Ibrahim Benter - Profile on Academia.edu (original) (raw)

Papers by Ibrahim Benter

Metabolism of vasoactive peptides by aminopeptidase M

Angiotensin-(1-7) corrects diabetes-induced activation of phosphodiesterase in rat corpus cavernosum

Clinical and Experimental Pharmacology, Aug 31, 2016

Autonomic and Autacoid Pharmacology, Oct 1, 2005

1 The purpose of this study was to examine the effect of inhibition of the formation of cytochrom... more 1 The purpose of this study was to examine the effect of inhibition of the formation of cytochrome P450 metabolites of arachidonic acid with 1-aminobenzotriazole (ABT) on the development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with nitric oxide synthesis inhibitor L-NAME (SHR-L-NAME). 2 Administration of L-NAME in drinking water (80 mg l )1 ) to SHR for 3 weeks significantly elevated mean arterial blood pressure (MABP) (223 ± 4 mmHg) as compared to SHR controls drinking regular water (165 ± 3 mmHg). The administration of ABT (50 mg kg )1 i.p. alt diem) for 6 days significantly attenuated elevation of blood pressure in SHR-L-NAME (204 ± 4 mmHg). 3 L-NAME-induced increase in urine volume and protein was significantly lower in ABTtreated animals. 4 The impaired vascular responsiveness to noradrenaline and isoprenaline in the perfused mesenteric vascular bed of SHR-L-NAME-treated animals was significantly improved by ABT treatment. 5 Morphological studies of the kidneys and hearts showed that treatment with ABT minimized the extensive arterial fibrinoid necrosis, arterial thrombosis, significant narrowing of arterial lumen with marked arterial hyperplastic arterial changes that were observed in vehicle treated SHR-L-NAME. 6 In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischaemia was significantly better in ABT-treated SHR-L-NAME. 7 These results suggest that in hypertensive individuals with endothelial dysfunction and chronic NO deficiency, inhibitors of 20-HETE synthesis may be able to attenuate development of high blood pressure and end-organ damage.

Inhibition of calcium/calmodulin-dependent protein kinase II normalizes diabetes-induced abnormal vascular reactivity in the rat perfused mesenteric vascular bed

Autonomic and Autacoid Pharmacology, Feb 1, 2003

Summary 1 Calcium/calmodulin‐dependent protein kinase II (CaMKII) has an important function in me... more Summary 1 Calcium/calmodulin‐dependent protein kinase II (CaMKII) has an important function in mediating insulin release but its role in the development of diabetes‐induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of KN‐93 (5 mg kg−1alt diem for 4 weeks), an inhibitor of CaMKII, to modulate the altered vasoreactivity of the perfused mesenteric bed to common vasoconstrictors and vasodilators in streptozotocin (STZ)‐induced diabetes. 3 The vasoconstrictor responses induced by noradrenaline (NE), endothelin‐1 (ET‐1), and angiotensin II (Ang II), were significantly increased whereas, vasodilator responses to carbachol and histamine were significantly reduced in the perfused mesenteric bed of the STZ‐diabetic rats as compared with non‐diabetic controls. 4 Inhibition of CaMKII by KN‐93 treatment did not affect blood glucose levels but produced a significant normalization of the altered agonist‐induced vasoconstrictor and vasodilator responses. KN‐93 did not affect agonist‐induced responses in control animals. In addition, KN‐93 significantly reduced weight loss in diabetic rats. 5 The present data suggest that CaMKII is an essential mediator in the development of diabetic vascular dysfunction and may also play an important role in signalling pathways leading to weight loss during diabetes.

Springer eBooks, Dec 2, 2013

Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hall mark of heart failure (HF). It ca... more Cardiac remodeling (cardiac hypertrophy and fibrosis) is a hall mark of heart failure (HF). It can be induced by the abnormal elevation of several endogenous factors including angiotensin II (Ang II), which is generated from its precursor angiotensin I (Ang I) by the action of angiotensin converting enzyme (ACE). The inhibition of this enzyme or the blockade of the Ang II receptors demonstrated a high clinical value against the progression of HF. Ang I and Ang II may also be converted into angiotensin 1-7 (Ang 1-7) and angiotensin 1-9 (Ang 1-9) respectively by the action of angiotensin converting enzyme-2 (ACE2). Both This article is protected by copyright. All rights reserved. derivatives demonstrated a promising anti-cardiac remodeling activity especially against the detrimental effects of Ang II. This manuscript thoroughly reviews the available in-vitro and in-vivo data on Ang 1-7 and Ang 1-9 in the context of the treatment of HF, and discusses the associated molecular mechanisms and the trials to clinically utilize Ang 1-7 mimetics for the treatment of that disease.

Cell Biochemistry and Function, 2007

The present study was designed to see if acute local inhibition of Ras-GTPase before or after isc... more The present study was designed to see if acute local inhibition of Ras-GTPase before or after ischemia (during perfusion) would produce protection against ischemia and reperfusion (I/R)-induced cardiac dysfunction. The effect of glibenclamide, an inhibitor of cardiac mitochondrial ATP-sensitive potassium (mitoK ATP ) channels, on Ras-GTPase-mediated cardioprotection was also studied. A 40 min episode of global ischemia followed by a 30 min reperfusion in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (P max ) and left ventricular end-diastolic pressure (LVEDP). Perfusion with Ras-GTPase inhibitor FPT III before I/R [FPT(pre)], significantly enhanced cardiac recovery in terms of left ventricular contractility. P max was significantly higher at the end of 30 min reperfusion in FPT(pre)-treated hearts compared to pre-conditioned hearts. However, the degree of improvement in left ventricular contractility was significantly less when FPT III was given only after ischemia during reperfusion [FPT(post)]. Combination treatment with FPT III and glibenclamide before I/R resulted in significant reduction of FPT III-mediated cardioprotection. These data suggest that activation of Ras-GTPase signaling pathways during ischemia are critical in the development of left ventricular dysfunction and that opening of mitoK ATP channels, at least in part, contributes to cardioprotection produced by Ras-GTPase inhibition.

Molecular Pharmaceutics, Mar 29, 2016

The effects of naked polyamidoamine (PAMAM) dendrimers on Renin-Angiotensin-System (RAS) signalin... more The effects of naked polyamidoamine (PAMAM) dendrimers on Renin-Angiotensin-System (RAS) signaling via Angiotensin (Ang) II-mediated transactivation of the epidermal growth factor receptor (EGFR) and the closely related family member, ErbB2 (HER2) were investigated. In primary aortic vascular smooth muscle cells, a cationic generation (G) 5 PAMAM dendrimer dose-and time-dependently inhibited Ang II-mediated transactivation of EGFR and ErbB2 as well as their downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2). Inhibition even occurred at non-cytotoxic concentrations, at short (1h) exposure times and was dependent on dendrimer generation (G7>G6>G5>G4) and surface group chemistry (amino-> carboxyl-> hydroxyl-). Mechanistically, cationic G5 PAMAM dendrimer inhibited Ang II-mediated transactivation of EGFR and ErbB2 via inhibition of the non-receptor tyrosine kinase, Src. This novel, early-onset, intrinsic biological action of PAMAM dendrimers as inhibitors of Ang II//Src/EGFR-ErbB2/ERK1/2 signaling pathway could have important toxicological and pharmacological implications.

Journal of diabetes research, 2014

Autonomic and Autacoid Pharmacology, Apr 1, 2005

1 G-protein-coupled receptor signalling, including transactivation of receptor tyrosine kinases (... more 1 G-protein-coupled receptor signalling, including transactivation of receptor tyrosine kinases (RTKs), has been implicated in vascular pathology. However, the role of specific RTKs in the development of diabetes-induced cardiovascular complications is not known. 2 We investigated the ability of a chronic administration of genistein, a broad-spectrum inhibitor of tyrosine kinases (TKs), AG1478, a specific inhibitor of epidermal growth factor receptor (EGFR) TK activity, and AG825, a specific inhibitor of Erb2, to modulate the altered vasoreactivity of isolated carotid artery ring segments to common vasoconstrictors and vasodilators in streptozotocin (STZ)-induced diabetes. 3 In diabetic carotid artery, the vasoconstrictor responses induced by noradrenaline (NE), endothelin-1 (ET-1), and angiotensin II (Ang II), were significantly increased whereas vasodilator responses to carbachol and histamine were significantly reduced. Inhibition of TKs, EGFR or Erb2 pathway did not affect the body weight or agonist-induced vasoconstrictor and vasodilator responses in the non-diabetic control animals. However, inhibition of TKs by genistein, EGFR TK by AG1478 or Erb2 by AG825 treatment produced a significant normalization of the altered agonist-induced vasoconstrictor responses without affecting blood glucose levels. Treatment with diadzein, an inactive analogue of genistein, did not affect the vasoconstrictor and vasodilator responses in the diabetic animals. 4 Treatment with genistein, AG1478 or AG825 resulted in a significant improvement in diabetes-induced impairment in endothelium-dependent relaxation to carbachol and histamine. 5 These data suggest that activation of TK-mediated pathways, including EGFR TK signalling and Erb2 pathway, are involved in the development of diabetic vascular dysfunction in the carotid artery.

Advanced Drug Delivery Reviews, Nov 1, 2021

Drug delivery systems or vectors are usually needed to improve the bioavailability and effectiven... more Drug delivery systems or vectors are usually needed to improve the bioavailability and effectiveness of a drug through improving its pharmacokinetics/pharmacodynamics at an organ, tissue or cellular level. However, emerging technologies with sensitive readouts as well as a greater understanding of physiological/biological systems have revealed that polymeric drug delivery systems are not biologically inert but can have innate or intrinsic biological actions. In this article, we review the emerging multiple innate biological/toxicological properties of naked polyamidoamine (PAMAM) dendrimer delivery systems in the absence of any drug cargo and discuss their correlation with the defined physicochemical properties of PAMAMs in terms of molecular size (generation), architecture, surface charge and chemistry. Further, we assess whether any of the reported intrinsic biological actions of PAMAMs such as their antimicrobial activity or their ability to sequester glucose and modulate key protein interactions or cell signaling pathways, can be exploited clinically such as in the treatment of diabetes and its complications.

Toxicogenomics of non-viral drug delivery systems for RNAi: Potential impact on siRNA-mediated gene silencing activity and specificity

Advanced Drug Delivery Reviews, Mar 1, 2007

RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene ... more RNA interference (RNAi) is an evolutionary conserved cellular process for the regulation of gene expression. In mammalian cells, RNAi is induced via short (21-23 nt) duplexes of RNA, termed small interfering RNA (siRNA), that can elicit highly sequence-specific gene silencing. However, synthetic siRNA duplexes are polyanionic macromolecules that do not readily enter cells and typically require the use of a delivery vector for effective gene silencing in vitro and in vivo. Choice of delivery system is usually made on its ability to enhance cellular uptake of siRNA. However, recent gene expression profiling (toxicogenomics) studies have shown that separate from their effects on cellular uptake, delivery systems can also elicit wide ranging gene changes in target cells that may impact on the &amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;off-target&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; effects of siRNA. Furthermore, if delivery systems also alter the expression of genes targeted for silencing, then siRNA activity may be compromised or enhanced depending on whether the target gene is up-regulated or down-regulated respectively. Citing recent examples from the literature, this article therefore reviews the toxicogenomics of non-viral delivery systems and highlights the importance of understanding the genomic signature of siRNA delivery reagents in terms of their impact on gene silencing activity and specificity. Such information will be essential in the selection of optimally acting siRNA-delivery system combinations for the many applications of RNA interference.

Vascular Pharmacology, Oct 1, 2008

We studied the effect an inhibitor of Ras-GTPase (FPTIII, 1.5 mg/kg alt diem for 4 weeks) on mean... more We studied the effect an inhibitor of Ras-GTPase (FPTIII, 1.5 mg/kg alt diem for 4 weeks) on mean arterial pressure (MAP), urine protein, vascular reactivity and cardiac function in streptozotocin (STZ)-induced diabetes in control normotensive (WKY) and spontaneously hypertensive rats (SHR). The increased urinary protein in STZ-treated WKY (D-WKY) and STZ-treated SHR (D-SHR) were significantly lower in FPTIII treated D-WKY and D-SHR. The abnormal vascular responsiveness to endothelin-1, angiotensin II, carbachol or histamine in isolated carotid artery from D-WKY and D-SHR was improved by chronic treatment with FPTIII. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly improved in FPTIII treated D-WKY and D-SHR. These results show that treatment with FPTIII can attenuate development of abnormal vascular reactivity and renal/cardiac dysfunction during simultaneous occurrence of hypertension and diabetes.

Role of epidermal growth factor receptor (EGFR) in corneal remodelling in diabetes

Acta Ophthalmologica, Dec 1, 2009

.Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on ... more .Purpose: This study examined the role of epidermal growth factor receptor (EGFR) signalling on the organization and remodelling of collagen fibrils (CFs) and proteoglycans (PGs) in the stroma of diabetic rat cornea.Methods: Diabetes was induced in female Wistar rats (n = 5) by streptozotocin (STZ) injection (55 mg/kg). Treatment with a selective inhibitor of EGFR tyrosine kinase, AG1478, was started on the same day as the induction of diabetes and administered every other day for 4 weeks. Corneas were fixed in 4% paraformaldehyde at 4 ° to allow for analysis of CF diameters and in 2.5% glutaraldehyde in sodium acetate buffer containing cuprolinic blue to enable the study of PG distribution. AnalySIS soft imaging software was used to analyse CFs and PGs.Results: Epithelial thickness, and median diameter and area fraction of CF in corneal stroma were decreased in diabetic rat cornea compared with normal cornea (p < 0.001), whereas the median PG area and area fractions were significantly increased (p < 0.001). Treatment with AG1478, although it had no action on normal cornea, prevented these diameter and area fraction changes in CFs and PGs. The cornea of AG1478‐treated diabetic rats showed a slight increase in CF diameter and area fraction and a decreased number density.Conclusions: These data show that the distribution of corneal stroma CFs and PGs was altered after 4 weeks of diabetes and that, furthermore, treatment with an EGFR signalling inhibitor normalized these abnormalities. The data suggest that EGFR plays an important role in the development of diabetes‐induced corneal remodelling.

Pressor and Reflex Sensitivity Is Altered in Spontaneously Hypertensive Rats Treated With Angiotensin-(1-7)

Hypertension, Dec 1, 1995

We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotens... more We have suggested that angiotensin-(1-7) [Ang-(1-7)] may oppose the pressor activity of angiotensin II (Ang II). This hypothesis was supported by the fact that long-term intravenous infusion of Ang-(1-7) transiently lowers blood pressure in spontaneously hypertensive rats (SHR). We now investigated whether the pressor sensitivity to bolus injections of either phenylephrine (PE) or Ang II was altered on day 12 of an Ang-(1-7) infusion when blood pressure in the SHR had returned to hypertensive levels. SHR (n=10) and WKY rats (n=8) were given Ang-(1-7) intravenously via osmotic minipumps at a dose of 24 μg/kg per hour for 2 weeks. On day 12 of the infusion, mean arterial pressure and heart rate in halothane-anesthetized rats were similar in Ang-(1-7)–treated SHR (142±6 mm Hg; 388±9 beats per minute) and those infused with vehicle (146±5 mm Hg; 392±13 beats per minute). Pressor responsiveness to PE in Ang-(1-7)–treated SHR was 22% less at a dose of 10 μg, while pressor responses to Ang II decreased by 20% and 25% at doses of 0.05 and 0.1 μg, respectively, compared with the vehicle-treated SHR ( P <.05). There were no effects of the Ang-(1-7) infusion on pressor responses to Ang II or PE in WKY rats. In the SHR infused with Ang-(1-7), there was a 35% improvement in sensitivity of the reflex control of heart rate to levels not different from those in the untreated WKY rats (slope of the change in pulse interval versus the change in pressure increased from 0.34±0.03 to 0.46±0.01 ms/mm Hg). These data suggest that Ang-(1-7) may selectively activate antihypertensive mechanisms at the level of the vascular wall or the baroreflex.

Journal of Clinical Investigation, Dec 3, 2007

Sequence-specific gene silencing using small interfering RNA (siRNA) is a Nobel prize-winning tec... more Sequence-specific gene silencing using small interfering RNA (siRNA) is a Nobel prize-winning technology that is now being evaluated in clinical trials as a potentially novel therapeutic strategy. This article provides an overview of the major pharmaceutical challenges facing siRNA therapeutics, focusing on the delivery strategies for synthetic siRNA duplexes in vivo, as this remains one of the most important issues to be resolved. This article also highlights the importance of understanding the genocompatibility/toxicogenomics of siRNA delivery reagents in terms of their impact on gene-silencing activity and specificity. Collectively, this information is essential for the selection of optimally acting siRNA delivery system combinations for the many proposed applications of RNA interference.

International Journal of Pharmaceutics, May 1, 2013

Polyamidoamine (PAMAM) dendrimers are cationic branch-like macromolecules that may serve as drug ... more Polyamidoamine (PAMAM) dendrimers are cationic branch-like macromolecules that may serve as drug delivery systems for gene-based therapies such as RNA interference. For their safe use in the clinic, they should ideally only enhance drug delivery to target tissues and exhibit no adverse effects. However, little is known about their toxicological profiles in terms of their interactions with cellular signal transduction pathways such as the epidermal growth factor receptor (EGFR). The EGFR is an important signaling cascade that regulates cell growth, differentiation, migration, survival and apoptosis. Here, we investigated the impact of naked, unmodified Superfect (SF), a commercially available generation 6 PAMAM dendrimer, on the epidermal growth factor receptor (EGFR) tyrosine kinase-extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway in human embryonic kidney (HEK 293) cells. At concentrations routinely used for transfection, SF exhibited time and dose-dependent stimulation of EGFR and ERK1/2 phosphorylation whereas AG1478, a selective EGFR tyrosine kinase antagonist, inhibited EGFR-ERK1/2 signaling. SF-induced phosphorylation of EGFR for 1 h was partly reversible upon removal of the dendrimer and examination of cells 24 later. Co-treatment of SF with epidermal growth factor (EGF) ligand resulted in greater EGFR stimulation than either agent alone implying that the stimulatory effects of SF and the ligand are synergistic. Dendrimer-induced stimulation of EGFR-ERK1/2 signaling could be attenuated by the antioxidants apocynin, catalase and tempol implying that an oxidative stress dependent mechanism was involved. These results show for the first time that PAMAM dendrimers, aside from their ability to improve drug delivery, can modulate the important EGFR-ERK1/2 cellular signal transduction pathway a novel finding that may have a bearing on their safe application as drug delivery systems.

Cell Biochemistry and Function, 2005

Diabetes mellitus is associated with vascular complications, including an impairment of vascular ... more Diabetes mellitus is associated with vascular complications, including an impairment of vascular function and alterations in the reactivity of blood vessels to vasoactive agents. Phosphatidylinositol 3-kinase (PI3K) is a signalling enzyme that plays key roles in vascular growth, proliferation and cellular apoptosis and is implicated in modulating vascular smooth muscle contractility. The aim of this study was to determine whether PI3K plays a role in development of diabetes-induced altered vascular reactivity to selected vasoconstrictors and vasodilators. The effect of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a selective PI3K inhibitor, on isolated segments of carotid arteries from streptozotocin (STZ)-diabetic rats was investigated. Ring segments of the isolated carotid arteries were mounted in organ baths to measure changes in isometric tension. Our results showed that STZ treatment produced an increase in the vasoconstrictor response to norepinephrine (NE), angiotensin II (Ang II) and endothelin-1 (ET-1) and an attenuated vasodilator response to carbachol and histamine in the isolated carotid arteries from STZ-diabetic animals. Diabetes-induced impaired vascular responsiveness to the vasoactive agonists was prevented by chronic inhibition of PI3K by LY294002 even though blood glucose levels remained high. This is the first study to show that selective inhibition of PI3K can attenuate the development of diabetes-induced abnormal vascular reactivity in the isolated carotid arteries of diabetic rats.

Peptides, Apr 1, 2017

Angiotensin-(1-7) ] exhibits blood pressure lowering actions, inhibits cell growth, and reduces t... more Angiotensin-(1-7) ] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT 1 receptor axis. Since the vascular actions of Ang-(1-7) and the associated receptor/signaling pathways vary in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1-7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (3 × 10 -7 M). Ang-(1-7) induced vasodilation of the rat renal artery with an ED 50 of 3 ± 1 nM and a maximal response of 42 ± 5% (N = 10). The two antagonists (10 -5 M each) for the AT 7 /Mas receptor (MasR) [D-Pro 7 ]-Ang-(1-7) and [D-Ala 7 ]-Ang-(1-7) significantly reduced the maximal response to 12 ± 1% and 18 ± 3%, respectively. Surprisingly, the AT 2 R receptor antagonist PD123319, the AT 1 R antagonist losartan and B 2 R antagonist HOE140 (10 -6 M each) also significantly reduced Ang-(1-7)-induced relaxation to 12 ± 2%, 22 ± 3% and 14 ± 7%, respectively. Removal of the endothelium or addition of the soluble guanylate cyclase (sGC) inhibitor ODQ (10 -5 M) essentially abolished the vasorelaxant response to Ang-(1-7) (10 ± 4% and 10 ± 2%, P < 0.05). Finally, the NOS inhibitor LNAME (10 -4 M) reduced the response to 13 ± 2% (p < 0.05), but the cyclooxygenase inhibitor indomethacin failed to block the Ang-(1-7) response. We conclude that Ang-(1-7) exhibits potent vasorelaxant actions in the isolated renal artery that are dependent on an intact endothelium and the apparent stimulation of a NO-sGC pathway. Moreover, Ang-(1-7)-dependent vasorelaxation was sensitive to antagonists against the AT 7 /Mas, AT 1 , AT 2 and B 2 receptor subtypes.

Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats

American Journal of Physiology-heart and Circulatory Physiology, Jul 1, 1995

Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiote... more Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiotensin II (ANG II) prompted an investigation of the effects of the heptapeptide on the maintenance of elevated blood pressure in spontaneously hypertensive rats (SHR). ANG-(1-7) (24 micrograms.kg-1.h-1) was infused into the jugular vein of 13-wk-old SHR (n = 64), Wistar-Kyoto (WKY, n = 50), and Sprague-Dawley (SD, n = 18) rats for 2 wk, with the use of osmotic minipumps. Blood pressure, fluid and electrolyte balance, plasma vasopressin, and urinary excretion of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured at days 2, 7, and 12 of the infusion. In SHR, ANG-(1-7) caused a sustained and significant reduction in plasma vasopressin concentration that was associated with an increase in urinary prostaglandin E2 and 6-keto-PGF1 alpha excretion at day 2 after the commencement of the infusion. These changes were accompanied by diuresis and natriuresis during the first 3 days of infusion in SHR but not in WKY or SD rats. Direct measurements of arterial pressure confirmed the lowering effect of ANG-(1-7) on systolic pressure of SHR on day 2 of treatment with a restoration of the pressure by days 7 and 12. These findings, along with our previous demonstration that ANG-(1-7) is an active depressor peptide in the intact animal, suggest that ANG-(1-7) may play a significant role as a vasodepressor system opposing the hemodynamic actions of ANG II in this genetic form of experimental hypertension.