Effects of celiprolol on cardiovascular responses to smoking in normotensive smokers.

Abstract

Dear Sir, Cigarette smoking is a major risk factor for cardiovascular disease and doubles the risk of myocardial infarction, sudden death, and stroke in patients with hypertension [1]. The mechanisms by which smoking might contribute to the development of cardiovascular complications include an acute increase in heart rate (HR), blood pressure (BP), cardiac contractility, and myocardial oxygen demand, primarily mediated by nicotine-induced activation of the sympathetic nervous system [2,3]. Previous studies have reported that beta-blocking agents attenuate the acute tachycardia induced by cigarette smoking but have little effect on the BP increase [4-9]. Furthermore, such drugs have been shown to enhance the vasoconstrictor effect of smoking on the systemic and coronary circulation, presumably due to the unopposed c~-adrenergic receptor stimulation [4-6, 10]. We recently evaluated the influence of acute oral administration of celiprolol, a new ~rselective antagonist with ~2agonist and mild a2-adrenergic blocking properties [11,12], on cardiovascular effects of cigarette smoking in normotensive smokers. Twenty-seven healthy smokers, 21 males and 6 females, aged 20-41 years, were studied. On the study morning the subjects presented having fasted from 21h00 on the preceding evening and having refrained from cigarette smoking and from drinking caffeine-containing beverages during this period. According to a double-blind, crossover design, each subject was asked to smoke four cigarettes during a 1-hour period, 120 minutes after oral administration of celiprolol 200 mg or placebo. BP and HR were measured immediately before and 10 minutes after each smoking episode. BP was measured using a standard mercury sphygmomanometer (I-V Korotkoff phase); HR was evaluated by pulse palpation. Doubleproduct (SBP x HR), which is considered a reliable index of oxygen consumption [13], was also calculated. The statistical analysis of the data was performed by analysis of variance and Student's t-test. The main results, expressed as mean values of SBP, DBP, HR, and double product before and after each smoking episode, are shown in Table 1. Under placebo, cigarette smoking induced an increase in SBP, HR, and double product, which was statistically significant after each smoking episode. DBP values were significantly affected only by the third and fourth cigarette smoked. After each smoking episode, the recovery towards baseline presmoking SBP and HR values became progressively slower, with a consequent progressive increase in the baseline values between the smoking episodes. These findings indicate that in heavy smokers the smoking-induced rise in BP values also persists in the intervals between smoking a cigarette and the following intervals, thus confirming previous reports [8,9,13]. The negative association between BP and cigarette smoking shown by epidemiological studies [14] could be explained by the fact that in such studies BP values were usually measured after a period of abstinence from smoking. Acute celiprolol administration reduced the baseline BP and HR mean values before the hour-long smoking period and significantly attenuated both the SBP and HR increase due to smoking, with a consequent reduction in the double product; the DBP increase was not significantly affected by the drug. These findings partially contrast with those reported with other beta blockers, particularly the non-~l-selective ones, which have been shown to attenuate the HR but not the BP increase due to smoking [4-9]. The effects of acute celiprolol administration on the cardiovascular responses to smoking are probably due to its peculiar pharmacological properties. Celiprolol combines ~l-antagonist and ~2-agonist activity and is provided with a nonadrenergic vasodilating action and a mild a2-adrenoceptor blocking influence [11,12]. In addition to all cardiac changes usually induced by beta blockade, these properties should lead to vasodilation. Probably due to such a vasodilating effect, celiprolol seems to counteract the pressor effect of cigarette smoking. Another point to be considered is the fact that some beta blockers are metabolized in the liver on first pass after absorption; as cigarette smoking stimulates first-pass metabolism, for a given dose the plasma concentration has been reported to reach only half that in nonsmokers, with consequent less effective BP control in smokers [15]. This problem may not occur with celiprolol, which is not metabolized in the liver. In conclusion, due to its capacity to attenuate the