Effects of the Selective H¹and H²Histamine Receptor Antagonists Loratadine and Ranitidine on Autonomic Control of the Heart

After obtaining approval from the Queen's University Research Ethics Board and written informed consent, 16 healthy male and female volunteers, aged 21–27 yr, were studied in a randomized, double-blinded, placebo-controlled, crossover protocol. Subjects were excluded on the basis of history or presence of symptoms or physical signs of cardiovascular disease, diabetes, pregnancy and lactation, history of allergy or atopy, current or previous use of tobacco products, documented history of intolerance to either test drug, and intake of any compound affecting cardiovascular or autonomic nervous system function, or gastrointestinal motility.

Continuous, noninvasive blood pressure (BP) was monitored using the volume clamp method (Finapres^®2300; Ohmeda; Englewood, CO), and electrocardiogram using lead II (Tektronix 400; Tektronix, Beaverton, OR) for calculation of R-R intervals. Data were acquired during low-light conditions with subjects seated in a semireclined position. A metronome was used to pace respiratory frequency at each subject's resting level, with a minimum frequency of 12 breaths per minute. After a period of quiet rest, 12 min of stable baseline BP and electrocardiogram data were acquired, after which subjects ingested either 20 mg of the H¹receptor antagonist loratadine (Claritin^®; Schering Canada, Point-Claire, Quebec, Canada), 300 mg of the H²receptor antagonist ranitidine hydrochloride (Gen-Rantidine, Genpharm, Etobicoke, Ontario, Canada), or an inactive placebo. The three treatments were prepared by the hospital research pharmacist in identical gelatin capsules packed with lactose powder. Three hours after drug administration, 12 min of repeat BP and electrocardiogram data were obtained.

Subjects were randomized to receive each of the study drugs on 1 of 3 separate testing days. Testing days were separated by a minimum of 48 h to minimize drug carryover effects. Study drugs were identically packaged, and dosing schedules were determined using computer-generated tables. Dosing codes were prepared and sealed by the hospital research pharmacist until completion of the protocol. Subjects abstained from caffeine, alcohol, tobacco, and heavy physical activity for 12 h before each study session.

Analog electrocardiogram and BP signals were acquired on-line and digitized using a 12-bit analog–digital converter at a sampling rate of 1,000 Hz (DAS-16^®; Metrabyte, Taunton, MA). During digitization, systolic and diastolic BP, as well as the R-R interval, were measured on a beat-by-beat basis. Electrocardiogram data were analyzed using customized software (Richard Hughson, Ph.D., Department of Kinesiology, University of Waterloo, Ontario, Canada). Power spectral analysis of heart rate variability was used to determine indices of the relative sympathetic and parasympathetic influences on the heart. 15Briefly, a fast Fourier transformation was applied to a string of 512 consecutive R-R intervals (obtained from stationary data) to generate a power spectral curve (in units of milliseconds squared per hertz). By integrating the power in the low-frequency (0–0.15 Hz), high-frequency (0.15–0.50 Hz), and total frequency (0–0.50 Hz) ranges of the spectral curve, indices of parasympathetic (high frequency/total frequency ratio) and sympathetic (low frequency/high frequency ratio) modulation of cardiovascular control were calculated. 15 

Cardiac baroreflex sensitivity was calculated using the spontaneous baroreflex (sequence) method. 16–18During each recording period, sequences of spontaneously occurring increases or decreases in BP that were accompanied by concordant (i.e. , baroreflex-mediated) changes in R-R interval were identified. The paired R-R interval and BP sequences were plotted on an x–y curve, and a regression slope was determined for each. The mean regression slope for all sequences represents the spontaneous baroreflex sensitivity, an index of parasympathetically mediated beat-by-beat heart rate control. These values have been shown to reflect those obtained using pharmacologic baroreflex stimulation during resting conditions. 18 

After each data collection session during drug treatment, subjects were questioned regarding the presence of side effects, including sedation, dry mouth, headache, or rash.

Using variance data from previous studies utilizing the same methodology, 14sample size analysis indicated a need to study at least 12 subjects to detect a 30% change in spontaneous baroreflex sensitivity with a power of 80% and P < 0.05. Between-drug comparisons, using percent change from baseline for each treatment, were conducted using one-way repeated-measures analysis of variance for normally distributed data (heart rate, BP) and repeated measures on ranks for nonnormally distributed data (heart rate variability data). Where significant differences were found (P < 0.05), post hoc  analyses were performed using the Tukey method.

Two subjects were withdrawn after enrollment: one on the basis of frequent premature contractions at baseline, making analysis of heart rate variability impossible; the other experienced a pronounced vasovagal episode during a baseline measurement and withdrew. All subjects tolerated the study drugs well, and none reported any adverse drug effects.

Baseline heart rate and BP were similar on all test days and remained unchanged after drug administration (table 1). Baseline measures of autonomic control were also consistent between subjects and within subjects across testing days.

Figure 1depicts a complete set of experiments on a representative subject, showing a reduction in high-frequency power (> 0.15 Hz) only after administration of ranitidine. Overall, neither placebo nor loratadine significantly altered sympathetic or parasympathetic indices of heart rate variability (figs. 2A and B, respectively) or baroreflex sensitivity (fig. 2C). By contrast, raniti-dine decreased the parasympathetic indicator, high frequency/total frequency ratio, by 25% (0.52 ± 0.04 to 0.39 ± 0.04;P < 0.01;fig. 2B). Likewise, ranitidine reduced baroreflex sensitivity by 23.3% (23.3 ± 2.8 to 17.8 ± 2.1 ms/mmHg;P < 0.05;fig. 2C). The reduction in parasympathetic indices was accompanied by a concordant increase of 103.8% in the low frequency/high frequency ratio (1.04 ± 0.15 to 2.12 ± 0.55;P < 0.01;fig. 2A), indicating a strong shift toward sympathetic predominance during conditions of H²receptor blockade with ranitidine.

Physiologic regulation of cardiac and hemodynamic function depends on intact neurohumoral and autonomic mechanisms. Accordingly, diverse receptor types, including those for catecholamines, acetylcholine, and autocoids such as histamine and bradykinin, are present throughout cardiac structures. 1–4,6It is well recognized that the heart is a target organ in anaphylaxis, 7yet localization of histamine receptors to the myocardium, coronary vessels, and nodal tissue suggests that modulation of physiologic cardiac control, possibly by resting concentrations of circulating histamine, may also be a function of cardiac histamine receptors.

Results of this study, indicating significant changes in cardiac autonomic balance after administration of ranitidine in the absence of gross hemodynamic changes, underscores the insight that indices of autonomic control can contribute to a comprehensive understanding of cardiovascular regulation. To our knowledge, this study represents the first investigation of the role of histamine receptor subtypes in resting autonomic control of the cardiovascular system. The contribution of histamine to autonomic heart rate control was investigated by selective pharmacologic antagonism of H¹and H²receptors. To minimize the side effects common to first-generation H¹blockers, we investigated potential H¹-mediated effects with the second-generation H¹antagonist loratadine. Loratadine is a tricyclic antihistamine that displays selective peripheral H¹antagonism and lacks anticholinergic and central nervous system side effects characteristic of the first-generation H¹blockers. 19Potential H²receptor–mediated contributions to autonomic cardiovascular control were characterized using the specific H²receptor antagonist ranitidine. Clinically, H²receptor antagonists are used to inhibit H²-mediated gastric acid secretion in the treatment of peptic ulcers and dyspepsia; however, these antagonists have also been shown to bind H²receptors in the myocardium and coronary vasculature. 20–23H²receptors are also found in the central nervous system. Although ranitidine does cross the blood–brain barrier, central side effects are rare and generally confined to the elderly and patients with impaired hepatic or renal function. 24However, a central, rather than end-organ, effect of ranitidine on brainstem cardiovascular integration cannot be ruled out.

Both loratadine and ranitidine are available in an oral preparation, facilitating their comparison in a double-blinded protocol. Drugs were administered at twice the usual therapeutic dose to achieve near-complete receptor antagonism. The time between drug administration and repeat electrocardiogram and BP sampling was based on a time-to-peak plasma concentration of 1.0–1.5 h for loratadine 25and 2–3 h for ranitidine. 26Percent maximal plasma concentrations are therefore similar at 3 h, given half lives of 7.8–14.4 and 4.8 ± 0.3 h for loratadine and ranitidine, respectively. 25,26 

In addition to the presence of cardiac H¹and H²receptor subtypes, a cardiac H³histamine receptor subtype is also recognized. 5,6Although a number of H³-specific antagonists have been developed [thioperamide, clobenpropit, (R)-α-methylhistamine], these agents are used exclusively in basic research and have not yet been made available for clinical use. This study was therefore limited to investigation of potential H¹- and H²-mediated effects.

The results of this study suggest that basal autonomic control of the normal healthy heart is not influenced by cardiac H¹receptor stimulation, as H¹antagonism with loratadine did not alter indices of autonomic heart rate regulation. By contrast, the reduction in parasympathetic measures and shift toward sympathetic predominance after ranitidine suggests a basal level of H²receptor activation in the normal healthy heart that enhances parasympathetic cardiac activity, possibly by suppressing tonic sympathetic drive. 27The finding of a relative increase in cardiac sympathetic influence on heart rate after H²blockade supplements previous work that demonstrated a prolongation of norepinephrine-mediated cardiac stimulation during H²receptor blockade. 28In addition, a ranitidine-mediated positive inotropic effect has been shown in the absence of gross changes in heart rate or BP in young healthy males. 29 

Although we have demonstrated a shift toward cardiac sympathetic predominance after H²blockade with ranitidine, conflicting case report data allude to an enhancement of parasympathetic cardiac input, including bradydysrhythmias, 30atrioventricular block, 31or asystole 32after administration of ranitidine. The additional finding that these hemodynamic responses were reversed with the muscarinic antagonist atropine 30,31emphasizes their likely parasympathomimetic origin. These effects are in keeping with experimental evidence showing an inhibitory effect of H²blockers on the cholinesterase enzyme. 33,34However, such effects are not evident clinically in healthy people, and the majority of the aforementioned cases involved elderly patients presenting with concomitant cardiovascular, renal, or gastrointestinal disease and variably receiving multiple medications.

Two further explanations for the observed shift toward sympathetic predominance after administration of ranitidine have been considered. First, certain H²blockers (i.e. , burimamide) show partial agonist effects, yet these findings are not uniformly attributable to all H²antagonists. 35Moreover, partial agonist activity has not been reported for ranitidine, making this explanation for the cardiac sympathetic prevalence after administration of ranitidine unlikely. Second, H²antagonists demonstrate cross-reactivity at histamine H³receptors. 36Because H³receptors are inhibitory to presynaptic norepinephrine release from sympathetic fibers in the heart, 5,6,36blockade of these receptors by ranitidine could result in uninhibited sympathetic outflow. 28It has been speculated that basal H³-mediated contributions to cardiovascular control are minimal, increasing only during episodes of cardiac stress such as myocardial ischemia. 5,37Thus, H³receptor inhibition may become particularly relevant in patients at risk for myocardial ischemia, where cardiac norepinephrine concentrations are increased and the threshold for dysrhythmias is reduced. 37Additional work is required to fully elucidate the clinical implications of these findings.

Although the current study documented effects in healthy resting volunteers, the clinical implications of this work are particularly relevant in situations of heightened histamine release, either related to drug administration during anesthesia or, in the extreme, during anaphylactic reactions. The common practice of treatment with H²antagonists before anesthesia to increase gastric pH could potentially increase the risk of disrupted autonomic cardiac control and resultant cardiac dysrhythmias in the event of an allergic response 11or myocardial ischemia. 37On the other hand, combined H¹and H²receptor blockade have been shown to be more effective that H¹receptor antagonism alone in reducing histamine-related cardiorespiratory disturbances during anesthesia. 38,39Future studies are needed to extend the findings of this investigation to conditions of heightened plasma histamine concentrations, including documenting the effects of combined H¹and H²blockade on autonomic balance, in the absence of and during conditions of heightened histamine release.

In summary, our findings suggest that cardiac H¹receptor stimulation by circulating histamine does not alter autonomic control of heart rate in healthy resting subjects. By contrast, H²receptor antagonism with ranitidine led to a decrease in indices of parasympathetic modulation of heart rate, suggesting a possible role of histamine receptors in resting autonomic balance. The implications of these findings to the perioperative setting or during conditions of histamine release merit further study.

The authors thank Nicole Avery, M.Sc. (Queen's University, Kingston, Ontario, Canada), for assistance with data acquisition and analysis.