Tonic action of endothelin type B and dopamine D3 receptors in spontaneously hypertensive and deoxycorticosterone acetate-salt hypertensive rats: effects of intrarenally applied selective antagonists.

Endothelins and renal dopamine contribute to control of renal function and arterial pressure in health and various forms of experimental hypertension, the action is mediated by tonic activity of specific receptors. We determined the action mediated by endothelin type B and by dopamine D3 receptors (ETB-R, D3-R) in anaesthetized spontaneously hypertensive (SHR) and in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In rats of both hypertension models infused during 60 min into the interstitium of in situ kidney were either ETB-R antagonist, BQ788 (0.

Effects of systemic and renal intramedullary endothelin-1 receptor blockade on tissue NO and intrarenal hemodynamics in normotensive and hypertensive rats.

Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO.

Chymase Dependent Pathway of Angiotensin II Generation and Rapeseed Derived Peptides for Antihypertensive Treatment of Spontaneously Hypertensive Rats.

The contribution of chymase, one of the enzymes responsible for angiotensin II generation in non-ACE pathway, remains unclear in the development of hypertension. The aim of the study was to investigate chymase inhibition as potential antihypertensive therapy in spontaneously hypertensive rats (SHR). To block chymase we employed chymostatin, a commercial inhibitor, and new analogues of rapeseed-derived peptides, VWIS and RIY.

Reinvestigation of the tonic natriuretic action of intrarenal dopamine: comparison of two variants of salt-dependent hypertension and spontaneously hypertensive rats.

The intrarenal dopamine system has been thoroughly investigated at all levels, especially its role in salt-dependent and other forms of hypertension. However, the evidence regarding dopamine's tonic influence on renal tubular transport of sodium remains equivocal. We reinvestigated its tonic influence on sodium excretion and systemic and renal haemodynamics.

Further evidence against the role renal medullary perfusion in short-term control of arterial pressure in normotensive and mildly or overtly hypertensive rats.

Earlier evidence from studies of rat hypertension models undermines the widespread view that the rate of renal medullary blood flow (MBF) is critical in control of arterial pressure (MAP). Here, we examined the role of MBF in rats that were normotensive, with modest short-lasting pressure elevation, or with overt established hypertension. The groups studied were anaesthetised Sprague-Dawley rats: (1) normotensive, (2) with acute i.

Altered renal medullary blood flow: A key factor or a parallel event in control of sodium excretion and blood pressure?

In the context of the ongoing debate on the mechanism of blood pressure (BP) regulation and pathophysiology of arterial hypertension ("renocentric" vs "neural" concepts), attention is focused on the putative regulatory role of changes in renal medullary blood flow (MBF). Experimental evidence is analysed with regard to the question whether an elevation of BP and renal perfusion pressure (RPP) is likely to increase MBF due to its impaired autoregulation. It is concluded that such increases have been clearly documented only in rats with extracellular fluid volume expansion.

Kynurenic acid selectively reduces heart rate in spontaneously hypertensive rats.

We found previously that intravenous kynurenic acid (KYNA), a native broad spectrum glutamate antagonist, increases renal blood flow and induces natriuresis in anesthetized spontaneously hypertensive rats (SHR). Since such changes may affect systemic circulation and can potentially find therapeutic application, in this study we examined long term influence of orally administered KYNA on systemic and renal hemodynamics and renal excretion in conscious SHR. KYNA was administered in drinking water at a dose of 25 mg/kg/day for 3 weeks.

Evidence against a crucial role of renal medullary perfusion in blood pressure control of hypertensive rats.

Key Points: The development of new effective methods of treating arterial hypertension is hindered by uncertainty regarding its causes. According to one widespread concept hypertension is caused by abnormal blood circulation in the kidney, specifically by reduction of blood flow through the kidney medulla; however, this causal relationship has never been rigorously verified. We investigated whether in rats with three different forms of experimental hypertension prolonged selective elevation of renal medullary blood flow using local infusion of the vasodilator bradykinin would lower arterial pressure.

Different blood pressure responses to opioids in 3 rat hypertension models: role of the baseline status of sympathetic and renin-angiotensin systems.

Opioids interact with sympathetic and renin-angiotensin systems in control of mean arterial pressure (MAP). Our earlier finding that biphalin, a synthetic enkephalin analogue, decreased MAP in anaesthetized spontaneously hypertensive rats (SHR) prompted us to further explore this action, to get new insights into pathogenesis of various forms of hypertension. Biphalin effects were studied in SHR, uninephrectomized rats on a high-salt diet (HS/UNX), and rats with angiotensin-induced hypertension (Ang-iH).

An antihypertensive opioid: Biphalin, a synthetic non-addictive enkephalin analog decreases blood pressure in spontaneously hypertensive rats.

Background: Endogenous opioid systems may be engaged in the control of arterial pressure (MAP), however, given the risk of addiction, opioid receptor agonists are not used in antihypertensive therapy. We examined cardiovascular effects of biphalin, a potentially non-addictive dimeric enkephalin analog, an agonist of opioid μ and δ receptors.

Methods: Biphalin was infused iv at 150μg/kg/h to anesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY).

Effects of systemic administration of kynurenic acid and glycine on renal haemodynamics and excretion in normotensive and spontaneously hypertensive rats.

Both NMDA receptor and kynurenic acid (KYNA), a glycine-site NMDA receptor antagonist, are present in the kidney yet their functional role remains unclear. Our aim was to examine effects of intravenous KYNA and glycine on arterial blood pressure (MAP) and renal haemodynamics and excretion in anaesthetized normotensive Sprague-Dawley (S-D) and in spontaneously hypertensive (SHR) rats. Renal blood flow (RBF, renal artery probe) and renal cortical (CBF) and outer- and inner medullary perfusion (laser-Doppler) were measured, along with diuresis (V) and sodium excretion (UNaV).

Vascular effects of a tripeptide fragment of novokinine in hypertensive rats: Mechanism of the hypotensive action.

Background: Activation of angiotensin AT2 receptors (AT2R) counteracts vasoconstrictor effects of AT1R stimulation and contributes to blood pressure control. We examined effects on mean arterial pressure (MAP) and renal hemodynamics of LKP, a tripeptide fragment of novokinine, an established AT2R agonist.

Methods: Effects of intravenous LKP infusion and then superimposed losartan (AT1R antagonist) on MAP, total renal (RBF, Transonic probe) and renal medullary blood flows (laser-Doppler), and on renal excretion, were examined in anesthetized (1) Wistar rats with acute norepinephrine-induced hypertension, untreated or pretreated with AT2R antagonist (PD 123319) and (2) spontaneously hypertensive rats (SHR) maintained on standard or high-sodium (HS) diet.

Experimental selective elevation of renal medullary blood flow in hypertensive rats: evidence against short-term hypotensive effect.

Aim: Renal medullary blood flow (MBF) can be selectively increased by intrarenal or systemic infusion of bradykinin (Bk) in anaesthetized normotensive rats. We reproduced this effect in a number of rat models of arterial hypertension and examined whether increased perfusion of the renal medulla can cause a short-term decrease in blood pressure (BP) that is not mediated by increased renal excretion and depletion of body fluids.

Methods: In uninephrectomized Sprague-Dawley rats, BP was elevated to approx.

Moderate intrarenal vasoconstriction after high pressor doses of norepinephrine in the rat: comparison with effects of angiotensin II.

Aims: Treatment of arterial hypotension with norepinephrine (NE) is associated with renal vasoconstriction and may lead to ischemic kidney injury; the risk involved is still a matter of debate.

Methods: In anesthetized, acutely uninephrectomized rats, we examined changes in intrarenal hemodynamics induced by intravenous infusion of NE and angiotensin II (Ang II), at doses that increased arterial pressure by ∼25 mm Hg (20%). Renal blood flow (RBF) was determined using a Transonic probe, and superficial cortical, outer and inner medullary flows (CBF, OMBF, IMBF) as laser-Doppler fluxes.

Differential action of bradykinin on intrarenal regional perfusion in the rat: waning effect in the cortex and major impact in the medulla.

The renal kallikrein-kinin system is involved in the control of the intrarenal circulation and arterial pressure but bradykinin (Bk) effects on perfusion of individual kidney zones have not been examined in detail. Effects of Bk infused into renal artery, renal cortex or medulla on perfusion of whole kidney (RBF, renal artery probe) and of the cortex, outer- and inner medulla (CBF, OMBF, IMBF: laser-Doppler fluxes), were examined in anaesthetized rats. Renal artery infusion of Bk, 0.

Intrarenal vasodilator systems: NO, prostaglandins and bradykinin. An integrative approach.

Intrarenal microcirculation is under hormonal, paracrine and neural control. Of particular interest is circulation in the renal medulla: its perfusion seems critical for long term control of arterial pressure. Exposure of the organism to adverse conditions often leads to activation of vasopressor factors, such as renin/angiotensin, renal sympathetic input or vasopressin; this helps maintain arterial pressure but endangers renal circulation.

Opposed effects of prostaglandin E2 on perfusion of rat renal cortex and medulla: interactions with the renin-angiotensin system.

While prostaglandin E(2) (PGE(2)) is an established renal vasodilator, studies of prostaglandin EP receptors suggest that it also has vasoconstrictor potential. Prostaglandin E(2) is much more abundant in the medulla than in the cortex, yet likely differences in effects between zones have not been defined. This study is focused on different vascular effects in the cortex and medulla and interaction with the renin-angiotensin system (RAS).

Cytochrome P-450 monooxygenases in control of renal haemodynamics and arterial pressure in anaesthetized rats.

The renal regulatory role of cytochrome P450 dependent metabolites of arachidonic acid (AA), vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE), was examined in anaesthetised rats. We measured renal artery flow (RBF), cortical (CBF) and medullary (MBF) perfusion (laser-Doppler) and medullary tissue nitric oxide (NO, selective electrode), after non-selective inhibition of CYP-450 pathway with 1-aminobenzotriazole (ABT, 10 mg/kg i.v.

Specific features and roles of renal circulation: angiotensin II revisited.

The status of intrarenal circulation determines in part renal excretion, affects body fluid homeostasis and has a role in long term control of arterial blood pressure. The vascular resistance in the renal cortex and medulla is determined by interaction of a vast array of vasoactive hormones and paracrine factors; among these the role of constrictor angiotensin II and dilator prostaglandins and nitric oxide may appear to be dominating. The focus of this review and underlying studies is on the mechanisms whereby the microcirculation of the renal medulla is protected against the vasoconstrictor action of angiotensin II.

Renal hemodynamic responses to intrarenal infusion of acetylcholine: comparison with effects of PGE2 and NO donor.

Acetylcholine (Ach) could serve as a selective renal medullary vasodilator in studies of the mechanism of arterial pressure regulation; however, effects of intramedullary Ach infusion were disparate. In anesthetized rats, the total renal blood flow (RBF) was measured by renal artery probe, and local perfusion of the cortex (CBF), outer medulla (OMBF) and inner medulla (IMBF) as laser-Doppler (l-D) flux. Renal artery infusion of Ach (60-150 microg/kg/h) significantly increased RBF by 17% and l-D parameters by 7-14%, without affecting arterial blood pressure (BP); the responses were prevented by inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME).

Effects of renal nerve stimulation on intrarenal blood flow in rats with intact or inactivated NO synthases.

Aim: We studied a possible action of nitric oxide (NO), an intrarenal vasodilator, to buffer a decrease in renal perfusion induced by electrical stimulation of renal nerves (RNS).

Methods: In anaesthetized rats RNS was performed (15 V, 2 ms pulse duration) for 10 s at the frequencies of 2, 3.5, 5 and 7.

Effect of exogenous angiotensin II on renal tissue nitric oxide and intrarenal circulation in anaesthetized rats.

Aim: The renal medullary circulation is protected against depressor action of angiotensin II (Ang II) because of the opposed action of a vasodilator agent, possibly nitric oxide (NO). This possibility was evaluated by a simultaneous determination of the effect of exogenous Ang II on renal cortical and medullary tissue NO and on intrarenal circulation.

Methods: In anaesthetized rats effects were determined of pressor and subpressor Ang II doses on tissue NO concentration in the renal cortex and inner medulla (selective NO electrodes), total renal blood flow (RBF, Transonic renal artery probe) and inner medullary blood flow (IMBF, laser Doppler flux).

Prostaglandins but not nitric oxide protect renal medullary perfusion in anaesthetised rats receiving angiotensin II.

Angiotensin II (Ang II) fails to constrict renal medullary vasculature, possibly due to the counteraction of local vasodilators, such as prostaglandins or nitric oxide (NO). The effects of exogenous Ang II on intrarenal circulation were determined in anaesthetised rats that were untreated or pretreated with indomethacin (Indo) or L-NAME. The total renal blood flow (RBF), representing cortical perfusion, and outer and inner medullary blood flow (OMBF and IMBF) were measured.

Differential effect of angiotensin II on blood circulation in the renal medulla and cortex of anaesthetised rats.

The renal medulla is sensitive to hypoxia, and a depression of medullary circulation, e.g. in response to angiotensin II (Ang II), could endanger the function of this zone.

Renal vascular effects of frusemide in the rat: influence of salt loading and the role of angiotensin II.

We showed recently that post-frusemide (furosemide) natriuresis was associated with a major depression of medullary circulation. In the present study, prior to administration of frusemide the tubular transport of NaCl was modified by loading the animals with 5% saline to elucidate a possible interrelation between the tubular and vascular effects of the drug. Moreover, a possible involvement of the renin-angiotensin system was examined by pharmacological blockade using captopril, an inhibitor of angiotensin converting enzyme (1 mg x kg(-1), I.