N. A. Medvedeva

Human Pro–B-Type Natriuretic Peptide Is Processed in the Circulation in a Rat Model

BACKGROUND The appearance of B-type natriuretic peptide (BNP) in the blood is ultimately caused by proteolytic processing of its precursor, proBNP. The mechanisms leading to the high plasma concentration of unprocessed proBNP are still poorly understood. The goals of the present study were to examine whether processing of proBNP takes place in the circulation and to evaluate the clearance rate of proBNP and proBNP-derived peptides. METHODS We studied the processing of human proBNP in the circulation and the clearance rate of proBNP and proBNP-derived peptides (BNP and N-terminal fragment of proBNP, NT-proBNP) in rats by injecting the corresponding peptides and analyzing immunoreactivity at specific time points. Glycosylated and nonglycosylated proBNP and NT-proBNP were used in the experiments. We applied immunoassays, gel filtration, and mass spectrometry (MS) techniques to analyze the circulation-mediated processing of proBNP. RESULTS ProBNP was effectively processed in the circulation into BNP (1-32) and various truncated BNP forms as confirmed by gel filtration and MS analysis. Glycosylation of proBNP close to the cleavage-site region suppressed its processing in the circulation. The terminal half-life for human glycosylated proBNP was 9.0 (0.5) min compared with 6.4 (0.5) min for BNP. For NT-proBNP, the terminal half-lives were 15.7 (1.4) min and 15.5 (1.3) min for glycosylated and nonglycosylated forms, respectively. CONCLUSIONS In rats, processing of human proBNP to active BNP occurs in the circulation. The clearance rate of proBNP is quite similar to that of BNP. These observations suggest that peripheral proBNP processing may be an important regulatory step rather than mere degradation.

[Effect of chronic administration of aminoguanidine on vascular reactivity of the greater circulation in rats with monocrotaline-induced pulmonary hypertension].

Pulmonary hypertension (PH) is a severe disease affecting both the pulmonary and systemic circulation. One of possible factors of these disturbances can be nitric oxide (NO) overproduction by inducible NO synthase (iNOS). To examine the effect of iNOS on systemic vascular reactivity, we used aminoguanidine (AG), a selective iNOS inhibitor. Using the model of monocrotaline-induced pulmonary hypertension, we demonstrated that chronic AG administration restores the decreased arterial pressure responses to NO donor and to nonspecific inhibitor of NO synthase as well as the decreased endothelium-dependent relaxation of isolated systemic artery. This points to an important role of iNOS in systemic pathogenesis of PH.

Chronic administration of interferon-α decreases blood pressure and heart rate in rats

We studied the effects of interferon-α on rat cardiovascular system. Intravenous administration of intron-A in a dose of 100,000 IU/kg for 3 days led to a permanent and statistically significant decrease in blood pressure (on days 2 and 3) and reduction in heart rate. These effects were not associated with changes in baroreflex regulation of the cardiovascular system.

Experimental Study of Hypotensive Effect of Kardos in Rats with Inherited Hypertension

Kardos, a preparation containing ultralow doses of antibodies to C-terminal fragment of type 1 receptor of angiotensin II, intragastrically administered to SHR rats with hereditary hypertension for 28 days reduced blood pressure by 14.8%. Kardos was not inferior to losartan and, in contrast to the latter reduced HR by 9.4%.

3-(3-[1,2,4]triazolo)-oxatriazolium-5-olate causes vasodilatation by NO-independent activation of soluble guanylate cyclase

Background Soluble guanylate cyclase (sGC) is a crucial enzyme at NO/cGMP-mediated vasodilation. There are NO-independent mechanisms of sGC activation besides wellknown enzyme activation by NO. Since 1966 oxatriazolium-5-olate derivatives are known as hypotensive agents at narcotized animals [1]. But the mechanism of their activity is not clarified. The goal of this research is to examine the ability of 3-(3-[1,2,4]triazolo)-oxatriazolium-5-olate (AS-6) to generate NO, to activate sGC, and to cause vasodilatation.

EFFECT OF ENDOTHELIN-1 ON CARDIOVASCULAR PARAMETERS OF LEWIS AND WISTAR RATS IN IMMOBILIZATION STRESS

Effect of low doses of endothelin-1 on the dynamics of blood pressure and heart rate is studied in Lewis and Wistar rats during 1-h immobilization stress. It is shown that endothelin-1 significantly lowers blood pressure in stress-sensitive Lewis rats during stress and has no effect on hemodynamic parameters in immobilized stress-resistant Wistar rats in comparison with the control.

SYNTHESIS AND HEMODYNAMIC EFFECTS OF A NEW ENDOTHELIN-CONVERTING ENZYME INHIBITOR

A new endothelin-converting enzyme inhibitor PP-35 including Nα-benzylsuccinyl group and Leu-Trp-OH dipeptide is synthesized. Similarly to phosphoramidon substance PP-35 abolishes elevation of systemic blood pressure and heart rate decrease in normotensive rats in response to bolus injection of big endothelin-1. Hemodynamic responses to endothelin-1 remain unchanged.

Effects of dose and administration mode of endothelin 1 on the mean arterial pressure and heart rate in awake rats

The effects of bolus administration and short-term infusion of endothelin 1 in four doses (2×10−16, 2×10−14, 2×10−12, and 2×10−10 mol/kg) on arterial pressure and heart rate were compared in awake rats. Infusion and bolus administration of the two highest doses increased arterial pressure and provoked bradycardia. Infusion of the two lowest doses increased heart rate without concomitant changes in arterial pressure, while bolus injection of endothelin 1 in the same doses decreased both arterial pressure and the heart rate.

Arterial pressure lability in hypotensive effects of clonidine in barodenervated spontaneously hypertensive rats

Hypotensive effect of clonidine and its effect on arterial pressure lability as the main index of stability of background blood pressure are studied in intact spontaneously hypertensive rats (SHR) and rats with chronic sinoaortic denervation. Barodenervation potentiates hypotensive and negative cardiochronotropic effects of clonidine, which is accompanied by reduced blood pressure lability. This indicates an increased sensitivity of central α2-and imidazoline receptors, which mediate the depressor effect of clonidine, against the background of chronic inhibition of the baroreceptor reflex.

Biochemical and physiological activity of new peptide inhibitors of angiotensin converting enzyme

The physiological and biochemical activity of new angiotensin converting enzyme inhibitors is studiedin vitro (in microsomal fractions from the pituitary gland and corpus striatum) andin vivo. Compound PP-09, an N-carboxyalkyl derivative of enalapril, displaying high inhibiting activity towards rat serum and tissue angiotensin converting enzyme and lowering arterial pressure in spontaneously hypertensive rats, is selected.