Biomedical subjects

D J DiPette

Publications and source records attributed to D J DiPette.

At least 55 records · Page 3Linked to original sources

PubMed1991

Decreased spinal cord content of calcitonin gene-related peptide in the spontaneously hypertensive rat.

Calcitonin gene-related peptide (CGRP), produced by alternative processing of the primary transcript of the calcitonin gene, is a potent vasodilator. We have shown that dietary calcium deficiency accompanied by decreased serum ionized calcium significantly decreases the neuronal content of CGRP in laminae I and II of the dorsal horn of the spinal cord in the growing rat. The spontaneously hypertensive rat (SHR) is characterized by decreased serum ionized calcium levels and is thought to most closely resemble human essential hypertension. To determine if the neuronal content of CGRP is decreased in the SHR compared to the Wistar-Kyoto (WKY) parent strain, CGRP was localized immunocytochemically in the dorsal horn of the spinal cord. The density of immunocytochemical staining was quantitated by computer-assisted image processing of laminae I and II of the upper thoracic spinal cord of 12-14 week old male SHR (n = 4) and WKY (n = 4) normotensive, control rats. The SHR had significantly decreased neuronal CGRP content compared to the WKY rats (107 +/- 5 vs 121 +/- 6 arbitrary units, P less than 0.01). In contrast, the neuronal density of substance P (SP), which frequently co-exists with CGRP in this neuronal population, was not different between the two groups (SHR, 91 +/- 6 (n = 4) vs WKY, 88 +/- 3 arbitrary units (n = 4)).

Animals↗

PubMed1991

Effect of intravenous versus intraperitoneal glucose injection on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats.

The effect of i.v. versus i.p. glucose injections on blood flow rate of Walker 256 carcinoma and several normal tissues of unanesthetized, unrestrained female Sprague-Dawley rats was measured, using the radioactive microsphere technique prior to and 60 min after glucose administration (6 g/kg, i.v. or i.p.). Changes in systemic hemodynamics were also investigated in an attempt to further quantify the mechanisms responsible for tumor blood flow reduction. Most of the normal tissues showed either no modification or a decrease in the blood flow rate following i.v. or i.p. glucose injections. The response was more pronounced following i.p. injection. Most of the tissues studied also exhibited significant modification in cardiac output distribution. A decrease in blood flow rate and cardiac output distribution was also observed in the tumors following i.v. or i.p. injections. However, as observed in the normal tissues, the response was more pronounced following i.p. injection. Mechanisms for blood flow reduction include systemic effects such as reduction and redistribution of cardiac output. An additional systemic mechanism following i.p. injection includes hypovolemic hemoconcentration which was evident by an increase in blood hematocrit. In rats, unlike observations in mice, the change in hematocrit following i.p. injection is not as large and cannot account for the total blood flow reduction. Local mechanisms include an increase in red blood cell rigidity due to glucose itself and tissue acidosis.

Animals↗

PubMed1991

Renin profile, race, and antihypertensive efficacy with atenolol and labetalol.

In this randomised double-blind parallel study, we compared the efficacy of labetalol and atenolol in a group of black (n = 33) and white (n = 34) hypertensives with uncomplicated essential hypertension after obtaining pretreatment renin profiles. After single-blind placebo (14-21 days), patients with standing diastolic BP between 105-119 mmHg were randomised to receive either labetalol (100-800 mg twice daily) or atenolol (50-100 mg once daily) to achieve a DBP less than 90 mmHg. Dosage titration occurred at weekly intervals for labetalol and biweekly for atenolol. The supine BP decrease with atenolol was -18/-14 vs. -6/-6 mmHg in whites vs. blacks respectively. With labetalol, it was -13/-12 in whites and -2/-7 mmHg in blacks. Standing BPs were: -19/-14 vs. -4/-5, whites vs. blacks with atenolol and -17/-17 vs. -19/-9 mmHg with labetalol. Neither labetalol nor atenolol was as effective in black compared with white hypertensives. The atenolol but not labetalol BP response was positively correlated with pretreatment renin values.

Atenolol↗

PubMed1991

Regional and systemic hemodynamic effects of parathyroid hormone-related protein: preservation of cardiac function and coronary and renal flow with reduced blood pressure.

It has been demonstrated previously that parathyroid hormone-related protein (PTHrp) has potent vasodilatory and cardiac stimulatory properties. However, the systemic and regional hemodynamic effects of PTHrp are unknown. In order to characterize these effects, we utilized the radioactive microsphere technique to examine the systemic and regional hemodynamics before and 2 min after the i.v. bolus administration of 0.03, 0.3 and 3.0 micrograms/ml/100 g b.wt. of PTHrp in conscious, unrestrained, normal rats. These effects were compared to those of synthetic rat parathyroid hormone (PTH), an agent known to affect cardiovascular function. PTHrp and PTH similarly and significantly decreased mean systemic blood pressure and total peripheral resistance but increased heart rate and cardiac output, all in a dose-dependent manner. Both peptides increased blood flow and decreased vessel resistance in regional vascular beds such as skin and heart. Renal resistance was reduced by PTH and PTHrp, but renal blood flow was not altered. Conversely, both peptides significantly decreased blood flow and increased vascular resistance to the splanchnic organs. Thus, PTHrp as well as PTH, preserved and enhanced cardiac function in the face of reduced systemic blood pressure while maintaining renal flow. These features are highly desirable in the treatment of some severe cardiovascular abnormalities. These results are consistent with the hypothesis that PTHrp may play an important hormonal, autocrine or paracrine role in systemic and regional blood flow regulation.

Animals↗

PubMed1990

Decrease in A1 adenosine receptors in adipocytes from spontaneously hypertensive rats.

We have investigated whether the insulin resistance reported to occur in hypertension is due to decreased insulin receptors or to adenosine receptors in adipocyte membranes. Membranes were isolated from adipocytes from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKy) rats and assayed for insulin receptors and A1 adenosine receptors. The two groups of membranes bound 125I-insulin equally, but in contrast the SHR membranes bound approximately 25% less 125I-HPIA ([(-)-N6-p-hydroxyphenylisopropyl adenosine], an A1 adenosine receptor agonist) than the WKy (P less than .005). Scatchard analysis demonstrated that this was due to a lower number of receptors in the SHR. The affinity of the receptor for HPIA was approximately 0.7 nmol/L in both groups. 5'-Nucleotidase activity was approximately 40% higher in membranes from SHR than WKy (P less than .001), indicating that adipocytes from SHR have a higher capacity for adenosine production. This may cause increased adenosine concentrations in the SHR adipose tissue, leading to adenosine receptor down-regulation. Since we have previously demonstrated that adenosine receptor down-regulation can lead to insulin resistance, these findings may partly account for the insulin resistance of hypertension.

5'-Nucleotidase↗

PubMed1990

Combined alpha/beta-blockade versus beta 1-selective blockade in essential hypertension in black and white patients.

The purpose of this multicenter investigation was to determine the efficacy and safety of the alpha/beta-blocker labetalol versus the beta 1-selective beta-blocker atenolol in white and black patients with essential hypertension. Equal numbers of black and white patients were enlisted to form four treatment groups (white patients taking either labetalol or atenolol and black patients taking either labetalol or atenolol). Two hundred ninety-two patients (152 white and 140 black patients) with essential hypertension characterized by a standing diastolic blood pressure of 105 to 119 mm Hg (inclusive) were recruited for this trial. Patients were randomized to either labetalol (dosage titrated from 200 to 1600 mg/day) or atenolol (dosage titrated from 50 to 100 mg/day). The therapeutic goal was achievement of a standing diastolic blood pressure of 90 mm Hg or less or a fall of 15 mm Hg in diastolic pressure from baseline value at the end of the placebo run in period. At the end of the study there were no significant differences in blood pressure or heart rate changes in the supine position between the labetalol and atenolol groups. In contrast, labetalol produced greater reduction in both the standing systolic and diastolic blood pressure (-12/-13 mm Hg, respectively) compared with atenolol (-7/-9 mm Hg; p less than 0.05; p less than 0.005, respectively). The greatest decrease in blood pressure was observed in white patients receiving labetalol. In black patients the decrease in blood pressure was greater in those treated with labetalol compared with atenolol, particularly with respect to the systolic blood pressure. We conclude that the alpha 1-blocking property of labetalol provides an additional lowering of the blood pressure over that seen with beta 1-blockade alone, especially in the standing position, and this enhanced efficacy is not confined to one radical group.

Atenolol↗

PubMed1990

Humoral factors determining the blood pressure response to converting enzyme inhibition and calcium channel blockade.

Renin and catecholamine levels were determined in patients with mild to moderate hypertension before and after treatment with sustained release diltiazem or captopril and were correlated with the blood pressure response to these antihypertensives. Eight weeks of treatment with either agent led to equal decreases in both systolic and diastolic blood pressure. Pretreatment plasma renin activity (PRA) and plasma norepinephrine did not predict the blood pressure response to either agent. Diltiazem significantly increased both PRA and supine norepinephrine levels. However, in the diltiazem treated patients, there was no correlation between the change in plasma norepinephrine and the change in systolic or diastolic blood pressure. In contrast, there was a negative correlation (P less than .05) between the reactive rise in PRA and the decrease in systolic blood pressure. Thus, the antihypertensive response to a calcium channel blocker may be determined, in part, by the reactive response of pressor systems.

Adult↗

PubMed1990

Effects of calcium channel blockade on calcium homeostasis in mild to moderate essential hypertension.

Calcium channel blockers may alter parathyroid hormone secretion in vitro, which would alter calcium homeostasis. To determine the chronic effect of calcium channel blockade in vivo, we conducted a randomized, double blind, 16 week study comparing the effects of two pharmacologic antihypertensive agents, the calcium channel blocker diltiazem and the angiotensin-converting enzyme inhibitor captopril on parameters of calcium homeostasis. Both diltiazem and captopril lowered blood pressure to a similar degree. Neither drug produced any significant change in blood levels of total and ionized calcium, magnesium, or phosphorus, which affect the regulation of parathyroid hormone and vitamin D. In addition, at eight or 16 weeks following initiation, neither drug altered the serum levels of parathyroid hormone (PTH) or 1,25-(OH)2-vitamin D3 (1,25-D). Chronic calcium channel blockade with diltiazem does not alter serum parameters of calcium homeostasis and, thus, should not affect bone mineralization.

Adult↗

PubMed1990

Effect of dietary calcium supplementation on blood pressure and calciotropic hormones in mineralocorticoid-salt hypertension.

In order to determine the effect of dietary calcium supplementation on blood pressure and calciotropic hormones, we studied two groups (n = 12 each) of mineralocorticoid [deoxycorticosterone (DOC)]-salt hypertensive rats, one receiving a normal-calcium diet (0.6% calcium, as calcium carbonate) and the other a high-calcium diet (2.5% calcium), over an 8-week period. Dietary calcium supplementation significantly attenuated the rise in blood pressure. Serum ionized calcium concentrations were significantly decreased from baseline levels in both groups but tended to be higher among the calcium-supplemented rats. Serum concentrations of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-D) were significantly higher in the DOC-salt rats than in normotensive rats fed normal rat chow [PTH: 49 +/- 4 versus 15 +/- 0.9 pg/ml (means +/- s.e.m.); 1,25-D: 108 +/- 7 versus 73 +/- 13 pg/ml, in DOC-salt and normotensive rats, respectively]. In the DOC-salt rats, dietary calcium supplementation did not significantly lower the elevated serum concentration of PTH (from 49 +/- 4 to 40 +/- 4 pg/ml; NS), but did significantly reduce that of 1,25-D (from 108 +/- 7 to 66 +/- 8 pg/ml; P less than 0.01). Since 1,25-D may increase vascular smooth muscle calcium uptake, dietary calcium supplementation may lower blood pressure in DOC-salt hypertension, in part, by suppressing 1,25-D.

Animals↗

PubMed1989

Dose-dependent systemic and regional hemodynamic effects of calcitonin gene-related peptide.

The dose-response effects of infused calcitonin gene-related peptide (CGRP), a potent vasodilator, on systemic and regional hemodynamics in the conscious rat remain incompletely defined. The radioactive microsphere technique provided these determinations before and after the intravenous administration of vehicle or 22, 65, 220, and 2200 pmol of CGRP. Neither vehicle nor 22 pmol of CGRP significantly changed any systemic or regional hemodynamic parameter. Starting at the 65-pmol dose, CGRP significantly decreased mean blood pressure and total peripheral resistance, while increasing heart rate without changing cardiac output. CGRP produced selective regional vasodilatory effects, with the coronary circulation being unusually sensitive. In contrast, CGRP caused significant increases in blood flow to the mesenteric and cutaneous circulations only at the two highest doses. CGRP increased plasma norepinephrine, epinephrine, and renin activity significantly at only the 2200-pmol dose. In conclusion, CGRP decreases blood pressure by peripheral vasodilation, with a threshold dose occurring between 22 and 65 pmol. In addition, the coronary circulation appears to be particularly sensitive to the vasodilatory properties of CGRP.

Animals↗

PubMed1989

Systemic and regional hemodynamic effects of dietary calcium supplementation in mineralocorticoid hypertension.

This study was undertaken to determine the systemic and regional hemodynamic effects of long-term dietary calcium supplementation in mineralocorticoid (DOC)-salt hypertension. Systemic and regional hemodynamic measurements were determined by the radioactive microsphere technique in conscious and unrestrained rats (kidneys intact) with DOC-salt-induced hypertension that were pair-fed either a normal calcium (0.6% by weight, n = 12) or a calcium-supplemented (high-calcium) diet (2.5% by weight, n = 12). After 7 to 8 weeks, there were no differences in weight, heart rate, or cardiac output between the two groups. In contrast, the high-calcium rats had a significantly lower mean blood pressure (125 +/- 4 mm Hg, mean +/- SEM) than the normal calcium rats (143 +/- 5 mm Hg); this finding appeared to result predominantly from a reduction in total peripheral resistance. The high-calcium rats had a higher renal blood flow (7.8 +/- 0.5% vs. 6.2 +/- 0.4% cardiac output; p less than 0.05) and lower renal (14.3 +/- 1 vs. 19.3 +/- 2 mm Hg/min/ml/g tissue; p less than 0.05) and jejunal vascular resistance than did the normal calcium rats. Two additional identical groups of normal calcium-and high-calcium-DOC-salt rats (n = 12 each) were also studied. In these rats, serum-ionized calcium decreased significantly (p less than 0.05) from baseline in both groups. Urinary sodium increased in both groups but did not differ significantly. In conclusion, dietary calcium supplementation attenuates the rise in peripheral vascular resistance that accompanies DOC-salt hypertension. This attenuated resistance appears to be relatively selective and is noted particularly in the renal vasculature.

Animals↗

PubMed1989

Hypotension and cardiac stimulation due to the parathyroid hormone-related protein, humoral hypercalcemia of malignancy factor.

Patients with humoral hypercalcemia of malignancy display markedly increased serum calcium levels, reduced blood pressure, and tachycardia. The causative agent, humoral hypercalcemia of malignancy factor [also called PTH-related protein (PTHrp)] has been shown to interact with PTH receptors in bone and kidney. We compared human PTHrp-(1-34) with rat PTH-(1-34) for the effects of each peptide on cardiovascular function in unrestrained conscious rats. Both PTHrp and PTH decreased blood pressure in a dose-dependent manner over the concentration range of 0.3-30 micrograms/kg. PTHrp was approximately 3-fold more potent than PTH, producing up to a 50 mm Hg decrease in pressure within 2 min at 10 micrograms/kg. Both peptides increased heart rate more than 70 beats/min at this dose. However, PTH appeared to exert greater efficacy and potency than PTHrp in increasing heart rate in vivo. In the isolated and perfused rat heart, PTHrp and PTH produced positive chronotropic and positive inotropic effects as well as increased coronary flow. PTHrp was more potent and more effective than PTH. The time courses of these effects in the perfused heart preparations indicated that both peptides produced maximal effects within 1 min, with all responses returning to baseline within 10 min. In isolated helical strips of rat aorta, PTHrp and PTH relaxed norepinephrine-contracted tissues in a concentration-dependent fashion. A functional endothelium was not required for the relaxing effects of either peptide. These studies indicate that PTHrp and PTH decrease blood pressure by relaxing vascular tissue in an endothelium-independent manner. Also, these peptides directly increased heart rate, contractility, and coronary flow. Since PTHrp has recently been found in normal human cells, these studies suggest the possibility of PTHrp as a regulator or modulator of cardiovascular function.

Animals↗

PubMed1988

Dietary calcium modulates spinal cord content of calcitonin gene-related peptide in the rat.

This study was undertaken to determine if calcium status modulates calcitonin gene-related peptide (CGRP) neuronal content. In two separate experiments, young, growing rats and mature rats were placed on low, normal, and high calcium diets for four weeks. CGRP immunostaining was localized immunocytochemically in laminae I and II of the upper thoracic spinal cord in young rats and in the upper thoracic and lumbar spinal cord in mature rats. Low calcium intake decreased dorsal horn CGRP content in young, growing rats, while high calcium diet significantly increased CGRP content, as determined by computer-assisted image processing, in both young and adult rats. A significant positive correlation was found between the serum ionized calcium and CGRP content in laminae I and II. Thus, calcium balance appears to modulate neuronal CGRP content.

Aging↗

PubMed1988

Diltiazem and captopril alone or in combination for treatment of mild to moderate systemic hypertension.

The efficacy and safety of sustained-release diltiazem, 60 to 180 mg twice daily, was compared with that of captopril, 25 to 75 mg twice daily, alone and in combination, in 132 patients with mild to moderate essential hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg). All patients received placebo for 4 to 6 weeks, followed by randomization to diltiazem or captopril during the double-blind monotherapy phase. Either study drug was titrated over 6 weeks to achieve a goal supine diastolic BP reduction of at least 10 mm Hg and a diastolic BP of less than 90 mm Hg. Patients achieving the goal BP reduction were maintained on monotherapy for an additional 8 weeks. Patients not achieving the treatment goal after 8 weeks with either drug alone received the other drug in combination, titrated to achieve goal BP response. Both drugs lowered BP significantly and, at the doses used, diltiazem had a greater effect on diastolic BP than did captopril. The mean changes from baseline at week 8 were -10.6 and -7.3 mm Hg, respectively, (p = 0.01). Goal BP was achieved in 38% of patients taking diltiazem monotherapy and in 34% of patients taking captopril monotherapy. There were no significant differences between diltiazem and captopril in diastolic or systolic BP reductions by race or age. The addition of alternate therapy for non-goal achievers at week 8 resulted in significant reductions in diastolic and systolic BP by week 16.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Metabolic effects of antihypertensive therapy with a calcium antagonist.

The effect of diuretics to increase serum glucose, low-density lipoprotein cholesterol and triglycerides, as well as the adverse changes in triglycerides and high-density lipoprotein cholesterol produced by nonselective beta blockers, have been largely ignored in the treatment of hypertension. However, a number of trials have shown that reductions in serum lipids can alter cardiovascular mortality. Calcium antagonists have become major drugs in the treatment of hypertension, and some data suggest that calcium antagonists may increase serum glucose levels. Significantly less data on lipid effects have been published. Lipid and glucose effects were examined in an 8-week antihypertensive study using a sustained-release preparation of diltiazem titrated from 240 to 360 mg/day in a twice-daily regimen in a randomized, double-blind, placebo-controlled parallel trial in 96 patients. Average supine blood pressure at week 8 was 156/98 mm Hg, standing blood pressure with placebo 152/100 mm Hg, and with diltiazem 147/91 and 144/93 mm Hg. There were no statistically significant changes in serum lipids or glucose in the diltiazem or placebo group or between the groups. Mean values (mg/dl) at baseline and week 8 in the diltiazem group were, respectively, for cholesterol 215 and 218, high-density lipoprotein cholesterol 50 and 51, low-density lipoprotein cholesterol 128 and 133, triglycerides 169 and 175, and glucose 113 and 110. Thus, this large and placebo-controlled study shows that diltiazem is among the antihypertensives with no adverse long-term lipid or glucose effects.

Blood Glucose↗

PubMed1988

Cardiac involvement in hypertension.

Despite improved patient detection and pharmacologic therapy, the effect of treatment of hypertension on mortality from coronary artery-related events remains unresolved. Left ventricular (LV) hypertrophy, a known consequence of hypertension, is associated with an excess mortality independent of other known cardiovascular risk factors. Recently, LV hypertrophy accompanying hypertension has been associated with ominous ventricular arrhythmias. However, it does not necessarily follow that regression of LV hypertrophy will reduce this increased mortality. Diastolic dysfunction, manifested by reduced ventricular distensibility of the hypertrophying left ventricle, appears to be an early characteristic of the hypertensive heart since echocardiographic techniques have demonstrated diastolic filling abnormalities in untreated essential hypertensives even before significant LV hypertrophy appears. Not all antihypertensive agents diminish LV mass and improve diastolic dysfunction. Certain sympatholytic agents, calcium antagonists, beta-adrenergic blockers, and the angiotensin-converting enzyme inhibitors appear to diminish LV hypertrophy. However, future studies are needed to determine if these agents that appear to reverse findings of LV hypertrophy and improve diastolic dysfunction will also reduce risk of coronary artery disease and related events.

Cardiomegaly↗

PubMed1988

Effect of galactose on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats.

The effect of galactose on systemic hemodynamics and blood flow rate of Walker 256 carcinomas and several normal tissues of unanesthetized, unrestrained female Sprague-Dawley rats was measured, using the radioactive microsphere technique, prior to and at 30 and 60 min after galactose administration (6 g/kg body weight, i.v.). Whereas heart rate remained unchanged following injection, cardiac output (CO) and cardiac index decreased by 35% (P less than 0.05). Mean arterial pressure immediately decreased during the injection but then increased reaching a value 10% (P less than 0.05) above the baseline 30 min following injection. Stroke volume (SV) decreased by 30% (P less than 0.05) and total peripheral resistance increased by 65% (P less than 0.05). Redistribution of blood flow, expressed as %CO, among normal tissues was seen to the brain, kidneys, liver, jejunum, and hindlimb muscle and away from the pancreas, stomach, and skin. Changes in %CO to the spleen, colon, forelimb muscle, and peritumor tissue were not significant. Blood flow rate in most normal tissues either decreased or remained constant following injection. An exception was in the liver where blood flow significantly increased. Blood flow significantly decreased in the tumor (approximately 60%) and this reduction in blood flow was larger than the reduction in CO. These results suggest that (a) the effect of galactose on systemic hemodynamics and blood flow rate are similar to those produced by glucose; (b) reduction in blood flow rate in tumors is due to both systemic and local effects; and (c) changes in blood flow to normal tissues should not be disregarded when using galactose in combination with hyperthermia and/or chemotherapy for cancer treatment.

Animals↗

PubMed1988

Compensatory pressor role of vasopressin following acute diuresis.

Recent interest has focused on the role of vasopressin (AVP) in blood pressure (BP) regulation. This study was performed to determine if vasopressin has a compensatory pressor role following acute diuresis in both normal rats and in rats with subtotal nephrectomy (SN) or in rats with SN-salt induced hypertension. An inhibitor (AVP-I), specific for the AVP vascular smooth muscle receptor, was administered intravenously to assess the AVP dependency of the BP. Furosemide administration significantly increased plasma AVP levels in all rats. Administration of AVP-I did not change BP in the normal rats with or without prior furosemide administration or in the SN rats without furosemide administration. In contrast, after furosemide administration, AVP-I significantly decreased mean BP in the SN rats. The administration of AVP-I to the SN-salt hypertensive rats, with or without furosemide administration, significantly decreased mean BP. In conclusion, AVP has a compensatory pressor role in SN rats after acute diuresis, with or without salt-induced hypertension, but not in the normal rat.

Animals↗