Autoregulation

As shown in Fig. 10, RBF and GFR remain relatively constant over a wide range of systemic blood pressures. To prevent changes in blood flow and GFR with changes in systemic blood pressure that occur normally during the day with changes in activity, the resistance to flow must change appropriately. As systemic blood pressure increases, total renal vascular resistance increases so that blood flow and GFR remain constant. Autoregulation, which is exhibited in the circulation of many organs, refers to an intrinsic adjustment of vascular resistance that counterbalances any extrinsic factors that would change flow other than by a direct effect on the vascular resistive elements themselves.

Clinical Note

Renovascular Hypertension

Because the juxtaglomerular cells release renin in response to lower renal vascular pressures and not systemic blood pressure, stenosis of a renal artery or one of its branches stimulates renin secretion. Even if renin secretion is augmented in only one portion of one kidney, it can be sufficient to raise systemic plasma renin levels. The resulting formation of angiotensin II has a direct pressor effect by increasing the resistance of arterioles throughout the body. Furthermore, as discussed in more detail in Chapters 27 and 29, angiotensin II stimulates aldosterone secretion, which drives salt retention by its effect on Na+ reabsorption in the connecting tubule and collecting duct.

Patients with atherosclerotic plaques or tumors that compress the renal artery and produce renal artery stenosis usually present clinically because of their hypertension. Laboratory work often reveals hypokalemia secondary to high plasma aldosterone levels because aldosterone drives K+ secretion. More specialized laboratory work may reveal an elevated plasma renin level, but in some cases the increased renin can be observed only by measuring unilateral renal vein renin levels, in which case the renin activity on the stenotic side is elevated but depressed in the contralateral renal vein. Renal arteriography is used to confirm the stenosis, its origin, and to determine the method of treatment.

Because renovascular hypertension (sometimes called renoprival hypertension) is treatable by relief of the occlusion (e.g., by angioplasty or surgery), it is imperative that this cause of hypertension be excluded early in the normal workup of the hypertensive patient.

In the kidney, autoregulation is more precise, and it appears to act primarily to regulate GFR rather than blood flow, because GFR remains constant not only with increased mean arterial pressure, but also with changes in venous pressure, increased ureteral pressure, and increased systemic plasma COP. For example, an increase in COP of the systemic plasma might be expected to decrease GFR but not to affect RBF, yet it has been found that GFR is maintained by a compensating increase in RBF. Similarly, obstruction of the lower urinary tract would decrease GFR by increasing the hydrostatic pressure in Bowman's space but, again,

FIGURE 10 Autoregulation of RPF and GFR with changes in arterial blood pressure. The relative resistance of the renal vasculature increases as the mean blood pressure in the renal artery increases, thereby maintaining relatively constant RPF and GFR over mean arterial blood pressures ranging from 80-180 mm Hg.

0 40 80 120 160 200

Mean Renal Artery Blood Pressure (mm Hg)

FIGURE 10 Autoregulation of RPF and GFR with changes in arterial blood pressure. The relative resistance of the renal vasculature increases as the mean blood pressure in the renal artery increases, thereby maintaining relatively constant RPF and GFR over mean arterial blood pressures ranging from 80-180 mm Hg.

unless the obstruction is severe, GFR is usually maintained nearly constant by an increase in RBF.

The maintenance of a constant GFR in the face of changes in mean arterial pressure, venous pressure, or obstruction (i.e., renal autoregulation) appears to be accomplished largely by changes in the resistance of the afferent arteriole. Decreasing afferent arteriolar resistance increases the effective filtration pressure and counteracts events tending to reduce GFR. Alternatively, increasing afferent arteriolar resistance counteracts increases in GFR. Two mechanisms, the myogenic response and tubuloglomerular feedback, contribute to this regulation of afferent arteriolar resistance.

When the pressure in the afferent arteriole increases, stretches the vessel wall, and this stretch directly stimulates the arteriolar smooth muscle to contract. The resulting constriction of the arteriole increases its resistance, thereby counteracting the tendency of increased blood pressure to increase flow. This intrinsic regulation is referred to as a myogenic response. Although this mechanism operates in many organs (see Chapter 17), it cannot be the only autoregulatory mechanism in the kidney because, as described earlier, GFR is the primary parameter that appears to be regulated, even at the sacrifice of a constant RBF. Thus, it seems reasonable that the parameter sensed and regulated is GFR or some factor dependent on GFR, rather than RBF.

The tubuloglomerular feedback mechanism is responsible for this sensitive autoregulation of GFR and it depends of the effect of changes in the GFR on the delivery to NaCl to the macula densa. When, for example, the filtration rate of a single nephron (the so-called single nephron GFR, or snGFR) increases, the rates of fluid and NaCl delivery to the loop of Henle and the macula densa increase in direct proportion. This increase in NaCl delivery is found to cause a decrease in the snGFR of that nephron, thus forming a negative feedback loop. In animal experiments, it has been shown that perfusion of the distal nephron with a maximal flow rate reduces snGFR by 40-80%. Alternatively, when distal nephron flow is reduced, snGFR is increased. This behavior is called tubuloglomerular feedback, and it provides a mechanism by which each nephron maintains a constant snGFR. Recent studies, such as the one illustrated in Fig. 11, have shown that increased NaCl delivery to the macula densa causes the cells to swell. This swelling causes the release of adenosine triphos-phate (ATP) and/or adenosine, which acts via receptors on the juxtaglomerular cells in the afferent arteriole to increase its resistance by contraction.

Taking all nephrons together, the result of tubulo-glomerular feedback would be the maintenance of a constant total kidney GFR. For example, if arterial pressure were to increase, the initial increase in glomerular capillary pressure would cause an increase in snGFR of all nephrons. The resulting increase in NaCl and water delivery to the macula densa would then produce an increase in afferent arteriolar resistance that would decrease glomerular capillary pressure and snGFR would fall toward normal. The increase in afferent arteriolar resistance would also maintain a constant RBF despite the increase in blood pressure.

Tubuloglomerular feedback depends on signaling between the macula densa cells that sense a change in NaCl delivery and the afferent arteriole, which is mediated by the release of either ATP or adenosine from the macula densa cells in response to increased NaCl delivery. However, students (and professors) are often confused by what seem to be contradictory effects of changes in salt delivery to the macula densa. According to the tubuloglomerular feedback mechanism, decreased NaCl delivery to the macula densa should produce relaxation of the afferent arteriole and an increase in GFR. However, as noted in the previous section, decreased NaCl delivery to the macula densa is a stimulus for renin release by the juxtaglomerular cells. The resulting increase in angiotensin II should constrict afferent and efferent arterioles and decrease the renal blood flow and GFR.

FIGURE 11 Effect of increased NaCl concentration on macula densa cells and afferent arteriole. Both panels show the same isolated glomerulus and adhering components of the juxtaglomerular apparatus. The cell membranes were visualized using a fluorescent dye, and optical sections were obtained by two-photon laser scanning fluorescence microscopy. (A) A micropipette was used to perfuse the thick ascending limb (upper left, arrowhead in lumen) with a solution containing 25 mmol/L NaCl. The macula densa cells form a plaque of cells on the side of the tubule toward which the arrowhead points. The diameter of the lumen of the afferent arteriole (aa) is indicated by the space between the two arrows. A portion of a capillary loop (cap) is shown at the lower edge of the glomerulus. (B) When the solution perfusing the thick ascending limb in the same preparation was changed to one containing 135 mmol/L NaCl, the macula densa cells swelled dramatically, while the lumen of the afferent arteriole was almost obliterated by constriction. The increased afferent arteriolar resistance and the reduction in blood flow are reflected by the reduction in the diameter of the capillary. (From Petri-Peteroli, J. et al. (2002). Am. J. Physiol. 283:F197-F201. With permission of the journal and the author.)

FIGURE 11 Effect of increased NaCl concentration on macula densa cells and afferent arteriole. Both panels show the same isolated glomerulus and adhering components of the juxtaglomerular apparatus. The cell membranes were visualized using a fluorescent dye, and optical sections were obtained by two-photon laser scanning fluorescence microscopy. (A) A micropipette was used to perfuse the thick ascending limb (upper left, arrowhead in lumen) with a solution containing 25 mmol/L NaCl. The macula densa cells form a plaque of cells on the side of the tubule toward which the arrowhead points. The diameter of the lumen of the afferent arteriole (aa) is indicated by the space between the two arrows. A portion of a capillary loop (cap) is shown at the lower edge of the glomerulus. (B) When the solution perfusing the thick ascending limb in the same preparation was changed to one containing 135 mmol/L NaCl, the macula densa cells swelled dramatically, while the lumen of the afferent arteriole was almost obliterated by constriction. The increased afferent arteriolar resistance and the reduction in blood flow are reflected by the reduction in the diameter of the capillary. (From Petri-Peteroli, J. et al. (2002). Am. J. Physiol. 283:F197-F201. With permission of the journal and the author.)

There are two important points to note in addressing this apparent contradiction. First, the tubuloglomerular feedback mechanism is mediated by direct signaling from macula densa cells to the afferent arteriole. This signaling does not involve renin release or angiotensin II production. Second, tubuloglomerular feedback is directed at the rapid regulation of the filtration rate of individual nephrons, whereas the release of renin when NaCl delivery is reduced has systemic effects but only when it involves many nephrons. The subsequent production of angiotensin II and aldosterone, and their effects to elevate systemic blood pressure and extracellular fluid volume, can be viewed as an emergency response to a general reduction in the filtration rate of all nephrons, which might occur in dehydration or when systemic blood pressure falls.

In summary, the tubuloglomerular feedback mechanism is a rapidly responding local mechanism for the regulation of snGFR, whereas the effect of flow and NaCl delivery to the macula densa on renin release is a more slowly responding system that has significant effects only when multiple nephrons are involved. Furthermore, flow and NaCl delivery to the macular densa is one of only several factors that regulate renin release see Chapter 29.

Reducing Blood Pressure Naturally

Reducing Blood Pressure Naturally

Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.

Get My Free Ebook


Post a comment