Michael D. Nyby

Blood pressure and hormone changes associated with weight reduction in the obese.

This study examines factors modulating blood pressure reduction in obese patients undergoing weight reduction on a low calorie protein diet. Plasma norepinephrine (NE) was correlated (r = 0.65, p less than 0.01) with blood pressure in 20 obese patients prior to weight loss. Reductions in blood pressure levels following upright posture and isometric handgrip exercise were related to reduction in NE levels after these maneuvers. While plasma epinephrine levels declined in parallel with NE levels, plasma dopamine actually increased (p less than 0.05) during the first 2 weeks of caloric restriction. Prior to weight loss the obese patients demonstrated a significant rise in prolactin levels following posture and exercise, but following caloric restriction this was not observed. Levels of plasma renin activity (PRA) and aldosterone obtained after posture and exercise maneuvers were reduced after 8 weeks of caloric restriction, and reductions in PRA were related to reductions in NE (r = 0.56, p less than 0.01). Reductions in blood pressure in association with caloric restriction in these obese patients seems to result, in part, from reduced sympathetic nervous system activity as well as secondary effects of reduced adrenergic activity on renal sodium excretion and the renin-angiotensin-aldosterone axis.

Vascular Angiotensin type 1 receptor expression is associated with vascular dysfunction, oxidative stress and inflammation in fructose-fed rats.

This study determined whether or not oxidative stress and vascular dysfunction in fructose-induced hyperinsulinemic rats are associated with activation of the vascular renin-angiotensin system (RAS). Four groups of rats were used. CONT rats were fed normal rat chow, CONT+CAP were fed normal rat chow and given 500 mg/L captopril in their drinking water, fructose-fed rats (FFR) were fed a high-fructose diet and FFR+CAP were fed the high-fructose diet plus captopril in water. After 8 weeks, the vascular reactivity of mesenteric artery segments was measured. Blood was analyzed for insulin, glucose, hydrogen peroxide and 8-isoprostane. Aortic and heart tissue were used for subjected to quantitative reverse transcription–polymerase chain reaction (qRT-PCR) analysis. Systolic blood pressure was significantly higher in FFR (p<0.05), and captopril treatment inhibited the blood pressure increase. Mesenteric artery dose-response curves to acetylcholine were shifted to the right in FFR (p<0.05) and were normal in FFR+CAP. Plasma insulin (p<0.05), hydrogen peroxide (p<0.02) and 8-isoprostane (p<0.05) were increased in FFR. Captopril treatment reducd hydrogen peroxide and 8-isoprostane concentrations. Aortic tissue mRNA expression levels were increased for angiotensin-converting enzyme (ACE, p<0.05), angiotensin type 1 receptor (AT1R, p<0.02), NOX4 (p<0.02) and VCAM-1 (p<0.05) in FFR aortic samples. Captopril treatment reduced AT1R, NOX4 and VCAM-1 expression in FFR to levels not different from CONT. Similar changes in heart tissue mRNA expression for angiotensinogen, AT1R and NOX4 were also observed. These results demonstrate that vascular RAS is upregulated in FFR and support the hypothesis that vascular RAS mediates vascular dysfunction and vascular oxidative stress in FFR.

Dopaminergic control of prolactin and blood pressure: altered control in essential hypertension.

This study examines the influence of dopamine on plasma catecholamine, prolactin (PRL), and mean arterial pressure (MAP) responses to upright posture and isometric handgrip exercise and the recumbent circadian PRL and MAP patterns in essential hypertension. Nine men with sustained essential hypertension and nine age- and weight-matched normotensive controls were studied after they had reached metabolic equilibrium on a constant intake of 100 mEq sodium and 80 mEq potassium. The hypertensive group, but not the normotensive group, displayed a PRL response to upright posture and isometric handgrip. Hypertensives and normotensives had similar basal supine catecholamine levels and similar epinephrine and dopamine responses to posture and handgrip. The hypertensives had greater (p < 0.01) norepinephrine (NE) responses to posture and handgrip than did the normotensives. Bromocriptine (BEC) depressed supine basal MAP in the hypertensives but not in the normotensives. BEC markedly decreased the basal PRL levels in both groups. BEC eliminated the PRL response to posture in the hypertensives and depressed the NE response to posture and handgrip to a greater extent (p < 0.01) in the hypertensives than in the normotensives. In the control period, a clear circadian rhythm of PRL and MAP was noted in both groups. In both groups an increase in PRL concentration occurred between 60 to 90 minutes after sleep onset, and was followed by several larger secretory episodes resulting in progressively higher levels during the night with peak values occurring at the end of the sleep period, generally at 0500 to 0600 hours. During the hour after awakening, a fall in PRL concentration began, and lowest levels were reached at approximately 1100 hours in both groups. The mean 24-hour PRL levels in the hypertensive group (12.6 ± 0.5 ng/ml) were higher (p < 0.01) than in the normotensives (10.8 ± 0.4 ng/ml). During the waking hours, there was a correlation (r = 0.57, p < 0.01) between recumbent PRL levels and MAP. BEC therapy lowered MAP levels throughout the 24 hours in the hypertensive group. BEC also eliminated the circadian rhythm of PRL secretion. Thus, circadian variations in PRL secretion and blood pressure appear to be modulated by a central and/or peripheral dopaminergic mechanism. Decreased dopaminergic activity in essential hypertension may account, in part, for aberrances in PRL secretion and elevated blood pressure in this disease state. (Hypertension 4: 431–438, 1982)

Dissociation of 24-hour catecholamine levels from blood pressure in older men.

Increased plasma norepinephrine levels have been observed in some persons with early essential hypertension. Although both plasma norepinephrine level and mean arterial blood pressure rise with age, little is known about the state of catecholamine secretion in elderly patients with essential hypertension. We studied the 24-hour cycle levels of plasma norepinephrine, epinephrine, and dopamine in 12 elderly hypertensive subjects and 13 age-matched normotensive controls (mean ages, 63.8 +/- 1.2 yr and 64.8 +/- 1.8 yr [SEM] respectively). Blood samples were obtained at bihourly intervals from 0900 to 2100 hours and every 30 minutes from 2100 to 0900 hours, during which time sleep and breathing were continuously monitored. A circadian rhythm was displayed in both groups by plasma epinephrine levels (mesor, 49 +/- 2 pg/ml and 38 +/- 1 pg/ml; amplitude, 15 +/- 2 pg/ml and 11 +/- 1 pg/ml; acrophase, 12.20 +/- 0.40 hr and 14.41 +/- 0.34 hr in the normotensive and hypertensive groups respectively) but not by plasma norepinephrine or dopamine levels. During the 24-hour cycle plasma epinephrine, but not norepinephrine or dopamine, levels were positively related to mean arterial blood pressure (r = 0.60 for the normotensive subjects, r = 0.57 for the hypertensive subjects, p less than 0.01 for both).(ABSTRACT TRUNCATED AT 250 WORDS)

Eicosapentaenoic acid inhibits Ca2+ mobilization and PKC activityin vascular smooth muscle cells*

BACKGROUNDnEicosapentaenoic acid is a fish oil fatty acid that has been shown to decrease blood pressure (BP) in humans. The mechanism by which this fatty acid produces this effect is unknown. Angiotensin II increases BP by inducing vasoconstriction of vascular smooth muscle cells, an event that is mediated by an increase of intracellular calcium and an increase of protein kinase C activity.nnnMETHODSnWe determined the effects of eicosapentaenoic acid on angiotensin II-induced calcium signaling, and protein kinase C activity in cultured rat aortic smooth muscle cells. Incorporation of eicosapentaenoic acid into cell phospholipids was determined by gas chromatography/mass spectrometry. Intracellular calcium concentration was determined using fura-2, and protein kinase C activity was assessed by an ELISA assay using a phospho-specific antiserum for protein kinase C substrates.nnnRESULTSnWe found that eicosapentaenoic acid was incorporated into cell phospholipids within 20 min. Eicosapentaenoic acid (10 or 25 micromol/L) did not alter basal intracellular calcium concentration, but decreased the peak response to 100 nmol/L angiotensin II. Eicosapentaenoic acid also decreased the amount of calcium released by thapsigargin, a drug that releases calcium from the sarcoplasmic reticulum, and decreased cation influx after angiotensin II stimulation. Angiotensin II stimulated phosphorylation of protein kinase C substrates. Preincubation of cells with 10 or 25 micromol/L eicosapentaenoic acid significantly inhibited this phosphorylation.nnnCONCLUSIONSnOur results demonstrate that acute incorporation of eicosapentaenoic acid into vascular smooth muscle cell phospholipids inhibits intracellular calcium mobilization and protein kinase C activation. These are potential mechanisms by which eicosapentaenoic acid reduces vasoconstriction.

Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto–Kakizaki rats

Sympathetic hyperactivity has an important role in cardiovascular mortality in patients with type 2 diabetes (T2D). Thyrotropin-releasing hormone (TRH)-containing fibers innervate autonomic motor and premotor nuclei of the brainstem and spinal cord that regulate cardiovascular functions. We compared cardiovascular responses to application of TRH-analog in the brainstem of Wistar and T2D Goto–Kakizaki (GK) rats. GK rats exhibited basal systolic hypertension (152±2u2009mmu2009Hg) and had a significantly potentiated, dose-related hypertensive response to intracisternal (i.c.) injection of the TRH-analog RX77368 (10–60u2009ng). In GK rats only, i.c. RX77368 (30–60u2009ng) markedly increased heart rate (HR; +88u2009b.p.m.) and induced acute cardiac mortality (100%), concurrent with extreme hyperglycemia (>26u2009mmolu2009l−1), increased plasma H2O2 and 8-isoprostane, and enhanced heart expression of NADPH oxidase 4 and vascular cell adhesion molecule-1 mRNAs. GK rats also had elevated basal plasma epinephrine, higher adrenal gene expression of tyrosine hydroxylase and dopamine β-hydroxylase (DβH), and greater plasma catecholamine and adrenal DβH responses to i.c. TRH-analog, compared with Wistar rats. In GK rats, hexamethonium blocked i.c. RX77368-induced hypertensive and tachycardic responses, and reduced mortality by 86%, whereas phentolamine abolished the hypertensive response but enhanced tachycardia (+160u2009b.p.m.), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented i.c. RX77368-induced increases in blood pressure, HR and mortality. In conclusion, sympathetic overactivation triggered by brainstem TRH contributes to the mechanism of cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to sympathetic drive, and a mediating role of the renin–angiotensin system.

Restoration of Hypoxic Pulmonary Vasoconstriction following Normoxia in Isolated Dog Lungs Occurs in the Presence but Not in the Absence of Prostaglandin Synthesis Inhibitors

We examined the possibility that eucapnic (6% CO2) alveolar hypoxia (3% O2) in isolated dog lungs not only produces an increase in pulmonary vascular resistance but also initiates the subsequent prostaglandin (PG) dependent reduction in this hypoxic pulmonary vasoconstriction (HPV). We determined that a reduction in HPV occurred after 45 min including a 35-min period of hypoxia (prolonged hypoxia), after 45 min of intermittent hypoxia, and after 45 min of normoxia (14% O2). These reductions were PG dependent, since they were reversed or prevented by PG synthesis inhibitors in the autologous blood perfusate. In addition to the PG-dependent reduction that required 45 min to develop, a separate reduction in HPV also occurred. This reduction occurred during prolonged hypoxia, was not prevented by PG synthesis inhibitors, was reversed after 6 min of normoxia, and was reproduced in a second period of prolonged hypoxia. We conclude that alveolar hypoxia did not initiate the PG-dependent reduction in HPV, since it occurred after normoxia as well as after hypoxia. However, hypoxia appeared to contribute to a separate PG-independent reduction in HPV, since this reduction was initiated and maintained exclusively during prolonged hypoxia and was unaffected by PG synthesis inhibitors.