To define the relation between atrial pressures and the release of atrial natriuretic peptide, we measured plasma concentrations of the peptide in 26 patients with cardiac disease--11 with normal atrial pressures and 15 with elevated atrial pressures (11 of these 15 had elevated pressures in both atria). Mean peptide levels (+/- SEM) in the peripheral venous blood were increased in the 11 patients with cardiac disease and normal atrial pressures, as compared with 60 healthy controls (48 +/- 14 vs. 17 +/- 2 pmol per liter). In the patients with elevated atrial pressures, peptide concentrations were increased twofold in peripheral venous, right atrial, pulmonary arterial, and systemic arterial plasma, as compared with the concentrations in the patients with normal atrial pressures. A step-up in peptide concentration was seen between the venous and right atrial plasma (P less than 0.002) and between the pulmonary and systemic arterial plasma (P less than 0.01), suggesting release of the peptide from the atria. A linear relation was found between right atrial pressure and right atrial peptide concentration (r = 0.835, P less than 0.001) and between pulmonary wedge pressure and the systemic arterial peptide concentration (r = 0.866, P less than 0.001). Right atrial pressure and the peptide concentration both increased with exercise testing in the nine patients evaluated. We conclude that the release of atrial natriuretic peptide is at least partly regulated by right and left atrial pressures. Distinguishing the relative contributions of the two atria and defining the role of peptide release in the pathogenesis of heart failure will require further investigation.
Circulating levels of the calcium-regulating hormones, calcitonin, calcitriol, and parathyroid hormone, were analyzed in relation to plasma renin activity in 10 persons with normal blood pressure and in 51 persons with essential hypertension. Calcitriol (p less than 0.008) and parathyroid hormone (p less than 0.01) levels were elevated in hypertensives with low renin activity, whereas calcitonin levels were higher in patients with high renin activity (p less than 0.008), compared with normotensive controls and other hypertensive patients. Continuous relationships were observed between calcitriol levels and plasma renin activity in all patients (r = -0.65, p less than 0.001) and between parathyroid hormone levels and urinary sodium excretion in hypertensive patients with low renin activity (r = -0.63, p less than 0.01). Together, these results support a linkage between calcium metabolism and renin-sodium factors in essential hypertension. Calcium-regulating hormones and the renin-aldosterone system may coordinately mediate the blood pressure effects of differing dietary calcium and sodium intakes at the cellular level by altering cellular handling of monovalent and divalent ions.
The vasodilating potency of a-human atrial natriuretic peptide (a-hANP) was investigated in the forearms of 16 normotensive subjects, 22 to 48 (mean 28) years old, with the use of venous occlusion plethysmography. a-hANP, 0.005 to 1.5 ,ug/min/100 ml forearm volume (FAV), infused in nine dose steps into the brachial artery increased forearm blood flow (FAF; ml/min/100 ml FAV) from 2.8 ± 0.4 (SEM) to a maximum of 9.6 ± 1.1. Forearm vascular resistance (mean arterial pressure/ FAF) decreased by 72%. The a-hANP dose that produced a 50% vasodilator response was 0.093 0.0 16 gg/min/100 ml FAV (n = 11) and it resulted in a venous plasma concentration of ANP (pANP) of 115 ± 7 pmol/liter (normal 2 to 80; radioreceptor assay). Intraindividually, the maximum dose of ahANP induced an increase in FAF that was 60% of the maximum response to sodium nitroprusside (14.1 ± 1.8). Combined infusions (n = 9) of maximum forearm vasodilator doses of a-hANP and nitroprusside increased FAF to 22.7 ± 3.4; this additive vasodilator effect of a-hANP and nitroprusside is consistent with their different actions on the guanylate cyclase system. In man, the direct vasorelaxant effect of a-hANP occurs at concentrations within the upper normal range of pANP, suggesting a physiologic vasodilator role for a-hANP. Circulation 75, No. 1, 221-228, 1987. ATRIAL PEPTIDES1 contained in specific granules of the mammalian atria5-9 and released into the circulation on atrial distention"'-2 may play a physiologic role in circulatory homeostasis because they exhibit potent vasorelaxant,'3 natriuretic, 7 8 14 and aldosterone-inhibiting effects.'5' 16 Atrial peptides oppose the vascular smooth muscle contraction induced by norepinephrine, angiotensin JJ,17 18 and serotonin, histamine, and methoxamine.'9 They have been shown to bind to specific high-affinity receptors in adrenal,20 renal, and
The antihypertensive efficacy of monotherapy with the calcium antagonists nifedipine (n = 60) and verapamil (n = 43) was investigated in patients with essential hypertension. Relationships between age, pretreatment blood pressure, pretreatment plasma renin activity, and hypotensive response were examined. Intraindividual differences in the responses to both drugs were also studied (n = 16). Treatment with verapamil had to be discontinued because of constipation in one patient; treatment with nifedipine was discontinued because of headache in 11 and ankle edema in one. The antihypertensive efficacy of nifedipine and verapamil was comparable and was positively related to pretreatment mean blood pressure (p less than 0.001) and inversely to pretreatment plasma renin activity (p less than 0.05). With verapamil, the fall in blood pressure correlated positively with the patient's age (p less than 0.001). Thus, calcium antagonists can be used as first-line drugs, especially in older and low renin patients. The relationship between the antihypertensive response and pretreatment blood pressure suggests that there may be a calcium influx-dependent vasoconstrictor mechanism in essential hypertension which may be more pronounced in patients with low plasma renin.
SUMMARY We previously provided evidence that atrial natriuretic factor (ANF) antagonizes angiotensin H-induced vascular contractility and angiotensin H-stimulated aldosterone production by isolated adrenal cells. To examine the importance of these effects in vivo, synthetic ANF (auriculin A) was administered intravenously (2 M&^g bolus followed by 0.3 ^ug/kg/min constant infusion) to conscious, unrestrained two-kidney, one-clip and one-kidney, one-clip rats on normal sodium intake and their sham-operated controls. The one-kidney, one-clip rats also were studied on a sodiumdeficient diet. Mean blood pressure, plasma renin activity, and plasma aldosterone levels were measured before and after 60-mlnute infusion. In saralasin-responsive two-kidney, one-clip rats (n = 10), ANF administration reduced blood pressure (from 187 ± 11 [SE] to 153 ± 11 mm Hg; p < 0.001) and plasma aldosterone levels (from 182 ± 61 to 125 ± 60 ng/dl; p < 0.05), while plasma renin activity increased (from 59 ± 16 to 82 ± 20 ng/ml/hr; p < 0.05). Lesser changes in blood pressure occurred in saralasin-nonresponsive two-kidney, one-clip rats (149 ± 10 to 143 ± 8 mm Hg; n = 5), sodiumreplete one-kidney, one-clip rats (183 ± 9 to 170 ± 11 mmHg;n = 9), two-kidney sham-operated rats (122 ± 3 to 115 ± 4 mm Hg; n = 8), and one-kidney sham-operated rats (117 ± 3 to 112 ± 3 mm Hg; n = 7). Control plasma renin and aldosterone levels were not elevated in these latter groups and did not change significantly with ANF administration. In sodium-depleted one-kidney, one-clip rats, which became saralasin responsive, ANF administration significantly reduced blood pressure (from 184 ± 11 to 156 ± 12 mm Hg; n = 8), plasma aldosterone levels (from 286 ± 41 to 179 ± 36 ng/dl), and plasma renin activity (from 69 ± 19 to 44 ± 13 ng/ml/hr). These data indicate that ANF has potent antihypertensive and aldosterone-suppressing effects in vivo, irrespective of induced changes in plasma renin activity. Both the vascular and adrenal effects of ANF appear to be enhanced when the activity of the renin-angiotensin system is increased. (Hypertension 7 [Suppl I]: I-43-I-48, 1985) KEY WORDS * angiotensin * auriculin * saralasin * rats * renovascular hypertension M AMMALIAN atrial myocytes contain potent natriuretic polypeptides that appear to be associated with secretory granules.
Background Klebsiella spp. are opportunistic pathogens which can cause severe infections, are often multi-drug resistant and are a common cause of hospital-acquired infections. Multiple new Klebsiella species have recently been described, yet their clinical impact and antibiotic resistance profiles are largely unknown. We aimed to explore Klebsiella group- and species-specific clinical impact, antimicrobial resistance (AMR) and virulence. Methods We analysed whole-genome sequence data of a diverse selection of Klebsiella spp. isolates and identified resistance and virulence factors. Using the genomes of 3594 Klebsiella isolates, we predicted the masses of 56 ribosomal subunit proteins and identified species-specific marker masses. We then re-analysed over 22,000 Matrix-Assisted Laser Desorption Ionization - Time Of Flight (MALDI-TOF) mass spectra routinely acquired at eight healthcare institutions in four countries looking for these species-specific markers. Analyses of clinical and microbiological endpoints from a subset of 957 patients with infections from Klebsiella species were performed using generalized linear mixed-effects models. Results Our comparative genomic analysis shows group- and species-specific trends in accessory genome composition. With the identified species-specific marker masses, eight Klebsiella species can be distinguished using MALDI-TOF MS. We identified K. pneumoniae (71.2%; n = 12,523), K. quasipneumoniae (3.3%; n = 575), K. variicola (9.8%; n = 1717), “K. quasivariicola” (0.3%; n = 52), K. oxytoca (8.2%; n = 1445), K. michiganensis (4.8%; n = 836), K. grimontii (2.4%; n = 425) and K. huaxensis (0.1%; n = 12). Isolates belonging to the K. oxytoca group, which includes the species K. oxytoca, K. michiganensis and K. grimontii, were less often resistant to 4th-generation cephalosporins than isolates of the K. pneumoniae group, which includes the species K. pneumoniae, K. quasipneumoniae, K. variicola and “K. quasivariicola” (odds ratio = 0.17, p < 0.001, 95% confidence interval [0.09,0.28]). Within the K. pneumoniae group, isolates identified as K. pneumoniae were more often resistant to 4th-generation cephalosporins than K. variicola isolates (odds ratio = 2.61, p = 0.003, 95% confidence interval [1.38,5.06]). K. oxytoca group isolates were found to be more likely associated with invasive infection to primary sterile sites than K. pneumoniae group isolates (odds ratio = 2.39, p = 0.0044, 95% confidence interval [1.05,5.53]). Conclusions Currently misdiagnosed Klebsiella spp. can be distinguished using a ribosomal marker-based approach for MALDI-TOF MS. Klebsiella groups and species differed in AMR profiles, and in their association with invasive infection, highlighting the importance for species identification to enable effective treatment options.
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