Permissive effect of nitric oxide in arachidonic acid induced dilation in isolated rat arterioles.

OBJECTIVE: Prostaglandins and nitric oxide play an important role in the regulation of arteriolar tone. L-Arginine analogues inhibit nitric oxide formation, but may also inhibit arachidonic-acid induced dilation. Nitric oxide was found to stimulate cyclooxygenase activity in cultured endothelial cells. Therefore, we hypothesized that the non-specific inhibition of prostaglandin-related dilation by L-arginine analogues is a consequence of the absence of nitric oxide. METHODS: To test this hypothesis, arteriolar segments from rat cremaster muscle were studied in a pressure myograph at 75 mmHg. Segments developed spontaneous tone, the diameter reduced from 179 +/- 3 to 98 +/- 3 microns (n = 41). In this condition, responses to exogenous arachidonic acid (1 microM) were recorded and compared with responses after addition of L-NNA, and addition of either SNAP, nitroprusside or 8-Br-cGMP in the presence of L-NNA. RESULTS: Inhibition of basal nitric oxide production with L-NNA (0.1 mM) reduced arachidonic acid-induced dilation (from 52 +/- 9 to 31 +/- 6 microns). In the presence of L-NNA, responses to arachidonic acid were augmented when exogenous nitric oxide was also present (SNAP, 31 +/- 6 microns vs. 75 +/- 5 microns; nitroprusside, 31 +/- 8 microns vs. 42 +/- 7 microns). Responses were not augmented with the second messenger of nitric oxide-mediated dilation 8-Br-cGMP (37 +/- 9 microns vs. 32 +/- 9 microns). CONCLUSIONS: These results indicate that nitric oxide directly increases arachidonic acid-induced dilation. Thus, the non-specific effect of L-arginine analogues can be explained by a permissive effect of nitric oxide on endothelial arachidonic acid metabolism.

Steady state and instantaneous pressure-flow relationships: characterisation of the canine abdominal periphery.

This study was performed to characterise a vascular bed in terms of pressure-flow relationships. Steady state and instantaneous relationships were obtained in the flow perfused isolated femoral beds of six mongrel dogs. The steady state pressure-flow relations were obtained by applying a series of stepwise changes of flow in random order. The relations were found to be straight and to have a zero-flow pressure intercept (P0). The slope of this relation is the differential resistance (Rd). On each steady state flow level a ramp-flow was superimposed. The pressure response was measured between 1.5 and 5 s after the start of the ramp-flow, to exclude compliance effects and (auto) regulatory effects, respectively. In this way instantaneous pressure-flow relations were obtained, the slope of this relation is the instantaneous resistance (Ri). The instantaneous resistance expresses the true physical resistance value at a working point of the steady state pressure-flow relation before the bed has performed its (auto)regulatory adaptation after a change in flow. Instantaneous resistance therefore characterises the vascular state that exists at that particular working point. After this particular vascular state has been modified by (auto)-regulation the steady state pressure-flow relation is reached again. Instantaneous resistance increases with increasing flow thereby approximating the value of the differential resistance. At the same flow a vasodilator decreases and a vasoconstrictor increases instantaneous resistance. The gain (G) of the system, that characterises the (auto)regulatory capability, was calculated as G = 1--Ri/Rd and was found to decrease with increasing flow. The (partial) reflection of travelling waves depends on both the characteristic impedance (Zc) and the instantaneous resistance rather than on differential or peripheral resistance. Furthermore it is the product of the instantaneous resistance (Ri) and vascular compliance (C) that determines the time constant of a vascular bed.

The arterial system characterised in the time domain.

When an impulse of flow is applied to the arterial system then the resulting pressure, the impulse response, is a characterisation of the arterial tree. The impulse is generated by means of an occluder around the ascending aorta. The impulse response shows an initial sharp peak followed by an exponential decay with two peaks superimposed on it. The exponential decay is due to diffuse reflection and is linked to the windkessel properties of the arterial tree. The superimposed peaks arise from two distinct reflection sites in the arterial tree. By means of the pulse wave velocity the location of these reflection sites may be calculated; one is found in the bed distal to the brachiocephalic and subclavian arteries and the other in the bed distal to the descending aorta. The distinct reflections are linked to the reflection sites in the asymmetric T-model of the arterial tree. Vasodilatation (nitroprusside) and vasoconstriction (angiotensin) mainly influence the diffuse reflections, while the locations of the distinct reflection sites appear to be unchanged. Inflation of a balloon in the descending aorta shows up as a sharp peak in the impulse response function. The results obtained are compared with the impulse response function computed from pressure and flow waves in the steady-state.

Signal transduction in spontaneous myogenic tone in isolated arterioles from rat skeletal muscle.

OBJECTIVE: The mechanism of spontaneous myogenic tone was investigated in isolated arteriolar segments. METHODS: Arterioles were isolated from rat cremaster muscle. Segments were endothelium-denuded and mounted in a pressure myograph at 75 mmHg. Under this condition, segments spontaneously constricted from a passive diameter of 167 +/- 3 to 82 +/- 4 microns (n = 41). The effects of several inhibitors were tested on the maintenance of myogenic tone. RESULTS: Gadolinium (10(-6)-10(-4) M), a putative inhibitor of stretch-activated cation channels, was ineffective. The phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (NCDC) induced a dose-dependent inhibition of tone. NCDC inhibited phenylephrine- (10(-6) M), but not potassium buffer-induced (100 mM) constriction. The protein kinase C (PKC) inhibitors staurosporine, chelerythrine and calphostin C inhibited myogenic tone in a concentration-dependent manner. At an intermediate concentration, calphostin C selectively inhibited phenylephrine-induced constriction. However, all PKC inhibitors abolished responses to phenylephrine and potassium buffer at higher concentrations. The cytochrome P450 inhibitor 17-ODYA (0.3-3 x 10(-6) M) did not inhibit myogenic tone. CONCLUSIONS: No evidence was found for a role of gadolinium-sensitive, stretch-activated cation channels or cytochrome P450 metabolites. On the other hand, both PLC and PKC contribute to the maintenance of myogenic tone.

Instantaneous and steady-state pressure-flow relations of the coronary system in the canine beating heart.

Steady-state and instantaneous pressure-flow relations were both obtained from the pump-perfused left coronary bed of the beating heart in seven mongrel dogs. The steady-state pressure-flow relation was obtained by changing flow, and measuring pressure after it reached a steady level; it showed a sigmoid shape, with flow-regulation around 70 ml . min-1 . 100 g-1, and it had an average zero-flow pressure intercept of 1.9 kPa (14 mmHg). This curve was represented by an equation, using four parameters. The quality of regulation of the coronary bed could be quantified with this equation by determining the pressure range, when flow was changed from 25% below to 25% above control level. We found this pressure range to be 8.7 +/- 2.4 kPa (65 +/- 18 mmHg) on the average. The tangent at each point of steady-state pressure-flow relation was called differential resistance. Instantaneous pressure-flow relations were obtained by superimposing stepwise changes of flow of different amplitude, at several steady-state levels of flow. Pressure followed these steps with a time-constant of 0.3 +/- 0.1 s, due to capacitive effects, then remained constant during 3 to 4 s, and thereafter changed due to regulation. Pressure was measured during the plateau, assuming it to be a regulation-free period. The instantaneous pressure-flow relations were found to be linear, and the slope was called instantaneous resistance. In the physiological range of flows, instantaneous resistance increased with flow. The ratio between instantaneous and differential resistance, the regulatory index, is suggested to quantify regulation at each point of the steady-state curve. This index was between one and zero up to the upper limit of the regulatory range; at higher flows it was negative. In the maximally vasodilated bed the instantaneous pressure-flow relations fell along the steady-state relation, and the regulatory index was thus equal to zero at all flow-levels.

Measurement of left ventricular wall stress.

Forces in the myocardial wall can be measured in several ways or calculated using certain simplifying assumptions. In this study we investigated the reliability of two measurement methods, one of which was introduced by Feigl et al (1967), whereas the other method was developed in our laboratory. Both methods were tested in actively contracting skeletal muscle and beating hearts of open-chest dogs by comparing the force transferred from the muscle to the transducer under various circumstances. It appeared that changes in muscle length, be it through initial length changes or through shortening during contractions, had a great influence on the transfer of force to the transducer, for both methods, in both preparations. In the heart a decrease in internal left ventricular diameter of 15% resulted in a 50% reduction of force transferred to the transducer, independent of whether the length took place as a change in filling or as a change in ejection volume. In skeletal muscle the length-dependent effects during shortening were larger and those resulting from initial length changes were more variable than in beating hearts. That the effects of muscle length changes are of such magnitude means that, if no other errors exist, they alone would invalidate that until principally different methods of measuring wall stress in the myocardium are discovered, attempts at accurate calculation of myocardial wall stress are a better approach than wall stress measurements.

Perfusion-induced changes in cardiac contractility and oxygen consumption are not endothelium-dependent.

OBJECTIVE: Are substances released from rat coronary endothelial cells responsible for the increase in contractility and oxygen consumption (Gregg phenomenon) seen with an increase in cardiac perfusion? METHODS: In an isovolumically contracting, Langendorff, crystalloid perfused rat heart (n = 6) at 27 degrees C, coronary flow was changed (from 4.4 to 15.4 ml.min-1.gww(-1)) before and after the endothelium was made dysfunctional by Triton X-100. Vascular endothelium and smooth muscle function were tested with bradykinin (BK, 1 microM, an endothelium-dependent dilator) and papaverine (PAP, 1 microM, an endothelium-independent dilator) in a preconstricted vascular bed (vasopressin, VP, 3 nM). RESULTS: Before Triton X-100, coronary resistance (at constant flow) decreased significantly in response to BK and to PAP. After Triton X-100 treatment the dilatory response to BK was abolished while the PAP response was still present, suggesting endothelial dysfunction with intact smooth muscle function. Due to Triton X-100 treatment, coronary resistance increased significantly. Therefore coronary flow changes were also applied during a similar increase in coronary resistance induced by VP infusion (3 nM) before Triton X-100 treatment. During control, developed left ventricular pressure (dev Plv) increased with 68 +/- 21% and oxygen consumption (VO2) increased with 122 +/- 25% in response to the maximal increase in coronary flow. During increased coronary resistance with and without functional endothelium, dev Plv increased by 57 +/- 16 and 64 +/- 22%, respectively, and VO2 increased by 126 +/- 21 and 103 +/- 20%, respectively, in response to the maximal increase in flow. These changes were not significantly different from control. CONCLUSION: The results suggest that the arterial endothelium is not involved in the Gregg phenomenon.

Control of cardiac output in exercising dogs using different types of workload.

The system which controls cardiac output was studied in dogs during exercise on the treadmill. The aim was to investigate whether the pattern of the workload influences the control system. To measure cardiac output, electromagnetic flow probes were implanted at least 10 days before the exercise study. During the experiments cardiac output was computed on a beat-to-beat basis. We compared changes in cardiac output resulting from stepwise, sinusoidally and randomly varying workloads, obtained by changing treadmill velocity accordingly. The time constants found with sinusoidally and randomly varying workloads were 11.6 and 10.0s respectively. The time constants of the alteration in cardiac output resulting from a step function was 9.9s for the positive step and 15.6s for the negative step. However when the stepwise change in workload was between a velocity of 0.67 and 1.56 m.s-1 positive and negative steps yielded the same time constant (13.5 s). It is concluded that the pattern of the workload has no influence on the control system of cardiac output during exercise.

Left coronary pressure-flow relations of the beating and arrested rabbit heart at different ventricular volumes.

OBJECTIVE: To study the effect of cardiac contraction on left coronary artery pressure-flow relations at different vascular volumes and to compare these relations in the beating heart with those in the heart arrested in systole and diastole. METHODS: Maximally vasodilated, Tyrode perfused, rabbit hearts (n = 6) with an intra-ventricular balloon were used. The left coronary artery was separately perfused via a cannula in the left main coronary artery. The slopes and the intercepts of left coronary pressure-flow relations were determined in the beating and arrested heart at different chamber volumes. A 3-factor design with repeated measures was used to compare the effect of three factors: phase of contraction (systole and diastole), chamber volume (V0 and V1, left ventricular end-diastolic pressure 1.4 and 20 mm Hg, respectively) and the type of contraction (beating and arrested; a measure of capacitive effects). RESULTS: The phase of contraction has a significant effect on the intercepts (> 40 mmHg, p = 0.00032) but not on the slopes of the pressure-flow relations. Chamber volume had a small effect on the intercepts (< 5 mm Hg, p = 0.037), but not on the slopes of the pressure-flow relations. The type of contraction has a significant effect on the slopes (approximately 10%, p = 0.00021) but not on the intercepts of the pressure-flow relations. CONCLUSIONS: In the isolated Tyrode perfused rabbit heart left coronary pressure-flow relations are mainly determined by contraction, while left ventricular chamber volume and capacitive effects contribute little.

Reflection in the systemic arterial system: effects of aortic and carotid occlusion.

Experiments were performed in seven closed-chest anaesthetized male dogs to determine the role of pulse wave reflection in the pattern of flow and pressure in the ascending aorta. Ten days after implantation of an electromagnetic flow transducer around the ascending aorta a balloon catheter was placed in the descending aorta via the femoral arteries. At the same time a tip manometer was introduced into the ascending aorta. Aortic occlusions at three different sites caused pressure pulses with secondary systolic rises and flow pulses with biphasic deceleration. Secondary rises occurred 45 +/- 9.0 ms after the initial pressure rise for high aortic occlusion; this time was 75 +/- 8.5 ms for occlusion at the level of the diaphragm and 114 +/- 16.5 ms for occlusion near the level of the renal arteries. These times approximate the times in which the pulse travels from the tip manometer to the inflated balloons and back. Forward and reflected pressure and flow waves were calculated from reflection coefficients. Aortic occlusion caused larger reflected waves and the recorded wave forms were caused by the summation of forward and backward waves, the latter contributing the secondary pressure rise and the increased flow deceleration. Occlusion of both carotid arteries showed no specific reflection site but reflected waves were larger. This increased reflection can probably be explained as the result of greater total reflection from distributed sites under increased peripheral resistance.

Reoxygenated effluent of Tyrode-perfused heart affects papillary muscle contraction independent of cardiac perfusion.

OBJECTIVE: We determined, via a bioassay, if inotropic factors are released in the coronary circulation of the rat heart and if changes in cardiac perfusion change papillary muscle inotropy. METHODS: An isolated isometrically contracting rat papillary muscle (n = 5, acceptor) was superfused with Tyrode or with reoxygenated coronary venous effluent from an isolated isovolumically beating rat heart (donor) at 27 degrees C, which was perfused with Tyrode according to Langendorff. The superfusion solution in the muscle bath was exchanged completely in 90 s. During coronary venous effluent superfusion, the flow of the heart (donor) was changed in steps. RESULTS: The peak force of the papillary muscle (acceptor) was unaffected by a change from Tyrode to coronary venous effluent superfusion, but time to half relaxation (RT 1/2) significantly increased by 23.0 +/- 9.0% (mean +/- s.d.) and positive dF/dtmax significantly decreased by 14.6 +/- 4.7%. These twitch characteristics were unaffected by changes in coronary perfusion while in the heart isovolumic developed left ventricular pressure did increase with perfusion (the Gregg phenomenon). CONCLUSIONS: Factors that affected papillary muscle contractility are released into the coronary circulation, but their effect is independent of the magnitude of coronary perfusion.

Effects of topical beta-blockers on the diameter of the isolated porcine short posterior ciliary artery.

PURPOSE: Based on diameter measurements on the short posterior ciliary artery, this study was intended to determine the direct pharmacologic effect of beta-blockers; to determine the differences among a selective beta-blocker betaxolol, a beta-blocker with intrinsic sympathetic activity befunolol, and a nonselective beta-blocker timolol; and to find experimental evidence for the indirect hemodynamic effect of beta-blockers. METHODS: A segment of isolated porcine short posterior ciliary artery was cannulated at both ends and mounted in a pressurized vessel chamber. Vessel diameter was measured as a function of beta-blocker concentration and as a function of change in transmural pressure. RESULTS: In the absence of flow, the mean effective doses (ED50) were 0.8 +/- 0.3 mM, 1.0 +/- 0.3 mM, and 11.6 +/- 6.6 mM (SEM) for betaxolol, befunolol, and timolol, respectively. In the presence of flow, vessel diameter increased with an increase of transmural pressure. The mean relative diameter increased 4.2% +/- 1.0% (SEM) at a transmural pressure step from 30 mm Hg to 60 mm Hg. This increase was not significantly dependent on the presence of any of the beta-blockers. CONCLUSIONS: Only at concentrations far exceeding their expected plasma concentrations, betaxolol, befunolol, and timolol increased the diameter of the isolated porcine short posterior ciliary artery, as a result of their direct pharmacologic effect. Only the difference between the vasodilatory potency of the selective and the nonselective beta-blocker was significant: ED50 of betaxolol was 15 times smaller than ED50 of timolol. There was a positive correlation between the diameter of the isolated porcine short posterior artery (when used as a model for an intraocular artery) and the transmural pressure, which corroborates the indirect hemodynamic effect of beta-blockers. It is speculated that instillation of topical beta-blockers into the conjunctival sac may increase the perfusion of the optic nerve head by an indirect hemodynamic mechanism, but not by a direct pharmacologic mechanism.

Aortic input impedance during Mueller maneuver: an evaluation of "effective length".

Aortic input impedance was calculated in seven subjects in the control state (normal reflection) and during the Mueller maneuver (increased reflection) to evaluate "effective arterial length" under altered physiological conditions. Regional foot-to-foot pulse wave velocities and pressure waveforms along the aorta were used to define an "apparent anatomic length" or distance to a dominant discrete site of reflection "seen" by the ejecting ventricle. Time of wave travel was taken to be one-half the interval from the foot of the incident wave to the midsystolic inflection point. Knowing the time of travel from the returning reflection and velocity, distances calculated to the "apparent anatomic length" were 35 +/- 2 and 34 +/- 2 during control and Mueller maneuver, respectively (P = NS). The frequency of the first minimum of the modulus (fmin) and the first zero crossing of the phase angle (f phi) were determined from the input impedance spectra. During baseline conditions, fmin (3.9 +/- 0.2 Hz) approximately equaled f phi (4.2 +/- 0.2 Hz), and the resulting "effective lengths" calculated using the quarter-wavelength formula were similar to the apparent anatomic length. These data suggested that the aortic region incorporating the renal arterial branches as a site of discrete reflection and that terminal load was not significantly frequency dependent. During Mueller maneuver, however, f min (3.3 +/- 0.2 Hz) and f phi (5.1 +/- 0.2 Hz) were significantly discordant, the terminal load became strongly frequency dependent, and effective length calculated from f min was dissimilar (P less than 0.05) from the unchanged apparent anatomic length.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of geometric taper on the derivation of the true propagation coefficient using a three point method.

We studied the effect of geometric taper on the derivation of the true propagation coefficient from three pressures determined 10 cm apart ('three-point method'). For this purpose the true propagation coefficients of a uniform latex tube (length 50 cm, outer diameter 12.73 mm, Womersley phase velocity 6.23-6.42 ms-1 (1-10 Hz), Womersley damping coefficient 0.05-0.14 m-1 (1-10 Hz) and of a tapered latex tube (length 50 cm, outer diameter varying from 15.88 to 9.45 mm, in the middle section with same properties as the uniform tube) were determined. The real part of the true propagation coefficient (the damping coefficient) was compared with apparent damping, and with the damping coefficient calculated using Womersley's theory. The imaginary part of the true propagation coefficient (the phase coefficient) was expressed in terms of phase velocity. True phase velocity was compared with measurements of apparent phase velocity, foot-to-foot velocity, and calculations of phase velocity parameters Womersley's theory and the Moens-Korteweg equation. The results show that in the uniform tube the three-point propagation coefficient is in agreement with all other estimates. Taper causes an error in the three-point propagation coefficient. At some frequencies the damping is reversed to amplification (values up to -2 m-1) and the phase velocity may be both overestimated or underestimated (up to 50%). The overestimation of true damping as reported in the literature cannot be explained from vessel taper.

High frequency characteristics of the arterial system.

Pressure, flow and diameter were measured in the abdominal aorta of five anesthetized dogs during normal heart beats and heart beats with a superimposed impulse (generated by rapidly injecting a small volume of saline into the system). From Fourier analysis it was found that the impulse enhanced the amplitudes of the higher harmonics so that frequencies up to 80 Hz could be studied. Both the input impedance and apparent phase velocity above 20 Hz were independent of frequency and their average values were designated as characteristic impedance and true phase velocity. Average characteristic impedance for all five animals was 2.0 +/- 0.1 X 10(8) Nsm-5 and average phase velocity was 8.3 +/- 0.6 ms-1. Phase velocities calculated from characteristic impedance (1.76-2.39 X 10(8) Nsm-5) and from the slope of the pressure-diameter relation (0.102-0.25 X 10(-8) Nm-3) were similar to the true phase velocity as defined above (6.79-9.85 ms-1). It may be concluded that the input impedance converges to characteristic impedance and apparent phase velocity converges to phase velocity for high frequencies.

Linear and nonlinear one-dimensional models of pulse wave transmission at high Womersley numbers.

The accuracy of nonlinear and linear one-dimensional models in describing pulse wave propagation in a uniform cylindrical viscoelastic tube, with Womersley's parameter alpha equal to 7.6 at 1 Hz, was evaluated. To this end calculations of wave propagation using these models were compared with the experimentally determined propagation of the pressure wave in the tube. The experimentally generated pressure pulse had an amplitude of 9.0 kPa and caused a relative radius change of about 17%. The static pressure vs cross-sectional area relation was found to be nonlinear for these pressure changes. Maximum fluid velocity was about 2.9 ms-1, while the phase velocity was about 5.4 ms-1. The radius change and the ratio of fluid and phase velocities violated the linear model assumptions. The nonlinear model with viscous fluid friction modelled on the basis of Poiseuille's law and treating the tube wall as purely elastic, underestimated the damping of the pulse wave and predicted the formation of shock waves, which were not found experimentally. In the linear models, the viscous friction of the blood was modelled according to either Poiseuille's law or Womersley's theory and the tube wall was treated as either linearly elastic or linearly viscoelastic. A description of the viscous friction of the blood based on Poiseuille's law underestimated damping. Disregarding the viscoelasticity of the tube wall resulted in an underestimation of both phase velocity and damping. In spite of the nonlinearity of the system, the linear viscoelastic Womersley model described the pulse wave propagation satisfactorily.

How cardiac contraction affects the coronary vasculature.

We modeled the influence of cardiac contraction on maximally dilated coronary blood vessels, whether single or in juxtaposition, taking into account the nonlinear material properties of both the vascular wall and the myocardium. We calculated pressure-area relations of single, embedded coronary blood vessels, and used these relations to calculate diastolic and systolic coronary pressure-flow relations in a model of the coronary vasculature. The model shows that the change in myocardial material properties during contraction can explain the decrease in coronary vessel area and coronary flow generally observed in experiments. The model also shows that arterioles can be protected from the compressive action of the cardiac muscle by the presence of accompanying venules, which is favorable for coronary blood flow.

Vasoactive properties of rat coronary artery: in the tissue and isolated.

Perfusion of the heart takes place mainly in diastole. It is therefore important to study the factors that affect coronary diastolic flow. One of the factors that may limit coronary artery vasoactive responses is the surrounding cardiac tissue. We have therefore studied the intramyocardial septal artery, both when still embedded in the diastolic, unstretched myocardial tissue and after complete dissection (n = 6). In situ, the average external diameter was 351 +/- 21 microns; after dissection, it was 362 +/- 21 microns. These values were not significantly different. The average response of the vessel to KCl (125 mM, receptor-independent constriction) reduced the diameter to 56.1 +/- 5.0% and 69.4 +/- 3.7% of the maximal diameter for in situ and dissected vessels, respectively. The reduction in diameter after dissection was significantly less than the reduction in situ. The response to vasopressin (1,000 microU/ml, a receptor-dependent constrictor) was a reduction to 62.6 +/- 4.7% and 70.4 +/- 4.5%, respectively. The reduction in diameter of the dissected vessel is significantly smaller than that of the in situ vessel. The average values of the ratios of the diameter reductions for vasopressin and KCl were 0.85 +/- 0.06 in the in situ condition and 0.95 +/- 0.08 after dissection and were not significantly different (paired t-test). The results show that the dilated diameter and the diameter responses of intramyocardial conduit arteries are not affected by the surrounding diastolic cardiac tissue.

Molecular mechanisms of acute renal failure following ischemia/reperfusion.

Acute renal failure (ARF) necessitating renal replacement therapy is a common problem associated with high morbidity and mortality in the critically ill. Hypotension, followed by resuscitation, is the most common etiologic factor, mimicked by ischemia/reperfusion (I/R) in animal models. Although knowledge of the pathophysiology of ARF in the course of this condition is increasingly detailed, the intracellular and molecular mechanisms leading to ARF are still incompletely understood. This review aims at describing the role of cellular events and signals, including collapse of the cytoskeleton, mitochondrial and nuclear changes, in mediating cell dysfunction, programmed cell death (apoptosis), necrosis and others. Insight into the molecular pathways in the various elements of the kidney, such as vascular endothelium and smooth muscle and tubular epithelium leading to cell damage upon I/R will, hopefully, open new therapeutic modalities, to mitigate the development of ARF after hypotensive episodes and to promote repair and resumption of renal function once ARF has developed.