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Biomedical subjects

M L Tuck

Publications and source records attributed to M L Tuck.

At least 73 records · Page 4Linked to original sources
PubMed1989

Hypotensive effects of the lipoxygenase inhibitor phenidone in two-kidney, one clip Goldblatt hypertension.

This study examined the role of the lipoxygenase (LO) pathway in the maintenance of hypertension in rats with two-kidney, one clip (2K,1C) Goldblatt hypertension. A single dose of the lipoxygenase blocker phenidone was injected intraperitoneally to 2K,1C rats during the early phase (14 days) of the development of hypertension (mean intraarterial blood pressure 137 +/- 3.9 mm Hg). Phenidone (60 mg/kg) markedly decreased arterial pressure to nadir levels of 58.9% of resting blood pressure. The maximal changes were observed 15 min after injection and the hypotensive response was sustained for at least 2 h. Plasma renin concentration (PRC) increased from 74.3 +/- 18.9 to 281.0 +/- 6.5 ng/mL/h after injection (P less than .05). Thus, the hypotensive effect of phenidone was not due to suppression of renin secretion but presumably due to inhibition of its effects. It is suggested that arachidonate metabolites of the LO pathway at the vascular bed may be involved in maintenance of high arterial pressure in 2K,1C renovascular hypertension in rat.

Animals↗
PubMed1989

Effects of central and peripheral dopamine antagonism on aldosterone secretion: evidence for adrenal mechanism.

Both domperidone (DOMP) and metoclopramide (MCP) are D2 receptor antagonists, MCP being a central and peripheral dopamine antagonist, whereas DOMP is exclusively a peripheral antagonist. MCP, but not DOMP, has been shown to stimulate aldosterone production. To elucidate whether aldosterone stimulation by dopamine antagonism is centrally mediated, we injected DOMP (28 micrograms/kg body wt) via a cannula into the third ventricle in Sprague-Dawley rats. Plasma aldosterone and renin concentration were measured before and 15 min after the injection. Centrally administered DOMP resulted in an increment in plasma aldosterone (23.8 +/- 7.4 ng/dl) that was not significantly greater than that induced by vehicle alone (15.8 +/- 4.5 ng/dl). This increase was inhibited by pretreatment with dexamethasone (100 micrograms three times daily) and attenuated by captopril (1 mg/kg ip) but not by L-beta-3,4-dihydroxyphenylalanine (30 mg/kg), thus reflecting a stress effect. Similarly, central administration of MCP (21 micrograms/kg) resulted in a significant rise in plasma aldosterone. This increase, however, was eliminated by pretreatment with dexamethasone and attenuated by captopril. Peripherally administered DOMP (280 micrograms/kg) had no effect on plasma aldosterone. The effect of DOMP and MCP on aldosterone secretion by freshly obtained adrenal capsules was also tested. Angiotensin II and MCP, but not DOMP, induced a dose-dependent increase in aldosterone secretion, with a maximal increment (15.7 +/- 5.8 ng.mg capsular protein-1.10 min-1; 50% increase) with MCP at 10(-7) M (P less than 0.01 compared with controls). Dopamine completely inhibited this MCP-induced rise in aldosterone release.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1989

Selective inhibition of angiotensin II-mediated vasoconstriction by lipoxygenase blockade.

We have previously demonstrated that the lipoxygenase (LO) pathway has a specific role in the effect of angiotensin II (ANG II) on aldosterone secretion. To elucidate whether the LO pathway also participates in the vascular effects of ANG II, the nonselective LO inhibitor phenidone (PHE; 30 mg/kg) was administered to rats 1 h before graded dose ANG II infusion. PHE reduced the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) in deendothelialized aortas by an average of 36% as determined by radiometric detection with high-performance liquid chromatography and radioimmunoassay methods. In parallel, the peak systolic pressor response to ANG II was lowered from 36.2 +/- 3.7 to 16.8 +/- 2.0 mmHg. The peak pressor responses to ANG II were also reduced by two other LO inhibitors, baicalein (30 mg/kg) and esculetin (60 mg/kg) (13.9 +/- 2.4 and 22.1 +/- 4.7 mmHg, respectively; P less than 0.01 compared with control rats for both), but not by the cyclooxygenase inhibitor indomethacin. The LO inhibitors baicalein (7.5 X 10(-5) M) and PHE (10(-4) M) markedly attenuated the in vitro contractile response to ANG II of femoral artery rings. In contrast, neither the in vivo nor in vitro constrictor responses to norepinephrine were affected by baicalein. Thus lipoxygenase blockade induces a direct and selective inhibition of ANG II-induced vasoconstriction. The LO pathway may have an important role in mediating the pressor effect of ANG II.

Angiotensin II↗
PubMed1989

Modulation of aortic smooth muscle cell membrane potential by extracellular calcium.

Removal of extracellular calcium may result in depolarization of the resting cell membrane potential. This has been attributed to the stabilizing action of calcium on the ionic permeability of the cell membrane. It is unknown whether this phenomenon is exclusively mediated by extracellular calcium or through associated changes in intracellular calcium. To examine this, we exposed rat aortic smooth muscle cells in culture to different calcium concentrations and studied their effects on the resting membrane potential and intracellular calcium activity. The resting membrane potential was dependent on the extracellular potassium concentration. Exposure to reduced extracellular calcium concentrations (0.25 and 0.5 mM) caused a steep and reversible depolarization of the membrane potential, but intracellular calcium, measured with fura 2-AM, was not reduced below that measured in control conditions (1.8 mM). Atomic absorption spectrophotometric measurements did not indicate a measurable gain in cell sodium after reduction of extracellular calcium levels. We conclude that extracellular calcium controls the resting cell membrane potential of vascular smooth muscle through a mechanism that is independent of cytosolic Ca2+ activity.

Action Potentials↗
PubMed1989

Selective inhibition of angiotensin-II-mediated aldosterone secretion by 5-hydroxyeicosatetraenoic acid.

We have previously demonstrated that the 12-lipoxygenase (12-LO) pathway plays a key role in angiotensin-II (AII)-dependent aldosterone production. In the present study we examined the role of the 5LO pathway on AII-induced aldosterone secretion in rat glomerulosa cells in vitro. The 5LO product 5-hydroxyeicosatetraenoic acid (5HETE) and its unstable precursor 5-hydroxyperoxyeicosatetraenoic acid did not significantly alter basal aldosterone secretion in concentrations from 10(-9)-10(-7) M. In contrast, 5HETE reduced peak AII-induced aldosterone production from 59.1 +/- 9.0 to 37.96 +/- 7.2 ng/10(6) cells (P less than 0.01). This was accompanied by inhibition of the AII-stimulated rise in 12HETE production (10(-9)M AII, 160 +/- 4% of control; 10(-9) M AII plus 10(-7) M 5HETE, 90 +/- 1% of control production). However, 5HETE had no effect on the aldosterone response to potassium or ACTH, secretagogues that cause no activation of the 12LO pathway. These results suggest that the 5LO product 5HETE can selectively modulate AII-dependent aldosterone secretion. Further, the selective inhibitory effect of 5HETE on the AII effect in rat glomerulosa cells may be exerted by blockade of arachidonate metabolism via the 12LO pathway. These results suggest that the 5LO pathway may negatively modulate AII action in the adrenal zona glomerulosa.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Evidence for cholinergic modulation of aldosterone secretion in man.

Acetylcholine stimulates aldosterone secretion in bovine glomerulosa cells in vitro via specific cholinergic receptors. In this study we examined the effect of peripheral muscarinic blockade with atropine on metoclopramide-, angiotensin-II-, and ACTH-stimulated aldosterone secretion in man. Atropine (0.6 mg, iv) administered 10 min before MCP delayed the onset of the plasma aldosterone response and attenuated the mean peak response from 502 +/- 103 (+/- SE) to 322 +/- 72 pmol/L (P less than 0.05) without affecting zero time mean plasma aldosterone levels (144 +/- 28 vs. 136 +/- 36 pmol/L for control and atropine, respectively). This inhibitory effect was not mediated by changes in PRA or plasma potassium or ACTH (as reflected by cortisol) concentrations. Atropine also attenuated the plasma aldosterone response to a low dose angiotensin II infusion (2 ng/kg.min; control, 449 +/- 99 pmol/L; atropine, 297 +/- 78 pmol/L; P less than 0.05). In contrast, atropine had no effect on the plasma aldosterone response to a bolus dose (250 micrograms) of ACTH. Neither atropine (0.6 mg, iv) nor the cholinergic muscarinic agonist bethanechol (5 mg, sc) alone elicited a change in plasma aldosterone. Collectively, these data provide evidence for cholinergic modulation of aldosterone secretion in man. We conclude that cholinergic mechanisms may facilitate the aldosterone responses to angiotensin-II and metoclopramide, but not to ACTH.

Adrenocorticotropic Hormone↗
PubMed1988

Effect of age and posture on human lymphocyte adenylate cyclase activity.

1. A number of age-related changes have been reported in the catecholamine-adrenoceptor-adenylate cyclase system. Most of the data available on these alterations come from resting subjects; the response to acute stress may provide additional insights into the age effect on these responses. 2. We measured supine and 10 min upright plasma noradrenaline and lymphocyte adenylate cyclase activity in ten healthy elderly subjects (age 66-80 years) and seven healthy young subjects (age 27-34 years). 3. Isoprenaline stimulation of lymphocyte adenylate cyclase activity was not significantly different between supine and upright positions or between elderly and young subjects. There was a marked increase in forskolin-stimulated adenylate cyclase activity in the upright posture in both elderly and young subjects. The increment over supine levels was 70% in the elderly (P less than 0.025) and 73% in the young (P less than 0.05). This enhanced forskolin activity was not seen in two young subjects who became syncopal. 4. These data suggest that enhanced forskolin-stimulated adenylate cyclase activity occurs after 10 min of upright posture in both elderly and young subjects, and may be relevant to immediate blood pressure regulation. We were unable to demonstrate any age-related differences in these acute adrenergic responses.

Adenylyl Cyclases↗
PubMed1988

Clinical care of the aging hypertensive patient.

That elderly hypertensive patients need to be treated is now well established, as major clinical trials have confirmed the reduction in serious complications and organ damage in the treated patient. However, the concomitant findings on the high rates of adverse side effects of drug therapies to lower blood pressure are of concern. The physiologic and disease changes that occur with aging may explain some of the adverse drug responses encountered in this population. Nondrug treatment of hypertension, including sodium restriction and weight reduction, would be desirable in the elderly, but there are no trials of the efficacy and safety of these methods in this population. Homeostatic fragility in the elderly is the loss of the ability to regulate cardiovascular and respiratory function, and fluid and electrolyte balance under conditions of stress. Introduction of antihypertensive agents with their global effects on these homeostatic processes leads to frequent complications such as orthostatic hypotension, cardiac depression, reduced cerebral blood flow, and abnormalities in metabolic, volume, and electrolyte control. Although these adverse reactions explain some of the compliance problems in the elderly, several psychosocial factors also hinder the ability of older patients to follow therapeutic protocols. The need for alternative and more appropriate therapies tailored to fit these problems associated with aging is the desired goal of future blood pressure intervention policies.

Aged↗
PubMed1988

Diabetes and hypertension.

Diabetes mellitus is associated with increased risk of cardiovascular morbidity and mortality which often can be attributed to the frequent coexistence of arterial hypertension. There is an additive effect of high blood pressure and elevated blood sugar on the severity, extent and rate of progression of atherosclerotic macrovascular disease. Current evidence has also linked hypertension to acceleration of the chronic microvascular complications of diabetes mellitus including diabetic nephropathy and retinopathy. These facts emerge to place diabetic hypertension as a most important public health issue. Questions of frequency, aetiology and the implications of intervention therapy for hypertension in diabetes mellitus are reviewed in this article and can be found in several recent reviews.

Diabetes Complications↗
PubMed1987

A kinetic study of cation transport in erythrocytes from uremic patients.

We previously described in red blood cells (RBCs) from uremic patients on dialysis a reduction in sodium (Na) efflux through the Na, potassium (K) cotransport system (Na,K CoT) while Na efflux through the Na,K pump was normal. We then examined Na efflux in fresh cells and in cells loaded to obtain one level of intracellular sodium (Nai) concentration at about 25 mmol/liter cell. In the present study we used similar cation flux methodology to examine the kinetics of cation efflux through the Na,K pump and Na,K CoT in uremic patients on dialysis. RBCs were Na-loaded to attain five different levels of Nai concentration over a range of 5 to 50 mmol/liter cells using the ionophore nystatin. At each level of Na-loading, the Nai achieved was similar in RBCs from controls and patients. Ouabain-sensitive Na efflux through the Na,K pump showed no difference in rate between normals and dialysis patients. When the kinetic parameters of this transport pathway were considered, the apparent affinity (K0.5) for sodium was not significantly different between controls and patients (18.4 +/- 2.3 vs. 20.0 +/- 2.6 mmol/liter cell) and the maximal velocity of efflux (Vmax) was also not different between controls and patients (9.6 +/- 0.7 vs. 8.5 +/- 1.2 mmol/liter cell/hr). Comparison of Nai-activated Na versus K efflux rates through the Na,K CoT in normal subjects demonstrated similar saturation kinetics, (K0.5 15.8 +/- 3.3 vs. 12.2 +/- 2.8 mmol/liter cell, Vmax 0.81 +/- 0.1 vs. 0.78 +/- 0.1 mmol/liter cell/hr) consistent with the known stoichiometric ratio of 1 Na:1 K:2 Cl described for this mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Effect of high calcium intake on pressor responsivity in hypertensive rats.

Some proposed mechanisms for the hypotensive effect of high calcium intake involve reduction in vascular responsivity. To assess the effect of dietary calcium on vascular responsivity, spontaneously hypertensive rats (SHR) were placed on normal (N-Ca; 0.4%) or high (H-Ca; 2.8%) casein-based synthetic diet for 4 wk. Intraarterial pressure, pressor response to graded intravenous infusion of norepinephrine (NE) and angiotensin II (ANG II), and in vitro vascular reactivity of tail artery segments to NE and transmural nerve stimulation (TNS) were studied. Urinary electrolyte excretion, plasma renin activity (PRA), aldosterone, NE, and epinephrine (EPI) were also determined. H-Ca SHR had a lower intraarterial systolic and diastolic pressure. However, H-Ca SHR had greater in vivo pressor response to both ANG II and NE. Maximal contractile force developed by tail artery segments in vitro in response to NE and TNS was slightly, but not significantly, higher in H-Ca SHR. In vitro dose-response curves to NE and TNS were not significantly different. Although H-Ca SHR had increased urinary excretion of sodium throughout the study period, PRA and aldosterone levels were similar in both groups. Plasma NE and EPI levels in the two groups were also not different. Despite lowered intra-arterial blood pressure, H-Ca SHR exhibited enhanced pressor response to ANG II and NE in vivo and a similar in vitro vascular reactivity to NE and TNS when compared with N-Ca SHR. Our results do not support a role for alterations in vascular reactivity to NE or ANG II in the hypotensive effect of high calcium intake in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1987

Effect of cyclosporin on blood pressure and renin-aldosterone axis in rats.

Although hypertension is a frequent complication of cyclosporin A (CSA) therapy in clinical practice, little experimental information is available on the nature and the mechanism of this form of hypertension. We studied the effect of currently recommended therapeutic dosages of CSA, i.e., 5 (CSA5) and 20 (CSA20) mg.kg-1.day-1, on blood pressure and the renin-aldosterone system (RAS) in spontaneously hypertensive rats (SHR). Influence of in vivo CSA treatment on in vitro angiotensin II (ANG II)-stimulated aldosterone secretion by isolated adrenal glomerulosa cells (AGC) was also measured. CSA treatment in SHR resulted in a consistent increase in systolic blood pressure. This increase in blood pressure occurred in the absence of significant changes in creatinine clearance in CSA5 rats, whereas in CSA20 rats a significant reduction in creatinine clearance was observed. Sodium balance and serum calcium and magnesium concentrations were not different between the control group and either of the two CSA-treated groups of rats. Plasma renin concentration (PRC) and inactive renin (IR) were markedly elevated, but plasma renin substrate remained unchanged with CSA administration. Despite the presence of hyperreninemia, plasma aldosterone was not elevated, suggesting that CSA may induce relative adrenal resistance to ANG II. This possibility was tested using AGC isolated from CSA-treated rats. ANG II-stimulated aldosterone secretion in AGC was diminished by low dose and aborted by high dose CSA-treatment. Thus CSA administration in SHR induces a predictable increase in blood pressure in association with "hyperreninemic hypoaldosteronism."

Adrenal Cortex↗
PubMed1987

Comparison of enalapril and thiazide diuretics in the elderly hypertensive patient.

One hundred seventy-four patients, 65 years of age or older, entered a double-blind, seven-center, 16-week, controlled study to compare the effects of enalapril and hydrochlorothiazide (HCTZ) in an elderly hypertensive population. Sixty-eight percent of the patients were men, 32% were women. Thirty-two percent of the patients had isolated systolic hypertension. Approximately 80% of the patients were white. After a 4-week placebo run-in period, patients with sitting diastolic BP (DBP) of 90-120 mm Hg or systolic BP (SBP) greater than or equal to 160 mg Hg and DBP less than 90 mm Hg (isolated systolic hypertension) were randomized to receive 10 mg of enalapril or 12.5 mg of HCTZ once daily. If after 4 weeks their BPs were not controlled (i.e., DBP greater than 85 mm Hg or SBP greater than 140 mm Hg), the dose of the drug was doubled. If after successive 4-week intervals, their BPs were still not controlled, the other drug was added to their regimen and this was then doubled. The initial mean BPs were 167/94 mm Hg in both groups. By the end of the monotherapy phase at 8 weeks, the mean BPs had fallen significantly (p less than or equal to 0.01) to 148/85 mm Hg in both groups. By 16 weeks, the mean BPs had again fallen similarly: in the enalapril group to 144/83 mm Hg, and in the HCTZ group to 145/83 mm Hg. Seventy-nine percent of the enalapril group and 85% of the HCTZ group had controlled BPs at this time (DBP less than or equal to 85 or SBP less than or equal to 140 mm Hg). White and nonwhite patients in both drug groups had similar falls in SBP and DBP both at the end of the monotherapy period and the overall study. The white patients experienced more rapid falls in BP with enalapril, the nonwhite patients with HCTZ. Three serious adverse experiences occurred in the enalapril group, none of which were considered likely to be due to the drug therapy. Overall, 49% of the enalapril group and 61% of the HCTZ group reported an adverse effect during the study (not significant). Laboratory adverse effects occurred 10% more frequently in the HCTZ group: enalapril, 22%; HCTZ, 32% (not significant); none was serious. Both drugs therefore appeared to be equally efficacious antihypertensive agents in these elderly patients.

Aged↗
PubMed1987

Kinetic analysis of erythrocyte Na+-K+ pump and cotransport in essential hypertension.

Alterations in red blood cell (RBC) Na+-K+ pump and Na+-K+ cotransport have been described in essential hypertension. We evaluated Na+-K+ pump and cotransport in 30 hypertensive and 26 normotensive subjects subdivided by race and family history of hypertension using an improved method to examine the kinetics of Na and K effluxes. RBCs were Na-loaded by the nystatin method to five different levels of internal Na with pump determined as ouabain-sensitive Na efflux and cotransport as furosemide-sensitive Na and K efflux. Two kinetic parameters were determined for both transport systems: the apparent affinity for Na (K0.5) and the velocity of efflux at saturating internal Na concentration (Vmax). Mean intracellular Na content in fresh RBCs (mmol/L cells) was higher in black hypertensive (12.6 +/- 1.8 mmol/L cells) and normotensive subjects (10.9 +/- 1.2 mmol/L cells) than in white hypertensive (8.7 +/- 1.0 mmol/L cells) or normotensive subjects (8.5 +/- 0.8 mmol/L cells). The Vmax and K0.5 for pump were not significantly different between study groups. The Vmax for cotransport was elevated in white hypertensive compared with normotensive subjects, but the K0.5 values were similar. Black normotensive and hypertensive subjects displayed a lower Vmax and increased K0.5 for cotransport compared with the white groups. A family history of hypertension had no influence on cotransport kinetics in blacks but did predict white normotensive and hypertensive subjects with low cotransport. The reduction in intracellular Na affinity for cotransport in black subjects may explain their higher intracellular Na in fresh RBCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Cyclosporin A-induced hyperreninemic hypoaldosteronism. A model of adrenal resistance to angiotensin II.

We studied the effects of cyclosporin A on the renin-aldosterone axis in Sprague-Dawley rats. Two weeks of intragastric administration of cyclosporin A (5 mg/kg/day or or 20 mg/kg/day) resulted in large increases in plasma renin concentration (23 +/- 5, 70 +/- 12, and 79 +/- 11 ng/ml/hr in control rats and rats receiving 5 mg and 20 mg of cyclosporin A, respectively), with no parallel increments in plasma aldosterone. In vitro angiotensin II (ANG II)-stimulated aldosterone secretion by zona glomerulosa cells obtained from cyclosporin A-treated rats was also reduced (4.8 +/- 0.5, 1.5 +/- 0.2, and 0.2 +/- 0.2 ng/10(5) cells in control rats and rats receiving 5 mg and 20 mg of cyclosporin A, respectively). In contrast, in vitro aldosterone response to graded increments of potassium (3.7-10.7 mmol/L) or adrenocorticotropic hormone (ACTH) (10(-11)-10(-8) M) was preserved in cyclosporin A-treated rats. When added in vitro to zona glomerulosa cells from untreated rats, cyclosporin A also attenuated ANG II-stimulated aldosterone secretion, but did not affect potassium or ACTH-mediated aldosterone production. Thus, cyclosporin A-induced hyperreninemic hypoaldosteronism in the rat depends on opposing renal and adrenal effects, with a direct or feedback stimulation of renin secretion and a specific blockade of ANG II-mediated aldosterone production.

Adrenal Glands↗
PubMed1987

Diminished aldosterone responses to angiotensin II and adrenocorticotropin in hypocalcemic subjects: restoration of responsiveness with normocalcemia.

ACTH-, angiotensin II (AII)-, and K+-mediated aldosterone responses in vitro are dependent on extracellular and intracellular Ca concentrations. This study examined in vivo the relationship of changes in ambient serum calcium (serum Ca) to ACTH- and AII-mediated aldosterone release in hypoparathyroid subjects. Plasma aldosterone (PA) responses to graded dose infusions of ACTH and AII were examined in hypoparathyroid (HypoPTH) patients before (n = 8) and after correction of hypocalcemia (n = 6) and compared to responses in 20 normotensive normocalcemic subjects. ACTH and AII were infused for 90 min at rates increasing from 12.5 to 50 mIU/30 min and 0.5 to 2.0 ng/kg X min, respectively. Pretreatment mean serum Ca was 6.8 +/- 0.2 (+/- SEM) mg/dl, and it rose to 9.3 +/- 0.2 mg/dl after 3-8 weeks of vitamin D administration. In the untreated HypoPTH patients, basal mean PA (5.4 +/- 1.3 ng/dl) was lower (P less than 0.01) than in the normal subjects (10.6 +/- 0.6 ng/dl) or treated HypoPTH patients (9.5 +/- 1.8 ng/dl). There was a marked reduction in PA responses to ACTH at all doses in the untreated HypoPTH patients compared to the normal subjects. With normalization of serum Ca in four patients, the mean peak PA response to ACTH (25.1 +/- 6.0 ng/dl) was not significantly different from normal (28.9 +/- 1.7 ng/dl). During graded dose AII infusion in five untreated HypoPTH patients, mean PA levels increased from 6.9 +/- 1.2 to 11.6 +/- 2.2 ng/dl; when the serum Ca was normal, the corresponding values were 8.7 +/- 1.8 and 20.2 +/- 3.61 ng/dl. There was a positive correlation (r = 0.475; P less than 0.05) between basal PA and serum Ca levels. In addition, maximum changes in mean arterial pressure in response to AII infusions were significantly greater after correction of hypocalcemia. These observations indicate that in HypoPTH patients, extracellular Ca concentrations can influence humoral aldosterone response to ACTH and AII and pressor responses to AII.

Adrenocorticotropic Hormone↗