Biomedical subjects

L Raij

Publications and source records attributed to L Raij.

At least 73 records · Page 4Linked to original sources

PubMed1990

Effects of endothelium-derived relaxing factor and nitric oxide on rat mesangial cells.

We have investigated whether endothelium-derived relaxing factor (EDRF) and nitric oxide (NO), a substance proposed to be one of the EDRFs, could elicit biochemical and biological responses in rat glomerular mesangial cells (MC). In wells with MC alone, guanosine 3',5'-cyclic monophosphate (cGMP) levels were 2.6 +/- 0.6 fmol/microgram protein, and bradykinin did not affect these levels, whereas in coincubation experiments with bovine aortic EC and rat MC, cGMP levels in MC increased to 44.6 +/- 21 fmol/micrograms protein after bradykinin stimulation (P less than 0.05). This effect was potentiated by superoxide dismutase and inhibited by hemoglobin and L-NG-monomethyl arginine, a specific inhibitor of EDRF synthesis. Increases in cGMP were also observed when MC were incubated directly with NO and were potentiated by superoxide dismutase and inhibited by hemoglobin. We also tested whether NO could inhibit angiotensin II (ANG II)-induced reductions in cross-sectional area (CSA) of MC. When MC were exposed to ANG II only, 65% of the cells underwent a significant reduction in CSA, as measured by digital image analysis. However, when MC were incubated with ANG II and NO, only 10% of cells responded (P less than 0.04). These studies demonstrate that EDRF and NO induce significant biochemical and functional responses in rat glomerular MC and suggest that communication between EC and MC may be important in regulation of glomerular function.

Angiotensin II↗

PubMed1990

Inhibition of human mesangial cell proliferation by calcium channel blockers.

Human mesangial cells in culture proliferate in response to platelet-derived growth factor (PDGF) and thrombin. Both of these agents also induce changes in cytosolic calcium that are dependent on both mobilization of intracellular calcium and influx of extracellular calcium. We hypothesized that calcium channel blockers, by preventing influx of extracellular calcium, may inhibit proliferation induced by these mitogens. We found that three different calcium channel blockers, diltiazem, nifedipine, and verapamil, were able to significantly inhibit [3H]thymidine incorporation into human mesangial cells induced by either PDGF or thrombin. The inhibitory effect of these agents was significant at 10(-5) M. The calcium channel blockers also attenuated the increases in cell number and percentage of labeled nuclei induced by these mitogens. In contrast, dantrolene, an inhibitor of intracellular calcium mobilization, had no significant effect on [3H]thymidine incorporation by PDGF or thrombin. Finally, the calcium channel agonist, Bay K 8644 was found to stimulate [3H]thymidine incorporation into mesangial cells. Although the mechanisms for these effects of calcium channel blockers are not proven, these studies suggest that influx of extracellular calcium is an important signal in mitogen-induced mesangial proliferation and that these agents can be beneficial in preventing or attenuating renal diseases characterized by proliferation of these cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Effects of NG-monomethyl-L-arginine and L-arginine on acetylcholine renal response.

Intrarenal infusion of acetylcholine in meclofenamate-treated dogs significantly increased renal blood flow, diuresis, and natriuresis. Intrarenal infusions of either NG-monomethyl-L-arginine (inhibitor of endothelium-derived relaxing factor formation), or L-arginine (precursor of endothelium-derived relaxing factor formation) did not modify basal levels of those parameters. However, the infusion of NG-monomethyl-L-arginine inhibited the acetylcholine-induced increases in renal blood flow and diuresis without affecting natriuresis, which increased significantly. The infusion of L-arginine failed to further enhance hemodynamic and excretory effects elicited by acetylcholine. The concomitant infusion of L-arginine and NG-monomethyl-L-arginine did not change renal blood flow, urine flow, or sodium excretion rate. L-Arginine administration prevented the inhibitory effect of NG-monomethyl-L-arginine on acetylcholine-induced renal vasodilatation and diuresis. Glomerular filtration rate and mean arterial pressure did not change throughout the experiment. The results indicate that the vasodilatory and diuretic responses to intrarenal acetylcholine in meclofenamate-treated dogs are largely dependent on endothelium-derived relaxing factor.

Acetylcholine↗

PubMed1990

Comparison of converting enzyme inhibitor and calcium channel blocker in hypertensive glomerular injury.

The protective effect of converting enzyme inhibitors in experimental hypertensive glomerular injury is associated with decreased systemic arterial and glomerular capillary pressure. Although calcium channel blockers effectively lower systemic blood pressure, their effect on glomerular capillary pressure and on hypertensive glomerular injury is uncertain. We compared equihypotensive treatment with the calcium antagonist TA 3090 or the converting enzyme inhibitor captopril in post-salt hypertensive Dahl salt-sensitive (DS) rats for up to 5 weeks after five sixths nephrectomy. Before the nephrectomy, all rats demonstrated hypertension (mean 177 mm Hg), proteinuria (mean 175 mg/day), and mild glomerulosclerosis (mean injury score 35). Rats treated with captopril or TA 3090 demonstrated a significant and equivalent decrease in systolic blood pressure compared with untreated rats at 2, 3, and 5 weeks after five sixths nephrectomy; however, only captopril reduced proteinuria. Final proteinuria was actually increased in rats treated with TA 3090 compared with untreated rats. Glomerular injury score was significantly decreased in captopril-treated compared with untreated rats at 2 weeks (33 +/- 9 versus 117 +/- 10, p less than 0.05) and 5 weeks (46 +/- 9 versus 94 +/- 24, p less than 0.05), whereas treatment with TA 3090 delayed but did not prevent progressive glomerular injury (2-week score 35 +/- 7, p less than 0.05 versus untreated; 5-week score 109 +/- 19, p = NS versus untreated). Thus, in hypertensive DS rats after subtotal nephrectomy, treatment with a converting enzyme inhibitor reduced systemic blood pressure, proteinuria, and glomerulosclerosis. However, equihypotensive treatment with a calcium channel blocker did not reduce proteinuria and delayed but did not prevent glomerulosclerosis. Thus, in the rat similar reductions in systemic blood pressure with these two classes of agents have disparate effects on the progression of chronic renal failure.

Animals↗

PubMed1990

Interactions of the endothelium and mesangium in glomerular injury.

Glomerular mesangial and endothelial cells have key roles in the regulation of glomerular blood flow, both under normal circumstances and in pathologic states. The anatomic structure of the glomerulus is such that the endothelial and mesangial cells are in close proximity to each other and consequently may communicate through a number of cellular mediators. Vasodilatory substances, such as prostacyclin and endothelium-derived relaxing factor, and vasoconstrictive substances, such as endothelin, are released by endothelial cells and can interact with mesangial cells to affect glomerular blood flow. The ability of plasma macromolecules to enter and circulate through the mesangium may play an important role in the development of glomerular injury. Angiotensin II has been shown to increase the uptake and decrease the rate of disappearance of certain macromolecules in the mesangium; this action is blocked, at least partially, by angiotensin II receptor antagonists and by calcium channel blockers. Experimental studies have suggested that angiotensin converting enzyme inhibitors and calcium channel blockers may prevent or arrest progression of renal injury. Angiotensin converting enzyme inhibitors may ave a beneficial effect by decreasing intraglomerular pressure through inhibition of angiotensin II predominant constriction of the glomerular efferent arteriole and possibly by decreasing mesangial trafficking of macromolecules. Calcium channel blockers may have beneficial effects on intracellular events that occur because of injury of either endothelial or mesangial cells.

Angiotensin II↗

PubMed1990

Angiotensin converting enzyme inhibitors and progression of chronic renal failure.

Renal failure, once established by loss of a critical amount of functional renal mass, tends to be progressive. A large body of experimental evidence supports the hypothesis that glomerular capillary hypertension is important in the pathogenesis of progressive chronic renal failure of diverse types, including subtotal renal ablation and diabetic nephropathy. Converting enzyme inhibitors are effective in slowing or arresting the progression of glomerular injury in these experimental models, in association with normalization of both systemic and intrarenal pressures. Clinical studies of diabetic nephropathy and chronic renal failure of other etiologies support the concept that these same renal hemodynamic factors are important in human renal disease and that treatment with converting enzyme inhibitors may prove to be a useful therapeutic intervention. Whether the converting enzyme inhibitors have specific advantages over other antihypertensive agents due to beneficial renal hemodynamic effects, as suggested by experimental studies, is a question that awaits further investigation. Furthermore, the pathogenesis of hypertensive glomerular injury is complex and involves the participation of diverse biologic systems. We predict that a wide variety of therapeutic maneuvers, with disparate mechanisms of action, may be effective in arresting or preventing glomerular injury.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

Concerns about diabetic nephropathy in the treatment of diabetic hypertensive patients.

Diabetic nephropathy ultimately develops in approximately, 40 percent of patients with insulin-dependent diabetes mellitus, as well as in a significant fraction of those with non-insulin-dependent diabetes. Consequently, diabetic nephropathy represents the most common single cause of end-stage renal failure in adults. Recent studies indicate that the subset of insulin-dependent diabetic patients who develop nephropathy may have a genetic susceptibility to renal injury resulting from the abnormal physiologic milieu associated with diabetes. This is perhaps due to abnormal glomerular hemodynamic responses resulting in glomerular capillary hypertension. Diabetic nephropathy progresses through a prolonged subclinical stage characterized by abnormal urinary albumin excretion rates (30 to 250 mg/24 hours, "microalbuminuria") and small, but significant, increases in arterial blood pressure. This stage of incipient diabetic nephropathy represents the earliest point at which patients destined to develop overt diabetic nephropathy (albumin excretion rate of more than 250 mg/24 hours, hypertension, and decreased glomerular filtration rate) can be identified, and targets a population that may benefit from therapy aimed at preventing progression of renal failure. Hypertension is intimately related to the development and progression of diabetic nephropathy. Control of hypertension has been clearly shown to slow or arrest the progression of diabetic nephropathy and represents the most important therapeutic option available. Preliminary studies suggest that treatment consisting of strict metabolic control and selective antihypertensive agents during the stage of incipient nephropathy could potentially prevent the development of overt nephropathy. Although control of hypertension with any regimen is most likely beneficial, those agents endowed with selective protective effects on the glomerulus may confer optimal preservation of renal function. Patients with diabetes mellitus, whether insulin-dependent or non-insulin-dependent, are at increased risk for developing systemic arterial hypertension. The treatment of hypertension in diabetic patients takes on importance beyond the usual concerns for reducing blood pressure in other hypertensive patients. In diabetic patients, hypertension is directly linked to the development and progression of nephropathy. If this devastating complication is to be minimized or prevented, then control of arterial hypertension must be a major goal of therapy from the earliest stages of the disease process.

Diabetes Complications↗

PubMed1989

Hypoxic pulmonary vasoconstriction is enhanced by inhibition of the synthesis of an endothelium derived relaxing factor.

Inhibition of the synthesis of endothelium derived relaxing factor by NG-monomethyl-L-arginine, a competitive inhibitor of the synthesis of nitric oxide from L-arginine, enhances hypoxic pulmonary vasoconstriction in pulmonary artery rings and isolated, Krebs albumin perfused rat lungs. L-arginine rapidly reduces hypoxic vasoconstriction, particularly in lungs treated with NG-monomethyl-L-arginine. Following administration of NG-monomethyl-L-arginine, bradykinin-induced vasodilatation is inhibited (p less than 0.01) and a bradykinin-induced vasoconstriction develops (p less than 0.001). NG-monomethyl-L-arginine does not significantly diminish acetylcholine-induced vasodilatation in the isolated lung. NG-monomethyl-L-arginine causes an endothelium-dependent vasoconstriction in pulmonary artery rings.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1989

Hydroxylamine is a vasorelaxant and a possible intermediate in the oxidative conversion of L-arginine to nitric oxide.

Our objective was to determine whether hydroxylamine is a possible intermediate in the oxidative conversion of L-arginine to nitric oxide. Vasorelaxation by hydroxylamine is known to be mediated by nitric oxide. The vasorelaxant properties of hydroxylamine were examined using rat aortic rings and an isolated rat lung perfusion model. Hydroxylamine and acetylcholine were equally effective in relaxing norepinephrine-contracted intact aortic rings, whereas only hydroxylamine relaxed aortic rings with endothelium removed. This endothelium-independent vasorelaxation by hydroxylamine indicated that the hydroxylamine-converting enzyme is not localized solely within endothelial cells. Catalase, an enzyme known to oxidize hydroxylamine to nitric oxide, was present in homogenates of intact and endothelium-denuded rings. Cyanamide, another catalase substrate and a known precursor of nitroxyl (HNO), was not a vasorelaxant of aortic rings or of isolated, hypoxia-constricted lungs. These results suggest that free nitroxyl is not an intermediate in the oxidation of hydroxylamine to nitric oxide. An overall pathway for the oxidative conversion of L-arginine through an hydroxylamine intermediate to nitric oxide is proposed.

Acetylcholine↗

PubMed1989

Converting enzyme inhibition in chronic renal failure.

Ten patients with chronic renal failure whose hypertension was controlled with triple drug therapy consisting of propranolol-hydralazine-furosemide were switched to the angiotensin-converting enzyme (ACE) inhibitor captopril for a period of 12 months. Control of hypertension was similar with both antihypertensive regimens. Clearance of inulin and of paraaminohippuric acid increased during the first 3 months of captopril therapy and remained stable thereafter. Moreover, the decline in the reciprocal of serum creatinine over time observed during triple drug therapy was arrested during therapy with the ACE inhibitor. If the salutary effects of captopril are sustained, the results obtained in the current studies would suggest that control of hypertension by ACE inhibition may be effective in slowing progression of renal failure. Future studies to answer this important question are necessary.

Adult↗

PubMed1989

Renal injury in DOCA-salt hypertensive C5-sufficient and C5-deficient mice.

We induced hypertension by uninephrectomy and treatment with desoxycorticosterone (DOCA) and 1% NaCl in the drinking water in congenic mice that differ in the single gene locus responsible for the presence or absence of the complement component C5 and compared them to uninephrectomized normotensive (no DOCA-NaCl) mice. In contrast to C5-sufficient (C5S) mice. C5-deficient (C5D) mice can neither generate C5a nor assemble C5b-9. After four weeks of treatment, DOCA-C5S and -C5D mice developed similar degrees of hypertension; mice receiving no DOCA remained normotensive. Only hypertensive mice developed glomerular injury. Hypertensive DOCA-C5D mice developed more glomerular capillary loop dilatation and larger glomerular capillary tuft volumes than DOCA-C5S mice (1.0 +/- 0.1 vs. 0.7 +/- 0.03 X 10(6) microns 3, respectively, P less than 0.05). However, DOCA-C5S mice, compared to DOCA-C5D mice, had significantly more glomerular cell proliferation (64.5 +/- 2 vs. 42 +/- 3 nuclei/glomerulus), cell necrosis (injury score 22 +/- 1 vs. 17 +/- 1), extracapillary proliferation (26 +/- 4 vs. 2.5 +/- 2% of glomeruli) and proteinuria (5.9 +/- 0.8 vs. 3.7 +/- 0.5 mg/24 hr; all P less than 0.05). By immunofluorescence microscopy both DOCA-C5S and -C5D had mesangial C3 deposits but only DOCA-C5S mice had C9 deposits. After 16 weeks of DOCA-NaCl C5S mice, in comparison to C5D mice, had more severe glomerulosclerosis (injury score 50 +/- 6 vs. 12 +/- 4), proteinuria (16.6 +/- 0.1 vs. 9 +/- 0.1 mg/24 hr), and renal insufficiency (serum creatinine 0.25 vs. 0.15 mg/dl), all P less than 0.05. These changes occurred despite levels of hypertension that were similar in DOCA-NaCl C5S and C5D throughout the whole study period. We conclude that C5a and/or C5b-9 may play an important role in hypertensive glomerular injury. Moreover, these studies demonstrate that differences in host responses may determine target organ susceptibility to similar injurious mechanisms.

Animals↗

PubMed1989

Possible mechanism for the renoprotective effect of angiotensin converting enzyme inhibitors.

Hypertension is an important risk factor in the progression of renal failure, particularly in patients with pre-existing glomerulopathies such as diabetes and chronic glomerulonephritis. The mechanisms involved in hypertensive glomerular injury are currently unclear and cannot be studied in humans because of the constraints of human experimentation. However, recent animal studies have elucidated mechanisms which may explain the variable relationship between systemic hypertension and glomerular injury. Experimentally, at similar levels of systemic hypertension, glomerular injury only develops when preglomerular resistances are ineffective, thus allowing the development of glomerular hypertension. The mechanisms by which the haemodynamic stress of elevated intracapillary pressures and flows lead to progressive glomerular damage are at present unknown. Endothelial cell injury, increased mesangial traffic and/or trapping of macromolecules and epithelial cell injury appear to occur early, followed by in situ inflammatory and microthrombotic mechanisms. The intrarenal renin-angiotensin system appears to play an important role in the pathogenesis of progressive glomerular injury. Haemodynamically, angiotensin II (Ang II) has a relatively greater vasoconstrictive effect on efferent than on afferent arterioles. In addition, Ang II decreases the glomerular ultrafiltration coefficient. These combined effects result in increased intraglomerular capillary pressures. Angiotensin II increases the uptake and decreases the egress of circulating macromolecules in the glomerular mesangium and fosters mesangial cell mitogenesis. Thus, inhibition of Ang II generation may explain why angiotensin converting enzyme (ACE) inhibitors may be effective in arresting or slowing the progression of renal failure in experimental animals and in man.

Angiotensin II↗

PubMed1989

Effects of antihypertensive agents on endothelium-dependent and endothelium-independent relaxations.

1. Antihypertensive agents normalize blood pressure and restore depressed endothelium-dependent relaxations in experimental models of hypertension, but little is known regarding whether antihypertensive agents themselves can directly modulate responses to agonists of endothelium-dependent or independent relaxations, or contractions. 2. Normal rats were treated with either tap water, captopril, hydralazine or enalapril in their drinking water for 2 weeks, following which endothelium-dependent and endothelium-independent relaxations were tested with acetylcholine and sodium nitroprusside, respectively, in aortic rings suspended in organ chambers. 3. All antihypertensive agents caused slight but similar potentiation of sodium nitroprusside-induced relaxations. However, their effects on acetylcholine-induced relaxations were quite different: captopril had a marked potentiating effect, hydrazaline a slight potentiating effect, and enalapril had no significant effect on these relaxations. 4. The relaxations induced by acetylcholine and potentiated by captopril were not altered when indomethacin was included in the tissue bath. However, pyrogallol, an inhibitor of endothelium-derived relaxing factor (EDRF), markedly inhibited these relaxations suggesting that captopril's effect may involve EDRF. 5. SQ 14,534, a stereoisomer of captopril which is 100 fold less potent in inhibiting angiotensin converting enzyme, also significantly enhanced acetylcholine induced relaxations. Thus the effects of both captopril and SQ 14,534 upon EDRF appear independent of the effects of these compounds on the angiotensin converting enzyme. 6. We conclude that certain antihypertensive agents may modulate endothelium-dependent relaxations in response to agonists, and that these properties may be of therapeutic importance in cardiovascular diseases.

Acetylcholine↗

PubMed1989

The pathobiology of the terminal complement complexes.

C5b and the other late-acting complement components can assemble the two terminal complexes (TCC) C5b-9 and SC5b-9. In addition to the lytic effects of C5b-9 it has been demonstrated that sublytic amounts of C5b-8 or C5b-9 can stimulate several important cellular activities. These effects may be important to explain the role of C5b-9 in the production and progression of several pathological conditions that has been demonstrated in experimental models of disease. With the help of antibodies that specifically recognize C9 neoantigens, deposits of TCC have been identified in human tissues, not only in immunological diseases but also in certain nonimmunological diseases. In the latter it has been shown that often there is no concordance between deposits of TCC and those of immunoglobulins and C3. Methods for measuring SC5b-9 in biological fluids have also been developed. Normal plasma was found to have low levels of SC5b-9. Increased plasma levels of SC5b-9 have been observed during the active phase of SLE nephritis, in certain infections and during cardiopulmonary bypass. Increased levels were also found in the cerebrospinal fluid of patients with inflammatory diseases of the central nervous system and in the synovial fluid of patients with rheumatoid arthritis. Autoantibodies to C9 neoantigens in plasma of certain patients with autoimmune, infectious or neoplastic diseases have recently been recognized. Additional work is needed to better delineate the potential usefulness of these findings for diagnosis and evaluation of disease activity.

Adult↗

PubMed1989

Role of platelet activating factor in endotoxemic acute renal failure in the male rat.

We have developed a model of endotoxemic acute renal failure in the anesthetized male rat in which acute endotoxin infusion induces renal vasoconstriction and decreased glomerular filtration rate (GFR) in the absence of systemic hypotension. Because increased levels of platelet activating factor (PAF) have been observed in experimental models of endotoxemia, we pretreated rats with PAF receptor antagonist BN 52021 or SRI 63-675 before administering endotoxin. Compared with treatment with vehicle, treatment with BN 52021 led to significant preservation of RBF, GFR, and urine flow rate. Pretreatment with SRI 63-675 resulted in significant improvement in RBF while completely preventing the fall in GFR and urine flow rate. Intrarenal artery infusion of exogenous PAF (30 ng/kg/min) resulted in renal vasoconstriction, decreased GFR, and oliguria. These effects were also prevented by pretreatment with SRI 63-675. Thus, the adverse renal hemodynamic effects of endotoxemia were blunted or prevented by pretreatment with PAF receptor antagonists. We conclude that endogenously produced PAF is an important mediator of endotoxemic acute renal failure.

Acute Kidney Injury↗

PubMed1988

Mechanisms of hypertensive glomerular injury.

Systemic hypertension complicates the course of most patients with chronic renal failure and accelerates the progression of experimental and clinical glomerular disease. Based on recent experimental studies, it is suggested that at similar levels of systemic hypertension, glomerular injury only develops when pre-glomerular resistances are ineffective, thus allowing the development of glomerular hypertension. The mechanisms by which the hemodynamic stress of elevated intracapillary flows and pressures leads to progressive glomerular damage, particularly to the development of focal glomerulosclerosis is currently unknown. Endothelial cell injury, increased mesangial traffic or trapping of macromolecules and epithelial cell injury, or a combination, appear to occur early, followed by in situ inflammatory and microthrombotic mechanisms. This may explain why various therapeutic approaches, whether dietary or pharmacologic, can have salutory effects despite their diverse mechanisms of action.

Animals↗

PubMed1988

Chronic amphotericin B nephrotoxicity in the rat, protective effect of prophylactic salt loading.

Amphotericin B (AMPHO) is the most effective and widely used antifungal agent for the treatment of systemic fungal disease in man. Its use is frequently limited by the development of nephrotoxicity, including renal vasoconstriction with depressed glomerular filtration rate (GFR) and renal plasma flow (RPF), inability to concentrate the urine, and renal potassium wasting. We investigated the effects of oral NaCl loading during chronic administration of AMPHO, on renal function in the rat. Rats were provided 150 mmol/L NaCl (AMPHO plus NaCl) or tap water (AMPHO plus H2O) as drinking water, 3 days prior to, and during chronic AMPHO (5 mg/kg/d intraperitoneal [IP] for 21 days). At the end of the experimental period, renal functional parameters were determined, including serum creatinine, urinary volume and electrolyte excretion rates, ability to maximally concentrate the urine after water deprivation, and renal hemodynamics. NaCl supplementation prevented the rise in serum creatinine (AMPHO plus NaCl, initial v final, 0.39 +/- 0.03 v 0.40 +/- 0.03 mg/dL [34.6 +/- 2.7 v 35.4 +/- 2.7 mumol/L], P = NS) seen in AMPHO plus H2O (0.34 +/- 0.01 v 0.51 +/- 0.04 mg/dL [30.0 +/- 0.9 v 45.2 +/- 3.5 mumol/L], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗

PubMed1988

Control of hypertension with the angiotensin converting enzyme inhibitor captopril reduces glomerular proteinuria.

Recent experimental and clinical data have suggested that angiotension converting enzyme (ACE) inhibitors may decrease glomerular proteinuria by specific effects on the glomerulus. We studied a group of 15 adult patients with chronic renal failure and proteinuria due to various glomerulopathies. These patients had mild to moderate hypertension which was effectively controlled with conventional antihypertensive therapy. We then treated the patients with captopril, maintaining a similar dietary protein and salt intake. After 6 months of study, proteinuria was reduced significantly without reduction in inulin or para-aminohippurate clearance. This supports the concept that captopril may have salutary effects on the glomerulus, independently of its effect on systemic blood pressure.

Blood Pressure↗