Dose-related Decreases In Heart Rate Research Articles

Analgesic and sympatholytic effects of low-dose intrathecal clonidine compared with bupivacaine: a dose–response study in female volunteers

BackgroundA wide range of doses has been suggested for intrathecal clonidine, but no dose-ranging study has examined analgesic effects below 100 µg. The primary aim of this volunteer study was to assess the dose vs analgesic effect relationship for doses of intrathecal clonidine below 100 µg. MethodsAfter IRB approval and signed informed consent, 11 healthy female volunteers participated in this randomized, double-blinded, cross-over study using a dose-ranging sparse-sampling technique. Participants received intrathecal clonidine (doses 0–100 µg; n=10) and intrathecal bupivacaine (doses 0–8.8 mg; n=9) on separate study days. At baseline, 30, and 60 min from drug administration, experimental heat pain tolerance was assessed at both a lumbar and a cranial dermatome. Heat and cold perception thresholds were assessed at the same time intervals. Heart rate (HR), arterial pressure, and forearm–finger and toe-leg cutaneous temperature gradients (Tfinger–arm and Ttoe–leg) were used as measures of sympatholysis. ResultsBoth intrathecal clonidine and bupivacaine caused significant, dose-dependent analgesic effects at the leg but not the head. Significant analgesia to experimental heat pain was detected above 25 µg clonidine and 3 mg bupivacaine. Administration of bupivacaine but not clonidine resulted in a significant dose-related decrease in HR and Ttoe–leg; neither drug caused dose-related sympatholytic effects in the doses used. ConclusionsAfter 50 µg clonidine or 5 mg bupivacaine, the heat pain tolerance increased by ∼1°C, similar to the analgesic effect of 5 mg epidural morphine or 30 µg epidural fentanyl in previous studies using this experimental heat pain model. Our results provide additional data for rational dose selection of intrathecal clonidine.

Cardiovascular responses to hypocretin-1 in nucleus ambiguus of the ovariectomized female rat

Experiments were done to investigate the effect of chronic estrogen (E; 30 pg/ml plasma) treatment (15–25 days) in the ovariectomized (OVX) female Wistar rat on the cardiovascular responses to hypocretin-1 (hcrt-1) in the nucleus ambiguus (Amb). Microinjections of hcrt-1 (0.5–2.5 pmol) into the external formation of Amb (Ambe) in the urethane anaesthetized, E treated OVX animal or OVX only animal, elicited a dose-related decrease in heart rate (HR). On the other hand, hcrt-1 injections into Ambe did not elicit consistent changes in mean arterial pressure (MAP). The HR response was mediated by vagal excitation as ipsilateral vagotomy abolished the bardycardia response. The bradycardia responses were consistently of greater magnitude and longer duration in the OVX+E animals compared to the OVX only female animals. Finally, it was found that the reflex bradycardia to activation of arterial baroreceptors, as a result of increasing systemic arterial pressure with phenylephrine, was only significantly potentiated in the OVX+E animals. These data suggest that hcrt-1 in the Ambe of the female elicits an increase in vagal cardiomotor neuronal activity to the heart, and that the circulating level of E alters not only the sensitivity of Ambe neurons to hcrt-1 but also the sensitivity of these neurons during activation of baroreceptor afferent inputs.

Estrogen alters the bradycardia response to hypocretin-1 in the nucleus tractus solitarius of the ovariectomized female

Experiments were performed to investigate the effect of 17β-estradiol (E; 30 pg/ml plasma) treatment (15–25 days) in the ovariectomized (OVX) female Wistar rat on the cardiovascular responses to hypocretin-1 (hcrt-1) in the nucleus tractus solitarius (NTS). In an initial series of experiments, the distribution of hcrt-1-like immunoreactivity within the region of the NTS was mapped in both OVX only and OVX+E animals. Hcrt-1 immunoreactivity was found throughout the NTS region in both groups of females, predominantly within the caudal interstitial, commissural, medial and lateral subnuclei of the NTS. The relative density of hcrt-1 immunoreactivity in all NTS subnuclei was similar in both female groups. Microinjections of hcrt-1 (0.5–10 pmol) into the caudal lateral and medial subnuclei of the NTS complex of the α-chloralose of the urethane-anaesthetized E-treated OVX rat elicited a dose-related decrease in heart rate (HR). On the other hand, although a dose–response effect on arterial pressure was evident, significant arterial pressure responses were observed only at the higher dose of hcrt-1 (>2.5 pmol). In the OVX only female rat, microinjection of hcrt-1 into similar NTS sites elicited a bradycardia and depressor response only at the highest dose of hcrt-1, and these responses were significantly smaller in magnitude than those elicited in the OVX+E animal. In addition, in the OVX only animals, a few sites within the caudal commissural subnucleus of the NTS complex were found at which hcrt-1 elicited tachycardia and pressor responses. Finally, it was found that the reflex bradycardia to the activation of arterial baroreceptors as a result of increasing systemic arterial pressure with phenylephrine (2–4 μg/kg) was significantly potentiated in the OVX+E animals only. These data suggest that hcrt-1 in the NTS of the female activates a neuronal circuit that controls the circulation and that the circulating level of E alters the sensitivity of these cardiovascular circuits to hcrt-1.

Cardiac effects of hypocretin-1 in nucleus ambiguus.

Although recent studies have reported hypocretin 1 (hcrt-1)-like-immunoreactivity (ir) within the region of the nucleus ambiguus (Amb) in the caudal brain stem, the function of hcrt-1 in the Amb on cardiovascular function is not known. Three series of experiments were done in male Wistar rats to investigate the effects of microinjections of hcrt-1 into Amb on heart rate (HR), mean arterial pressure (MAP), and the arterial baroreceptor reflex. In the first series, a detailed mapping of the distribution of hcrt-1- and hcrt-1 receptor (hcrtR-1)-like-ir was obtained of the Amb region. Although hcrt-1-like- and hcrtR-1-like-ir were found throughout the rostrocaudal extent of the Amb and adjacent ventrolateral medullary reticular formation, most of the hcrtR-1-like-ir was observed in the area just ventral to the compact formation of Amb, in the region of the external formation of the nucleus (Ambe). In the second series, the Amb region that contained hcrt-1 and hcrtR-1-ir was explored for sites that elicited changes in HR and MAP in urethane and alpha-chloralose-anesthetized rats. Microinjections of hcrt-1 (0.5-2.5 pmol) into the Ambe elicited a dose-related decrease in HR, with little or no direct change in MAP. The small decreases in MAP were found to be secondary to the HR changes. The largest bradycardia responses were elicited from sites in the Ambe. Administration (iv) of the muscarinic receptor antagonist atropine methyl bromide or ipsilateral vagotomy abolished the HR response, indicating that the HR response was due to activation of vagal cardiomotor neurons. In the final series, microinjections of hcrt-1 into the Ambe significantly potentiated the reflex bradycardia elicited by activation of the baroreflex as a result of the increased MAP after the intravenous injection of phenylephrine. These data suggest that hcrt-1 in the Ambe activates neuronal systems that alter the excitability of central circuits that reflexly control the circulation through the activation of vagal preganglionic cardioinhibitory neurons.

Mibefradil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of hypertension and angina pectoris.

Mibefradil belongs to a new class of calcium antagonists, the tetralol derivatives. It selectively blocks T-type calcium channels in contrast to other calcium antagonists which block only L-type channels. Mibefradil relaxes coronary arteries without suppressing myocardial contractility and causes a dose-related decrease in heart rate. When given orally once daily to patients with hypertension mibefradil produces a dose-related decrease in blood pressure which is sustained for 24 hours and improves exercise performance in patients with stable angina pectoris. In patients with generally mild to moderate hypertension oral mibefradil was superior to nifedipine SR and diltiazem CD, tended to be more effective than nifedipine GITS and had similar efficacy to amlodipine. Mibefradil 50 to 100mg once daily also has antianginal and anti-ischaemic effects. The drug improves the duration of symptom-limited exercise and the time to onset of ischaemia, and reduces the frequency of anginal attacks and consumption of nitroglycerin. Its efficacy is similar to that of diltiazem and tends to be greater than that of amlodipine in patients with stable angina. Mibefradil is generally well tolerated and is associated with a lower incidence of leg oedema than amlodipine and nifedipine. Thus, mibefradil is a calcium antagonist with a predictable cardiovascular profile, which, on the basis of available clinical data, is an effective alternative to other drugs widely used in the treatment of hypertension and stable angina pectoris.

Antianginal and Anti-ischemic Effects of Mibefradil in the Treatment of Patients with Chronic Stable Angina Pectoris

Five placebo-controlled, double-blind, multicenter, parallel-design studies were performed to evaluate the antianginal and anti-ischemic characteristics of the novel T-channel-selective calcium antagonist, mibefradil, in the treatment of patients with chronic stable angina pectoris. Of the 5 studies, 2 were monotherapy dose-finding trials and 3 were conducted in patients receiving background antianginal therapy: either β blockers (2 studies) or long-acting nitrates (1 study). A total of 865 patients were randomized to 1 of 4 mibefradil dose groups (25, 50, 100, and 150 mg; n = 565) and placebo (n = 300). The antianginal and anti-ischemic effects of mibefradil were assessed across all 5 studies by evaluating exercise tolerance test variables, weekly number of anginal attacks and short-acting nitroglycerin consumption, and in both dose-finding studies, the number and total duration of silent ischemic episodes (48-hour Holter monitoring). A statistically significant increase in exercise duration was achieved in 3 of 5 studies with the 50-mg dose of mibefradil and in 3 of 3 studies with the 100-mg dose of the compound over the effects observed in the placebo groups. A significant delay in time to onset of ischemia during exercise was induced in all studies with the 50- and 100-mg doses of mibefradil. The 25-mg dose of mibefradil was not significantly better than placebo, and the effects of the 150-mg dose of the compound were similar to those observed with the 100-mg dose. Across all studies, a dose-related decrease was observed in the number of weekly anginal attacks and in weekly nitroglycerin consumption. Similarly, a significant dose-related decrease in the number and duration of silent ischemic episodes was observed during Holter monitoring for 48 hours in the 2 dose-finding studies. The antianginal and anti-ischemic effects were associated with a dose-related decrease in heart rate and double product both at rest and at exercise termination. Treatment with the 50- and 100-mg doses of mibefradil was found to be well tolerated and safe compared with placebo, a finding that held true for patients on chronic β-blocker or long-acting nitrate therapy. Taken together, these studies indicate that mibefradil is an effective and well-tolerated once-daily treatment for chronic stable angina pectoris at doses of 50 and 100 mg, which are the lowest and highest effective doses of the compound, respectively.

Isoflurane and halothane produce similar alterations in aortic distensibility and characteristic aortic impedance.

The effects of volatile anesthetics on arterial mechanical properties in vivo are incompletely understood. The present investigation tested the hypothesis that isoflurane and halothane cause differential actions on the mechanical characteristics of the aorta in barbiturate-anesthetized dogs instrumented for measurement of aortic blood pressure, blood flow, and diameter. Aortic distensibility and characteristic aortic impedance were calculated from aortic diameter measurements. Oscillatory (Wo) and mean (Wm) hydraulic power were determined from aortic pressure and blood flow waveforms. Hemodynamics and aortic pressure, blood flow, and diameter were recorded before, during, and after 0.5, 0.75, and 1.0 minimum alveolar anesthetic concentration (MAC) (end-tidal) isoflurane (n = 7), or halothane (n = 8). Isoflurane and halothane caused significant (P < 0.05) and dose-related decreases in heart rate, mean arterial pressure, peak and end-diastolic aortic diameters, and aortic distensibility (e.g., from 0.16% +/- 0.03% during control to 0.24% +/- 0.04% mm Hg during 1.0 MAC isoflurane). Characteristic aortic impedance remained unchanged by either drug. In contrast to the findings with isoflurane, halothane increased the ratio of Wo to Wm (from 6.7 +/- 1.1 during control to 11.3 +/- 3.1 x 10(-2) during 1.0 MAC), suggesting that this drug decreases left ventricular mechanical efficiency. The results indicate that isoflurane and halothane do not alter characteristic aortic impedance and produce similar increases in aortic distensibility concomitant with reductions in aortic pressure. These findings support the contention that volatile anesthetic-induced alterations in aortic mechanical properties do not contribute to the differential effects of these drugs on left ventricular afterload in vivo.

Cardiovascular effects of beta-carbolines in conscious rats.

The beta-carbolines have a high affinity for the benzodiazepine receptor, where they demonstrate actions opposite to those of the benzodiazepines and elicit anxiogenic effects. We tested the acute cardiovascular effects of beta-carbolines in conscious unrestrained rats. Intravenous infusion of ethyl-beta-carboline-3-carboxylate (BCCE) or methyl-beta-carboline-3-carboxylate (BCCM) caused dose-related decreases in heart rate. Pretreatment with RO 15-1788 (10.0 mg/kg, i.v.), a benzodiazepine receptor antagonist, or atropine (1.0 mg/kg, i.v.) prevented the bradycardia elicited by BCCE (3.0 mg/kg, i.v.). In contrast, tetrahydro-beta-carboline (THBC; 3.0 mg/kg, i.v.) increased both heart rate and blood pressure significantly as compared with controls. However, larger doses of THBC failed to elicit further increases in heart rate or blood pressure. These experiments indicate that in conscious unrestrained rats, beta-carbolines given acutely do not routinely elicit the cardiovascular changes normally associated with stress or anxiety. We next extended our observations to rats given the beta-carboline noreleagnine, 2 mg/kg, or vehicle twice daily intraperitoneally for 4 weeks. The rats were fed either a high salt (8%) or a low salt (0.9%) diet. At 4 weeks, rats given noreleagnine and high salt had higher tail cuff pressures (146 +/- 4 vs. 134 +/- 4 mmHg) than those given noreleagnine and low salt. However, with direct arterial measurement, these differences disappeared. These data suggest that beta-carbolines do not provide a useful model for investigating the effects of chronic stress on cardiovascular function in rats.

The Effects of the Stereoisomers of the α2-Adrenergic Agonist Medetomidine on Systemic and Coronary Hemodynamics in Conscious Dogs

The alpha 2-adrenergic agonist medetomidine produces systemic hemodynamic effects that are mediated by both peripheral and central nervous system actions. The current investigation was designed to characterize coronary and systemic hemodynamic effects of the D- and L-stereoisomers of medetomidine in conscious, chronically instrumented dogs with and without autonomic nervous system blockade. Dogs were instrumented for measurement of aortic pressure, coronary blood flow velocity, cardiac output, left ventricular pressure, rate of change in pressure (dP/dt), and subendocardial systolic shortening. Administration of the D-isomer of medetomidine (doses of 1.25, 2.5, and 5.0 micrograms/kg, each administered over 10 min, with 60 min between doses) significantly altered systemic hemodynamics, in a biphasic fashion. A decrease in respiratory rate without change in arterial blood gas tensions occurred. With the 5 micrograms/kg dose of D-medetomidine, an initial pressor response was followed by secondary, significant (P less than 0.05), and dose-related decreases in heart rate (74 +/- 3 to 57 +/- 4 beats per min), mean arterial pressure (109 +/- 2 to 100 +/- 3 mmHg) and the rate-pressure product (10.5 +/- 0.4 to 7.0 +/- 0.5 beats.min-1.mmHg.10(3] accompanied by a reduction in plasma concentrations of norepinephrine. No changes in left ventricular end diastolic pressure or coronary blood flow velocity occurred. In contrast to the D-isomer, the L-isomer (1.25, 2.5 and 5.0 micrograms/kg) produced no changes in hemodynamics or plasma concentrations of norepinephrine. In dogs pretreated with hexamethonium (20 mg/kg), propranolol (2 mg/kg), and atropine methylnitrate (3 mg/kg) to produce autonomic nervous system blockade, D-medetomidine also produced an initial pressor response, but no secondary reduction in heart rate or arterial pressure occurred. The results indicate that the D-isomer of medetomidine is stereospecific for alterations in hemodynamics: the active D-isomer produces decreases in heart rate, arterial pressure, and the rate-pressure product via diminished sympathetic and/or augmented parasympathetic tone. This conclusion is supported by the absence of these changes after pharmacologic blockade of the autonomic nervous system.

Purinergic receptors in the brainstem mediate hypotension and bradycardia.

Adenosine acts at many sites to modulate neuronal activity. The purpose of this study was to investigate a possible role for adenosine as a neuromodulator of brainstem cardiovascular control. Microinjections of adenosine (0-2.3 nmol) were made stereotaxically into various brainstem sites. Injection of adenosine into the nucleus tractus solitarii (NTS) produced dose-related decreases in heart rate and systolic and diastolic blood pressures. Maximal changes occurred 90 seconds after injection. Injection into the area postrema also produced decreased heart rate and systolic and diastolic blood pressures. No significant effect occurred following injection into the C1 area. Adenosine 5'-triphosphate and its analogue, beta, gamma-methylene adenosine 5'-triphosphate also produced dose-related and potent vasodepressor and bradycardia effects in the NTS. Injection of 1,3-dipropyl-8-p-sulfophenylxanthine (0.92 nmol), a potent adenosine receptor antagonist, produced no effect itself, but abolished for 45 minutes the actions of further injections of adenosine and adenosine 5'-triphosphate (but not L-glutamate) in both the NTS and area postrema. Thus, NTS and area postrema injections of adenosine decrease blood pressure and heart rate in anesthetized normotensive rats through adenosine receptors located in these areas. These findings support a role for endogenous adenosine as a central modulator in cardiovascular control.

Effect of the New Specific Bradycardic Agent AQ-A39 (Falipamil) on Coronary Collateral Blood Flow in Dogs

The effect of two doses (0.5 and 1.0 mg/kg i.v.) of a new specific bradycardic agent, AQ-A39 (5,6-dimethoxy-2-[3- [( alpha- (3,4,-dimethoxy)phenylethyl]methyl-amino)propyl]phthalimidine hydrochloride), on three indices of collateral function--retrograde pressure, retrograde flow, and tissue blood flow (radioactive microspheres)--was studied in anesthetized dogs following acute occlusion of the left anterior descending coronary artery. AQ-A39 produced a significant (p less than 0.05) dose-related decrease in heart rate without any other hemodynamic changes. Retrograde flow and subendocardial blood flow were significantly increased by the lower dose of AQ-A39, whereas retrograde pressure, retrograde flow, and midmyocardial and subendocardial flow were increased by the higher dose. Atrial pacing to the control heart rate eliminated the beneficial effects of AQ-A39 on collateral function. These results suggest that an increase in collateral perfusion may be one mechanism by which AQ-A39 alleviates myocardial ischemia.

Cardiovascular responses to catecholamines at 12 degrees C in the American bullfrog (Rana catesbeiana).

The effects of epinephrine, norepinephrine, phenylephrine, and isoproterenol on blood pressure and heart rate were studied in cannulated American bullfrogs, Rana catesbeiana. The bullfrogs were chronically cannulated with a T cannula in the right sciatic artery. In warm-acclimated (22 degrees C) bullfrogs, preinjection mean systemic arterial pressure (SAP) prior to experimental treatment was 13.1 +/- 0.7 mm Hg. Preinjection heart rate was 34.8 +/- 1.8 beats per minute. These parameters were lower in cold-acclimated (12 degrees C) bullfrogs. Cold-acclimated animals had mean SAP values of 8.2 +/- 0.3 mm Hg, and heart rate was 11.1 +/- 1.1 beats per minute. Epinephrine, norepinephrine, and phenylephrine increased blood pressure to an equivalent degree in warm- and cold-acclimated animals. Dose-related decreases in heart rate in response to these catecholamines were observed in warm- but not in cold-acclimated bullfrogs. Warm-acclimated animals were more responsive to isoproterenol from 0.03 micrograms/kg body weight (bw) to 10 micrograms/kg bw than were cold-acclimated animals. The response to isoproterenol was effectively blocked by propranolol (5 mg/kg bw) in both warm- and cold-acclimated animals. Propranolol alone decreased mean SAP in both warm- and cold-acclimated animals, suggesting blockade of endogenous sympathetic activity. Beta receptor response thus appears diminished, but not absent at 12 degrees C. However, the alpha receptors responsible for elevation of blood pressure equally responsive at 12 degrees and 22 degrees C.

Autonomic changes elicited by chemical stimulation of mediodorsal nucleus of the thalamus

Chronic indwelling cannulas were implanted in the mediodorsal nucleus (MD) of the thalamus in New Zealand albino rabbits. Heart rate (HR), blood pressure (BP), respiration and electromyographic activity (EMG) were recorded subsequent to the injection of saline, l-glutamate, or carbachol through the previously implanted cannulas. Dose related decreases in HR and increases in BP were obtained after administration of both l-glutamate and carbachol at doses in the micromolar range. Control injections through cannulas chronically implanted in the overlying hippocampus or adjacent ventricles resulted in dramatic HR and BP baseline changes in a parasympathetic direction (viz HR and BP decreases) suggesting that the effects obtained with MD placements were due to chemical stimulation of MD. Responses elicited from MD in the present experiment were similar, but not identical, to those produced by electrical stimulation of MD, suggesting that the latter effects were not due to stimulation of fibers of passage.

The cardiovascular effects of centrally administered 5-hydroxytryptamine in the conscious normotensive and hypertensive rat.

The cardiovascular effects of centrally administered 5-hydroxytryptamine (5-HT) have been analysed in conscious normotensive and hypertensive rats. In conscious normotensive rats, 5-HT, (1-30 micrograms) administered intracerebroventricularly (i.c.v.) produced profound and immediate dose-related decreases in heart rate and small increases in blood pressure. The initial pressor responses were followed by secondary secondary depressor responses at high doses of 5-HT. Similar effects were produced by 5-HT i.c.v. in conscious DOCA-salt and spontaneously hypertensive rats, although the magnitude of the pressor responses was substantially greater in hypertensive than normotensive rats. Pretreatment with either N-methylatropine or atenolol intra-arterially reduced the 5-HT-induced bradycardia in normotensive rats; the reduction was enhanced when both antagonists were given in combination. The 5-HT2 antagonist, cyproheptadine (10 micrograms i.c.v.) increased basal blood pressure and heart rate in normotensive rats. Subsequent administration of 5-HT i.c.v. produced biphasic effects on heart rate consisting of an initial tachycardia followed by a marked bradycardia. Methysergide (10 micrograms i.c.v.) pretreatment did not alter resting heart rate, but attenuated the 5-HT induced bradycardia. A higher dose of methysergide, (30 micrograms i.c.v.), decreased resting blood pressure and heart rate. This study has demonstrated, therefore, that the 5-HT induced bradycardia is produced by not only a centrally mediated decrease in sympathetic tone, but also an increase in vagal drive to the heart. The bradycardia is antagonised by centrally administered methysergide, but not by cyproheptadine, which suggests that it is probably mediated through a '5-HT1-like' receptor mechanism.

Role of medullary cholinoceptors in baroreflex bradycardia.

Cholinergic receptors present in three medullary nuclei namely, the nucleus tractus solitarii (NTS), nucleus ambiguous (AMB) and the dorsal motor nucleus of the vagus nerve (DMV) have been studied with regard to their role in regulation of heart rate (HR), blood pressure (BP) and baroreceptor reflex activation induced bradycardia in cats. Microinjection of carbachol into NTS was without effect while administration of carbachol or pilocarpine into AMB and DMV elicited dose related decrease in HR without affecting BP. These effects were completely antagonized by ethylbenztropine. Bilateral muscarinic cholinoceptor blockade of either AMB or DMV, with ethylbenztropine, produced a partial inhibition of the baroreflex bradycardia while intracisternal ethylbenztropine completely abolished this reflex response. Involvement of muscarinic cholinoceptors of AMB or DMV in baroreflex mediated adjustments of HR is therefore suggested.

Electromechanical effects of bepridil on rabbit isolated hearts.

Electromechanical effects of a new antianginal agent, bepridil, on Langendorff-perfused rabbit hearts were compared with those of verapamil and lidocaine. Bepridil at concentrations above 2 X 10(-7)M caused a dose-related decrease in heart rate (HR), a prolongation of the atrio-His bundle conduction time (A-H interval) and a prolongation of the functional refractory period (FRP) of the atrioventricular (A-V) node. Similar changes in HR, A-H interval and the FRP of the A-V node were observed with verapamil at concentrations above 2 X 10(-8)M. Lidocaine at above 4 X 10(-5)M prolonged slightly the A-H interval and the FRP of the A-V node but did not decrease the HR. Bepridil at concentrations above 10(-6)M prolonged both the His bundle-ventricular conduction time (H-V interval) and the effective refractory period (ERP) of ventricular muscles. Similar changes in the H-V interval and in the ERP of ventricular muscles were observed with lidocaine at above 10(-5)M. Verapamil ranging between 5 X 10(-8)M and 8 X 10(-7)M had no effect on the H-V interval and appreciably shortened the ERP of ventricular muscles. Bepridil at concentrations above 2 X 10(-6)M reduced the developed tension as did verapamil at above 10(-7)M. On a molar basis, the depressant effect of bepridil on HR and the A-V nodal conduction, which may reflect inhibitory action on the slow channels, was less than one tenth that of verapamil. Bepridil was more potent than lidocaine in prolonging the H-V interval and the ERP of ventricular muscles indicating a possible inhibition of the fast sodium channels. Both of these electrophysiological effects of bepridil may afford significant bases for the antiarrhythmic action of the drug.

Acute effects of intravenous prifuroline and amiodarone on canine cardiac automaticity, conduction, and refractoriness.

We compared the acute electrophysiologic properties of prifuroline (P), a new aminopyrroline derivative, to those of amiodarone (A) in pentobarbital-anesthetized dogs using His bundle recordings and programmed stimulation. Ten dogs received in randomized order four cumulative doses of P (2.5-20 mg/kg) and of A (1.25-10 mg/kg) with a 14-day interval between drug administrations. In a control group of four dogs receiving the diluent of the drugs, no significant changes occurred in cardiac automaticity, conduction, and refractoriness except for the atrioventricular (AV) nodal functional refractory period (RP), which increased with time (p less than 0.05). P and A produced a significant dose-related decrease in heart rate and in sinus node recovery time, with A being 3.7-3.1 times more potent than P. While atrionodal conduction time increased with both drugs, only P resulted in a significant dose-related increase in the His-Purkinje system conduction time. Prifuroline was 2.9 times more potent than A in increasing the atrial effective refractory period, while A was 2.5 times more potent than P in increasing the ventricular effective refractory period. Both drugs increased the AV nodal refractoriness in a dose-dependent way. These results suggest that the new compound prifuroline possesses some properties similar to intravenous amiodarone on sinus automaticity, atrionodal conduction, and atrial and ventricular refractoriness. However, its effects on the His-Purkinje System are typical of those of a class I quinidine-like agent.

Hypotensive Effects of Adenosine and Adenosine Triphosphate Compared with Sodium Nitroprusside

Hypotensive effects of the intravenous injection of adenine compounds [adenosine triphosphate (ATP), adenosine] were compared with those of sodium nitroprusside (SNP) in rabbits during light, stable halothane anesthesia. ATP and adenosine were almost equipotent in their effects on blood pressure and heart rate. The hypotensive potencies of ATP and adenosine were approximately 1/6 (bolus injection) and 1/40 (continuous infusion) that of SNP, but the adenine compounds had a more rapid onset of action and shorter recovery times than SNP. With bolus injection, SNP invariably caused a baroreceptor-mediated reflex increase in heart rate. In contrast, ATP and adenosine caused a dose-related decrease in heart rate and hypotension. With continuous infusion, ATP and adenosine produced immediate onset of hypotension without tachycardia. Blood pressure remained remarkably stable throughout the infusion; neither tachyphylaxis nor rebound hypertension were observed. Thus, the adenine compounds offer possible advantages over SNP as they are physiologic agents with little or no acute toxicity and may be devoid of tachycardia, tachyphylaxis, and rebound hypertension.

Heart rate changes caused by chemical stimulation of the amygdaloid body

The modification of cardiovascular parameters resulting from the injection of norepinephrine (NE) or acetylcholine (ACh) into the amygdala was investigated in the chronically prepared unanesthetized restrained beagle. Blood pressure was obtained via an aortic catheter while heart rate was determined from Lead II of the ECG. Depth electrodes implanted into the hippocampus and ventromedial hypothalamus were used to record the EEG from these respective sites. NE caused a dose-related decrease in heart rate while ACh induced a tachycardia of short duration. Methyl atropine injected into the amygdala prior to ACh blocked the ACh induced tachycardia while physostigmine mimicked the cholinergic response. These responses were not associated with changes in blood pressure or respiration. It is concluded that there are two chemically coded systems within the amygdaloid body that are capable of modifying heart rate: an adrenergic system that induces bradycardia and a cholinergic system that causes tachycardia.

Protective action of amiodarone against ventricular fibrillation in the isolated perfused rat heart

The pretreatment of rats with amiodarone for 2 minutes to 3 weeks before the excision of their hearts caused a dose-related decrease in heart rate and an increase in the ventricular fibrillation threshold both before and after coronary arterial ligation. Similarly, amiodarone decreased the incidence of ventricular premature extrasystoles, ventricular tachycardia and fibrillation during the period of regional ischemia after coronary arterial ligation and also after reperfusion of the ischémie myocardium. There was no evidence of a metabolic protective effect on ischemic myocardium because tissue high energy phosphate content decreased to a similar extent in ischemic myocardium from control and amiodarone-treated rats. Instead, the protective effect of amiodarone against fibrillation was accompanied by attenuation of the increase in tissue cyclic adenosine monophosphate in ischemic myocardium after coronary arterial ligation. It is proposed that amiodarone exerts a potent antifibrillatory effect by decreasing tissue cyclic adenosine monophosphate in ischemic myocardium.