Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region

Amiodarone was selectively perfused into the sinus node artery and atrioventricular node artery of 51 dogs. Amiodarone had an immediate negative chronotropic and dromotropic effect. Threshold concentration was 2.5 micrograms/ml. 25 and 50 micrograms/ml of amiodarone injected into the sinus node artery slowed the heart by 25.6 +/- 3.1 and 33.7 +/- 2.6 beats/min (mean +/- 1 SEM), respectively. Amiodarone 25 and 50 micrograms/ml injected into the AV node artery during AV junctional rhythm slowed the AV junctional pacemaker by 12.2 +/- 1.8 and 17.4 +/- 1.7 beats/min, respectively. Injections of amiodarone into the AV node artery during sinus rhythm regularly increased AV conduction time sometimes causing 2 degrees AV block at the highest concentration used. Impaired conduction was exclusively measured at the level of the A-H interval in the His electrogram. Neither atropine nor propranolol prevented the negative chronotropic effects of amiodarone. Amiodarone had no significant effect on sinus node response to either stellate stimulation or intranodal administration of norepinephrine. The negative chronotropic action of amiodarone was significantly enhanced when amiodarone was administered in a perfusate containing low (0.6 mM) instead of normal calcium. Taken collectively these observations indicate that amiodarone has immediate depressant electrophysiologic effects on both the sinus node and the AV junction and that these early effects might involve the blockade of the slow channel.     

Effect of transdermal clonidine on the endocrine responses to insulin-induced hypoglycemia in essential hypertension

Clonidine hydrochloride via the central nervous system lowers blood pressure, inhibits ACTH and catecholamine release, and stimulates growth hormone secretion. To evaluate the effect of this drug on the release of glucoregulatory hormones during hypoglycemia, we studied the responses to insulin-induced hypoglycemia (0.1 units/kg) in 10 patients with mild essential hypertension before and after treatment for 16 weeks with transdermal clonidine. Clonidine significantly lowered blood pressure, basal plasma norepinephrine levels, and epinephrine and renin activity but did not affect basal growth hormone concentrations. Clonidine significantly reduced the norepinephrine and epinephrine responses to hypoglycemia (norepinephrine AUC from 207 +/- 16 SE to 156 +/- 25 nmol/L/min, epinephrine from 157 +/- 28 to 99 +/- 29 nmol/L/min; both p less than 0.05) and increased the growth hormone response (AUC from 763 +/- 148 ng/min/ml to 1164 +/- 292 ng/min/ml; p less than 0.05) but did not affect the cortisol response or the magnitude or rate of glucose recovery from hypoglycemia. Thus transdermal clonidine has several effects on glucose counterregulatory hormones that do not significantly alter insulin sensitivity or impair recovery from hypoglycemia.     

Dopamine1 receptor agonist and alpha-2 adrenoceptor antagonist effects of fenoldopam in rabbits

Neurochemical and circulatory effects of fenoldopam were studied in pithed rabbits with electrically stimulated sympathetic outflow and in strips of the rabbit pulmonary artery. In pithed rabbits, fenoldopam (1-30 micrograms/kg/min) decreased the arterial blood pressure. Fenoldopam (3-30 microgram/kg/min) also increased the norepinephrine spillover rate (the rate at which endogenous norepinephrine enters into the plasma after having been released from postganglionic sympathetic nerves) and decreased the [3H]norepinephrine plasma clearance. The selective dopamine (DA)1 antagonist SCH 23390 (bolus injection of 10 micrograms/kg followed by infusion of 2 micrograms/kg/hr) antagonized markedly and the DA2-selective antagonist domperidone (bolus injection of 200 micrograms/kg followed by infusion of 50 micrograms/kg/hr) antagonized slightly the hypotensive effect. The increase in the norepinephrine spillover rate was enhanced after treatment with desipramine. Clonidine (0.3 microgram/kg/min) reduced the spillover of norepinephrine, and this effect was abolished by fenoldopam (30 micrograms/kg/min). In pulmonary artery strips preincubated with [3H]norepinephrine, fenoldopam (10(-7) and 10(-6) M) increased the electrically evoked overflow of tritium. The effect of fenoldopam (10(-6) M) was prevented in the presence of a supramaximal concentration of clonidine (10(-5) M). The results suggest that fenoldopam lowers blood pressure mainly by activation of vascular smooth muscle DA1 receptors. In addition, however, it blocks prejunctional alpha-2 autoreceptors at postganglionic sympathetic axons.     

Effects of opioid agonists on sympathetic and parasympathetic transmission to the dog heart

Effects of leu- and met-enkephalin, pentazocine and morphine on negative or positive chronotropic response to vagal nerve stimulation or cardiac sympathetic nerve stimulation were examined in anesthetized dogs in order to determine whether opioid receptors modulate vagal and sympathetic transmission. Leu- and met-enkephalin (10-100 micrograms/kg i.v.) and pentazocine (100-1000 micrograms/kg i.v.) inhibited bradycardic response to vagal nerve stimulation (1-4 Hz) in a dose-dependent manner. Morphine (300 and 1000 micrograms/kg i.v.) did not affect vagal bradycardia. The inhibitory effect of leu-enkephalin (30 micrograms/kg) and pentazocine (300 micrograms/kg) was effectively antagonized by naloxone (1000 micrograms/kg i.v.). Bradycardic response to intracoronary injection of methacholine (0.1, 0.3 and 1 microgram) into the right coronary artery was unaffected by leu-enkephalin (30 micrograms/kg). On the other hand, leu-enkephalin and pentazocine did not modify tachycardic response to sympathetic nerve stimulation (1-8 Hz). Morphine attenuated sympathetic tachycardia only slightly. These results suggest that presynaptic opioid receptors, probably delta type, are present in the vagus nerves, and that the activation of opioid receptors inhibit vagal transmission to the dog heart. In contrast, the presence of opioid receptors in the cardiac sympathetic nerves is not evident.     

Evidence for two subtypes of alpha adrenergic receptors in canine airway smooth muscle

The contractile response of canine tracheal muscle to i.a. phenylephrine, clonidine and norepinephrine was studied isometrically in situ in 32 dogs after beta adrenergic and ganglionic blockade. Intra-arterial phenylephrine caused dose-related tracheal contraction which was not altered by yohimbine (5 microgram/kg i.a.). Prazosin (4 mg/kg i.v.) caused a 77 +/- 3% decrease in tracheal response to i.a. phenylephrine. Clonidine also caused dose-related tracheal contraction, which was not altered by prazosin (4 mg/kg i.v.) but was 95 +/- 2% blocked by 5 microgram/kg i.a. of yohimbine. Norepinephrine caused tracheal muscle contraction which was greater than both phenylephrine (P less than .05) and yohimbine (P less than .001). Prazosin (4 mg/kg i.v.) caused 53 +/- 6% blockade and yohimbine (5 microgram/kg i.a.) caused 76 +/- 2% blockade of the response to i.a. norepinephrine; prazosin plus yohimbine caused greater than 98% blockade of the response to i.a. norepinephrine. The dose-response curve to i.a. acetylcholine was not altered by treatment with prazosin (4 mg/kg i.v.) plus yohimbine (5 microgram/kg i.a.). These results demonstrate that tracheal contraction induced by sympathomimetic amines is mediated by two subtypes of alpha adrenergic receptors on tracheal muscle, alpha-1 for phenylephrine, alpha-2 for clonidine and both alpha-1 and alpha-2 for norepinephrine.     

Intravenous clonidine produces hypoxemia by a peripheral alpha-2 adrenergic mechanism

Intravenous injection of the alpha-2 adrenergic agonists, clonidine and xylazine, have been previously shown to produce hypoxemia in sheep. To characterize this effect further, clonidine and ST-91, a clonidine analog that does not cross the blood-brain barrier, were injected i.v. in 10 conscious ewes. Although both clonidine (3-15 micrograms/kg) and ST-91 (3-30 micrograms/kg) produced arterial hypoxemia, clonidine was more effective (arterial PO2 was 91 +/- 4 mm Hg after saline, 30 +/- 3 mm Hg after 15 micrograms/kg of clonidine and 43 +/- 6 mm Hg after 30 micrograms/kg of ST-91; mean +/- S.E., P less than .0001). ST-91 increased mean arterial blood pressure in a dose-dependent manner (P less than .0001), whereas clonidine did not affect blood pressure. Clonidine-induced hypoxemia was inhibited in a dose-dependent manner by the alpha-2 adrenergic antagonist idazoxan (0.01-1 mg/kg, complete inhibition after 1 mg/kg; P less than .0001), the hydrophilic alpha-2 adrenergic antagonist DG-5128 (0.1-10 mg/kg, 62 +/- 7% inhibition after 10 mg/kg; P less than .0005) and by infusion of prostacyclin (0.15-0.5 microgram/kg/min, 57 +/- 7% inhibition after 0.5 micrograms/kg/min; P less than .05). Hypoxemia was not inhibited by the opiate antagonist naloxone (1 mg/kg), the alpha-1 adrenergic antagonist prazosin (1 mg/kg) or the prostaglandin synthetase inhibitor ibuprofen (12.5 mg/kg). To characterize pulmonary vascular effects, clonidine was injected i.v. in four anesthetized, mechanically ventilated ewes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of alpha 2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system.

We studied the effects of clonidine, an alpha 2-adrenoreceptor agonist, and yohimbine, an alpha 2-adrenoreceptor antagonist, on blood pressure, heart rate, and plasma catecholamines in 12 patients with autonomic dysfunction. Clonidine (0.1 mg, orally) lowered blood pressure 18 +/- 3 torr in six subjects and raised it 5 +/- 1 torr in six. The change in blood pressure in response to this dose of clonidine was inversely proportional to the supine level of norepinephrine (P less than 0.05). Yohimbine (4-64 micrograms/kg) raised plasma norepinephrine and blood pressure in six patients with degenerative autonomic dysfunction. Yohimbine also attenuated by 50% (P less than 0.05) the hypotensive response to head-up tilt of patients with degenerative autonomic dysfunction. Clonidine depends upon postjunctional hypersensitivity and the degree of autonomic insufficiency to elicit its pressor response. In contrast, the pressor response to yohimbine is related to the capacity of the sympathetic nervous system to be activated and release norepinephrine. If plasma norepinephrine levels following yohimbine administration are monitored, the biochemical and hemodynamic response to the drug may provide a sensitive indication of the capacity of the sympathetic nervous system to be activated in patients with autonomic dysfunction.     

Alpha 2 adrenoceptor-mediated vasoconstriction of arteries

We investigated the possibility that adrenoceptors of the alpha 2 subtype mediate vasoconstriction of arteries in response to administered catecholamines. Clonidine, which in vitro, stimulates alpha 2-adrenoceptors was infused into a brachial artery in 12 subjects (0.48 micrograms/min/100 ml tissue for 3 min). Afterward, prazosin was infused intraarterially in the first six subjects (0.5 micrograms/min/100 ml for 10 min) and in the remaining subjects, phentolamine was infused (0.12 micrograms/min/100 ml) for 10 min. Subsequently, the clonidine infusion was repeated. Clonidine decreased forearm blood flow from 3.5 +/- 0.52 to 1.8 +/- 0.32 in the first six subjects and from 4.2 +/- 0.84 to 2.7 +/- 0.61 ml/min/100 ml in the other subjects. Alpha 1-Adrenoceptor blockade by prazosin increased forearm blood flow by 122.7 +/- 33.8% and combined alpha 1 and alpha 2 blockade by phentolamine by 127.2 +/- 29.9%, indicating much the same degree of postjunctional alpha-adrenoceptor blockade. Alpha 2-Adrenoceptor-mediated vasoconstriction by clonidine was abolished after phentolamine (9.1 +/- 2.29 and 9 +/- 2.51 ml/min/100 ml) but was still present after prazosin (7.8 +/- 1.7 and 4.8 +/- 1.6 ml/min/100 ml). The results suggest that, apart from the classical alpha 1 adrenoceptor, there is a second type of adrenergic receptor on smooth muscle cells that can mediate vasoconstriction, resembling the alpha 2-adrenoceptor pharmacologically.     

Comparison of the autonomic effects of procainamide and N-acetylprocainamide in the dog

The autonomic effects of procainamide (PA) and N-acetylprocainamide (NAPA) were studied in anesthetized dogs. High plasma concentrations of PA (31 +/- 1.3--64 +/- 3.4 micrograms/ml) and NAPA (64 +/- 3.4--127 +/- 8.3 micrograms/ml)) reduced base-line mean arterial pressure and heart rate and attenuated the pressor and positive chronotropic responses to bilateral carotid occlusion and the negative chronotropic response to vagal stimulation. Neither drug reduced the pressor or positive chronotropic responses to catecholamines (epinephrine, phenylphrine, isoproterenol), however. In fact, at some doses PA and NAPA accentuated the pressor and positive chronotropic effects of epinephrine. Similarly, the depressor response to acetylcholine was not reduced by these drugs; it was significantly increased at some doses. In the isolated hindlimb (constant flow) PA and NAPA reduced the pressor response to preganglionic (sympathetic chain) stimulation but not to postganglionic (femoral and sciatic nerves) stimulation. We conclude that NAPA, like PA, at high plasma levels is vagolytic and attenuates baroreceptor-mediated reflexes associated with reduced arterial pressure. These effects appear to be due to ganglionic blockade.     

Interaction between autonomic tone and the negative chronotropic effect of adenosine in humans

Prior studies have demonstrated that sympathetic tone may influence the effects of adenosine on His-Purkinje automaticity, and that enhanced vagal tone may influence its effects on the sinus node. However, the interaction between autonomic tone and the effects of adenosine on the sinus node in humans remains unknown. Therefore, this study was designed to investigate the interaction between different states of autonomic tone and the bradycardiac response of the sinus node to adenosine. In 11 patients without structural heart disease who underwent a clinically indicated electrophysiology procedure, the sinus cycle length was measured before and after a 12-mg bolus of adenosine in the baseline state, during an infusion of 2 mcg/min of isoproterenol, after the administration of 0.2 mg/kg of propranolol, and again after the administration of 0.04 mg/kg of atropine. Adenosine significantly lengthened the sinus cycle length in the baseline state (760 +/- 165 vs 909 +/- 188 ms, P < 0.05), during isoproterenol infusion (516 +/- 67 vs 766 +/- 146 ms, P < 0.05), after propranolol (850 +/- 153 vs 914 +/- 143 ms, P < 0.05) and after the combination of propranolol and atropine (662 +/- 76 vs 801 +/- 121 ms, P < 0.05). The degree of lengthening in sinus cycle length was significantly greater (P < 0.05) during isoproterenol infusion (253 +/- 157 ms, or 51% +/- 40%) than in the baseline state (149 +/- 85 ms, or 20% +/- 12%), after propranolol (68 +/- 53 ms, or 8% +/- 8%), and after propranolol and atropine (140 +/- 110 ms, or 21% +/- 18%). The negative chronotropic effect of adenosine is influenced by autonomic tone. The effect of adenosine on the sinus node is accentuated by beta-adrenergic stimulation and unaffected by beta-adrenergic blockade or combined beta-adrenergic and cholinergic blockade.     

Effects of epinephrine, isoproterenol and IPS-339 on sympathetic transmission to the dog heart: evidence against the facilitatory role of presynaptic beta adrenoceptors

The autoregulation of norepinephrine (NE) release mediated by presynaptic alpha and beta adrenoceptors on sympathetic nerve terminals in the heart of pentobarbital-anesthetized dog was studied. NE overflow elicited by left cardiac sympathetic nerve stimulation was determined from the coronary sinus blood, by using high-performance liquid chromatography with electrochemical detection. Intracoronary infusion of epinephrine (1,3 and 10 micrograms/min) into the left circumflex artery increased basal left ventricular dp/dt maximum (LV dp/dt max) and coronary sinus blood flow. The epinephrine infusion decreased coronary sinus output of NE (NE output) during left cardiac sympathetic nerve stimulation. Intracoronary infusion of isoproterenol (0.03, 0.1 and 0.3 microgram/min) increased the basal LV dp/dt max and coronary sinus blood flow, whereas the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow were not altered by its infusions. Intravenous injection of IPS-339 (0.03, 0.1 and 0.3 mg/kg), a selective beta-2 adrenoceptor antagonist, diminished the stimulation-induced increases in LV dp/dt max and coronary sinus blood flow in a dose-dependent manner, whereas it did not decrease the stimulation-induced increase in NE output. Intracoronary infusion of yohimbine (10, 30 and 100 micrograms/min), a preferentially selective alpha-2 adrenoceptor antagonist, facilitated the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow. There was no significant difference in the facilitation of the stimulation-induced increases in NE output, LV dp/dt max and coronary sinus blood flow between intracoronary infusion of both isoproterenol (0.1 microgram/min) and yohimbine (100 micrograms/min) and the infusion of yohimbine alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of vasoactive intestinal polypeptide on the canine cardiovascular system

Our purpose was to determine the effect of vasoactive intestinal polypeptide (VIP) on the cardiovascular system with special emphasis on coronary vascular effects. In section I, VIP was infused into six healthy and six cobalt-cardiomyopathic dogs at two infusion rates (0.02 and 0.05 micrograms/kg/min). Left ventricular end diastolic pressure and mean systemic pressure fell significantly in both groups. Heart rate rose in both, and maximum systolic dP/dt increased in the myopathic group. Cardiac output and regional blood flows were determined by serial left atrial injections of radioactive 15 +/- 3 mum (mean +/- SD) microspheres. In both groups, blood flow increased significantly to the esophagus, pancreas, atria, and ventricles and to the endocardial and epicardial regions of the left ventricular free wall. Blood flow to the brain decreased. In section II, VIP was infused intravenously at 0.1 micrograms/kg/min into six anesthetized dogs with coronary sinus flow, pulmonary artery, and systemic artery catheters inserted. Cardiac index rose from baseline (3.1 +/- 0.5 to 4.8 +/- 1.3 L/min/m2, P less than 0.005), as did coronary blood flow (90 +/- 25 to 159 +/- 54 ml/min, P less than 0.005) during the VIP infusion. Myocardial oxygen consumption rose from 14.1 +/- 3.9 to 19.8 +/- 5.4 ml/min (P less than 0.001), but the aorta-to-coronary sinus O2 difference decreased from 157 +/- 19 ml/L to 132 +/- 42 ml/L (P less than 0.05), and the percent O2 extracted from coronary blood also decreased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gentamicin penetration into cerebrospinal fluid in experimental Haemophilus influenzae meningitis.

We studied the effect of meningitis and the method of parenteral gentamicin administration (intramuscular injection, a 30-min intravenous infusion, or intravenous bolus administration) on achievable concentrations of drug in cerebrospinal fluid (CSF). In normal animals, only intravenous bolus administration of 2 to 8 mg/kg produced a gentamicin concentration of greater than 0.1 microgram/ml in CSF in some animals. All CSF samples contained less than the limit of detection (0.1 microgram/ml) after the intramuscular administration of 6 mg/kg. In animals with meningitis, gentamicin penetration into cisternal CSF was increased significantly after a bolus administration of 6 mg/kg (mean, 0.197 +/- 0.063 microgram/ml in normal animals versus 1.68 +/- 0.38 micrograms/ml in animals with meningitis; P less than 0.01). In meningitic animals that received 6 mg/kg as an intravenous bolus, lumbar CSF had the highest maximum concentration (4.25 +/- 1.08 micrograms/ml), in comparison with ventricular CSF (3.10 +/- 0.66 micrograms/ml). The gentamicin concentration in cisternal CSF decreased more slowly than it did in serum (elimination half-life, 238.70 +/- 64.56 min in cisternal CSF versus 82.73 +/- 2.91 min in serum), yielding a relative increase in the percentage of penetration. We conclude that maximum penetration by gentamicin into CSF occurs after intravenous bolus administration and that the maximum concentration occurs in lumbar CSF.     

Apparent frequency-dependent effect of clonidine on cardiac sympathetic transmission: the role of neuronal uptake

Decreases in spontaneous atrial period (tachycardia) were measured in atropinized guinea-pig isolated right atria in response to intramural sympathetic nerve stimulation. Electrical field pulses were applied only during the atrial refractory period to avoid arrhythmias. Responses to one to six field pulses delivered in a single refractory period were substantially reduced by clonidine (1-1000 nM), providing no evidence that the blocking action of this drug is frequency-dependent. Stimulus-response lines to one, two or four field pulses delivered as one field pulse per refractory period (1/1) were displaced to the right by clonidine (0.1 microM) such that 8, 16 and 32 field pulses were required to obtain responses equivalent to control. Stimulus-response lines to lower frequencies of field stimulation (one field pulse every 4 or 8 refractory periods) were lower in slope and displaced further by clonidine, whereas lines from stimuli at higher frequencies (2/1 and 4/1) were steeper and less displaced by clonidine. These findings confirmed an "apparent" frequency-dependent blocking action of clonidine. However, substantial blockade of neuronal uptake by desipramine (0.1 microM) raised the slope and decreased the shift of the stimulus-response lines to the lower frequencies of field stimulation compared with 2/1 or 4/1. Clonidine (0.1 microM) had no effect on the responses to exogenous norepinephrine. We suggest that clonidine reduces the amount of norepinephrine released per field pulse independently of the frequency of stimulation. The decrease in tissue response may appear to be frequency-dependent under some circumstances due to the effects of uptake and removal processes.     

Pharmacological analysis of dopamine action on the isolated dog atrium.

The isolated right atrium of the dog was perfused with arterial blood introduced from a carotid artery of a support dog. The selective injection of dopamine, tyramine and norepinephrine into the cannulated sinus node artery induced dose-relatedly positive chronotropic and inotropic effects. However, for an equal increase in sinus rate, dopamine caused less increase in tension development than norepinephrine. Tyramine caused least increase in contractility. Effects induced by dopamine were not blocked by treatment with tetrodotoxin which blocked those induced by nicotine. Desmethylimipramine treatment significantly suppressed dopamine-induced effects and completely blocked tyramine-induced ones but rather enhanced norepinephrine-induced ones. Alprenolol inhibited effects of dopamine, tyramine and norepinephrine. From these results, it is concluded that positive chronotropic and inotropic effects of dopamine are partly due to tyramine-like effect which causes the release of norepinephrine from sympathetic storage sites.     

Dose selective dissociation of water and solute excretion after renal alpha-2 adrenoceptor stimulation

In vitro studies have demonstrated an antagonism of the renal effects of vasopressin after alpha-2 adrenoceptor stimulation. Whether the effect of alpha-2 adrenoceptor stimulation in relation to sodium and water excretion in vivo is mediated through independent mechanisms is unclear. The dose-response relationship between renal alpha-2 adrenoceptor stimulation (clonidine) and water and electrolyte excretion was evaluated in anesthetized rats. Rats were nephrectomized unilaterally 7 to 10 days before the experimental day to allow isolation of renal function. A base-line level of sodium and water excretion was established by the infusion of saline (0.097 ml/min i.v.). In separate groups of rats, clonidine was infused directly into the renal artery at 0 (vehicle), 0.1, 0.3, 1 or 3 micrograms/kg/min at 0.0034 ml/min. The lower doses (0.1, 0.3 and 1 microgram/kg/min) produced a dose-related increase in urine volume and free water clearance and a decrease in urine osmolality. Electrolyte or solute excretion was not altered at these infusion rates even though urine volume increased 4-fold. The highest dose investigated (3 micrograms/kg/min) increased urine volume (9-fold) and sodium excretion (4-fold). Free water clearance and osmolar clearance were also increased. The effects of clonidine were attenuated by yohimbine but not prazosin indicating these effects were mediated by alpha-2 adrenoceptor stimulation. These results demonstrate a dose-related selectivity of alpha-2 adrenoceptor stimulation for water and sodium excretion. The increase in water excretion at the lower infusion rates would be consistent with the antagonism of the renal effects of vasopressin. The potent natriuresis observed only at higher doses indicates another mechanism may be involved.     

Clonidine and prazosin effects in hypernoradrenergic vasodilator-treated and beta-blocker-treated patients

Our subjects were seven severely hypertensive patients with blood pressures (BPs) over 140/90 who were using minoxidil, propranolol, and diuretics. Clonidine followed by prazosin was added to their regimen on an outpatient basis to establish the dose-response for BP and catecholamines. Plasma renin activity (PRA), body weight, and renal function were measured. Clonidine was given in doses of 0.2, 0.4, 0.6, and 0.8 mg/day. Supine and standing systolic BP decreased at all dose levels of clonidine (P less than 0.01, P less than 0.05). Diastolic BP decreased in the standing position with doses of 0.4, 0.6, and 0.8 mg (P less than 0.01, P less than 0.05). Subjects were hypernoradrenergic initially with plasma norepinephrine (PNE) 895 +/- 122 pg/ml. PNE was suppressed by 0.2 to 0.8 mg clonidine (P less than 0.01) with near maximal suppression at 0.4 mg daily. Systolic BP correlated with PNE (r = 0.59, P less than 0.001). Supine and standing PRA decreased after 0.2 mg clonidine (P less than 0.05) but not after higher doses. Our findings suggest the antihypertensive action of clonidine is related to PNE suppression but not to that of PRA. Plasma epinephrine (PE), body weight, and renal function did not change. Prazosin was given after clonidine to the same patients in a dose range of 3 to 40 mg/day. With doses of 6 to 40 mg, systolic and diastolic and supine and standing BP fell (P less than 0.001, P less than 0.01). PNE remained elevated throughout all dose levels and did not correlate with BP. Weight rose with prazosin (P less than 0.02) but PE, PRA, and renal function did not change. Hence, clonidine and prazosin induced additional lowering of BP but had different effects of PNE and weight.     

Inhibition of respiratory neural discharges by clonidine and 5-hydroxytryptophan

Activation of receptors for norepinephrine or serotonin in the central nervous system by i.v. injection of clonidine (10-50 micrograms/kg) or 5-hydroxytryptophan (20-40 mg/kg) inhibits phrenic neural discharges in anesthetized, artificially ventilated cats. Clonidine induces a rapid and complete inhibition of phrenic nerve activity which lasts for 1 to 3.2 hr. The inhibition is prevented by prior administration of phenoxybenzamine (10 mg/kg) or tolazoline (3 mg/kg). 5-Hydroxytryptophan, injected after inhibition of peripheral amino acid decarboxylase (carbidopa, 30-50 mg/kg), elicits a gradual but complete inhibition of phrenic nerve discharges which persists for 1 to 10 hr and is unaltered by alpha or beta adrenoceptor blocking agents. The inhibitions produced by clonidine and 5-hydroxytryptophan are overcome transiently during hypercapnia. Stimulation of carotid body chemoreceptors by i.a. injections of lobeline, doxapram or 0.015 N HCl in saline also briefly reinstates phrenic nerve discharges after inhibition by clonidine. Inhibition is also overcome during electrical stimulation of the carotid sinus nerve.     

Mechanism of suppression of vasopressin and adrenocorticotropic hormone secretion by clonidine in anesthetized dogs

Studies were performed in anesthetized dogs to investigate the mechanism of the suppression of vasopressin and adrenocorticotropic hormone (ACTH) secretion by clonidine. Injection of clonidine (30 micrograms/kg i.v.) produced an initial increase in arterial pressure followed by hypotension, decreased heart rate, increased right atrial pressure and decreased plasma renin activity. Plasma vasopressin concentration decreased from 14.6 +/- 3.0 to 2.2 +/- 0.4 pg/ml (P less than .01), and this was accompanied by increases in urine volume and free water clearance from 0.15 +/- 0.02 to 1.03 +/- 0.28 and -0.50 +/- 0.05 to 0.30 +/- 0.27 ml/min, respectively (P less than .01), and a decrease in urinary osmolality from 1450 +/- 124 to 372 +/- 97 mOsmol/kg of H2O (P less than .01). Plasma corticosteroid concentration, used an an index of ACTH secretion, decreased from 8.9 +/- 1.6 to 2.2 +/- 0.3 micrograms/dl (P less than .01). Plasma osmolality did not change. Pretreatment of dogs with the alpha adrenoceptor antagonist yohimbine (2 mg/kg i.p.) blocked all cardiovascular, endocrine and renal responses to clonidine. Bilateral cervical vagotomy did not block the suppression of vasopressin or corticosteroid secretion by clonidine. Intraventricular injection of yohimbine blocked the hypotension and suppression of plasma corticosteroid concentration produced by clonidine but did not block the decrease in plasma vasopressin concentration or the associated renal effects of clonidine. Intracarotid infusion of clonidine caused small decreases in plasma vasopressin and corticosteroid concentrations even though blood pressure decreased by 22 mm Hg. Intraventricular and intravertebral clonidine had no significant effect on plasma vasopressin or corticosteroid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions between digoxin and brief vagal bursts influencing atrioventricular conduction

The interaction between intravenous injections of digoxin (20 microgram/kg every 15 minutes) and brief electrical bursts of vagal stimulation was determined in chloralose-anesthetized dogs. Vagal effect curves were generated to characterize the effect of brief vagal stimulus bursts on atrioventricular conduction. These curves were fit with an analytic expression from which the following parameters were derived as the experimental observations: 1) the maximal change in atrioventricular conduction (deltaPRmax), 2) the time after the stimulus at which atrioventricular conduction was maximally inhibited (Tmax) and 3) the width of the vagal effect curve at one-half the maximal amplitude (TD). Digoxin administration significantly (P less than .05) increased deltaPRmax, Tmax and TD by 21.6 +/- 4.3, 50.0 +/- 16.1 and 125.5 +/- 42.4 msec, respectively, before the disruption of sinus rhythm. Diluent or saline administration did not alter deltaPRmax, Tmax or TD. In addition, digoxin produced dose-dependent increases in deltaPRmax. These results suggest that digoxin vagal interactions not only affect the PR interval but also the time to the maximum delay in atrioventricular conduction and the length of time for depressed conduction after brief bursts of vagal activity.