Harold H. Smookler

Relationships between brain catecholamine synthesis, pituitary adrenal function and the production of hypertension during prolonged exposure to environmental stress

Abstract Male rats were subjected to environmental stresses consisting of flashing lights, audiogenic stimulation and oscillation for 20 weeks on a randomized schedule. The mean systolic blood pressure in the stressed animals rose to 150mm Hg±1.01 by week 8 and ranged between 150 and 160 mm Hg for the remaining 12 weeks, whereas the mean systolic pressure of the non-stressed animals fluctuated between 110 and 120mm Hg throughout this same period of time. Serum corticosterone level in the stressed animals were approximately 3 times higher than controls for the first 4 weeks of exposure; however, by the end of week 5. serum corticosterone declined dramatically in the stressed group and was significantly lower than controls, after which serum corticosterone levels exhibited a cyclic pattern at approximately 6-week intervals. No significant alterations were observed in brain NE and DA and serum FFA throughout the 20-week stress exposure. In a second study, rats received 100 mg kg p.o. of L -α-methyltyrosine. At the end of weeks 2 and 4, brain NE was depleted by more than 80° in the stressed treated group, whereas brain NE in the non-stressed treated animals was depleted by approximately 45°. indicating a significant increase in the turnover of brain NE The elevated turnover of brain NE returned to control values by the end of the 6th week. In addition, a-MT prevented the stress-induced elevation in systolic blood pressure. These data indicate a close temporal relationship between brain NE synthesis rate and adrenocortical steroid secretion as well as demonstrating that a-MT is an effective antihypertensive agent in stress-induced hypertension.

Sympathetic nerve function and DOCA-NaCl induced hypertension

Abstract Repeated treatment with 6-hydroxydopamine (6-HD) failed to influence the onset or maintenance of DOCA-NaCl induced hypertension in rats or to produce a sustained hypotension in normotensive rats. The DOCA-NaCl induced decrease in serum potassium and increase in urinary excretion and skeletal muscle water content were also unaffected by 6-HD. Measurements of adrenergic cardiovascular reactivity demonstrated a severe deficiency of sympathetic nerve function as a result of the 6-HD treatment. These results indicate that sympathetic postganglionic nerve function is not necessary for the pathogenesis or maintenance of DOCA-NaCl induced hypertension.

Cardiovascular and Biochemical Effects of Chronic Intermittent Neurogenic Stimulation

Investigators have called attention to the unresolved psychologic conflicts which give rise to chronic emotional tension which they believe are specific etiological factors in the development of such diseases as hypertension, coronary vascular disease and gastrointestinal ulcers in man (1–3). Selye (4–6) has postulated that organisms subjected to alarming stimuli will respond in a given manner, which he termed “the general adaptation syndrome” or “stress syndrome.” Barry and Buckley (7) have reviewed in detail the effects of exposing animals to stress upon their behavioral performance as well as physiological, biochemical, and endocrinological function. Various types of stimuli can act as the systemic stressors and produce all three stages of the general adaptation syndrome. Audiogenic stimuli have been found to induce cardiovascular changes (8,9), changes in adrenal weights and adrenal ascorbic acid (10) and death (11). Herrington and Nelbach (12) exposed rats to a complex type of stimulation including audiogenic and cage vibration and observed changes in the experimental animals similar to those produced by thyroid overdosage. Hudak and Buckley (13) modified this procedure and subjected rats to a combination of audiogenic stimuli, visual stimuli, and motion.

Cardiovascular effects of chronic reserpine administration in mongrel dogs

Abstract Twenty-four mongrel dogs received small oral doses of reserpine daily for 12–13 months. Chronic administration of low doses of reserpine did not induce significant alterations in arterial blood pressures; however, there was a gradual, significant decrease in heart rate. Studies on autonomic function revealed a certain degree of impairment of cardiovascular reflexes and sympathetic tone. Hypotensive response to hexamethonium was inhibited in reserpine-treated dogs. At the termination of the study, left ventricular work was significantly lower and cardiac output decreased in the reserpine-treated group under pentobarbital anesthesia. Although the right ventricular contractile force and rate of tension development were significantly greater in the reserpine-treated group, the stroke volumes were not. Greater pressor responses obtained to intravenous administration of epinephrine and norepinephrine in the reserpine group were due to a greater elevation of total peripheral resistance rather than cardiac output. It is concluded that the efficiency of the right ventricular myocardium was attenuated in the dogs treated with reserpine.

Prolonged Administration of Hydrochlorothiazide on Cardiac Function in Beagle Dogs

Conclusions Chronic administration of hydrochlorothiazide (10 mg/kg, po for 12 months) to beagle dogs failed to produce any alterations in blood pressure and heart rate, despite a significant reduction in cardiac output, stroke volume, and stroke work. Analysis of ventricular function curves indicates a diminution in contractility of the myocardium in the treated animals. It is concluded from this investigation that the adverse effects of HCT on the myocardium in the face of increased total peripheral resistance noted in this study may warrant careful reevaluation of this agent in cardiovascular therapy. This study was supported by Public Health Service Grant GM-15587. The authors express their appreciation to Dr. John E. Baer of Merck Institute of Therapeutic Research, West Point, PA, for generously supplying hydrochlorothiazide, and to Messrs. Charles Parham and David Snyder for their valuable technical assistance.

Acute effects of 6-hydroxydopa and its interaction with dopa on brain amine levels

Abstract The intravenous administration of 400 mg/kg of DL-6-hydroxydopa (6-OH-DOPA) to mice markedly depleted whole brain norepinephrine (NE). Whole brain levels of dopamine (DA) were not affected whereas 5-hydroxytryptamine (5-HT) levels were slightly elevated. These findings show that even after a high dose of 6-OH-DOPA only brain NE appears to be markedly affected. This action might be mediated indirectly, through the endogenous formation of 6-hydroxydopamine. DL-DOPA (DOPA), 400 mg/kg given intraperitoneally, failed to alter the whole brain level of NE, but depleted brain 5-HT while elevating brain DA. The increase in DA and reduction in 5-HT caused by DOPA were greatly potentiated by prior treatment with 6-OH-DOPA. Although the mechanism of this interaction is unknown, the enhanced effectiveness of DOPA following 6-OH-DOPA administration provides in vivo evidence that DOPA-induced depletion of 5-HT may be mediated by endogenously formed DA.

A CENTRAL SITE OF ACTION OF ANGIOTENSIN II AND ITS POSSIBLE ROLE IN THE CENTRAL REGULATION OF THE CARDIOVASCULAR SYSTEM

Publisher Summary Angiotensin II is capable of evoking a neurally mediated hypertensive response when administered into the vascularly isolated, neurally intact head of the recipient animal in the dog cross-circulation preparation. The centrally induced pressor responses were neither a result of activation of reflexogenic mechanisms nor hypoxia. This chapter discusses the central neurologic components of the angiotensin-induced pressor responses and identifies the central sites of action of angiotensin II when administered into the cerebrospinal fluid. Angiotensin I administered via the cerebral lateral ventricles of α-chloralose anesthetized cats produces marked pressor effects. The chapter also presents the data supporting the hypothesis that the centrally induced pressor effects are caused by an increase in adrenergic outflow from the central nervous system, as phenoxybenzamine—5 mg/kg administered via the femoral vein—markedly attenuated the pressor response to angiotensin II administered into the cerebrospinal fluid in an earlier study.