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Biomedical subjects

M G Currie

Publications and source records attributed to M G Currie.

At least 91 records · Page 5Linked to original sources
PubMed1987

Profound elevation of ventricular and pulmonary atriopeptin in a model of heart failure.

Recently, the concept of an atrial endocrine system has expanded to that of a cardiac endocrine system. In support of this expanded view, the cardiac ventricles have been demonstrated to be a source of the atrial hormone (atriopeptin). Markedly enhanced ventricular expression of atriopeptin has been shown to be associated with cardiac hypertrophy. In this study, we measured the levels of atriopeptin in atrial and extra-atrial tissues of the BIO 14.6 hamster, a genetic model of cardiomyopathy and congestive heart failure. The BIO 14.6 hamsters (approximately 1 year of age) weighed 7.4% more than their age-matched controls, an indication of edema, and showed overt cardiac hypertrophy (control vs. BIO 14.6 heart weight: .556 +/- .045 g vs. .990 +/- .043 g). A survey of extra-atrial tissues indicated that pulmonary and ventricular tissue from both control and BIO 14.6 hamsters possessed measurable levels of immunoreactive atriopeptin. However, a comparison of atriopeptin levels in the lungs and cardiac ventricles, respectively, of control and BIO 14.6 hamsters revealed profound differences. Pulmonary atriopeptin levels were 30-fold greater, and ventricular atriopeptin levels were 13.3-fold greater, in the BIO 14.6 hamsters. In addition, the total content of atriopeptin was 2.2-fold greater in the atria of BIO 14.6 hamsters. Dot blot analysis indicated that atriopeptin mRNA levels were greater in the atria (3.4-fold) and ventricles (17.9-fold) of BIO 14.6 hamsters. A similar analysis of atriopeptin mRNA in pulmonary tissue proved inconclusive. The function of the marked increase of pulmonary and ventricular atriopeptin is unknown; however, it is plausible that the peptide hormone serves to regulate the formation of pulmonary and peripheral edema.

Animals↗
PubMed1987

Ventricular atriopeptin. Unmasking of messenger RNA and peptide synthesis by hypertrophy or dexamethasone.

Left ventricular hypertrophy or treatment with dexamethasone caused a 2.5-fold to threefold increase in both immunoreactive atriopeptin (AP) and AP messenger RNA (mRNA), primarily in left ventricular tissue. The combined treatments increased immunoreactive AP and AP mRNA more than either treatment alone. In the animals in which cardiac hypertrophy had been produced by abdominal aortic constriction, there was a decrease in atrial levels of AP and an increase in plasma levels of immunoreactive AP. The increase in left ventricular immunoreactive AP was confirmed by immunohistochemical staining of tissue from hypertrophied and/or dexamethasone-treated rats. The mRNA accumulated in the left ventricle was identical to atrial AP mRNA, as judged by transcriptional start site and by size on Northern blots. Because the mass of ventricular tissue is substantially greater than that of atrial tissue, the induced mRNA levels may represent a total abundance approaching one third of the total AP mRNA in the atria. High performance liquid chromatographic purification of ventricular extracts primarily demonstrated the presence of the high molecular precursor and small amounts of C-terminal peptide AP. Induction of ventricular AP (mRNA and peptide) may represent regression of the tissue to an earlier developmental form. These data provide a unique example of regulation of AP biosynthesis in nonatrial tissue.

Animals↗
PubMed1986

Evidence for alpha-1 adrenergic receptor regulation of atriopeptin release from the isolated rat heart.

Atrial myocardium is the source of a recently described peptide hormone termed atriopeptin. Atriopeptin is thought to have a role in the regulation of systemic arterial pressure, fluid balance and plasma electrolyte homeostasis. Isolated rat hearts release atriopeptin into the coronary effluent, and we have found that this release is stimulated by the administration of norepinephrine, a compound with alpha and beta adrenergic properties. Infusion of the pure beta-receptor agonist, isoproterenol, failed to stimulate the release; however, the alpha-1 receptor agonist phenylephrine induced the release in a dose-dependent manner. The stimulation of atriopeptin release by norepinephrine and phenylephrine was inhibited by alpha-blockade with phentolamine. Administration of BHT-920, a selective alpha-2 agonist, had no effect on atriopeptin release. We conclude that atriopeptin secretion by the atrial myocyte is stimulated by activation of the alpha-1 adrenergic receptor. This finding suggests an involvement of the sympathetic nervous system in the physiologic regulation of the secretion of this hormone.

Adrenergic alpha-Antagonists↗
PubMed1986

Atriopeptin distribution in the developing rat heart.

The embryonic distribution of atriopeptin (atrial natriuretic factor) in the Sprague-Dawley rat heart was mapped by immunoperoxidase staining of embryonic and neonatal hearts using rabbit antiserum to atriopeptigen purified from adult rat atrium. During the period of cardiac septation (days 14 and 16), immune serum reacted strongly with myocardial cytoplasmic granules in two sites: the inner cell layer along the cephalic curvature of the atria and the trabeculae of the incompletely divided ventricles. The youngest hearts studied (gestational day 11) displayed only nonspecific diffuse peroxidase reactivity within blood cells, indistinguishable from control sections incubated with normal rabbit serum. One week following birth, intense anti-atriopeptin reactivity was widely distributed through both atria. In addition, immunoreactive cytoplasmic granules were found at several sites in the ventricular myocardium. Along the fiber tracts of the concentric layers of the ventricular walls and interventricular septum, scattered granular foci were seen between nuclei of contiguous elongated myocytes. Positive staining was also seen within the papillary muscles and trabeculae carnae, regions shown by Alcian blue/periodic acid-Schiff base staining of sister sections to be relatively rich in glycogen. These patterns of antibody reactivity suggest the coupling of early atriopeptin secretory activity with developing cardiac function.

Aging↗
PubMed1985

Atriopeptin-immunoreactive neurons in the brain: presence in cardiovascular regulatory areas.

Antisera to atriopeptin III and to a cyanogen bromide fragment of the precursor molecule atriopeptigen were prepared and used to examine the distribution of atriopeptin-like immunoreactive material in the heart and brain of the rat. Granules of this material were seen in myocytes throughout the right and left atria and were densest in the perinuclear region. The distribution of atriopeptin-like immunoreactive material in the heart is consistent with previous reports of atrial secretory granules. In the brain neurons containing the material were observed in the hypothalamus and the pontine tegmentum. Atriopeptin in the brain may serve as a neurotransmitter in neural systems controlling blood volume and composition, the same physiological functions regulated by blood-borne atriopeptin.

Animals↗
PubMed1985

Atriopeptins: renal-specific vasodilators in conscious dogs.

Conscious dogs were instrumented to study the effects of atriopeptins (I, II, III) on renal, iliac, mesenteric, and coronary blood flow. Intravenous injection of atriopeptins II and III caused a dose-related increase in renal blood flow, whereas atriopeptin I had no effect. Atriopeptins II and III at 5 micrograms/kg increased renal blood flow 27 +/- 5.0% from 252 +/- 29 ml/min and 18 +/- 2.9% from 238 +/- 32 ml/min and reduced renal vascular resistance 24 +/- 3.2% from 0.431 +/- 0.048 mmHg X ml-1 X min and 15.1 +/- 1.2% from 0.443 +/- 0.023 mmHg X ml-1 X min, respectively. Atriopeptin I, II, or III exerted no significant effect on systemic arterial pressure, heart rate, coronary, mesenteric, or iliac blood flows. Doses of nitroglycerin (25 micrograms/kg) that increased renal blood flow (28 +/- 5.0%) to a degree comparable to atriopeptins II and III also caused increases in coronary, iliac, and mesenteric blood flows and produced falls in systemic blood pressure and a reflex tachycardia. Thus in the conscious dog, atriopeptins II and III are potent selective renal vasodilators that do not exhibit systemic hemodynamic effects in contrast to nitroglycerin, a nonselective vasodilator. Cleavage at the carboxy terminal end of these peptides to yield atriopeptin I abolishes the renal vasodilator action entirely.

Anesthesia↗
PubMed1985

Atriopeptins: correlation between renal vasodilation and natriuresis.

The effect of atrial peptides on renal function was studied in intact anesthetized dogs. A quantitative comparison of bolus intra-arterial injections demonstrated a rank order potency as renal vasodilators and natriuretic/diuretic agents as follows: ser-leu-arg-arg-atriopeptiin III (SLRR-APIII) greater than high molecular weight artrial peptide greater than or equal to atriopeptin (AP)III = APII much greater than API (essentially inactive). A sustained infusion of APIII was employed in order to study the temporal and quantitative correlation of the renal functional changes induced by the atrial peptide. Both intra-arterial and intravenous administration of the peptide produced concentration-dependent increases in renal blood flow, urine volume, sodium excretion, and osmotic clearance. Infusion of APIII into the renal artery did not alter systemic blood pressure or heart rate. Intravenous infusions of APIII required 10 times higher doses to induce the changes in renal vascular resistance and electrolyte excretion, and a fall in blood pressure and tachycardia resulted. The natriuretic-diuretic effect of the atriopeptins appears to be closely associated with renal vasodilation, exhibiting a positive linear correlation between the peptide-induced changes in sodium excretion and changes in renal blood flow.

Animals↗
PubMed1985

Comparative vascular pharmacology of the atriopeptins.

The atriopeptins are potent relaxants of norepinephrine-constricted aortic strips or are dilators of renal blood vessels in isolated perfused rat kidneys that are constricted by norepinephrine. This vasorelaxant property of the atriopeptins requires the presence of phenylalanine arginine (i.e., atriopeptin II, III, or ser-leu-arg-arg atriopeptin III) residues in the carboxy terminus which are considerably more effective than atriopeptin I (the 21 amino acid peptide which lacks the phe-arg C-terminus) or the core peptide (residues 3-19). However, these artificially in vitro precontracted preparations do not accurately predict the vascular effectiveness of the atriopeptins in intact rats. Intravenous administration of the atriopeptins (including atriopeptin I) to anesthetized rats produces concentration-dependent hypotension, a selective decrease in renal resistance in low doses (determined with microspheres), and pronounced diuresis. At higher doses, atriopeptins increase blood flow in other vascular beds. On the other hand, in the anesthetized dog, injection (intraarterially) of the phe-arg-containing peptides produces a concentration-dependent increase in both renal blood flow and sodium excretion, whereas atriopeptin I is inactive. Although there is a species difference in responsiveness to atriopeptin I, these data demonstrate a direct correlation between the renal vasodilation and diuresis produced by this novel family of atrial peptides.

Animals↗
PubMed1985

Inhibition of aldosterone biosynthesis by atriopeptins in rat adrenal cells.

The effect of synthetic atriopeptins on basal and stimulated aldosterone secretion was determined in isolated adrenal glomerulosa cells of the rat. Neither atriopeptin I (1-21) or III (1-24, i.e., the Phe-Arg-Tyr carboxy-terminal extension of atriopeptin I) altered basal aldosterone release. However, if the cells were prepared from adrenals of sodium-depleted rats, the basal aldosterone release was increased by 9-fold, compared with cells from normal rats. This elevated release was inhibited by 32% by atriopeptin I and atriopeptin III. Atriopeptin III was more potent than atriopeptin I. Angiotensin II and adrenocorticotropin stimulated the release of aldosterone in a concentration-related manner. Both atriopeptin I and atriopeptin III inhibited the stimulation by the peptides. Atriopeptin I inhibited angiotensin II- and adrenocorticotropin-induced aldosterone production by 50% at concentrations of 12 and 11 nM, respectively, and 0.5 and 0.2 nM, respectively, for atriopeptin III. Potassium-stimulated aldosterone production was also inhibited by atriopeptin I and atriopeptin III with 50% inhibition at concentrations of 10 and 0.4 nM, respectively. Shorter peptides (1-20, 1-19, and 3-19) were equipotent to atriopeptin I (1-21) as inhibitors of angiotensin II-induced steroidogenesis. To determine the site at which atriopeptins inhibit aldosterone synthesis, we used cyanoketone to inhibit 3 beta-hydroxy-dehydrogenase and dissociate the early and late pathways. Angiotensin II (2 nM) increased the synthesis of pregnenolone (early pathway), as well as the conversion of [3H]corticosterone to [3H]aldosterone (late pathway). Atriopeptin III inhibited basal pregnenolone synthesis by 36% and completely blocked angiotensin II-stimulated synthesis. The peptide similarly inhibited the late pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1985

Vasodilator properties of a family of bioactive atrial peptides in isolated perfused rat kidneys.

The isolated Krebs-perfused rat kidney was used for the quantitative and qualitative evaluation of the family of peptides derived from rat atrial extracts. Renal resistance changes were measured in perfused rat kidneys continuously infused with norepinephrine. The low molecular weight peptide fraction from rat atrial extracts was purified to obtain six peptides. The 21 amino acid peptide, designated atriopeptin I, was previously demonstrated to be natriuretic and to relax intestinal but not vascular smooth muscle strips (in vitro) and to be an extremely weak renal spasmolytic in the isolated perfused rat kidney. On the other hand, the 23 amino acid peptide (which has a Phe-Arg carboxy-terminal extension on atriopeptin I), designated atriopeptin II, and atriopeptin III (the Phe-Arg-Tyr carboxy-terminal extension) were natriuretic and spasmolytic (in vitro) on both intestinal and vascular smooth muscle. Both atriopeptin II and III produced a profound concentration-dependent decrease in renal resistance in the norepinephrine-constricted rat kidney preparation. A comparative study of the six peptides isolated from atrial extracts indicates that the Phe-Arg or Phe-Arg-Tyr carboxy-terminal extension of the basic 21 amino acid sequence is essential for the renal vasorelaxant activity. A purified high molecular weight peptide (designated atriopeptigen) is impotent relative to the low molecular weight atriopeptin II and III as a renal spasmolytic in isolated perfused rat kidneys and reduces renal resistance only after in vitro proteolytic cleavage. Thus, the low molecular weight peptides atriopeptin II and III appear to be the active species that mediate the renal vasodilation produced by atrial extracts.

Animals↗
PubMed1984

Atriopeptin release from the isolated perfused rabbit heart.

Mammalian atrial extracts have been shown to contain bioactive peptides which exert natruiretic, diuretic, and smooth muscle relaxant effects. These extracts include several low molecular weight (less than 5,000 Mr) atrial peptides (atriopeptins) which exhibit identical sequences over a central core region which are derived from the high molecular weight peptide (atriopeptigen) precursor which has been purified and sequenced. In the current study we found that extracts of rabbit atria possess both high and low molecular weight bioactive atrial peptides, however, the coronary venous effluent obtained from the isolated perfused rabbit heart only contained the low molecular weight peptide. This trypsin labile activity causes a dose-dependent relaxation of rabbit aorta and chicken rectum assay strips. Separation of the bioactivity with gel filtration chromatography and reversed phase HPLC indicates the heart releases a single substance similar to atriopeptin III. There was no evidence that atriopeptigen was released from the isolated perfused rabbit heart. We suggest that atriopeptigen is proteolytically processed in the atria to an atriopeptin which is subsequently the released form of the atrial peptide.

Animals↗
PubMed1984

The sequence of an atriopeptigen: a precursor of the bioactive atrial peptides.

The high molecular weight fraction ( atriopeptigen -APG) obtained by gel filtration chromatography of rat atrial extracts was fractionated by isoelectric focusing and reverse phase HPLC to obtain a pure APG. Purification of cyanogen bromide digests of the crude high molecular weight fraction resulted in the isolation of a single biologically active cyanogen bromide cleavage peptide. Sequence analyses of these peptides coupled with recent reports of sequence analyses of intermediate molecular weight atrial peptides ( Thibault , et al. (1984) FEBS Letters 167, 352-356, and Kangwa , et al., Biochem. Biophys. Res. Commun 119, 933-940) provide the complete primary structure of an 111 residue APG.

Amino Acid Sequence↗
PubMed1984

Atriopeptins: a family of potent biologically active peptides derived from mammalian atria.

Extracts of rat atria are potent stimulators of sodium and urine excretion, and relax vascular and intestinal smooth muscle preparations. The structures of six biologically active peptides obtained from atrial extracts are reported here. Ion exchange chromatography of a low molecular weight fraction obtained by gel filtration of atrial extracts produced two natriuretic fractions: the first induced relaxation of intestinal smooth muscle strips only, whereas the second also relaxed vascular strips as well. From the first fraction four pure biologically active peptides obtained by reverse phase HPLC have been sequenced: the 21 amino acid peptide, designated atriopeptin I, and three homologs (des- ser1 -, des- ser1 -ser2-, and des- ser21 - atriopeptin I). From the second fraction two pure biologically active peptides were obtained, which had C-terminal extensions of atriopeptin I: atriopeptins II (23 amino acid residues) and III (24 residues), having respectively phe-arg and phe-arg-tyr C-termini. These results suggest that this family of six peptides, sharing the same 17 membered ring formed by an internal cystine disulfide, is derived from a common high molecular weight precursor.

Amino Acid Sequence↗
PubMed1984

Kallikrein activation of a high molecular weight atrial peptide.

Mammalian atrial extracts contain bioactive peptides that exert profound effects upon renal function and isolated smooth muscle preparations. Gel filtration chromatography of rat atrial extract separates the activity into two peaks having apparent molecular weights of 20,000 to 30,000 and less than 10,000. Mild proteolytic treatment (trypsin 1 U/ml) of the high molecular weight fraction enhances the smooth muscle relaxant activity of this fraction and concomitantly reduces the apparent molecular weight of this fraction to less than 10,000. In this report we show that urinary and submaxillary kallikrein enhances the activity of rat atrial extracts in a similar fashion. Pretreatment of the high molecular weight fraction with either kallikrein (1 microgram/ml) enhances the smooth muscle relaxant activity of this fraction. Similar treatment of the low molecular weight fraction had no effect. The enhancement of the bioactivity of the high molecular weight substance(s) by the kallikreins was abolished by aprotinin but was unaffected by soybean trypsin inhibitor. These results suggest that exogenous addition of tissue kallikrein activates a high molecular weight peptide by limited proteolysis. Analysis of the kallikrein-treated high molecular weight peptide fraction by gel filtration indicates that the biological activity comigrates with the low molecular weight peptides present in the original atrial extract.

Animals↗
PubMed1984

Purification and sequence analysis of bioactive atrial peptides (atriopeptins).

Mammalian cardiac atria have several biologically active peptides that exert profound effects on sodium excretion, urine volume, and smooth muscle tone. In the present study two such peptides of low molecular weight were purified and separated from each other on the basis of differences in charge, hydrophobicity, and biological profile. The first peptide, designated atriopeptin I, exhibits natriuretic and diuretic activity and selectivity relaxes intestinal smooth muscle but not vascular smooth muscle strips. The second peptide, atriopeptin II, is a potent natriuretic and diuretic that relaxes both intestinal and vascular strips. Sequence analysis of atriopeptin I indicates that it is composed of 21 amino acids, of which serine and glycine residues predominate. The amino terminal sequence of atriopeptin II up to residue 21 is the same as that of atriopeptin I, with the addition of the Phe-Arg extension at the carboxyl terminus. Both peptides appear to be derived from a common high molecular weight precursor (designated atriopeptigen); their biological selectivity and potency may be determined by the site of carboxyl terminal cleavage.

Amino Acid Sequence↗
PubMed1984

Proteolytic activation of a bioactive cardiac peptide by in vitro trypsin cleavage.

Mammalian cardiac atria possess several unidentified biologically active peptides. Fractionation of rat atrial extracts by gel filtration chromatography revealed two major fractions [apparent molecular weights of 20,000-30,000 (peak I) and less than 10,000 (peak II)], both of which were potent natriuretic agents (eliciting a 25-fold increase in sodium excretion) and smooth muscle relaxants. Vigorous treatment with trypsin (100 units/ml at 37 degrees C for 15 min) of both fractions abolished all biological activity. Further purification of the lower molecular weight fraction (peak II) by ion-exchange chromatography indicated two subfractions that possessed potent natriuretic activity and that preferentially relaxed either intestinal (designated peak IIA) or vascular (peak IIB) smooth muscle assay tissues. The similarity of the biological effect of the high (peak I) and low (peak II) molecular weight peptides led us to test the possibility of precursor-product relationship. Mild proteolytic treatment of the high molecular weight peptide with trypsin (1 unit/ml at room temperature) markedly enhanced the smooth muscle relaxant activity. Subsequent analysis of the trypsin (1 unit/ml)-treated high molecular weight peptide (peak I) by gel filtration and ion-exchange chromatography revealed that the peptide now resembled the low molecular weight peptides (peaks IIA and IIB) present in the original atrial extract. These data suggest that the cardiac atria contain a relatively inactive (smooth muscle relaxant) high molecular weight peptide and suggest that biologically active low molecular weight peptides can subsequently be generated by proteolytic cleavage.

Animals↗
PubMed1984

An atrial peptide is a potent renal vasodilator substance.

Renal intra-arterial administration of rat atrial extracts elicits a concentration dependent renal vasodilation (independent of prostaglandin or dopamine release) in anesthetized rats. The atrial extracts do not alter skeletal musculature (hindlimb) vascular resistance or systemic arterial blood pressure. The high molecular weight peptide fraction of atrial extracts obtained by gel filtration, reduces renal resistance intra-arterially only after proteolytic activation (in vitro) or following intravenous (i.e., systemic in vivo activation) administration. The low molecular weight peptide fraction of the atrial extract which is active intra-arterially as a renal vasodilator has been further purified to yield two major peptides. The 21 amino acid peptide, designated atriopeptin I, was previously demonstrated to be natriuretic and to relax intestinal but not vascular smooth muscle strips. This peptide exerted little or no intra-arterial effect on renal resistance. The 23 amino acid peptide (the phenylalanine-arginine C terminal extension of atriopeptin I), designated atriopeptin II, was natriuretic and spasmolytic (in vitro) on both intestinal and vascular strips and was a potent renal vasodilator in vivo. Thus, the renal vasodilator activity present in cardiac atrial extracts appears to derive from a proteolytic process which selectively generates the 23 amino acid peptide, atriopeptin II. Further cleavage with the loss of phenylalanine-arginine C-terminal, as occurs with atriopeptin I, markedly suppresses the renal vasodilation.

Animals↗