Reduced Renal Mass Hypertension Research Articles

Effect of salt loading on baroreflex sensitivity in reduced renal mass hypertension

ABSTRACTBackground: High dietary salt, as well as renal mass reduction, is known to decrease baroreflex sensitivity in rats. However, the effect of high salt intake on baroreflex sensitivity is unknown in reduced renal mass (RRM) hypertension; therefore, the aim of this study was to investigate the effects of salt loading on arterial baroreflex sensitivity and mean arterial pressure (MAP) in RRM hypertension.Methods: Both RRM and sham-operated control (SO) rats were loaded with 0.25 or 0.5% NaCl for five weeks. Plasma Na+, K+, and creatinine levels were measured, and baroreflex sensitivity was evaluated before and after β1 blockade. In addition, cardiac vagal tone and intrinsic heart rate (IHR) were measured. RESULTS: RRM decreased full baroreflex sensitivity of the tachycardic response under 0.5% NaCl loading and the parasympathetic bradycardic response under 0% NaCl loading. The NaCl loading did not affect the severity of RRM hypertension. Cardiac vagal tone and IHR decreased in RRM rats versus SO controls under all NaCl loading conditions. RRM decreased plasma K+ under 0% NaCl loading and increased plasma Na+ under 0.5% NaCl loading. High (0.5%) NaCl loading decreased IHR and increased plasma creatinine and left ventricular weight in RRM rats. CONCLUSIONS: RRM in combination with 0.5% NaCl loading led to a decrease in the sensitivity of full baroreflex and of the parasympathetic component of baroreflex. Changes in plasma Na+ and K+ levels, due to NaCl loading, may have contributed to the decrease in baroreflex sensitivities and IHR but had no effect upon MAP in RRM rats.

Microvascular flow and tissue PO(2) in skeletal muscle of chronic reduced renal mass hypertensive rats.

This study determined whether arteriolar blood flow, capillary red blood cell (RBC) velocity, capillary hematocrit (Hct(cap)), and tissue PO(2) are altered in cremaster muscles of rats with chronic reduced renal mass hypertension (RRM-HT) relative to normotensive rats on high- or low-salt (NT-HS vs. NT-LS) diet. The blood flow in first- through third-order arterioles was not different between NT and HT rats, either at rest or during maximal relaxation of the vessels with 10(-4) M adenosine. Capillary RBC velocity was similar between the groups at rest but was elevated in RRM-HT and NT-HS rats during adenosine superfusion. Hct(cap) was reduced at rest in RRM-HT and NT-HS rats compared with NT-LS and was reduced in RRM-HT rats during adenosine-induced dilation. Tissue PO(2) was reduced in RRM-HT and NT-HS rats compared with NT-LS rats during control conditions and was lower in RRM-HT than in NT-LS rats during adenosine-induced dilation. These results indicate that both RRM-HT and chronic exposure of normotensive rats to a high-salt diet lead to reduced tissue oxygenation, despite the maintenance of normal arteriolar blood flow.

Contribution of Extrinsic Factors and Intrinsic Vascular Alterations to Reduced Arteriolar Reactivity with High-Salt Diet and Hypertension

To determine whether the impaired relaxation of skeletal muscle arterioles of rats on high-salt diet or with reduced renal mass hypertension (RRM-HT) represents intrinsic alterations to microvessels alone, or whether extravascular influences also contribute to reduced dilator responses. Normotensive (NT) Sprague-Dawley rats were fed low-salt (LS) or high-salt (HS) diets, and RRM-HT rats were fed HS diet for 4-6 weeks. In situ and isolated cremaster muscle first-order arterioles (1A) were examined using television microscopy, and a video micrometer was used to measure diameter changes in response to acetylcholine (ACH), cholera toxin (CT), and sodium nitroprusside (SNP). Compared to normotensive low-salt (NT-LS) rats, responses of 1A to the agonists were reduced in normotensive high-salt (NT-HS) and RRM-HT rats. Arteriolar reactivity to the agonists in NT-LS rats aid in NT-HS rats was not different between in situ and in vitro environments. However, in RRM-HT rats, the reactivity of 1A to each agonist was greater in isolated arterioles than in in situ arterioles. These results suggest that the impaired response of skeletal muscle arterioles to vasodilator stimuli in normotensive rats on high-salt diet primarily reflects alterations to microvessels alone, while reduced dilator responses in RRM-HT rats represent a combination of extravascular influences and intrinsic alterations to arterioles themselves.

Contribution of cytochrome P-450 omega-hydroxylase to altered arteriolar reactivity with high-salt diet and hypertension.

The present study evaluated the contribution of cytochrome P-450 omega-hydroxylase in modulating the reactivity of cremaster muscle arterioles in normotensive rats on high-salt (HS) and low-salt (LS) diet and in rats with reduced renal mass hypertension (RRM-HT). Changes in arteriolar diameter in response to ACh, sodium nitroprusside (SNP), ANG II, and elevated O(2) were measured via television microscopy under control conditions and following cytochrome P-450 omega-hydroxylase inhibition with 17-octadecynoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In normotensive rats on either LS or HS diet, resting tone was unaffected and arteriolar reactivity to ACh or SNP was minimally affected by cytochrome P-450 omega-hydroxylase inhibition. In RRM-HT rats, cytochrome P-450 omega-hydroxylase inhibition reduced resting tone and significantly enhanced arteriolar dilation to ACh and SNP. Treatment with 17-ODYA or DDMS inhibited arteriolar constriction to ANG II and O(2) in all the groups, although the degree of inhibition was greater in RRM-HT than in normotensive animals. These results suggest that metabolites of cytochrome P-450 omega-hydroxylase contribute to the altered reactivity of skeletal muscle arterioles to vasoconstrictor and vasodilator stimuli in RRM-HT.

Reduced Renal Mass Hypertension, but Not High Salt Diet, Alters Skeletal Muscle Arteriolar Distensibility and Myogenic Responses

The effects of high salt diet and reduced renal mass hypertension (RRM-HT) on skeletal muscle arteriolar distensibility and myogenic responses were investigated in male Sprague-Dawley rats. Rats were enclosed in an air-tight box with the in situ cremaster muscle exteriorized and viewed via television microscopy. Normotensive rats were fed low salt (0.4% NaCl) or high salt (4.0% NaCl) diet and RRM-HT rats were fed high salt diet for 4–6 weeks. With the cremaster muscle superfused with either physiological salt solution (for myogenic responses) or Ca2+-free physiological salt solution (for arteriolar distensibility), box pressure (and therefore, intravascular pressure) was increased in 5 mm Hg increments to a maximum of +30 mm Hg. The myogenic responses of arterioles were not altered by high salt diet, but were enhanced with RRM-HT. Arteriolar distensibility was not affected by high salt diet, but was reduced in RRM-HT rats compared to either normotensive rat group. These data suggest that high salt diet does not significantly alter either myogenic responses or the distensibility of rat cremasteric arterioles. However, RRM-HT enhances myogenic responses of these vessels while reducing arteriolar distensibility. The impact of these effects must be taken into account when interpreting data describing alterations in skeletal muscle microvessel reactivity for animals on high salt diet or with RRM hypertension.

Development and Reversibility of Altered Skeletal Muscle Arteriolar Structure and Reactivity with High Salt Diet and Reduced Renal Mass Hypertension

To determine the development and reversibility of the altered vasodilator reactivity of cremasteric arterioles in rats on high-salt diet and with reduced renal mass hypertension (RRMHT). Sprague Dawley rats were fed high-salt (HS) or low-salt (LS) diet and RRMHT rats were fed HS diet (HSRRM) over 4 weeks, after which a group of HS and HSRRM rats were fed LS diet for 4 additional weeks (HS/LS and HS/LSRRM), while all others remained on their original diet. Changes in arteriolar diameter to dilator agonists (acetylcholine, iloprost, cholera toxin, forskolin, and sodium nitroprusside) and to Ca2+ free solution plus adenosine (to determine maximum diameter) were measured with a videomicrometer. Reduced vasodilator reactivity developed over 4 weeks with HS diet and RRMHT, although more rapidly and to a greater extent with RRMHT. In HS rats, the reduced reactivity was completely reversible with restoration of LS diet. Complete recovery of dilator reactivity to control levels did not occur with restoration of LS diet and normotension in HS/LSRRM rats, although the slope of the recovery over the final 4 weeks was comparable to that in normotensive HS/LS animals. Impaired vasodilator reactivity, occurring with high-salt diet, appears to be fully reversible. Impaired vascular reactivity may recover after restoration of normal blood pressure in RRMHT, although over a longer period than with high-salt diet alone.

Distinct mechanisms of modulation of angiotensin II type I receptor gene expression in heart and aorta.

The purpose of the present study was to test the hypothesis that hypertension induced by reduced renal mass (RRM) upregulates gene expression of the type 1 angiotensin II (Ang II) receptor (AT1) in the thoracic aorta and heart through an Ang II-dependent mechanism. Three groups of rats were given 1% NaCl water and subjected to RRM, RRM plus captopril (RRM+Cap, 30 mg/kg per day), or sham surgery. Tail-cuff systolic blood pressure was significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. The ratios of the medial wall area of the thoracic aorta and heart weight to body weight were significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. Northern blot analysis indicated that the ratio of AT1 to GAPDH mRNA in the aorta was significantly higher in RRM (1.85 +/- 0.52) compared with sham-operated (0.21 +/- 0.04) and RRM+Cap (0.55 +/- 0.20) rats. In contrast, the ratio of AT1 to GAPDH mRNA in the heart was significantly increased in both RRM (1.09 +/- 0.23) and RRM+Cap (1.00 +/- 0.09) compared with sham-operated (0.34 +/- 0.06) rats. Thus, RRM hypertension upregulates AT1 mRNA expression in both the hypertrophied aorta and heart. Captopril treatment without altering blood pressure in RRM rats prevents the increase in AT1 mRNA in the aorta but not the heart. These results suggest that different tissue-specific mechanisms of AT1 gene regulation exist; ie, in aorta, an Ang II-or kinin-dependent mechanism is operant, whereas in heart, RRM-induced upregulation of AT1 mRNA may be pressure dependent.

Regulation of ANG II receptor in hypertension: role of ANG II.

To investigate the role of angiotensin II (ANG II) in the development of hypertension induced by reduced renal mass (RRM) and the gene expression of ANG II type 1 (AT1) receptors in the remnant renal tissue, four groups of rats were given 1% NaCl in water and subjected to RRM, RRM+ ramipril, RRM+ losartan, or sham surgery (control). Tail-cuff systolic blood pressure was significantly higher in RRM rats than in the other three groups. Northern blot showed that AT1 gene expression was significantly decreased in RRM, RRM + ramipril, or RRM + losartan vs. control. There was no significant difference among the three RRM groups. Renal transforming growth factor-beta 1 (TGF-beta 1) mRNA levels were increased threefold (P < 0.05) in RRM, RRM+ ramipril, and RRM+ losartan vs. control. There was no significant difference among the three RRM groups. We conclude that the development of RRM hypertension is ANG II dependent but not mediated by AT1 gene expression. RRM downregulates AT1 mRNA and upregulates TGF-beta 1 mRNA in the remnant renal tissue, regardless of blood pressure or plasma levels of ANG II, suggesting that these gene responses are triggered by an effect of local injury.

Hemodynamic and microcirculatory changes during development of renal hypertension

To study the progression of vessel loss (rarefaction) during the development of hypertension, a plastic window was chronically implanted over the biceps femoralis muscle of reduced renal mass (RRM) and sham-operated control (SOC) rats on a low-salt diet (0.4%). Blood pressure was measured directly via a catheter implanted in the femoral artery, and tissue blood flow was measured by laser-Doppler flowmetry before and after local topical application of sodium nitroprusside. Measurements were made on the control day and after an increase in sodium intake (4.0%) in RRM rats on days 5, 10, 14, 21, and 28. SOC rats on a low-salt diet served as the control group. RRM rats became hypertensive (167 mmHg), and vascular resistance increased after a change in sodium intake. Resting tissue blood flow decreased by 19% by day 28 in RRM but did not change in SOC. Sodium nitroprusside administration reduced vascular resistance to the same level in both RRM and SOC during control and at day 10; however, on all other days, sodium nitroprusside was not able to fully dilate the RRM microcirculation compared with that of SOC. At the same time, microvascular density estimated by computer fluorescence microscopy was decreased by 25% in RRM rats. These studies indicate that the development of RRM hypertension is characterized by a transition from increased tone and vessel closure (functional rarefaction) to anatomic vessel loss (structural rarefaction).

Structural alterations of microvascular smooth muscle cells in reduced renal mass hypertension.

Loss of microvessels (anatomic rarefaction) occurs in chronic reduced renal mass (RRM) hypertension and is mediated via structural degeneration of vascular smooth muscle (VSM) and endothelial cells. The purpose of the present study was to determine if structural changes occur in VSM cells of the microvessels that remain in the tissue of rats with chronic RRM hypertension. Samples of cremaster muscles were taken from normotensive control rats and rats with acute (3-7 days) and chronic (14-28 days) RRM hypertension (75% reduction in kidney mass with 4% NaCl loading). The samples were fixed in situ and processed for light and electron microscopy. Ultrastructural morphology of VSM cells in terminal arterioles of control animals was normal. Although VSM morphology in many microvessels of RRM hypertensive rats was also normal, some vessels exhibited structural changes that were not present in arterioles of the normotensive animals. The most striking change was the appearance of more extensive dense bodies anchoring the contractile filaments around the outer membrane of the cells. Extreme vasoconstriction was observed in some arterioles of RRM rats as long as 2 weeks after salt loading. Focal areas of VSM cell proliferation were evident. Many of the changes occurring in RRM were detected as early as 1 week after the onset of hypertension. These observations suggest that renal mass reduction-salt loading hypertension is associated with early structural and functional changes in the VSM cells.

Increased arterial potassium transport in reduced renal mass hypertension of the rat.

Aortic potassium turnover was studied during the development of hypertension induced by salt load in male rats after 70-75% of total renal mass was removed. Systolic blood pressure in the saline-drinking experimental reduced renal mass (RRM) rats steadily increased until the fourth week after surgery and thereafter stayed at the same level. Control RRM rats given tap water for drinking, and unilaterally nephrectomized saline-drinking control rats maintained normal blood pressure. Compared to controls, experimental RRM rats exhibited increased plasma aldosterone concentration while plasma renin activity was low in all groups with no significant difference. Aortic hypertrophy, greater 42K turnover, and elevated 42K exchange were observed with experimental RRM hypertension. Sensitivity to the effect of norepinephrine (NE) on aortic 42K turnover was increased four- to ninefold in the experimental RRM group as compared to controls. These results indicate that reduced renal mass hypertension is associated with increased potassium permeability and NE supersensitivity in vascular smooth muscle.