Marta Kuczeriszka

Effects of ATP on rat renal haemodynamics and excretion: role of sodium intake, nitric oxide and cytochrome P450

Aim:  Adenosine‐5′‐triphosphate (ATP) affects intrarenal vascular tone and tubular transport via P2 receptors; however, the actual role of the system in regulation of renal perfusion and excretion remains unclear and is the subject of this whole‐kidney study.

Interaction of nitric oxide and the cytochrome P-450 system on blood pressure and renal function in the rat: dependence on sodium intake

Aim:  Interaction was examined of nitric oxide (NO) and cytochrome P‐450 (CYP‐450)‐dependent arachidonic acid derivatives, 20‐HETE and EETs, in control of arterial pressure (MABP) and renal function. Modification of this interaction by changing sodium intake was also studied.

Renal nerves and nNOS: roles in natriuresis of acute isovolumetric sodium loading in conscious rats

It was hypothesized that renal sympathetic nerve activity (RSNA) and neuronal nitric oxide synthase (nNOS) are involved in the acute inhibition of renin secretion and the natriuresis following slow NaCl loading (NaLoad) and that RSNA participates in the regulation of arterial blood pressure (MABP). This was tested by NaLoad after chronic renal denervation with and without inhibition of nNOS by S-methyl-thiocitrulline (SMTC). In addition, the acute effects of renal denervation on MABP and sodium balance were assessed. Rats were investigated in the conscious, catheterized state, in metabolic cages, and acutely during anesthesia. NaLoad was performed over 2 h by intravenous infusion of hypertonic solution (50 micromol.min(-1).kg body mass(-1)) at constant body volume conditions. SMTC was coinfused in amounts (20 microg.min(-1).kg(-1)) reported to selectively inhibit nNOS. Directly measured MABPs of acutely and chronically denervated rats were less than control (15% and 9%, respectively, P < 0.005). Plasma renin concentration (PRC) was reduced by renal denervation (14.5 +/- 0.2 vs. 19.3 +/- 1.3 mIU/l, P < 0.005) and by nNOS inhibition (12.4 +/- 2.3 vs. 19.6 +/- 1.6 mlU/l, P < 0.005). NaLoad reduced PRC (P < 0.05) and elevated MABP modestly (P < 0.05) and increased sodium excretion six-fold, irrespective of renal denervation and SMTC. The metabolic data demonstrated that renal denervation lowered sodium balance during the first days after denervation (P < 0.001). These data show that renal denervation decreases MABP and renin secretion. However, neither renal denervation nor nNOS inhibition affects either the renin down-regulation or the natriuretic response to acute sodium loading. Acute sodium-driven renin regulation seems independent of RSNA and nNOS under the present conditions.

High salt intake increases blood pressure in normal rats: putative role of 20-HETE and no evidence on changes in renal vascular reactivity.

Background/Aims. High salt (HS) intake may elevate blood pressure (BP), also in animals without genetic salt sensitivity. The development of salt-dependent hypertension could be mediated by endogenous vasoactive agents; here we examined the role of vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). Methods. In conscious Wistar rats on HS diet systolic BP (SBP) was examined after chronic elevation of EETs using 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB), a blocker of soluble epoxide hydrolase, or after inhibition of 20-HETE with 1-aminobenzotriazole (ABT). Thereafter, in acute experiments the responses of renal artery blood flow (Transonic probe) and renal regional perfusion (laser-Doppler) to intrarenal acetylcholine (ACh) or norepinephrine were determined. Results. HS diet increased urinary 20-HETE excretion. The SBP increase was not reduced by c-AUCB but prevented by ABT until day 5 of HS exposure. Renal vasomotor responses to ACh or norepinephrine were similar on standard and HS diet. ABT but not c-AUCB abolished the responses to ACh. Conclusions. 20-HETE seems to mediate the early-phase HS diet-induced BP increase while EETs are not engaged in the process. Since HS exposure did not alter renal vasodilator responses to Ach, endothelial dysfunction is not a critical factor in the mechanism of salt-induced blood pressure elevation.

Adenosine Effects on Renal Function in the Rat: Role of Sodium Intake and Cytochrome P450

Background/Aims: Adenosine (ADO) causes vasodilation in most tissues. In the kidney it can induce vasoconstriction or vasodilation, depending on the prevailing stimulation of A1 or A2 receptors (A1R, A2R). ADO-induced alterations of renal excretion may be secondary to haemodynamic changes, or reflect a direct influence on tubular transport. This whole-kidney study explored renal excretory responses to ADO receptor stimulation as related to renal haemodynamics sodium intake and cytochrome P450 (CYP-450) activity. Methods: The effects of ADO or an A2aR agonist (DPMA) on urine flow (V), sodium excretion (UNaV) and total solute excretion were examined in anaesthetized Wistar rats on a low-sodium or high-sodium (HS) diet. Total renal blood flow (RBF; renal artery probe), and outer- and inner-medullary blood flows (OM-BF, IM-BF; laser-Doppler fluxes) were also determined. Results: Consistent opposed effects of ADO and DPMA were only observed with the HS diet. ADO increased V (150%) and UNaV (100%); there were also significant increases in RBF, OM-BF and IM-BF. These changes were prevented by 1-aminobenzotriazol, a CYP-450 inhibitor. In HS rats, DPMA significantly decreased arterial blood pressure and renal excretion. Conclusions: Post-ADO diuresis/natriuresis was in part secondary to renal hyperperfusion; the response was probably mediated by CYP-450-dependent active agents. Selective A2aR stimulation induced systemic vasodilation, major hypotension, and a secondary decrease in renal excretion.

An endomorphine analog ([d-Ala2]-Endomorphin 2, TAPP) lowers blood pressure and enhances tissue nitric oxide in anesthetized rats

BACKGROUND Activation of opioid receptors can alter cardiovascular function, an action possibly mediated by nitric oxide (NO). In this study we examined the effects of ([d-Ala(2)]-Endomorphin 2, TAPP), a synthetic opioid μ-receptor agonist, on blood pressure (MABP), tissue NO bioavailability and renal hemodynamics and excretion. METHODS In acute experiments with anesthetized normotensive male Sprague-Dawley rats TAPP was given as a short iv infusion at a dose of 1.2 or 12mg/kg and then MABP, renal medullary NO signal (polarographic electrode), total renal blood flow (RBF, renal artery Transonic probe), renal regional perfusion (laser-Doppler fluxes) and renal excretion were simultaneously measured over 2h. RESULTS After 1.2mg/kg dose MABP decreased progressively from 121±7 to 114±9mmHg (-6%, p<0.05) while kidney tissue NO signal increased from 29.1±2.7 to 31.7±3.1nA (6%, p<0.04). Both effects were prevented by Naloxone methiodide, a peripheral opioid receptor inhibitor. RBF and renal regional perfusion were not altered by either dose of TAPP; renal sodium excretion changes were highly variable and were not affected by Naloxone pretreatment. CONCLUSIONS Briefly, we found that in anesthetized normotensive rats stimulation of peripheral opioid receptors with TAPP caused a prolonged decrease in arterial pressure, a change that was associated and probably causally related to an increase in tissue NO. The data suggest that synthetic opioids that do not penetrate the blood-brain barrier and are potentially non-addictive could be considered for antihypertensive therapy.