Abstract 266: Renovascular Remodeling in Hypertensive Dahl-SS Rats: Role of MMP Inhibitor as a Hypertension Ameliorating Agent

High salt diet has long been associated with chronic hypertension. The development of renal injury in Dahl salt-sensitive (SS) hypertensive rats is characterized by structural and functional changes involving vascular remodeling. Increased activity of matrix metalloproteinases (MMPs) leading to alteration in the extracellular matrix (ECM) is the main mechanism contributing to increased peripheral vascular resistance. In this study, we hypothesized that inhibition of MMPs will modulate ECM remodeling by decreasing MMP activity and thus reduce mean arterial blood pressure. METHODS: We used Dahl-salt sensitive (Dahl-SS) and Lewis rats fed on high salt diet. The groups were 1) Dahl-SS, 2) Dahl-SS+GM6001 (non-specific MMP inhibitor), 3) Lewis, and 4) Lewis+GM6001. GM6001 was given at 0.5mg/mL by intra-peritoneal injection on alternate days for 3 weeks. Blood pressure, laser doppler flowmetry for renal cortical blood flow and barium angiography for renal vascular density were measured. Results: Mean arterial blood pressure was 172.10 ± 0.57 mm Hg in hypertensive Dahl-SS rats compared to 136.12 ± 1.22 mm Hg in Dahl-SS+GM6001 rats. The mean arterial pressures in lewis and lewis+GM6001 groups were 97.08 ± 0.56 and 87.63 ± 2.93 mm Hg respectively. Laser doppler flowmetry showed reduced renal cortical blood flow (1333.33 flux units) in Dahl-SS rats compared to Dahl-SS rats treated with GM6001 (1605 flux units). Lewis rats showed similar renal cortical flow with (1488.33 flux units) or without GM6001 (1425 flux units). Barium angiography demonstrated increased renal vascular density with patent branches in the renal cortex of animals treated with MMP inhibitor, GM6001. Conclusion: Our results suggest that in hypertensive Dahl-SS rats, inhibition of MMP attenuates high blood pressure, maintains patency of renal cortical vessels thus improving cortical blood flow.

Exaggerated muscle mechanoreflex control of reflex renal vasoconstriction in heart failure

In heart failure (HF) patients, reflex renal vasoconstriction during exercise is exaggerated. We hypothesized that muscle mechanoreceptor control of renal vasoconstriction is exaggerated in HF. Nineteen HF patients and nineteen controls were enrolled in two exercise protocols: 1) low-level rhythmic handgrip (mechanoreceptors and central command) and 2) involuntary biceps contractions (mechanoreceptors). Renal cortical blood flow was measured by positron emission tomography, and renal cortical vascular resistance (RCVR) was calculated. During rhythmic handgrip, peak RCVR was greater in HF patients compared with controls (37 ± 1 vs. 27 ± 1 units; P < 0.01). Change in (Δ) RCVR tended to be greater as well but did not reach statistical significance (10 ± 1 vs. 7 ± 0.9 units; P = 0.13). RCVR was returned to baseline at 2–3 min postexercise in controls but remained significantly elevated in HF patients. During involuntary muscle contractions, peak RCVR was greater in HF patients compared with controls (36 ± 0.7 vs. 24 ± 0.5 units; P < 0.0001). The Δ RCVR was also significantly greater in HF patients compared with controls (6 ± 1 vs. 4 ± 0.6 units; P = 0.05). The data suggest that reflex renal vasoconstriction is exaggerated in both magnitude and duration during dynamic exercise in HF patients. Given that the exaggerated response was elicited in both the presence and absence of central command, it is clear that intact muscle mechanoreceptor sensitivity contributes to this augmented reflex renal vasoconstriction.

Baroreceptor and prostanoid control of fetal renal cortical blood flow and plasma renin activity

Renal function in the fetus is important for maintenance of fetal fluid and electrolyte balance. This study was performed to test the role of prostaglandins and their interaction with arterial baroreceptors and chemoreceptors in the control of renal cortical blood flow during hypotension produced by vena caval obstruction in late-gestation fetal sheep. We studied 18 time-dated, chronically catheterized, fetal sheep (124–136 days gestation). Fetuses were either studied intact (n = 11) or sinoaortic denervated (n = 7), and each fetus was studied twice, with and without pretreatment with indomethacin (0.2 mg kg –1 , i.v.). Each fetus was subjected to hypotension caused by vena caval obstruction for 10 min. Before hypotension, renal cortical blood flow was higher in the vehicle-treated sinoaortic denervated fetuses than in vehicle-treated intact fetuses. The increased renal cortical blood flow observed in the sinoaortic denervated fetuses was counteracted by indomethacin, so that the difference between sinoaortic denervated and intact fetuses was eliminated after indomethacin treatment. Hypotension decreased renal blood flow equally in all groups. Plasma renin activity was increased in response to hypotension in the intact fetuses, but not in the sinoaortic denervated fetuses. Indomethacin treatment, by itself, did not alter plasma renin activity. It is concluded that both arterial baroreceptors and prostanoids influence renal blood flow. Further, renin secretion is influenced by arterial baroreceptors and chemoreceptors and there is no apparent modulatory effect of prostanoids on the baroreflex control of renin secretion.

Increased activity and expression of Ca2+-dependent NOS in renal cortex of ANG II-infused hypertensive rats

We have previously demonstrated that nitric oxide (NO) exerts a greater modulatory influence on renal cortical blood flow in ANG II-infused hypertensive rats compared with normotensive rats. In the present study, we determined nitric oxide synthase (NOS) activities and protein levels in the renal cortex and medulla of normotensive and ANG II-infused hypertensive rats. Enzyme activity was determined by measuring the rate of formation ofl-[14C]citrulline froml-[14C]arginine. Western blot analysis was performed to determine the regional expression of endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms in the renal cortex and medulla of control and ANG II-infused rats. Male Sprague-Dawley rats were prepared by the infusion of ANG II at a rate of 65 ng/min via osmotic minipumps implanted subcutaneously for 13 days and compared with sham-operated rats. Systolic arterial pressures were 127 ± 2 and 182 ± 3 mmHg in control ( n = 13) and ANG II-infused rats ( n = 13), respectively. The Ca2+-dependent NOS activity, expressed as picomoles of citrulline formed per minute per gram wet weight, was higher in the renal cortex of ANG II-infused rats (91 ± 11) than in control rats (42 ± 12). Likewise, both eNOS and nNOS were markedly elevated in the renal cortex of the ANG II-treated rats. In both groups of rats, Ca2+-dependent NOS activity was higher in the renal medulla than in the cortex; however, no differences in medullary NOS activity were observed between the groups. Also, no differences in medullary eNOS levels were observed between the groups; however, medullary nNOS was decreased by 45% in the ANG II-infused rats. For the Ca2+-independent NOS activities, the renal cortex exhibited a greater activity in the control rats (174 ± 23) than in ANG II-infused rats (101 ± 10). Similarly, cortical iNOS was greater by 47% in the control rats than in ANG II-treated rats. No differences in the activity were found for the renal medulla between the groups. There was no detectable signal for iNOS in the renal medulla for both groups. These data indicate that there is a differential distribution of NOS activity, with the Ca2+-dependent activity and protein expression higher in the renal cortex of ANG II-infused rats compared with control rats, and support the hypothesis that increased constitutive NOS activity exerts a protective effect in ANG II-induced hypertension to maintain adequate renal cortical blood flow.