Biomedical subjects

S W Rabkin

Publications and source records attributed to S W Rabkin.

At least 37 records · Page 2Linked to original sources

PubMed1997

Angiotensin II induces activation of phosphatidylinositol 3-kinase in cardiomyocytes.

BACKGROUND: Phosphatidylinositol 3-kinase phosphorylates membrane lipids at the third position of the inositol ring producing phosphoinositides, not on the pathway for production of 1,4,5-triphosphate. OBJECTIVE: To test the hypotheses that angiotensin II (Ang II) activates phosphatidylinositol 3-kinase in cardiomyocytes and that this pathway is involved in Ang II-induced protein synthesis. METHODS: Cardiomyocytes, in culture, from 7-day-old chick embryonic hearts were treated with Ang II and the activation of phosphatidylinositol 3-kinase was assessed after immunoprecipitation with antibodies to the p85 subunit of phosphatidylinositol 3-kinase by the conversion of PI (phosphatidylinositol) to phosphatidylinositol 3-monophosphate (PIP) in the presence of gamma-[32P]-ATP and analyzed by thin-layer chromatography. Western blotting was performed after antiphosphotyrosine immunoprecipitation with antibodies to the p85 subunit of phosphatidylinositol 3-kinase. Protein synthesis was assessed by [35S]-methionine incorporation and polyacrylamide gel electrophoresis. RESULTS: Ang II stimulated phosphatidylinositol 3-kinase activity dramatically, with 4.5- and 3.5-fold increases in PIP formation after 1 and 5 min, respectively. The involvement of tyrosine kinases was demonstrated by Western blotting in which Ang II increased tyrosine phosphorylation of a protein recognized by antibodies to the 85 kDa subunit of phosphatidylinositol 3-kinase. Furthermore, the tyrosine kinase inhibitor lavendustin A blocked Ang II-stimulated phosphatidylinositol 3-kinase activity and conversion of phosphatidylinositol to PIP. Ang II increased new protein synthesis as reflected by the significantly (P < 0.05) greater incorporation of [35S]-methionine into cardiomyocytes treated with Ang II. The link between Ang II and protein synthesis was mediated in part through phosphatidylinositol 3-kinase because the phosphatidylinositol 3-kinase inhibitor wortmannin blocked the effect of Ang II on protein synthesis. Increased production both of nuclear and of cytosolic proteins was demonstrated by agarose gel electrophoresis of these cellular components of Ang II-treated cardiomyocytes. Wortmannin produced a general inhibition of the synthesis of nuclear and cytosolic proteins, with a greater effect on nuclear proteins. The action of wortmannin on nuclear protein synthesis was confirmed by similar findings with another phosphatidylinositol 3-kinase inhibitor, LY294002. CONCLUSION: Phosphatidylinositol 3-kinase activation by Ang II occurs through a pathway utilizing tyrosine phosphorylation. Furthermore, this pathway is involved in cardiomyocyte protein synthesis and the possibility that it is operative in Ang II-mediated cardiac hypertrophy arises.

Angiotensin II↗

PubMed1997

Increased cardiac ppENK mRNA in cardiac hypertrophy and effects on blood pressure of its peptide products.

The objective of this study was to examine the expression of preproenkephalin (ppENK) in the heart in cardiac hypertrophy and the effects on cardiac contractility and blood pressure regulation of its peptide products. The ppENK-derived peptides Leu5-enkephalin (LE), Met5-enkephalin (ME), Met5-enkephalin-Arg6-Gly7-Leu8 (MEAGL), and Met5-enkephalin-Arg6-Phe7 (MEAP) were administered intravenously to unanesthetized Sprague-Dawley rats and to an isolated heart preparation from the same species. LE, ME, MEAGL, or MEAP (360 nmol iv) produced an immediate decrease in heart rate, reaching its maximum within 10 s and returning to baseline by 30 s. The blood pressure response for each enkephalin was a small initial decrease followed by a marked and significant increase (P < 0.05 for MEAP). In the isolated heart preparation, neither LE, ME, MEAGL, nor MEAP altered left ventricular contractility. Cardiac hypertrophy was produced in the Dahl salt-dependent model of hypertension with a significantly greater heart weight-to-body weight ratio in the Dahl salt-sensitive (S) compared with the Dahl salt-resistant (R) rat on a high-salt diet (P < 0.05). Tissue RNA was extracted, and Northern blot analysis identified and quantitated mRNA with a 0.93-kilobase cDNA of ppENK A. There was more ppENK mRNA in the left than in the right ventricle and much less in the atria than in the ventricles. The amount of ppENK mRNA was markedly and significantly increased in the left ventricle of the Dahl S compared with the Dahl R rat (P < 0.05). In contrast, there were no differences in ppENK mRNA levels in different brain regions between the R and S rats on a high-salt diet. Interestingly, a larger ppENK mRNA of 1.75 kilobases was abundantly expressed in testicular tissue. These data showing increased ppENK expression raise the possibilities of 1) an autocrine/paracrine role for enkephalins in cardiac hypertrophy and 2) an endocrine role for the hypertrophic heart, with an increased production of enkephalins, especially MEAP, that produces vasoconstriction and further increases in blood pressure.

Animals↗

PubMed1997

Visualization of muscarinic cholinergic receptors on chick cardiomyocytes and their involvement in phosphatidylcholine hydrolysis.

The purpose of this study was to visualize muscarinic receptors and their distribution on cardiomyocytes and to examine the effects of muscarinic cholinergic receptor (mACh-R) stimulation with carbachol on phosphatidylcholine hydrolysis. Cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Cardiomyocytes, grown on cover slips, were labelled with BODIPY PZ, a fluorescent analog of the muscarinic receptor antagonist pirenzepine, and examined with a laser scanning confocal microscope, mACh-R clusters were visualized and were fairly homogeneous in size with diameters ranging from 0.5 to 1.0 micron. The number of receptor clusters per cell was 83.5 +/- 6.8 (mean +/- SEM) and clusters were found at the periphery of the cell. Cardiomyocytes, grown as a monolayer in dishes, were treated with the 10(-4) M carbachol, a mACh-R agonist, and the effects on phosphatidylcholine hydrolysis were ascertained in cells preincubated with [methyl-3H]choline for 18 h. Cells were washed, lysed, and subjected to thin-layer chromatography to separate [3H]choline in various metabolites of phosphatidylcholine. Carbachol significantly (p < 0.05) increased intracellular free choline and decreased cellular phospholipid consistent with phosphatidylcholine hydrolysis. Carbachol increased the amount of [3H]choline that effluxed out of the cardiomyocyte into the medium. Carbachol-induced choline efflux was not prevented by pretreatment with n-butanol, a phospholipase D inhibitor, suggesting that other lipases such as phospholipase C are the major enzyme involved in phosphatidylcholine hydrolysis. Pertussis toxin prevented carbachol-induced choline efflux and the changes in intracellular free choline and phospholipid. An action of carbachol through G proteins was supported by the ability of pertussis toxin to antagonize the carbachol-induced reduction in cAMP generation from isoproterenol. In summary, mACh-Rs, visualized in living cardiomyocytes, were peripheral to the nucleus. Phosphatidylcholine hydrolysis induced by mACh-R stimulation may be a signal transduction pathway for mACh-R in the cardiomyocyte, operating through inhibitory G proteins sensitive to pertussis toxin.

1-Butanol↗

PubMed1996

Cardiac hypertrophy in the Dahl rat is associated with increased tyrosine phosphorylation of several cytosolic proteins, including a 120 kDa protein.

Because of the well established role that tyrosine phosphorylation (tyr phos) plays in growth factor signalling and regulating cell growth, we hypothesized that cardiac hypertrophy might be associated with altered tyr phos of certain cellular proteins in the heart. Furthermore, we hypothesized that angiotensin II (ang II), a putative growth factor for cardiac cells, might be useful as a probe to highlight any differences in intracellular signalling between normal and hypertrophied hearts. The heart and, for comparison, skeletal muscle, from Dahl S rats, which are predisposed to cardiac hypertrophy, and Dahl R rats, which are not, were examined. Antiphosphotyrosine immunoprecipitation and immunoblotting of heart cell extracts revealed the presence of a constitutively tyr phos 120 kDa cytosolic protein. Hearts from Dahl R rats on a high salt diet displayed a smaller amount of constitutive tyr phos of this protein. In the hearts of both Dahl R and S rats maintained on low salt diets there was little evidence of constitutive tyr phos of this protein. Ang II induced tyr phos of this protein in Dahl S rats on a low salt diet and Dahl R rats on a high salt diet, both of which show mild cardiac hypertrophy. In contrast, the markedly hypertrophied ventricle showed a minimal response to Ang II. Thus the severity of cardiac hypertrophy correlated directly with the tyr phos level of this protein. In an attempt to identify this protein, immunoblotting was carried out with antibodies to the signal transducing proteins rasGAP, JAK2 iNOS, p125FAK, and the Src substrate, pp120, but all proved negative. Ang II also stimulated an increase in tyr phos of proteins with apparent molecular masses of 42, 55, and 69 to 85 kDa in hearts from Dahl S rats on high salt diet. By comparison, there was no 120 kDa tyr phos protein in skeletal muscle even in response to Ang II. Silver stained sodium dodecyl sulfate gels demonstrated that this 120 kDa tyr phos protein is present in substantial amounts in the ventricles of rats fed high salt diets. Thus cardiac hypertrophy is characterized by an abundant 120 kDa cytosolic tyr phos protein, which is apparent with Ang II stimulation in milder degrees of cardiac hypertrophy, and is most likely an as yet uncharacterized protein.

Angiotensin II↗

PubMed1996

Indapamide accentuates cardiac chronotropic responses to epidermal growth factor in chick cardiomyocytes.

We have previously shown that indapamide [chloro-4-N-(methyl-2-indolinyl-1)-sulfamoyal-3-benzamide] has a direct action on the heart to alter ion fluxes. This study sought to examine the potential interaction between indapamide and epidermal growth factor (EGF). Cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts as aggregates that have a pattern of consistent spontaneous contraction. Indapamide enhanced the positive chronotropic response to EGF observed in chick embryonic ventricular myocyte aggregates while indapamide itself did not alter cardiac contractile frequency. Taken in conjunction with data that calcium channel blockade, inhibition of sodium entry or Na(+)-Ca2+ exchange in the cardiomyocyte opposes the positive chronotropic action of EGF on the cardiomyocyte, this study has identified an agent, indapamide, that accentuates the cardiomyocyte response to EGF.

Animals↗

PubMed1996

Serum insulin, IGF-I,IGF-II and growth hormone, and left ventricular mass in noninsulin-dependent mellitus.

OBJECTIVE: To investigate whether serum insulin, insulin-like-growth factor I (IGF-I),insulin-like-growth factor II (IGF-II) and growth hormone (GH)--each of which is a known trophic factor in vitro for the cardiomyocyte, and levels of which can be altered in noninsulin-dependent diabetes mellitus (NIDDM)--related of left ventricular (LV) mass in patients with NIDDM. DESIGN: Observational study. SETTING: University teaching hospital. PATIENTS AND METHODS: Patients with NIDDM without signs, symptoms or past history of hypertension, ischemic or valvular heart disease, or heart failure were recruited from the diabetes clinic of an university hospital. Fasting patients had blood drawn for determination of serum insulin, IGF-I, IGF-II and GH by radioimmunoassay. Height, weight, and blood pressure were recorded. An electrocardiogram was obtained and echocardiography were performed for calculation of LV mass. RESULTS: Patients' average age was 54.7 +/-1.6 years, and duration of NIDDM was 9.3 +/- 1.2 years. LV mass was 113.7 +/- 8.9 g/m2 in men (n=13) and 104.1 +/- 10.8 g/m2 in women (n=10). Serum insulin was 25.3 +/- ng/mL, IGF-I was 255 +/- 15 ng/mL, IGF-II was 0.62 +/- 0.05 microg/mL and GH was 5.4 +/- 0.5 ng/mL. There were no significant differences in LV mass among patients with serum insulin, IGF-I, IGF-II or GH in the upper compared with the lower 50th percentile. There were no significant differences in serum insulin, IGF-I, IGF-II or GH among patients in the upper compared with the lower 50th percentile for LV mass. Standardization of LV mass for body size, either by height or body surface area, did not alter the relationships. The correlation coefficients from linear least squares regression analysis between these hormones and LV mass were low (r<0.003), suggesting that even much larger sample sizes might not alter these findings. CONCLUSIONS: These data suggest that circulating total serum concentrations of growth factor (insulin, IGF-I, IGF-II and GH) are not determinants of LV mass in nonhypertensive patients with NIDDM.

Blood Pressure↗

PubMed1996

The angiotensin II subtype 2 (AT2) receptor is linked to protein kinase C but not cAMP-dependent pathways in the cardiomyocyte.

To define the signal transduction pathway linked to the cardiac angiotensin II (AII) receptor type 2 (AT2-R), cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Protein kinase C (PKC) activity was assayed in membrane and cytosolic fractions of the cardiac cells. AII significantly (p < 0.05) increased membrane PKC activity and decreased cytosolic PKC activity, in a concentration-dependent manner, suggesting a translocation of PKC from cytosol to membrane. AT2-R blockade by its antagonist, PD123319, produced a dose-dependent antagonism of AII-induced activation of PKC. PD123319, at 10(-6) M or greater concentrations, completely antagonized AII-induced PKC activation, in contrast to a small reduction in PKC activity by the AII receptor type 1 (AT1-R) antagonist losartan. Isoproterenol-induced cAMP generation was significantly (p < 0.05) blunted by AII. AT2-R blockade did not alter AII-induced reduction of beta-adrenoceptor-mediated increases in cAMP generation, in contrast with AT1-R blockade, which abolished AII-induced reduction of beta-adrenergic-mediated cAMP production. These data suggest that AT2 receptors have a previously unrecognized, role in the heart, namely, coupling AII to PKC.

Adrenergic beta-Agonists↗

PubMed1996

Differences in pituitary expression of proopiomelanocortin in Dahl salt-resistant and salt-sensitive rats on a high salt diet.

The Dahl strain of genetically salt resistant (R) and salt sensitive (S) rats affords an opportunity to explore mechanisms for salt resistance and sensitivity. Because of the evidence that opioid peptides and their receptors can be involved in cardiovascular regulation, the objective of this study was to test the hypothesis that proopiomelanocortin (POMC), the precursor of beta-endorphin, is involved in the development of hypertension, through the determination of POMC mRNA in the pituitary. Three-week-old inbred Dahl R and S rats were maintained on a high salt diet (8% NaCl) or low salt diet (0.4% NaCl) for 6 weeks. POMC mRNA and for comparison preproenkephalin A (preproENK) mRNA were examined from tissues of Dahl R and S rats as determined by Northern blot analysis using beta-actin as an internal standard. POMC mRNA was abundant in the pituitary tissues. There was more POMC mRNA in the pituitary tissue of R rats compared with that of S rats on the high salt diet. Differences in POMC mRNA in the pituitary were not observed between R and S on the low salt diet. There were no differences in the levels of preproENK mRNA in the pituitary tissues of R and S rats on high or low salt diet. From these data, we propose that inefficient production of POMC mRNA is a characteristic of the Dahl S rat on a high salt diet.

Animals↗

PubMed1994

Indapamide alters the cyclic AMP signal transduction pathway in cardiomyocytes in culture.

The cellular mechanism of action on the heart of the antihypertensive/diuretic agent indapamide is uncertain. Because of the importance of cAMP in signal transduction in the heart, the present study was designed to examine the hypothesis that indapamide interacts with the cAMP signal transduction pathway. Ventricular cardiomyocytes were isolated from 7-day-old chick embryo hearts and were maintained in culture. Indapamide did not alter basal and isoproterenol-stimulated cAMP levels in cardiomyocytes. However, indapamide pretreatment markedly accentuated forskolin-stimulated cAMP production. It also accentuated cholera toxin-induced increases in cAMP. Thus these data indicate that indapamide has an effect directly on the heart as manifested by its action on the ventricular cardiomyocytes. An effect of indapamide on cAMP generation by cholera toxin and forskolin suggests both a direct effect on adenylyl cyclase as well as an action through Gs. These findings may provide a cellular mechanism of action explaining indapamide's effect on the heart.

Animals↗

PubMed1994

Comparative effects of central administration of naloxone and clonidine on the blood pressure and heart rate response to anterior and posterior hypothalamic stimulation.

The purpose of this study was to examine the roles of brain opioid receptors, using the opioid receptor antagonist naloxone, and brain alpha 2 adrenergic and imidazole receptors, using their agonist clonidine, in the hypertension and tachycardia induced by electrical stimulation of the AHA and PHA area. Unanesthetized and unrestrained Wistar rats 300-400 g that had previously had catheters inserted into the lateral cerebral ventricle and femoral artery and electrodes in AHA or PHA areas received intracerebral (ICV) administration of naloxone or clonidine prior to hypothalamic stimulation. AHA and PHA stimulation with current strength from 0.5 to 2.0 mA produced a significant (p < 0.05) and dose dependent increase in BP and heart rate. Naloxone reduced the increase in BP with AHA stimulation at all but the highest stimulation current intensity. Clonidine also blunted the BP increase to AHA stimulation but to a lesser degree than naloxone. The combination of both naloxone and clonidine completely prevented the increase in BP even at high current intensities. Both naloxone and clonidine prevented the increase in heart rate with AHA stimulation. In contrast to AHA stimulation, naloxone did not alter the BP increase produced by PHA stimulation while clonidine prevented the effects of PHA stimulation. Heart rate did not increase with PHA stimulation. These data suggest that (i) the mechanisms involved in the hypertensive response to AHA are different from that of PHA. (ii) the endogenous opioid system is more operative in mediating the BP elevation produced by AHA but not PHA stimulation (iii) activation of the central alpha adrenergic or imidazole receptors can suppress hypertensive response to both AHA and PHA but is more effective for PHA than AHA stimulation.

Animals↗

PubMed1994

Nifedipine does not alter the increased cystolic free magnesium during inhibition of mitochondrial function in isolated cardiac myocytes.

1. The objectives of this investigation were to determine the effect of inhibition of mitochondrial function on intracellular free Mg concentration, [Mg2+]i, in the heart and to determine whether the calcium channel antagonist nifedipine would alter the response. 2. Cardiac myocytes were prepared as primary cultures from 7-day-old chick embryonic hearts. [Mg2+]i was determined in single ventricular cells with mag-fura-2. 3. Inhibition of mitochondrial function with carbonyl cyanide m-chlorophenylhydrozone (CCCP, 3 microM, plus amobarbital, 3 mM, produced a cessation of cardiac contractile frequency that was reversible. This was associated with an increase in [Mg2+]i from 0.48 to 0.98 mM which returned to near basal levels with removal of the drugs. [Ca2+]i oscillations with cell contraction were diminished in the presence of CCCP plus amobarbital and returned to normal following their removal. 4. In contrast, CCCP plus iodoacetate led to increased [Mg2+]i beyond 2 mM which was associated with elevated [Ca2+]i and cell death. 5. Nifedipine did not alter the cardiac contractile response to CCCP plus amobarbital. The increment in [Mg2+]i produced by CCCP plus amobarbital was not altered by nifedipine. These data suggest that [Mg2+]i is regulated by mitochondrial metabolism and nifedipine does not alter the increase in [Mg2+]i produced by inhibition of mitochondrial function suggesting increments in [Mg2+]i were from internal sources. Nifedipine may not interfere with the potentially beneficial actions of increased [Mg2+]i.

Adenosine Triphosphate↗

PubMed1994

Verapamil has antiarrhythmic effects that are mediated in brain through endogenous opioids.

The purpose of this study was to examine the hypothesis that the calcium channel blocker verapamil modulates catecholamine-induced arrhythmias in brain and to explore potential mechanisms of action. Wistar rats with catheters previously inserted in the lateral cerebral ventricle and femoral artery received verapamil 10 or 50 micrograms/kg or the diluent (intracerebroventricularly, i.c.v.) into the lateral cerebral ventricle. Epinephrine was infused to produce arrhythmias. Onset of ventricular arrhythmias, premature ventricular complexes (PVCs), occurred at a significantly (p < 0.05) higher epinephrine dose after the higher dose of verapamil. Development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly (p < 0.05) higher epinephrine concentrations with verapamil 50 micrograms/kg i.c.v. as compared with controls. Comparison of the two enantiomers of verapamil (50 micrograms/kg i.c.v.) showed that S(-)verapamil had the same effect as the racemic mixture whereas R(+)verapamil was intermediate between the control and S(-)verapamil. The antiarrhythmic action of verapamil could not be explained by alteration of the blood pressure (BP) response to epinephrine. Endogenous opioids were implicated in this action of verapamil because the (-)enantiomer of naloxone, which is an opioid antagonist, significantly (p < 0.05) antagonized the antiarrhythmic effects of centrally administered verapamil to suppress epinephrine-induced arrhythmias. In contrast the (+)enantiomer of naloxone did not alter verapamil-induced increase in arrhythmia threshold. Pretreatment with pertussis toxin i.c.v. antagonized the effects of verapamil. Verapamil did not alter the cyclic AMP response to isoproterenol in lymphocytes isolated from Wistar rats not exposed to any other drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1994

Angiotensin II induced alteration of cyclic adenosine 3',5'-monophosphate generation in the hypertrophic myocardium of Dahl salt-sensitive rat on a high-salt diet.

The objective of this study was to explore the action of angiotensin II (AII) on cardiac contractility and cyclic AMP (cAMP) generation by forskolin and isoproterenol in the hypertrophic myocardium of the salt-sensitive Dahl rat. Inbred Dahl S and Dahl R rats that had been on a diet supplemented with 6% NaCl were studied. The functional effects of the interaction of AII and forskolin on cardiac contractility were assessed in the isolated heart preparation. The effect on the cAMP signal transduction pathway was assessed in cardiomyocytes isolated from hearts of Dahl S and R rats. Dahl S rats developed cardiac hypertrophy on a high-salt diet, whereas Dahl R rats did not. Forskolin increased cardiac contractility, which was differently affected by AII, depending on whether the heart was from hypertrophied Dahl S rat or from the control Dahl R rat. AII accentuated forskolin-induced increases in cardiac contractility in hypertrophic hearts but diminished forskolin-induced increases in contractility in the nonhypertrophied hearts. This response was reflected in the cAMP response to forskolin, in that AII decreased forskolin-induced increases in cAMP in the nonhypertrophic heart. AII had the reverse effect in cardiomyocytes from hypertrophied hearts, as AII increased forskolin-induced cAMP production. This was shown to be due to an AII receptor mediated effect, as it was antagonized by the AII receptor antagonist saralasin. The same effects of AII were found on isoproterenol-induced increases in cAMP. Similar results occurred in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), suggesting that the effect was on cAMP production rather than cAMP degradation. This was attributed to an inhibitory G protein (Gi) mechanism, as the muscarinic agonist carbachol, which acts through Gi, produced the same effects as AII. Furthermore, the effects of AII were abolished by pertussis toxin, which inactivates Gi. These data indicate a reversal of control by AII in the hypertrophic Dahl S heart in response to forskolin, which activates adenylyl cyclase directly on the catalytic subunit, converting the substrate, ATP, to cAMP, independent of the guanine nucleotide activated protein, and in response to isoproterenol, which activates adenylyl cyclase through G protein mechanisms. All accentuated the forskolin-induced increase in cardiac contractility and cAMP generation in the hypertrophied ventricle but decreased both contractility and cAMP generation in nonhypertrophied hearts, suggesting that the process of cardiac hypertrophy in salt-sensitive Dahl rat may compensate for the reduction in intracellular cAMP by altering its regulatory control by AII.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study.

A randomized double-blind trial comparing the alpha-adrenergic blocker doxazosin and the beta-adrenergic blocker atenolol was completed by 131 patients with mild to moderate hypertension. Blood pressure and fasting blood lipids were determined at baseline and 4, 12, and 24 weeks of treatment. At entry, plasma lipids and lipoproteins were similar in those patients randomized to doxazosin or atenolol. After 24 weeks of treatment with atenolol, there were significant (P < .05) decreases in high-density lipoprotein cholesterol (HDL-C) and increases in triglycerides and very-low-density triglycerides (VLDL-T). In contrast, doxazosin was associated with significant (P < .05) increases in HDL-C and decreases in triglycerides and VLDL-T. There were no significant differences in HDL apolipoprotein (apo) A-I or low-density lipoprotein apoB between the drugs, but atenolol decreased the ratio of HDL-C to apoA-I, and doxazosin increased this ratio, differences that were statistically significant (P < .002). Neither apoA-I nor apoB concentration at baseline nor apoE phenotype was predictive of the lipid responses during antihypertensive treatment with either drug. Thus, there are significant favorable changes in HDL-C, total triglycerides, and VLDL-T between patients with mild to moderate hypertension and normal plasma lipids when treated with the alpha-blocker doxazosin compared with the beta-blocker atenolol. Plasma lipid or apo concentrations were not predictive of their lipid response during antihypertensive therapy with either of these agents.

Apolipoproteins E↗

PubMed1993

Report of the Canadian Hypertension Society Consensus Conference: 2. Diagnosis of hypertension in adults.

OBJECTIVE: To update recommendations for the diagnosis of mild hypertension in adults and to assess the role of echocardiography, self-measurement of blood pressure and ambulatory blood pressure monitoring. DATA SOURCES: Literature reviews of previous consensus conferences were updated with searches of MEDLINE for the period Jan. 1, 1988, to Nov. 15, 1991, and supplemented by reference lists and personal files. STUDY SELECTION: Panel members selected relevant articles and rated them according to methodologic criteria. DATA EXTRACTION: The data extracted concerned the measurement of blood pressure, the diagnosis of hypertension, the treatment of mild hypertension, and the reliability and validity of echocardiography, self-measurement of blood pressure and ambulatory blood pressure monitoring in the diagnosis of mild hypertension. The recommendations made were graded according to the level of evidence available, circulated to many experts and approved at a consensus conference. MAIN RESULTS: Previous recommendations for the accurate measurement of blood pressure remain mostly unchanged. Antihypertensive treatment should be prescribed for patients (including the elderly) with an average diastolic blood pressure of at least 100 mm Hg, for those with isolated systolic hypertension (systolic blood pressure of at least 160 mm Hg and diastolic blood pressure of less than 90 mm Hg) and for patients with a diastolic blood pressure of 90 to 99 mm Hg and target-organ damage. Clinical judgement is required in treating patients with a diastolic blood pressure of 90 to 99 mm Hg without target-organ damage, and individual risk for cardiovascular disease must be taken into account. There is insufficient evidence to warrant the routine use of echocardiography, self-measurement of blood pressure or ambulatory blood pressure monitoring in diagnosis. CONCLUSIONS: Recent high-quality evidence supports several new recommendations for the diagnosis of mild hypertension in adults. Additional research is needed to determine the role of echocardiography, self-measurement of blood pressure and ambulatory blood pressure monitoring.

Adult↗

PubMed1993

Lisinopril increases the recovery during reoxygenation and resistance to oxidative damage in cardiomyocytes.

The action of the angiotensin-converting enzyme (ACE) inhibitor lisinopril on the consequences of myocardial reoxygenation and oxidative damage was assessed in cultured chick embryonic ventricular cardiomyocytes. Lisinopril, 10(-8) M to 10(-6) M, produced a significant (P < 0.05) dose-dependent enhancement of the restoration of contractile frequency occurring during myocardial reoxygenation but did not alter the depression in contractile frequency during hypoxia. Lisinopril significantly (P < 0.05) shifted the dose-response relationship of ammonium persulfate-induced reduction in cardiac contractile frequency. Lisinopril significantly (P < 0.05) reduced the effect of another oxidative agent, tertbutylhydroperoxide which produced a time-dependent reduction in cardiac contractile frequency. Lisinopril did not alter cardiac contractile frequency in the absence of hypoxia or ammonium persulfate or tertbutylhydroperoxide. The viability of cardiomyocytes, assessed by trypan blue exclusion, paralleled the changes in cardiac contractile frequency. Lisinopril significantly (P < 0.05) improved viability of cardiomyocytes exposed to either ammonium persulfate or tertbutylhydroperoxide. Lisinopril did not display any antioxidant properties against the free radical alpha,alpha-diphenyl-beta-picrylhydrazyl. These data suggest that lisinopril accelerates the recovery of cardiomyocytes during reoxygenation and blunts the effects of oxidative agents through mechanisms involving the endogenous renin angiotensin system and/or a direct cellular action.

Ammonium Sulfate↗

PubMed1993

Effect of exogenous CDP-choline on choline metabolism in isolated adult rat ventricular myocytes under normoxic and hypoxic conditions.

The purpose of this study was to examine the effect of exogenous CDP-choline on choline metabolism and phosphatidylcholine biosynthesis in adult rat ventricular myocytes. Choline uptake and metabolism were examined, using [methyl3H] choline. CDP-choline in the medium produced a concentration dependent reduction in the amount of radio-label in phosphocholine and phospholipid but it did not alter choline uptake into the myocytes. CDP-choline also did not antagonize the effect of hypoxia on phosphatidylcholine synthesis; rather it accentuated the hypoxia-induced reductions in cellular phosphocholine and phosphatidylcholine biosynthesis. These results indicate that the exogenous administration of CDP-choline alters choline metabolism in the heart by reducing the formation of phosphocholine and phosphatidylcholine without altering choline uptake and suggest an effect of a CDP-choline metabolite on choline metabolism which is not effective in opposing the effect of hypoxia on phosphatidylcholine biosynthesis.

Animals↗

PubMed1993

Mechanisms of action of adrenergic receptor blockers on lipids during antihypertensive drug treatment.

The objective of this article is to focus on the antihypertensive agents blocking adrenergic receptors, both alpha and beta blockers, and attempt to construct potential explanations for their effects on lipids in a mechanistic manner. The essential thesis is that adrenergic control of lipid metabolism is responsible for the effect on lipids and lipoproteins of antihypertensive agents that block adrenergic receptors. Agonists and antagonists show the opposite action on lipoprotein lipase, lecithin:cholesterol acyltransferase (LCAT) and LDL-cholesterol uptake by LDL receptors in a manner that might explain the findings of increases in triglycerides and LDL cholesterol with decreases in HDL cholesterol in patients receiving beta blockers without intrinsic sympathomimetic activity and the reverse in patients on treatment with alpha adrenergic receptor blockers.

Adrenergic alpha-Antagonists↗