Reflex inhibition of renal sympathetic nerve activity during myocardial ischemia mediated by left ventricular receptors with vagal afferents in dogs.

The major goal of this investigation was to determine if activation of cardiac receptors during coronary artery occlusion could inhibit efferent renal sympathetic nerve activity. In nine chloralose anesthetized dogs with only carotid (n = 3) or with sinoaortic (n = 6) baroreceptors operative, anterior descending coronary artery (LAD) occlusion resulted in a small decrease in mean arterial pressure (-9.8+/-5.1 mm Hg, NS) and in a significant (P < 0.05) increase in renal nerve activity (24.0+/-4.1%). In these dogs, circumflex coronary artery (Cx) occlusion resulted in greater hypotension (-18.4+/-4.0 mm Hg), and yet no change (1.1+/-9%) in renal nerve activity was noted. Changes in left atrial pressure during LAD and Cx occlusion were not different. In seven dogs with carotid sinus denervation, coronary occlusions resulted in decreases both in arterial pressure and in renal nerve activity which were consistently greater during Cx occlusion. The responses to coronary occlusion in six dogs after sinoaortic deafferentation were similar to those observed with only carotid sinuses denervated. In all experiments, vagotomy abolished the difference in the blood pressure responses and the decreases in renal sympathetic nerve activity during Cx occlusion. Vagotomy also abolished the decrease in nerve activity during LAD occlusion in dogs with carotid or sinoaortic denervation. These data show that Cx occlusion and, to a lesser degree, LAD occlusion resulted in reflex withdrawal of renal sympathetic nerve activity mediated by left ventricular receptors with vagal afferents. The reflex withdrawal of renal nerve activity during Cx occlusion occurred in spite of hypotension and the presence of functioning sinoaortic baroreceptors.

Inhibition of cardiac sympathetic nerve activity during intravenous administration of lidocaine.

The antiarrhythmic action of lidocaine has been attributed solely to its direct electrophysiological effects on the heart. However, lidocaine is particularly effective in treating ventricular arrhythmias associated with increased sympathetic activity, e.g., in myocardial infarction and digitalis toxicity. We tested the hypothesis that lidocaine administered intravenously depressed cardiac sympathetic nerve activity (CSNA). We measured CSNA in six dogs in control state and after lidocaine in doses of 0.625, 1.25, and 2.5 mg/kg i.v. over 2 min. These doses of lidocaine produced graded decreases of CSNA of -8 +/- 2, -18 +/- 1, and -41 +/- 5%, respectively (P less than 0.05, mean +/- SE). In six additional experiments the bolus of lidocaine was followed by an infusion for 20 min (1.25 mg/kg followed by 100 micrograms/kg per min and 2.5 mg/kg followed by 200 micrograms/kg per min). Infusion of lidocaine maintained depression of CSNA at a level that was 23 +/- 3 and 35 +/- 5% less than control (P less than 0.05), respectively, at plasma lidocaine levels of 5.2 +/- 0.6 and 7.5 +/- 1.4 micrograms/ml, respectively. CSNA returned to control during recovery periods. CSNA did not decrease with the passage of time or administration of vehicle. In five dogs with vagi intact, carotid sinuses isolated and held at a pressure of 100 mmHg, and aortic baroreceptors denervated, administration of lidocaine (2.5 mg/kg followed by 200 micrograms/kg per min) decreased renal nerve activity to 71 +/- 8% of control. Increases in left ventricular systolic pressure and maximum derivative of pressure with respect to time (dP/dtmax) resulting from electrical stimulation of preganglionic sympathetic nerves were not significantly altered by lidocaine, but were markedly attenuated by hexamethonium, a ganglionic blocker. In conclusion, lidocaine administered intravenously produces dose-dependent and sustained decreases in cardiac sympathetic nerve activity. These decreases can occur with therapeutic plasma levels. We speculate that this effect is due to central nervous system effects of the drug and that this effect may contribute to the antiarrhythmic actions of lidocaine.

Interaction of cardiopulmonary and somatic reflexes in humans.

Activation of cardiopulmonary receptors with vagal afferents results predominantly in reflex inhibition of efferent sympathetic activity, whereas activation of somatic receptors reflexly increases sympathetic activity to the heart and circulation. Previous studies in experimental animals indicate that there is an important interaction between these excitatory and inhibitory reflexes in the control of the renal circulation. The purpose of this study was to determine whether there is a similar interaction between somatic and cardiopulmonary reflexes in humans. The activity of the cardiopulmonary receptors was altered (reduced) with lower body negative pressure (-5 mm Hg), which causes a decrease in cardiac filling pressure and a small reflex increase in forearm vascular resistance without accompanying changes in arterial pressure. Activation of somatic receptors by isometric handgrip for 2 min at 10 and 20% of maximum voluntary contraction resulted in reflex vasoconstriction in the nonexercising arm. Lower body negative pressure at -5 mm Hg produced a threefold augmentation in the forearm vasoconstrictor response to isometric handgrip in the nonexercising arm. This increase in resistance was significantly greater (P < 0.05) than the algebraic sum of the increases in resistance resulting from lower body suction alone plus isometric handgrip alone. Furthermore, it occurred despite a greater rise in arterial pressure, which would be expected to decrease forearm vascular resistance through activation of arterial baroreceptors and through passive dilatation of forearm vessels. Thus, removal of the inhibitory influence of cardiopulmonary receptors by pooling blood in the lower extremities enhances the somatic reflex. These data suggest an interaction between cardiopulmonary and somatic reflexes in the control of forearm vascular resistance in man.

Ionic strength and the contraction kinetics of skinned muscle fibers.

The influence of KCl concentration on the contraction kinetics of skinned frog muscle fibers at 5-7 degrees C was studied at various calcium levels. The magnitude of the calcium-activated force decreased continuously as the KCl concentration of the bathing solution was increased from 0 to 280 mM. The shortening velocity at a given relative load was unaffected by the level of calcium activation at 140 mM KCl, as has been previously reported by Podolsky and Teichholz (1970. J. Physiol. [Lond.]. 211: 19), and was independent of ionic strength when the KCl concentration was increased from 140 to 280 mM. In contrast, the shortening velocity decreased as the KCl concentration was reduced below 140 mM; the decrease in velocity was enhanced when the fibers were only partially activated. In the low KCl range, the resting tension of the fibers increased after the first contraction cycle. The results suggest that in fibers activated at low ionic strength some of the cross bridges that are formed are abnormal in the sense that they retard shortening and persist in relaxing solution.

Responses of sympathetic nerves to programmed ventricular stimulation.

Ventricular arrhythmias generally result in a decrease in arterial pressure and increases in atrial and ventricular filling pressures which would be expected to induce reflex changes in efferent sympathetic nerve activity to the heart and peripheral circulation. Experiments were performed in 14 anesthetized dogs in order to determine whether programmed ventricular stimulation produces changes in renal sympathetic nerve activity; quantitate these changes; and determine the cardiovascular reflexes that mediate these changes. Arterial and right atrial pressures and renal sympathetic nerve activity were recorded in dogs before and after administration of single and double programmed ventricular stimuli. In a group of 10 dogs after single extrastimuli, diastolic arterial pressure decreased by 18 +/- 2 mm Hg (mean +/- SEM) while renal sympathetic nerve activity increased by 39 +/- 15 impulses/s. These changes were directly related to degree of stimulus prematurity. After double extrastimuli, diastolic arterial pressure decreased by 22 +/- 2 mm Hg whereas renal sympathetic activity increased by 55 +/- 8 impulses/s. In an additional four dogs, double extrastimuli decreased arterial pressure (-34 +/- 1 mm Hg) and increased cardiac (86 +/- 16%) and renal (82 +/- 12%) sympathetic traffic. After sinoaortic denervation, neither single nor double programmed ventricular stimuli resulted in alterations in cardiac or renal sympathetic nerve activity. It is concluded that the decreased arterial pressure caused by single and double programmed ventricular stimuli leads to increases in cardiac and renal sympathetic nerve activity that are mediated by sinoaortic baroreflexes.

Abnormalities of baroreflex control in heart failure.

This brief review summarizes abnormalities of arterial and cardiopulmonary baroreflex control of heart rate and sympathetic nerve activity. The potential role of these abnormalities in the development of the neurohumoral excitatory state associated with heart failure is discussed. Major emphasis is placed on the identification of important issues still to be investigated in this area. The potential importance of altered cardiovascular reflexes in the context of the interaction of the patient with heart failure and environmental stresses is discussed. The use of the canine rapid ventricular pacing model of biventricular failure in the investigation of abnormalities of baroreflexes in heart failure is emphasized. Insights obtained from this model should be extended to human investigations.

Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure.

OBJECTIVES: This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity. BACKGROUND: Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes. METHODS: We assessed baroreflex control of sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography. RESULTS: Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group. CONCLUSIONS: Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.

Subnormal heart period variability in heart failure: effect of cardiac transplantation.

Heart period variability and arterial baroreceptor-cardiac reflex function were studied in cardiac transplant patients to determine if correction of heart failure restores parasympathetic control mechanisms toward normal. Heart period variability (standard deviation [SD] of 120 consecutive RR or PP intervals) was measured at supine rest in 34 patients with congestive heart failure (23 patients receiving diuretics, digoxin or vasodilators and 11 patients weaned from all medications), 30 cardiac transplant patients (both innervated recipient and denervated donor atrial rates) and 16 age-matched healthy control subjects. Arterial baroreflex gain was evaluated with intravenous bolus injections of phenylephrine in 22 transplant patients. Mean heart period variability (+/- SEM) was significantly lower (p less than 0.05) in the heart failure groups (22 +/- 3 ms for medicated and 17 +/- 3 ms for nonmedicated) than in the transplant patients (41 +/- 5 ms) or control subjects (58 +/- 5 ms). Heart period variability of the transplant patients was less than that of the control patients (p less than 0.05). A stepwise regression model revealed that heart period variability was inversely related to systolic arterial pressure and directly related to time after transplantation (R2 = 0.39; p = 0.03) in the transplant patients. Baroreflex gain of normotensive transplant patients was normal (11.7 +/- 1.0 ms/mm Hg) and correlated directly with heart period variability (r = 0.62; p less than 0.001). These data suggest that subnormal levels of cardiac parasympathetic activity at rest associated with congestive heart failure can be restored progressively toward normal by correction of congestive heart failure after cardiac transplantation. Post-transplant hypertension opposes this correction of baseline parasympathetic activity.

Effect of transmural versus nontransmural myocardial infarction on inducibility of ventricular arrhythmias during sympathetic stimulation in dogs.

Transmural myocardial infarction interrupts sympathetic nerves and denervates viable muscle distal to myocardial infarction. The effect of sympathetic stimulation on responses to programmed ventricular stimulation was studied in dogs without myocardial infarction (Group I: n = 5), with transmural anterior wall myocardial infarction (Group II: n = 6) and with nontransmural anterior wall myocardial infarction (Group III: n = 9). Ventricular effective refractory period during sympathetic stimulation decreased by 16 +/- 18, 1 +/- 2 and 12 +/- 8 ms (mean +/- SD) in viable muscle of the inferoapical left ventricle in Groups I, II and III, respectively, suggesting efferent sympathetic denervation by transmural myocardial infarction only. Sustained ventricular tachycardia or fibrillation was induced more easily during sympathetic stimulation in six of the six dogs with transmural infarction, but in only two of the nine dogs with nontransmural infarction (p less than 0.01). It is concluded that the partial sympathetic denervation produced by transmural myocardial infarction enhances the ease of induction of ventricular tachycardia and fibrillation during sympathetic stimulation. A similar mechanism may lead to increased risk for lethal arrhythmias during periods of high sympathetic tone in patients with transmural myocardial infarction.

Afferent reinnervation of the autotransplanted heart in dogs.

Patients have been observed with a chest pain syndrome after cardiac transplantation. For this pain to be cardiac in origin the afferent nerves carrying sensory information from the heart would have to reinnervate the heart. A previous study in dogs indicated that afferent reinnervation is uncommon during the first 2 years after transplantation. The purpose of this study was to determine whether afferent reinnervation of the heart occurs in the long term. The decreases in arterial pressure and renal nerve activity resulting from chemical stimulation of left ventricular sensory receptors with vagal afferents with cryptenamine (veratrum alkaloid) were assessed in three dogs 8 to 12 years and in four dogs 6 to 8 weeks after cardiac autotransplantation and in six sham-operated dogs (thoracotomy-pericardiotomy 6 to 8 weeks before study). Responses of renal nerve activity to physiologic stimulation of cardiac receptors by volume expansion were also determined. Left ventricular cryptenamine inhibited renal nerve activity by 72 +/- 8% in dogs with long-term and by 10 +/- 6% in dogs with short-term autotransplantation and by 92 +/- 5% in sham-operated dogs. Decreases in mean arterial pressure in these groups were 34 +/- 4, 11 +/- 3 and 67 +/- 16 mm Hg, respectively. Volume expansion inhibited renal nerve activity in long-term autotransplant (43%) and sham-operated (48%) groups but less in the short-term transplant group (33%) for comparable increases in cardiac filling pressure. It is concluded that in dogs there is extensive afferent reinnervation of the long-term autotransplanted heart that results in relatively normal cardiopulmonary baroreflex responses to volume expansion.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial norepinephrine, epinephrine and dopamine concentrations after cardiac autotransplantation in dogs.

Myocardial norepinephrine is markedly reduced after cardiac transplantation because of interruption of postganglionic cardiac sympathetic nerves. There are also substantial stores of dopamine in the myocardium, but the influence of cardiac denervation on dopamine remains unknown. The effect of cardiac transplantation was determined and, thus, the effect of denervation on myocardial norepinephrine, dopamine and epinephrine. Myocardial catecholamines were measured with high-performance liquid chromatography with electrochemical detection in five dogs 6 to 8 weeks and in four dogs 8 to 12 years after cardiac autotransplantation and in six sham-operated dogs with intact cardiac innervation. Norepinephrine, dopamine and epinephrine levels were determined from samples obtained from the right and left atria and ventricles. Samples from the left ventricular apex and base were analyzed separately. There was a striking depletion of norepinephrine in all cardiac chambers after short-term autotransplantation. The norepinephrine content of the left atrium in sham-operated dogs (1,659 +/- 219 ng/g) was significantly higher than that of dogs with long-term autotransplanted hearts (754 +/- 372 ng/g). Sham-operated dogs and dogs with long-term autotransplanted hearts had statistically significant (p less than 0.05) differences in norepinephrine content in the left ventricular apex (480 +/- 197 versus 294 +/- 198 ng/g), left ventricular base (876 +/- 2204 versus 654 +/- 156 ng/g) and right ventricle (766 +/- 133 versus 247 +/- 29 ng/g). In contrast to norepinephrine, dopamine concentrations were relatively preserved in the short-term group despite the virtual depletion of myocardial norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired responses of sympathetic nerves to cardiac receptor stimulation in hypertension.

We recently reported that the vagal cardiopulmonary baroreceptor reflex inhibition of renal nerve traffic is impaired in rabbits with renal hypertension. The purpose of this study was to determine if the locus of the abnormality is mainly in the brain or in the afferent limb of the reflex. Experiments were done in alpha-chloralose-anesthetized rabbits with (n = 10) or without (n = 10) hypertension induced 6 to 8 weeks before study by wrapping the left kidney in cellophane followed by removal of the right kidney. The left side of the chest was opened, and a pericardial cradle was made. Nicotine was applied to the epicardial surface of the heart in concentrations of 10 to 500 micrograms/ml, and changes in arterial pressure and renal nerve traffic were measured. Dose-dependent decreases in traffic and arterial pressure resulted that were significantly smaller in hypertensive than in normotensive rabbits. After sinoaortic baroreceptor denervation, a similar impairment in the responses of hypertensive rabbits was observed. Vagotomy nearly abolished the responses of the renal nerves to epicardial nicotine. The responses of the lumbar sympathetic nerves to epicardial nicotine also were impaired in renal hypertensive (n = 8) compared with normotensive rabbits (n = 8). If the behavior and number of chemically sensitive endings are assumed to be unaltered in hypertension, then these findings are explained best by an abnormality in the central nervous system. These results support the view that the previously reported impairment in the vagal cardiopulmonary baroreceptor reflex control of renal nerve traffic is due mainly to a central abnormality, although they do not exclude an abnormality in the afferent limb of the reflex.

Effects of hydrochlorothiazide and diltiazem on reflex vasoconstriction in hypertension.

The purpose of our study was to determine the effects of treatment with hydrochlorothiazide (n = 10) or diltiazem (n = 8) on reflex humoral, hemodynamic, and vascular responses to graded lower body negative pressure in subjects with mild to moderate hypertension (supine diastolic pressure, 95-114 mm Hg). All subjects received placebo for 2 to 4 weeks followed by either hydrochlorothiazide (25-50 mg b.i.d.) or diltiazem (120-180 mg b.i.d.) to achieve a reduction in supine diastolic pressure of 10 mm Hg or more and a final pressure below 90 mm Hg. Mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and renin responses to graded lower body negative pressure (-10, -20, -40 mm Hg) and head-up tilt were examined before and after 12 weeks of treatment with either drug. Pretreatment basal values of mean arterial pressure (114 +/- 2 vs 117 +/- 2 mm Hg), forearm vascular resistance (29 +/- 3 vs 35 +/- 7 units), and plasma renin activity (0.7 +/- 0.2 vs 0.6 +/- 0.2 ng angiotensin I/ml/hr) were not significantly different between groups. There were no significant differences in basal plasma norepinephrine or in the increases of norepinephrine in response to lower body negative pressure before and after treatment in either group. Forearm vascular resistance responses to lower body negative pressure were virtually abolished in the diltiazem-treated group but not in the hydrochlorothiazide-treated group despite similar levels of mean arterial pressure and basal forearm vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Central effect of intravenous phenylephrine on baroreflex control of renal nerves.

Responses of renal sympathetic nerve activity were determined in eight chloralose-anesthetized rabbits during sustained (1-3 minutes) increases in arterial pressure induced by phenylephrine infusion, and as arterial pressure returned to control. In four of the eight experiments, aortic baroreceptor traffic was also recorded. When arterial pressure was raised from 81 +/- 5 to 110 +/- 7 mm Hg, renal nerve activity decreased from 30 +/- 7 to 1 +/- 1 imp/sec. Aortic nerve activity increased from 208 +/- 35 to 346 +/- 49 imp/sec. When pressure returned to control (81 +/- 5 mm Hg), renal nerve activity remained inhibited (7 +/- 2 imp/sec), even though aortic nerve activity had also returned to control (195 +/- 33 imp/sec). Arterial pressure and traffic in the renal and aortic nerves returned to control over the succeeding 1 to 5 minutes. Transient increases in arterial pressure (lasting less than 1 minute) due to bolus injections of phenylephrine resulted in inhibition of renal nerve traffic followed by rapid recovery. In five rabbits with aortic and vagal nerves sectioned and both carotid sinuses isolated from the circulation, intravenous phenylephrine infusion augmented the gain of the isolated carotid baroreflex (particularly at low carotid sinus pressures). In nine experiments, injection of phenylephrine (0.01, 0.1, or 1.0 microgram) into the lateral ventricles did not change the basal renal nerve traffic but augmented the gain of the baroreflex control of the renal nerves. Our data indicate that peripherally infused phenylephrine can alter the arterial baroreflex control of the renal nerves by a central effect. The similar influence of intracerebroventricular phenylephrine on baroreflex control of the renal nerves is consistent with this view.

Prevalence and chromosomal map location of Staphylococcus aureus adhesin genes.

Using genomic DNA from 25 unrelated strains and probes specific for each gene, we assessed the prevalence of the Staphylococcus aureus (Sa) adhesion genes cna, fnbA, fnbB, fib, clfA, fbpA, ebpS and map. All 25 strains encoded fib, clfA, ebpS, map and at least one of the fnb genes. fbpA and coa appeared to be allelic variants of the same gene with the fbpA variant being present in only four of 25 isolates. cna was present in 10 of 25 strains. Using Southern blot analysis of SmaI-digested genomic DNA resolved by pulsed-field gel electrophoresis, the adhesion genes were mapped to SmaI fragments A (ebpS), B (fib and clfA), C (fnbA/fnbB), E (fbpA), F (map) and G (cna). Despite variations in SmaI restriction profiles, co-localization of adhesin genes with genes known to map to specific SmaI fragments in the Sa 8325-4 chromosome strains suggests that the chromosomal location of each adhesin gene is conserved.

New insights into pacemaker syndrome gained from hemodynamic, humoral and vascular responses during ventriculo-atrial pacing.

Ventricular pacing is performed during programmed electrical stimulation and during normal functioning of single chamber (VVI or VVIR) pacemakers. In many patients, retrograde ventriculoatrial (V-A) conduction may occur and evoke hemodynamic and reflex neurohumoral responses, which are unique to this pacing mode. Accordingly, forearm blood flow, forearm vascular resistance, mean and phasic arterial pressure, cardiac output and plasma norepinephrine, epinephrine and dopamine were measured during atrial, ventricular and V-A pacing at a cycle length of 600 ms (100 beats/min) before and after regional alpha blockade with intraarterial phentolamine in 16 patients with a left ventricular ejection fraction greater than 35% and little or no symptoms of congestive heart failure. During V-A pacing, cardiac output decreased by 10%, whereas forearm vascular resistance increased from 52 +/- 7 to 70 +/- 9 U (p less than 0.001) and plasma norepinephrine increased from 183 +/- 27 to 232 +/- 27 pg/ml (p less than 0.01). Phentolamine nearly abolished the increase in forearm vascular resistance in response to V-A pacing (18 +/- 4.1 U before vs 5.8 +/- 1.5 U after, p less than 0.05). The change in forearm vascular resistance with V-A pacing correlated with systolic arterial pressure, but not with changes in mean arterial pressure, pulse pressure, cardiac output, mean or peak right atrial pressure, pulmonary artery or pulmonary capillary wedge pressure. These results suggest that forearm vascular resistance responses to V-A pacing are mediated mainly by alpha-adrenergic receptors, through the arterial baroreflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of diltiazem on hormonal and hemodynamic responses to lower body negative pressure and tilt in patients with mild to moderate systemic hypertension.

Mean arterial blood pressure, forearm vascular resistance, plasma norepinephrine, plasma renin activity and aldosterone responses to graded lower body negative pressure and tilt at 80 degrees were examined in 10 men with mild to moderate essential hypertension before and after 12 weeks of diltiazem (240 to 360 mg/day) therapy. Diltiazem therapy lowered basal supine systolic and diastolic blood pressures without affecting basal heart rate. Mean arterial blood pressure and forearm vascular resistance were decreased from 114 +/- 1.5 to 105 +/- 1 mm Hg, p less than 0.01 and from 29.3 +/- 3.5 to 18.9 +/- 2.1 units, p less than 0.01, respectively. Diltiazem therapy had no effect on basal supine levels of norepinephrine, plasma renin activity or aldosterone, nor on the responses of these hormones to lower body negative pressure. Diltiazem did decrease the forearm vascular resistance responses to lower body negative pressure and tilt. Diltiazem abolished an orthostatic increase (10 +/- 0.3 mm Hg) in mean arterial blood pressure and this was associated with a greater plasma norepinephrine response to tilt. These results suggest that diltiazem decreases vascular resistance through a reduction in the postjunctional effects of norepinephrine on vascular smooth muscle.

Changes in regional adrenergic tone during sustained ventricular tachycardia associated with coronary artery disease or idiopathic dilated cardiomyopathy.

The hemodynamic tolerance of an episode of ventricular tachycardia (VT) can vary widely from no decrease in systolic blood pressure to severe hypotension. Little is known about the factors responsible for these different responses in man. Previous animal studies have suggested an important role for vasoconstriction mediated by the alpha-adrenergic nervous system. To determine the magnitude and time course of changes in alpha-adrenergic tone during symptomatic sustained monomorphic VT, VT cycle length, mean and phasic arterial pressure, forearm blood flow (by venous occlusion plethysmography) and forearm vascular resistance were measured in 15 patients. Nine of these patients were studied before and after regional intraarterial alpha blockade with phentolamine. After the induction of VT (350 +/- 68 ms), mean forearm blood flow decreased from 3.2 +/- 1.1 to 2.2 +/- 0.8 ml/min/100 ml (p = 0.0002) and the forearm vascular resistance increased from 32 +/- 14 to 40 +/- 14 units (p = 0.01). There were no significant differences for forearm vascular resistance during the first and last 30 seconds of VT (41.3 +/- 14 vs 37 +/- 13 units). After the infusion of intraarterial phentolamine, there were no significant changes in the VT cycle length or mean arterial pressure, but the forearm vascular resistance increase during VT was blunted by 60 to 70%. Most patients with symptomatic VT demonstrate sympathetic vasoconstriction and these changes are maximal during the first 30 seconds of VT. This sympathoexcitatory response is due largely to stimulation of alpha-adrenoreceptors and may be mediated by arterial baroreflexes.

Subnormal parasympathetic activity after cardiac transplantation.

Heart period variability (standard deviation of 120 consecutive RR or PP intervals) was used to assess baseline parasympathetic activity in 18 patients with congestive heart failure before and after orthotopic cardiac transplantation, and was compared to that of 16 age-matched control subjects. Mean heart period variability (+/- standard error of the mean) was significantly greater (p less than 0.05) in control subjects (58 +/- 5 ms) than in the patients at any time before or after transplantation. Heart period variability of innervated recipient atria did not change significantly early (1 to 4 weeks) after transplantation (16 +/- 2 to 24 +/- 5 ms; p = 0.11), but increased significantly between weeks 15 and 37 after transplantation (30 +/- 5 ms, p less than 0.002 versus before transplantation). A stepwise regression model (R2 = 0.35; p = 0.01) showed that heart period variability was directly related to time after transplantation and inversely related to systolic arterial pressure after transplantation and degree of rejection. Heart period variability of the denervated donor atria did not change from early to late periods after transplantation, suggesting that vagal reinnervation of the donor heart had not occurred. These data indicate that baseline parasympathetic activity does not increase significantly during the first month after transplantation but increases significantly between months 3 and 6.

Cardiopulmonary reflexes do not modulate exercise pressor reflexes during isometric exercise in humans.

Previous studies that measured reflex vasoconstrictor responses during isometric exercise have suggested that these responses were modulated by arterial and cardiopulmonary baroreflexes. The purpose of these experiments was to determine forearm vasoconstrictor responses to isometric handgrip alone and during two levels of cardiopulmonary baroreceptor unloading with lower body negative pressure (-5 and -10 mmHg LBNP). Handgrip combined with -5 mmHg LBNP produced vasoconstrictor responses that were significantly greater than the algebraic sum of the separate responses to handgrip and LBNP alone, thus confirming earlier studies. However, with -10 mmHg LBNP, the vasoconstrictor responses to LBNP plus handgrip were not different from the algebraic sum of the separate response to LBNP and handgrip alone. These results indicate that when the influence of cardiac baroreceptors was reduced to a greater degree (-10 mmHg LBNP) than in previous studies, no interaction was observed, whereas with less reduction (-5 mmHg LBNP) an apparent interaction was noted. These data, together with recent studies in which sympathetic nerve activity to the lower leg was measured during similar protocols, suggest nonlinearities in the relationship between sympathetic nerve activity and vasoconstrictor responses.