report of 102 cases

One hundred and two patients with mild to moderate hypertension, non responding to a placebo therapy, were given an antihypertensive drug for a mean period of 6 weeks (range: 3-12 weeks). Their blood pressure (BP) was measured before and after active treatment by both a mercury manometer at the clinic and an ambulatory apparatus (Spacelabs 5200 or 90202). The clinic BP figures were poorly correlated with the 24 hour ambulatory BP levels, as well as the magnitude of decrease in clinic BP with the reduction in ambulatory BP. Twenty eight patients who were considered as "clinic responders" had in fact not significantly lowered their ambulatory DBP and, conversely, 16 patients were "clinic non responders" whereas they were "ambulatory responders". The patients were divided into 2 groups, according to White's and Morgan Roth's recommendations: group I (n = 61) with a percentage of pathological DBP readings (greater than 90 mmHg) during daytime as high as 50% or more, and group II (n = 41) with a percentage less than 50%. The correlations between the 2 methods of BP measurement were closer within the group I than within the group II and the rate of discrepancies between the "clinic" and "ambulatory responders" was lower. On the other hand, we identified the group II patients as being often "clinic responders" but rarely "ambulatory responders", whereas the inverse trend was observed in the group I. In conclusion: even in non placebo responding hypertensive patients the clinic BP measurement might be not sufficient for proper evaluation of an antihypertensive drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of cysteinyl leukotrienes in angiotensin II-induced contraction in isolated aortas from transgenic (mRen-2)27 rats

OBJECTIVES : We have previously reported that 5-lipoxygenase-derived products, and particularly the cysteinyl leukotrienes (CysLTs), were involved in angiotensin II (Ang II)-induced contractions in isolated aortas from spontaneously hypertensive rats. DESIGN : The aim of this study was to assess the role of CysLTs in the vascular response to Ang II in an Ang II-dependent model of hypertension, the (mRen-2)27 transgenic rats (TGs). METHODS : Intact aortic rings from TG and normotensive Sprague-Dawley rats (SDs) were suspended in organ chambers for isometric tension development in response to Ang II. In addition, the release of CysLTs in response to Ang II (0.3 micromol/l) was measured by enzyme immunoassay. RESULTS : In isolated aortas from TG rats, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 micromol/l) or the CysLT1 receptor antagonist (MK571, 1 micromol/l) significantly (P < 0.05) reduced Ang II-induced contractions by 52 and 42%, respectively. In addition, Ang II induced a 2.6-fold increase in CysLT release (pg/mg dry weight tissue: 58.3 +/- 17.9 (Ang II, n = 7) versus 22.5 +/- 5.9 (basal, n = 7) P < 0.05), which was inhibited by the AT1 receptor antagonist losartan (1 micromol/l). In contrast, in aortas from SD rats, pretreatment with AA861 or MK571 did not alter Ang II-induced contraction and CysLT production remained unchanged after exposure to Ang II. CONCLUSION : These data suggest that CysLTs are involved in the contractile responses to Ang II in isolated aortas from TG but not from SD rats.     

Limited treatment adaptation despite poor asthma control in asthma patients treated with inhaled corticosteroids

Objective: Current asthma guidelines recommend use of inhaled corticosteroids (ICS) in patients with persistent disease. This study was designed to investigate (1) the proportion of patients prescribed ICS-containing maintenance treatment who achieve asthma control, (2) determinants of control and (3) how physicians adapt treatment to the level of control. Methods: General practitioners (GPs) and chest physicians (CPs) in France recruited patients consulting for asthma and prescribed an ICS. Over a 2-year follow-up period, asthma symptoms in the previous 3 months and treatments prescribed were documented at each visit. Variables independently associated with asthma control were determined by multiple logistic regression. Results: Data were available for 924 patients recruited by GPs and 455 recruited by CPs. Asthma control was acceptable in only 24% of patients at inclusion, and in 33.6% at the last follow-up visit. Five factors were independently associated with asthma control: age (or time since diagnosis), gender, smoking status, allergic aetiology of asthma and treatment. Most patients (56.3%) were prescribed the same ICS dose regimen at the end of follow-up as at inclusion. The intensity of controller therapy had been increased in only 12.2% of patients unacceptably controlled at inclusion. Conclusions: Asthma was unacceptably controlled in most patients receiving ICS-containing maintenance treatment and remained so during follow-up. Despite this, treatment adaptations by GPs and CPs were very infrequent. This unsatisfactory situation may be improved by adopting a more dynamic approach to tailoring controller therapy to the needs of the patient.     

Effects of amifostine on perfused isolated rat heart and on acute doxorubicin-induced cardiotoxicity

Purpose: To determine the effects of amifostine on an isolated perfused rat-heart model and its protective activity with regard to cardiotoxic doxorubicin perfusion. Methods: Langendorff constant-pressure isolated rat-heart preparations were used to analyze the effects of the drugs during a 40-min period of perfusion after a 20-min stabilization interval. The first study was conducted with amifostine alone (controls and 10⁻⁶, 10⁻⁵, and 10⁻⁴ M amifostine; n=6 in each group). The second study was conducted with amifostine and doxorubicin (controls, 2.5 × 10⁻⁵ M doxorubicin, 2.5 × 10⁻⁵ M doxorubicin and 10⁻⁵ M amifostine, and 2.5 × 10⁻⁵ M doxorubicin and 10⁻⁴ M amifostine; n=4 in each group). Results: Amifostine had no significant effect on hemodynamic parameters at 10⁻⁶, 10⁻⁵, and 10⁻⁴ M concentrations. However, amifostine increased the coronary flow expressed as a percentage ± SEM of the baseline flow as follows: 82 ± 4% for controls, 95 ± 6% for 10⁻⁶ M amifostine, (P=0.13), 111 ± 4% for 10⁻⁵ M amifostine (P < 0.01), and 104 ± 3% for 10⁻⁶ M amifostine (P < 0.01). When we commenced an amifostine perfusion 20 min in advance of and then during a 40-min perfusion with doxorubicin, at a cardiotoxic concentration of 2.5 × 10⁻⁵ M the left ventricular pressures (LVDP, expressed as percentages ± SEM of the baseline LVDP before doxorubicin) were 55 ± 3% for the doxorubicin controls, 68 ± 2% for doxorubicin with 10⁻⁵ M amifostine (P=0.05), and 80 ± 3% for doxorubicin with 10⁻⁴ M amifostine (P < 0.01). Whether this protective effect might be related to the known free-radical-scavenging activity of amifostine remains to be determined. Conclusion: On a Langendorff-type model of rat heart, 10⁻⁵ and 10⁻⁴ M amifostine alone induced a coronary dilation and, when associated with a cardiotoxic concentration of 2.5 × 10⁻⁵ M doxorubicin, 10⁻⁵ and 10⁻⁴ M amifostine displayed a cardioprotective effect. Received: 9 March 1998 / Accepted: 6 July 1998