David P. Henry

Transmural myocardial infarction in the dog produces sympathectomy in noninfarcted myocardium.

Because sympathetic fibers travel in the subepicardium and generally follow the coronary arteries in a basal to apical course, we tested the hypothesis that transmural myocardial infarction that involves this subepicardial region interrupts sympathetic axons traveling through the infarct and produces sympathetic denervation at noninfarcted sites apical to the infarction. A rapidly hardening vinyl latex solution injected into the first diagonal branch of the left anterior descending coronary artery produced the transmural myocardial infarction by embolizing the vasculature. Ten dogs were studied 90 minutes after coronary artery embolization (acute) and 12 dogs were studied 7–21 days after infarction (chronic). The integrity of the sympathetic innervation was tested in an open-chest preparation of the acutely and chronically infarcted dogs by measuring endocardial and epicardial effective refractory period changes during left and right stellate stimulation. Additionally, regional myocardial norepinephrine content and fluorescence were examined in the chronically infarcted dogs. Transmural infarction was verified using nitroblue tetrazolium staining. In the 10 acutely infarcted dogs, left and right stellate stimulation shortened the effective refractory period at all 56 sites examined before infarction and at 30 sites basal or lateral to the infarction after embolization. Twenty-six noninfarcted sites apical to, but not within, the zone of infarction did not respond to left or right stellate stimulation after infarction. In the 12 chronically infarcted dogs, left and right stellate stimulation shortened the effective refractory period at all 20 sites basal to infarction. In noninfarcted sites apical to the infarction, left stellate stimulation did not shorten the eifective refractory period at 23 of 41 sites, while right stellate stimulation was ineffective at 24 of 41 sites. Both left and right stellate stimulation were ineffective at 18 of 41 sites. Twelve of 41 sites apical to the infarct had normal effective refractory period shortening during left and right stellate stimulation. In both groups of dogs, norepinephrine infusion, 0.05, ug/kg/min, i.v., shortened the refractory period at all sites apical to the infarct that did not shorten refractory period in response to stellate stimulation. In chronically infarcted dogs, myocardial norepinephrine content was reduced at the denervated sites, and histologically reduced norepinephrine fluorescence in noninfarcted, denervated myocardium was found. We conclude that transmural myocardial infarction produces heterogeneous sympathetic denervation in noninfarcted sites apical to the area of necrosis. This denervation is probably the result of interrupting sympathetic nerves coursing from base to apex.

Vasopressin response to orthostatic hypotension: Etiologic and clinical implications

Plasma vasopressin was measured before and after tilt testing in 18 patients with orthostatic hypotension of various causes. In six patients, all of whom had normal osmotic regulation of vasopressin, normal stimulation of vasopressin did not occur on tilt testing; all six had clinical evidence of defects in the afferent or central connections of the baroregulatory reflex arc. In the remaining 12 patients, plasma vasopressin increased to levels appropriate for the degree of hypotension; none of these patients had clinical evidence of defects in afferent or central portions of the baroregulatory arc. Those with subnormal vasopressin response had significantly more severe orthostatic hypotension than the patients with normal vasopressin response, but none had plasma hypotonicity, an abnormality present in one-quarter of those with normal response. It is concluded that the vasopressin response to orthostatic hypotension may serve as a test of the integrity of the afferent and central components of the baroregulatory reflex arc. Furthermore, this study suggests that the normal vasopressin response to orthostatic hypotension may moderate the fall in blood pressure but may adversely affect water balance.

Direct effect of beta-adrenergic stimulation on renin release by the rat kidney slice in vitro.

Controversy exists regarding the mechanism by which catecholamines stimulate rennin secretion in vivo. A sensitive rat kidney slice system was utilized to study the direct effects of adrenergic agonists and antagonists on renin release in vitro. Catecholamines were protected from degradation by the addition of ascorbic acid to the incubation medium. Significant dose-related stimulation of renin release was observed with epinephrine and norepinephrine in concentrations from 1.5 x 10−9 to 1.5 x 10−7M and with isoproterenol in concentrations from 2 x 10−9 to 2 x 10−7M. No significant stimulation was seen with 10−10M concentrations of the three agents. Methoxamine (10−6M) stimulated renin release significantly (P < 0.01). The stimulation observed with epinephrine, norepinephrine, or isoproterenol was blocked by d, l- and l-propranolol (2 x 10−4M) but not by d-propranolol (2 x 10−4M) or phentolamine (9 x 10−4M). Methoxamine-induced stimulation was abolished by d, l-propranolol but not by phentolamine. These data indicate that the in vitro kidney slice system is responsive to physiological concentrations of catecholamines when they are protected from degradation. The results further demonstrate a direct stimulatory role for β-adrenergic agents on renin release and suggest that α-adrenergic effects seen in vivo are mediated indirectly by hemodynamic, vascular, or functional changes in the kidney.

Decarboxylation of p-Tyrosine: A Potential Source of p-Tyramine in Mammalian Tissues

The question of the existence of a p‐tyrosine decarboxylase pathway for the formation of p‐tyramine in mammalian tissues remains unresolved. Development of a sensitive and specific assay for p‐tyrosine decarboxylase has permitted demonstration of this activity in rat tissues and human kidney. Tyrosine decarboxylase was purified to electrophoretic homogeneity by pH 5.0 precipitation, ammonium sulfate precipitation, gel filtration, phenyl‐Sepharose chromatography, DEAE‐Sephacel chromatography, and preparative isoelectric focusing. A specific rabbit antiserum to tyrosine decarboxylase was also obtained. Purified tyrosine decarboxylase possessed a narrow pH dependency with an optimum at 8.0. Benzene and certain other organic solvents dramatically stimulated tyrosine decarboxylase activity of purified enzyme. Purified tyrosine decarboxylase activity also decarboxylated L‐DOPA, 5‐hydroxytryptophan, 3,4‐dihydroxyphenylserine, o‐tyrosine, m‐tyrosine, phenylalanine, histidine, and tryptophan, which suggested that the purified enzyme was aromatic L‐amino acid decarboxylase. This conclusion was supported by a constant ratio of 5‐hydroxytryptophan decarboxylase to tyrosine decarboxylase throughout the purification scheme and by parallel immunoprecipitation of decarboxylase activities by the specific antityrosine decarboxylase antisera. Thus, we report that p‐tyrosine is decarboxylated by aromatic L‐amino acid decarboxylase and that this metabolic transformation may be an important source of p‐tyramine in mammalian tissues. In conclusion, neuronal tissues that synthesize catecholamines or serotonin should now be considered capable of synthesizing p‐tyramine and other biogenic amines.

Effect of hypoxemia on sodium and water excretion in chronic obstructive lung disease

To determine the role of hypoxemia in the pathogenesis of impaired sodium and water excretion in advanced chronic obstructive lung disease, 11 clinically stable, hypercapneic patients requiring long-term supplemental oxygen were studied. The renal, hormonal, and cardiovascular responses to sodium and water loading were determined during five-and-a-half-hour studies on a control day (arterial oxygen tension = 80 +/- 6 mm Hg) and on an experimental day under hypoxic conditions (arterial oxygen tension = 39 +/- 2 mm Hg). Hypoxemia produced a significant decrease in urinary sodium excretion but did not affect urinary water excretion. Hypoxemia also resulted in concomitant declines in mean blood pressure, glomerular filtration rate, and filtered sodium load. Renal plasma flow and filtration fraction were unchanged whereas cardiac index rose. On the control day, plasma renin activity and norepinephrine levels were elevated whereas aldosterone and arginine vasopressin levels were normal; none of these four hormones was affected by hypoxemia. Renal tubular function did not appear to be altered by hypoxemia as there was no significant change in fractional reabsorption of sodium. The concurrent decreases in glomerular filtration rate, filtered sodium load, and mean blood pressure at constant renal plasma flow suggest that the reduction in urinary sodium excretion was due to an effect of hypoxemia on glomerular function, possibly related to impaired renovascular autoregulation.

Diagnosis and localization of pheochromocytoma: Detection by measurement of urinary norepinephrine excretion during sleep, plasma norepinephrine concentration and computerized axial tomography (CT-scan)

The feasibility of differentiating patients with pheochromocytoma from other hypertensive patients by measuring urinary excretion rates of norepinephrine during sleep, a period of physiologic suppression of norepinephrine release, was investigated. The mean excretion rates of norepinephrine in 248 normal subjects and in 109 patients with essential hypertension were 1.03 +/- 0.03 and 1.12 +/- 0.06 (SEM) micrograms/hour, respectively, whereas the lowest excretion rate among the six patients with pheochromocytoma was about seven times higher. Plasma norepinephrine concentration in patients with pheochromocytoma was also consistently above the range observed in both normotensive and hypertensive subjects. CT scan correctly identified the same tumors visualized by selective arteriography. It is suggested that the usefulness of these approaches will provide simpler means of screening and detecting pheochromocytoma.

Release of histamine in rat hypothalamus and corpus striatum in vivo

Histamine has remained a putative neurotransmitter for many years, partially because some of the criteria necessary to define it as a central nervous system neurotransmitter have not been established. The demonstration of in vitro release and the quantification of turnover as an indirect measure of release have been complicated by the histological evidence for multiple histamine pools in the central nervous system. In brain, there are multiple cell types which probably contain histamine. These cells include mast cells, neurolipomastocytoid cells, microvascular endothelial cells, and a histaminergic neuronal system which has been visualized using immunocytochemical methods. Using in situ brain microdialysis and a sensitive and specific radioenzymatic assay for histamine, we have identified histamine in the extracellular space of the rat hypothalamus and corpus striatum in vivo. Following neuronal selective stimuli, significant increases in extracellular histamine levels only were observed in the posterior hypothalamus, where dense histaminergic neuronal terminals have been described. However, after manipulations targeted towards histamine-containing mast cells, such increases were seen in both the posterior hypothalamus and corpus striatum. In summary, this study demonstrates that endogenous histamine can be released from the posterior hypothalamus by stimuli targeted towards histamine neurons and that histamine may also be released by non-neuronal mast cell elements.

The possible role of the catecholamines of the corpora in penile erection.

The etiology of impotence, which effects 50 per cent of the men with diabetes, is unknown. The neurotransmitter (norepinephrine) released from adrenergic neurons is thought to be the most direct regulator of vascular smooth muscle. We have measured the norepinephrine content of the erectile tissue of diabetic men. Our results indicate the presence of a dual neural regulator mechanism of the corpora that controls penile erection.

Increase in plasma norepinephrine during prazosin therapy for chronic congestive heart failure.

To investigate the mechanism of pharmacodynamic tolerance reported to occur during prazosin therapy of chronic congestive heart failure, we measured plasma norepinephrine, plasma epinephrine, plasma renin activity (PRA) and plasma aldosterone, as well as hemodynamics in eight patients with chronic congestive heart failure, functional class III and IV (NYHA), before and during 10 weeks of prazosin therapy. Initially, prazosin therapy produced significant hemodynamic improvement, but no significant changes were noted in norepinephrine, epinephrine, plasma renin activity or aldosterone. During ambulatory therapy, fluid retention developed in four patients, and three of them had symptoms or clinical evidence of congestive heart failure for which they required an increase in diuretic or prazosin therapy. Plasma norepinephrine levels for the whole group were significantly higher after four weeks of therapy (p less than 0.01). Repeat inpatient studies after 10 weeks showed a persistent hemodynamic response to prazosin in seven patients. One patient demonstrated complete hemodynamic tolerance whereas three others showed partial tolerance. In these four patients the cardiac output increased only to 3.78 +/ 1.17 liters/min compared to 5.04 +/- 2.11 liters/min during initial prazosin therapy. Plasma norepinephrine increased further and levels were significantly higher for the whole group than before prazosin therapy (p less than 0.05). No significant changes in epinephrine, plasma renin activity or aldosterone were demonstrated. This increase in plasma norepinephrine suggests that the sympathetic nervous system could be involved in the pharmacodynamic tolerance to prazosin therapy in congestive heart failure. Further studies are necessary to extend these results.

Shock in an infant with bullous mastocytosis

Abstract: A 6‐month‐old infant had bullous lesions on his posterior neck, upper trunk, and extremities for two months prior to admission for fever and shock. He had an elevated white blood cell count with left shift and normal platelet count, but abnormal coagulation studies. He was treated with intravenous antibiotics, crystalloids, fresh‐frozen plasma, and pressor agents. A histamine H2 receptor antagonist was started for guaiac‐positive nesogastric tube drainage. The patient recovered after four days of treatment. A skin biopsy confirmed mastocytosis. A week iater the child passed grossly bloody stools with blood clots. No source of gastrointestinal bleeding was identified by extensive work‐up. Blood histamine level measured one day before gastrointestinal bleeding was 16,400 pg/ml (normal 263±202 pg/ml). The bleeding resolved spontaneously. The patient was maintained on cimetidine. Results of a subsequent bone scan were normal. Shock or gastrointestinal bleeding associated with unusual skin lesions should alert the pediatrician to the possibility of mastocytosis.