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Rodger Loutzenhiser

Publications and source records attributed to Rodger Loutzenhiser.

13 recordsLinked to original sources
PubMed2006

Effects of inhibition of the Na+/K+/2Cl- cotransporter on myogenic and angiotensin II responses of the rat afferent arteriole.

The Na(+)/K(+)/2Cl(-) cotransporter (NKCC) plays diverse roles in the kidney, contributing sodium reabsorption and tubuloglomerular feedback (TGF). However, NKCC is also expressed in smooth muscle and inhibitors of this transporter affect contractility in both vascular and nonvascular smooth muscle. In the present study, we investigated the effects of NKCC inhibitors on vasoconstrictor responses of the renal afferent arteriole using the in vitro perfused hydronephrotic rat kidney. This preparation has no tubules and no TGF, eliminating this potential complication. Furosemide and bumetanide inhibited myogenic responses in a concentration-dependent manner. Bumetanide was approximately 20-fold more potent (IC(50) 1.0 vs. 20 micromol/l). At 100 and 10 micromol/l, furosemide and bumetanide inhibited myogenic responses by 72 +/- 4 and 68 +/- 5%, respectively. The maximal level of inhibition by bumetanide was not affected by nitric oxide synthase inhibition (100 micromol/l N(G)-nitro-l-arginine methyl ester). However, the time course for the dilation was slowed (from t(1/2) = 4.0 +/- 0.5 to 8.3 +/- 1.7 min, P = 0.04), suggesting either a partial involvement of NO or a permissive effect of NO on relaxation kinetics. Bumetanide also inhibited ANG II-induced afferent arteriolar vasconstriction at similar concentrations. Finally, NKCC1, but not NKCC2, expression was demonstrated in the afferent arteriole by RT-PCR and the presence of NKCC1 in afferent arteriolar myocytes was confirmed by immunohistochemistry. In concert, these results indicate that NKCC modulation is capable of altering myogenic responses by a mechanism that does not involve TGF and suggest a potential role of NKCC1 in the regulation of vasomotor function in the renal microvasculature.

Angiotensin II↗
PubMed2006

Systolic blood pressure as the trigger for the renal myogenic response: protective or autoregulatory?

PURPOSE OF REVIEW: The ability of the kidney to autoregulate renal blood flow and glomerular filtration rate has long been viewed as existing to prevent fluctuations in blood pressure from causing parallel fluctuations in renal function and distal delivery of filtrate. This review, however, points out that the primary consequence of the loss of this autoregulatory capacity is not a disturbance in volume regulation, but rather an increased susceptibility to hypertensive injury. Moreover, the kinetic requirements for renal protection indicate that current views of dynamic autoregulation cannot explain how the kidney is normally protected against acute elevations in systolic blood pressure. RECENT FINDINGS: Recent findings suggest that the kinetics of the myogenic mechanism of the afferent arteriole are uniquely suited to protect against acute elevations in the systolic blood pressure, in that this vessel not only senses this rapidly oscillating blood pressure component, but that its response is exclusively dependent on this signal. SUMMARY: These new findings are consistent with recent data indicating that it is the systolic blood pressure elevations that most closely correlate with target organ damage. The fact that the myogenic mechanism is also a necessary component of renal autoregulation may explain the strong linkage between autoregulatory impairment and increased susceptibility to hypertensive injury.

Animals↗
PubMed2006

Renal autoregulation: new perspectives regarding the protective and regulatory roles of the underlying mechanisms.

When the kidney is subjected to acute increases in blood pressure (BP), renal blood flow (RBF) and glomerular filtration rate (GFR) are observed to remain relatively constant. Two mechanisms, tubuloglomerular feedback (TGF) and the myogenic response, are thought to act in concert to achieve a precise moment-by-moment regulation of GFR and distal salt delivery. The current view is that this mechanism insulates renal excretory function from fluctuations in BP. Indeed, the concept that renal autoregulation is necessary for normal renal function and volume homeostasis has long been a cornerstone of renal physiology. This article presents a very different view, at least regarding the myogenic component of this response. We suggest that its primary purpose is to protect the kidney against the damaging effects of hypertension. The arguments advanced take into consideration the unique properties of the afferent arteriolar myogenic response that allow it to protect against the oscillating systolic pressure and the accruing evidence that when this response is impaired, the primary consequence is not a disturbed volume homeostasis but rather an increased susceptibility to hypertensive injury. It is suggested that redundant and compensatory mechanisms achieve volume regulation, despite considerable fluctuations in distal delivery, and the assumed moment-by-moment regulation of renal hemodynamics is questioned. Evidence is presented suggesting that additional mechanisms exist to maintain ambient levels of RBF and GFR within normal range, despite chronic alterations in BP and severely impaired acute responses to pressure. Finally, the implications of this new perspective on the divergent roles of the myogenic response to pressure vs. the TGF response to changes in distal delivery are considered, and it is proposed that in addition to TGF-induced vasoconstriction, vasodepressor responses to reduced distal delivery may play a critical role in modulating afferent arteriolar reactivity to integrate the regulatory and protective functions of the renal microvasculature.

Animals↗
PubMed2004

Redundant signaling mechanisms contribute to the vasodilatory response of the afferent arteriole to proteinase-activated receptor-2.

We previously demonstrated that stimulation of proteinase-activated receptor-2 (PAR-2) by SLIGRL-NH(2) elicits afferent arteriolar vasodilation, in part, by elaborating nitric oxide (NO), suggesting an endothelium-dependent mechanism (Trottier G, Hollenberg M, Wang X, Gui Y, Loutzenhiser K, and Loutzenhiser R. Am J Physiol Renal Physiol 282: F891-F897, 2002). In the present study, we characterized the NO-independent component of this response, using the in vitro perfused hydronephrotic rat kidney. SLIGRL-NH(2) (10 mumol/l) dilated afferent arterioles preconstricted with ANG II, and the initial transient component of this response was resistant to NO synthase (NOS) and cyclooxygenase inhibition. This NO-independent response was not prevented by treatment with 10 nmol/l charybdotoxin and 1 mumol/l apamin, a manipulation that prevents the endothelium-derived hyperpolarizing factor (EDHF)-like response of the afferent arteriole to acetylcholine, nor was it blocked by the addition of 1 mmol/l tetraethylammonium (TEA) or 50 mumol/l 17-octadecynoic acid, treatments that block the EDHF-like response to bradykinin. To determine whether the PAR-2 response additionally involves the electrogenic Na(+)-K(+)-ATPase, responses were evaluated in the presence of 3 mmol/l ouabain. In this setting, SLIGRL-NH(2) induced a biphasic dilation in control and a transient response after NOS inhibition. The latter was not prevented by charybdotoxin plus apamin or by TEA alone but was abolished by combined treatment with charybdotoxin, apamin, and TEA. This treatment did not prevent the NO-dependent dilation evoked in the absence of NOS inhibition. Our findings indicate a remarkable redundancy in the signaling cascade mediating PAR-2 -induced afferent arteriolar vasodilation, suggesting an importance in settings such as inflamation or ischemia, in which vascular mechanisms might be impaired and the PAR system is thought to be activated.

Angiotensin II↗
PubMed2004

Effects of calcium channel blockers on "dynamic" and "steady-state step" renal autoregulation.

Renal autoregulation (AR) mechanisms provide the primary protection against transmission of systemic pressures and hypertensive renal damage. However, the relative merits of the "step" change vs. "dynamic" methods for the assessment of AR capacity remain controversial. The effects of 48-72 h of orally administered amlodipine (L-type) and mibefradil (T-type) calcium channel blockers (CCBs) on step and dynamic AR in Sprague-Dawley rats were compared. Both CCBs significantly impaired "steady-state step" AR (autoregulatory indexes = approximately 0.5 vs. approximately 0.1 in controls, P < 0.05; n = 9-10/group). By contrast, dynamic AR compensation in separate conscious rats (n = 12) was not significantly altered by either amlodipine (n = 10) or mibefradil (n = 6; fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). However, both CCBs tended to attenuate the myogenic resonance peak along with shifting it to a significantly slower frequency (P < 0.001) during dynamic AR, but no consistent effects were observed on the tubuloglomerular feedback resonance peak. While the reasons for the insensitivity of dynamic vs. steady-state step AR capacity estimates to CCBs remain to be established, the present data indicate that dynamic AR methods may have a limited utility for assessing AR capacity but may provide potentially important insights into the operational characteristics of AR control mechanisms. A strong correlation was also observed between the average conductance and the admittance gain at the heart beat frequency (r = 0.77, P < 0.001), suggesting that such parameters may provide additional and possibly more meaningful indexes of BP transmission in conscious animals during dynamic AR.

Amlodipine↗
PubMed2003

Myosin heavy chain expression in renal afferent and efferent arterioles: relationship to contractile kinetics and function.

The physiological role of smooth muscle myosin heavy chain (MHC) isoform diversity is poorly understood. The expression of MHC-B, which contains an insert at the ATP binding pocket, has been linked to enhanced contractile kinetics. We recently reported that the renal afferent arteriole exhibits an unusually rapid myogenic response and that its kinetic features allow this vessel to modulate tone in response to alterations in systolic blood pressure. In the present study, we examined MHC expression patterns in renal afferent and efferent arterioles. These two vessels regulate glomerular inflow and outflow resistances and control the pressure within the intervening glomerular capillaries (PGC). Whereas the afferent arteriole must respond rapidly to increases in blood pressure, the efferent arteriole plays a distinctly different role, maintaining a tonic elevation in outflow resistance to preserve function when renal perfusion is compromised. Using RT-PCR, Western analysis, and immunofluorescence imaging of intact isolated arterioles, we found that the afferent arteriole predominantly expresses the MHC-B isoform, whereas the efferent arteriole expresses only the slower-cycling MHC-A isoform. We examined the kinetics of angiotensin II- and norepinephrine-induced vasoconstriction and found that the afferent arteriole responds approximately 3-fold faster than the efferent arteriole. Our findings thus point to the renal microcirculation as a unique and important example of smooth muscle adaptation in regard to MHC isoform expression and physiological function.

Angiotensin II↗
PubMed2003

Determinants of renal afferent arteriolar actions of bradykinin: evidence that multiple pathways mediate responses attributed to EDHF.

The determinants of bradykinin (BK)-induced afferent arteriolar vasodilation were investigated in the in vitro perfused hydronephrotic rat kidney. BK elicited a concentration-dependent vasodilation of afferent arterioles that had been preconstricted with ANG II (0.1 nmol/l), but this dilation was transient in character. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (100 micromol/l) and the cyclooxygenase inhibitor ibuprofen (10 micromol/l) did not prevent this dilation when tone was established by ANG II but fully blocked the response when tone was established by elevated extracellular KCl, which suggests roles for both NO and endothelium-derived hyperpolarizing factor (EDHF). We had previously shown that the EDHF-like response of the afferent arteriole evoked by ACh was fully abolished by a combination of charybdotoxin (ChTX;10 nmol/l) and apamin (AP; 1 micromol/l). However, in the current study, treatment with ChTX plus AP only reduced the EDHF-like component of the BK response from 98 +/- 5 to 53 +/- 6% dilation. Tetraethylammonium (TEA; 1 mmol/l), which had no effect on the EDHF-induced vasodilation associated with ACh, reduced the EDHF-like response to BK to 88 +/- 3% dilation. However, the combination of TEA plus ChTX plus AP abolished the response (0.3 +/- 1% dilation). Similarly, 17-octadecynoic acid (17-ODYA) did not prevent the dilation when it was administered alone (77 +/- 9% dilation) but fully abolished the EDHF-like response when added in combination with ChTX plus AP (-0.5 +/- 4% dilation). These findings suggest that BK acts via multiple EDHFs: one that is similar to that evoked by ACh in that it is blocked by ChTX plus AP, and a second that is blocked by either TEA or 17-ODYA. Our finding that a component of the BK response is sensitive to TEA and 17-ODYA is consistent with previous suggestions that the EDHF released by BK is an epoxyeicosatrienoic acid.

Animals↗
PubMed2003

Bidirectional regulation of renal hemodynamics by activation of PAR1 and PAR2 in isolated perfused rat kidney.

Proteinase-activated receptors (PARs) are activated by either serine proteinases or synthetic peptides corresponding to the NH2-terminal tethered ligand sequences that are unmasked by proteolytic cleavage. Although PARs are highly expressed in the kidney, their roles in regulating renal function are not known. In the present study, we evaluated the impact of PAR activation on renal hemodynamics using PAR1- and PAR2-activating peptides (TFLLR-NH2 and SLIGRL-NH2) and proteinases (thrombin and trypsin) as PAR agonists in the isolated perfused rat kidney preparation. PAR1 activation resulted in renal vasoconstriction and a marked reduction in the glomerular filtration rate (GFR). In contrast, PAR2 activation caused vasodilation, partially reversing the vasoconstriction induced by TFLLR-NH2 and ANG II and increasing GFR that had been prereduced by ANG II. The vasoconstrictor actions of PAR1 activation were abolished by protein kinase C inhibition. The PAR2-induced vasodilation was only partially blocked by NG-nitro-l-arginine methyl ester, suggesting both nitric oxide-dependent and -independent mechanisms. Although PAR4 mRNA was detected in renal parenchyma, the PAR4-activating peptide AYPGKF-NH2 had no effect on renal perfusion flow rate. We conclude that PAR1 and PAR2 play bidirectional roles in the regulation of renal hemodynamics.

Animals↗
PubMed2003

"Step" vs. "dynamic" autoregulation: implications for susceptibility to hypertensive injury.

Renal autoregulatory (AR) mechanisms provide the primary protection against transmission of systemic pressures, and their impairment is believed to be responsible for the enhanced susceptibility to hypertensive renal damage in renal mass reduction (RMR) models. Assessment of AR capacity by the "step" change methodology under anesthesia was compared with that by "dynamic" methods in separate conscious control Sprague-Dawley rats and after uninephrectomy (UNX) and (3/4) RMR (RK-NX) (n = 7-10/group). Substantially less AR capacity was seen by the dynamic vs. the step methodology in control rats. Moreover, dynamic AR capacity did not differ among controls, UNX, and RK-NX rats (fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). By contrast, significant impairment of step AR was seen in RK-NX vs. control or UNX rats (AR indexes 0.7 +/- 0.1 vs. 0.1 +/- 0.02 and 0.2 +/- 0.04, respectively, P < 0.01). We propose that the step and dynamic methods evaluate the renal AR responses to different components of blood pressure (BP) power with the step AR assessing the ability to buffer large changes in average BP (DC power), whereas the present "dynamic" methods assess the AR ability to buffer slow BP fluctuations (<0.25 Hz) superimposed on the average BP (AC power), a substantially smaller component of total BP power. We further suggest that step but not dynamic AR methods as presently performed provide a valid index of the underlying susceptibility to hypertensive glomerular damage after RMR.

Animals↗
PubMed2003

Determinants of renal microvascular response to ACh: afferent and efferent arteriolar actions of EDHF.

The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 +/- 2 and 75 +/- 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 micromol/l N(G)-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (COX; 10 micromol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 +/- 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 micromol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0micromol/l) attenuated the response when administered alone (63 +/- 7% and 37 +/- 5%, respectively) and abolished the response when coadministered (0.1 +/- 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry.

4-Aminopyridine↗
PubMed2002

Renal myogenic response: kinetic attributes and physiological role.

The kinetic attributes of the afferent arteriole myogenic response were investigated using the in vitro perfused hydronephrotic rat kidney. Equations describing the time course for pressure-dependent vasoconstriction and vasodilation, and steady-state changes in diameter were combined to develop a mathematical model of autoregulation. Transfer functions were constructed by passing sinusoidal pressure waves through the model. These findings were compared with results derived using data from instrumented conscious rats. In each case, a reduction in gain and increase in phase were observed at frequencies of 0.2 to 0.3 Hz. We then examined the impact of oscillating pressure signals. The model predicted that pressure signals oscillating at frequencies above the myogenic operating range would elicit a sustained vasoconstriction the magnitude of which was dependent on peak pressure. These predictions were directly confirmed in the hydronephrotic kidney. Pressure oscillations presented at frequencies of 1 to 6 Hz elicited sustained afferent vasoconstrictions and the magnitude of the response depended exclusively on the peak pressure. Elevated systolic pressure elicited vasoconstriction even if mean pressure was reduced. These findings challenge the view that the renal myogenic response exists to maintain glomerular capillary pressure constant, but rather imply a primary role in protecting against elevated systolic pressures. Thus, the kinetic features of the afferent arteriole allow this vessel to adjust tone in response to changes in systolic pressures presented at the pulse rate. We suggest that the primary function of this mechanism is to protect the glomerulus from the blood pressure power that is normally present at the pulse frequency.

Animals↗
PubMed2002

PAR-2 elicits afferent arteriolar vasodilation by NO-dependent and NO-independent actions.

Proteinase-activated receptors (PARs) are a novel class of G protein-coupled receptors that respond to signals through endogenous proteinases. PAR activation involves enzymatic cleavage of the extracellular NH(2)-terminal domain and unmasking of a new NH(2) terminus, which serves as an anchored ligand to activate the receptor. At least four PAR subtypes have been identified. In the present study, we used the in vitro perfused hydronephrotic rat kidney to examine the effects of activating PAR-2 on the afferent arteriole. The synthetic peptide SLIGRL-NH(2), which corresponds to the exposed ligand sequence and selectively activates PAR-2, did not alter basal afferent arteriolar diameter but caused a concentration-dependent vasodilation (3-30 microM) of arterioles preconstricted by angiotensin II (0.1 nM). A modified peptide sequence (LSIGRL-NH(2), inactive at PAR-2) had no effect. This vasodilation was characterized by an initial transient component followed by a smaller sustained response. A similar pattern of vasodilation was seen when SLIGRL-NH(2) was administered to isolated perfused normal rat kidney. The sustained component of the PAR-2-induced afferent arteriolar vasodilation was eliminated by nitric oxide (NO) synthase inhibition (100 microM nitro-L-arginine methyl ester). In contrast, the transient vasodilation persisted under these conditions. This transient response was not observed when afferent arterioles were preconstricted with elevated KCl, suggesting involvement of an endothelium-derived hyperpolarizing factor. Finally, RT-PCR revealed the presence of PAR-2 mRNA in isolated afferent arterioles. These findings indicate that PAR-2 is expressed in the afferent arteriole and that its activation elicits afferent arteriolar vasodilation by NO-dependent and NO-independent mechanisms.

Acetylcholine↗