James R. Sowers

Enhanced 24-hour norepinephrine and renin secretion in young patients with essential hypertension: relation with the circadian pattern of arterial blood pressure.

This study examines the possibility that 24-hour differences in blood pressure (BP) regulation between hypertensive and normotensive subjects is related to changes in 24-hour secretory patterns in circulating pressor hormones. Nine young subjects with normal BP and 9 patients with essential hypertension (EH) were studied during 24-hour recumbency. Every 20 minutes samples were taken to determine plasma norepinephrine (NE) levels and plasma renin activity (PRA). BP was measured every 20 minutes by automatic recording. A distinct circadian rhythm was demonstrated for mean BP, NE and PRA in both groups. Nocturnal reductions in mean BP, NE and PRA related best to the sleep-wakefulness cycle in both groups. Circadian changes in mean BP correlated with NE levels in both normal subjects and patients with EH. The most striking difference between the 2 groups was the absolute levels of mean BP, NE and PRA, which were higher in the EH group at most time points in the 24-cycle. Differences in levels of NE and PRA between the 2 groups were most accentuated during sleep. Thus, young persons with EH show evidence of enhanced sympathetic nervous activity throughout the 24-hour cycle, which is most pronounced during sleep. The multiple sampling approach offers a more sensitive indicator of the role of pressor hormones in BP maintenance.

Salt sensitivity and systemic hypertension in the elderly

Aging in industrialized societies is accompanied by increases in the incidence and prevalence of hypertension, with a disproportionately greater increase occurring among aging blacks than among aging whites. This geriatric hypertension is generally of a salt-sensitive nature with a disproportionate frequency of isolated systolic hypertension. Although salt-taste acuity declines with age, salt sensitivity among the elderly does not appear to result from a compensatory increase in salt intake. Rather, age-related increases in salt sensitivity result, in part, from a reduced ability to appropriately excrete a salt load, which is due to a decline in renal function and to a reduced generation of natriuretic substances such as prostaglandin E2 and dopamine. Age-associated declines in the activity of membrane sodium/potassium-adenosine triphosphatase (Na/K-ATPase) may also contribute to geriatric hypertension because this results in increased intracellular sodium that may cause reduced sodium-calcium exchange and thereby increase intracellular calcium and vascular resistance. Reductions in cellular calcium efflux due to reduced calcium-ATPase activity may similarly cause an increase in intracellular calcium and vascular resistance. Increasing dietary calcium intake may represent an effective nonpharmacologic treatment for some salt-sensitive persons because it appears to reduce intracellular calcium by (1) suppressing parathyroid hormone-mediated calcium influx, (2) increasing Na/K-ATPase activity, and (3) reducing intravascular volume due to calcium-induced natriuresis.

Sleep related breathing disorders in older men: A search for underlying mechanisms ☆

The incidence of sleep-related breathing disorders (SRBDs) associated with hemoglobin desaturation was determined by nocturnal polygraphic evaluations in 26 healthy men, aged 55-70 years. Sixteen subjects (62%) had abnormal rates of at least 12 episodes per hour of sleep: 8 had occlusive, and 8 had central apnea or hypopnea. During waking ten of 16 SRBD subjects and only one subject without SRBDs exhibited either an elevated nasopharyngeal airway resistance (n = 4) or a reduced ventilatory response to hypercapnia (n = 4) and/or hypoxia (n = 3). However, these abnormalities were not related to the type or severity of SRBDs, and 6 subjects with SRBDs demonstrated no respiratory defect. We conclude that SRBDs have a very high incidence in older males and are not usually secondary to pulmonary cardiac, neurological, or behavioral disorders. Additionally, we hypothesize that abnormalities in ventilatory control or upper airway resistance contribute to SRBDs, but depression of brain stem reticular formation activity during sleep plays a primary role in these disorders. Factors related to both aging and SRBDs are reviewed. These include reduced chemoreceptor responses, altered steroid hormone metabolism, and use and metabolism of hypnotic drugs and alcohol.

Oxidative Stress-Mediated Mitochondrial Dysfunction Contributes to Angiotensin II-Induced Nonalcoholic Fatty Liver Disease in Transgenic Ren2 Rats

Emerging evidence indicates that impaired mitochondrial fatty acid beta-oxidation plays a key role in liver steatosis. We have recently demonstrated that increased angiotensin (ANG) II causes progressive hepatic steatosis associated with oxidative stress; however, the underlying mechanisms remain unclear. We hypothesized that ANG II causes hepatic mitochondrial oxidative damage and impairs mitochondrial beta-oxidation, thereby leading to hepatic steatosis. We used the Ren2 rat with elevated endogenous ANG II levels to evaluate mitochondrial ultrastructural changes, gene expression levels, and beta-oxidation. Compared with Sprague-Dawley littermates, Ren2 livers exhibited mitochondrial damage and reduced beta-oxidation, as evidenced by ultrastructural abnormalities, decrease of mitochondrial content, percentage of palmitate oxidation to CO(2), enzymatic activities (beta-HAD and citrate synthase), and the expression levels of cytochrome c, cytochrome c oxidase subunit 1, and mitochondrial transcription factor A. These abnormalities were improved with either ANG II receptor blocker valsartan or superoxide dismutase/catalase mimetic tempol treatment. Both valsartan and tempol substantially attenuated mitochondrial lipid peroxidation in Ren2 livers. Interestingly, there was no difference in the expression of key enzymes (ACC1 and FAS) for fatty acid syntheses and their transcription factors (SREBP-1c and ChREBP) between Sprague-Dawley, untreated Ren2, and valsartan- or tempol-treated Ren2 rats. These results document that ANG II induces mitochondrial oxidative damage and impairs mitochondrial beta-oxidation, contributing to liver steatosis.

Increased basal arterial smooth muscle glucose transport in the zucker rat

Insulin has recently been reported to stimulate glucose transport in vascular smooth muscle cells (VSMC). This observation suggests a role for this hormone in hypertension associated with insulin resistance. To determine whether VSMC glucose transport abnormalities exist in a state of insulin resistance, we studied basal and insulin-stimulated glucose transport in VSMC derived from Zucker lean (normotensive, insulin sensitive) and obese (hypertensive, insulin resistant) rats. Basal glucose transport, as measured by tracer quantities of [3H]2-deoxyglucose, was 4.2 +/- 0.8 and 7.4 +/- 0.9 fmol/10(6) cells/min for lean and obese cells, respectively (P < .05). Kinetic analyses utilizing variable concentrations of unlabeled 2-deoxyglucose in the media revealed that increased transport in the obese rat was due to an increased Vmax of the transporter system: Vmax = 5.9 +/- 0.8 and 12.1 +/- 1.2 fmol/10(6) cells/min for lean and obese cells, respectively (P < .05); no changes in Km were noted for the two populations: Km = 1.14 +/- 0.24 and 0.96 +/- 0.10 mmol/L. Insulin (10 microU/mL) increased the Vmax of the transporter in both preparations, but greater stimulation was seen in the lean VSMC: 32 +/- 4.8% v 11.5 +/- 2.1% (P < .05). Insulin had no effect on the Km of the transporter in either strain. These data suggest that increased basal glucose transport in obese VSMC may predispose the vessel to increased glucose-mediated events, while blunted insulin-stimulated glucose transport in these cells mirrors insulin-resistant glucose disposal in other tissues of the obese rat.

Metoclopramide, a dopamine antagonist, stimulates aldosterone secretion in rhesus monkeys but not in dogs or rabbits.

Abstract This study was designed to investigate the role of dopamine in the control of aldosterone secretion in three frequently used laboratory animals. Five New Zealand rabbits, five mongrel dogs and five rhesus monkeys received metoclopramide (MCP) (200 μg/kg iv) and blood samples were collected at 0,5,15,30 and 45 minutes after drug administration. MCP had no effect on plasma aldosterone concentrations at any sampling time in the rabbits or dogs. However, MCP produced a rapid and marked increase in plasma aldosterone from 6.5±0.6 ng/dl to 18.1±2.8 ng/dl at 5 min. and a maximum level of 40.5±4.4 ng/dl at 10 min. after drug administration in the monkeys. MCP had no significant effect on plasma cortisol or plasma renin activity levels in the three species. Prolactin rose in the monkeys from 8.6±1.2 ng/ml to a maximum of 123.5±8.5 ng/ml at 15 min. after MCP. Administration of MCP resulted in a rise in plasma 18-hydroxycorticosterone in the monkeys from 12.5±1.4 ng/dl to a maximum concentration of 50.0±5.1 ng/dl 15 min. after drug administration. Plasma corticosterone, 11-deoxycorticosterone, and 18-hydroxydeoxycorticosterone were not altered by MCP. Although unlikely, it is possible that ketamine may have accounted for some of the changes in plasma aldosterone and 18-hydroxycorticosterone observed after metoclopramide in the monkeys. The findings suggest that dopamine modulates aldosterone biosynthesis in the monkey probably by regulating glomerulosa 18-hydroxylase activity.

Dopaminergic Modulation of Renin Activity and Aldosterone and Prolactin Secretion in the Spontaneously Hypertensive Rat

Abstract The effect of metoclopramide, a dopamine antagonist, and L-dopa on plasma aldosterone (PA), plasma renin activity (PRA), and plasma prolactin (PRL) was studied in eight spontaneously hypertensive rats (SHR) and eight Wistar-Kyoto normotensive rats (WKY). Basal PRL levels were greater (P < 0.005) in the SHR (24.3 ± 1.0 ng/ml) than in the WKY (13.7 ± 0.7 ng/ml). Baseline PA in the SHR (49.9 ± 7.2 ng/dl), although higher, were not statistically different from those in the WKY (38.0 ± 7.0 ng/dl). Basal PRA in the SHR (11.0 ± 0.6 ng/ml hr-1) was not different from that of WKY (11.4 ± 0.8 ng/ml hr-1). Although both groups of rats displayed significant PA, PRA, and PRL responses to metoclopramide the responses were greater (P < 0.01) in the SHR. These responses to metoclopramide remained exaggerated even after the rats were pretreated with L-dopa. However, administration of L-dopa resulted in similar suppression of all three hormones in the SHR and in the WKY. These findings suggest that there is altered dopaminergic modulation of secretion of PA, PRA, and PRL in the SHR. Alterations in peripheral and central dopamine control of hormone secretion may play a role in the pathogenesis of essential hypertension in the SHR.

Osmotic control of the release of prolactin and thyrotropin in euthyroid subjects and patients with pituitary tumors

The effects of acute changes in serum osmolality on basal serum PRL and TSH levels and on responses of prolactin (PRL) and thyrotropin (TSH) to the thyrotropin-releasing hormone (TRH) analogue, N3im-methyl-TRH, were studied in ten euthyroid subjects and in three patients with PRL-secreting pituitary tumors. An oral water load of 20 ml/kg had no effect on basal serum PRL or TSH levels but did result in an increased PRL response to methyl-TRH in the ten euthyroid patients. Intravenous infusion of 5% sodium chloride in the ten euthyroid subjects significantly depressed basal serum PRL levels but had no effect on the PRL response to methyl-TRH. Infusion of hypertonic saline significantly decreased the TSH response to methyl-TRH. In the three patients with pituitary tumors, oral water loading and hypertonic saline infusion had no significant effect on the basal serum PRL and TSH or the PRL and TSH responses to methyl-TRH. The patients with pituitary tumors had a higher basal serum osmolality and a proportionately higher serum concentration of arginine vasopressin than the euthyroid patients. These data suggest that changes in osmolality in euthyroid patients may have a direct effect on the anterior pituitarys PRL and TSH response to a releasing factor.

The effect of neoplasia-induced hypercalcemia on the neuroendocrine axis of the Fischer rat

The effects of neoplasia-induced hypercalcemia on the hypothalamic-pituitary axis of the Fischer rat were determined by measuring the responses of TSH to TRH, PRL to TRH and haloperidol, and LH to LHRH in 3 groups of 8 rats prior to and at 4 and 8 days after transplantation of a Leydig cell tumor. The mean serum calcium was 8.2 +/- 0.2 mg/dl in 8 Fischer rats pretransplantation; had risen at 4 days posttransplantation to 9.8 +/- 0.2 mg/dl; and at 8 days was 11.2 +/- 0.1 mg/dl. TSH response to TRH was greater in the pretransplant rats than in the groups studied at 4 and 8 days posttransplant. Basal PRL levels and PRL responses to TRH and haloperidol were less in the groups studied at 4 and 8 days posttransplant. Basal LH values were similar in all 3 groups, but the LH response to LHRH was less for the posttransplant groups. The TSH response to TRH, PRL responses to TRH and haloperidol, and LH responses to LHRH were less in the 8 days posttransplants than in the groups studied at 4 days posttransplantation. There were significant negative correlations between TSH (r = -0.79) and PRL (r = -0.80) responses to TRH, PRL responses (r = -0.94) to haloperidol and LH responses (r = -0.91) to LHRH and the serum calcium. The results indicate that increasing levels of serum calcium following Leydig cell tumor transplantation are associated with suppression of adenohypophysial release of TSH, PRL, and LH; the degree of suppression is related to the magnitude of hypercalcemia achieved in this model.

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.