Abstract P186: Selective ET A Receptor Antagonism versus Dual ET A /ET B Receptor Blockade for Preventing Angiogenesis Inhibitor-induced Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Katrina M Mirabito Colafella ◽  
Richard van Veghel ◽  
Renè de Vries ◽  
Jorie Versmissen ◽  
Anton H van den Meiracker ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pressor Response ◽  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
Receptor Blockade ◽  
Sunitinib Treatment ◽  
Vegf Inhibitor ◽  
Induced Hypertension ◽  
Vehicle Treatment ◽  
Stimulation Of

Angiogenesis inhibitors are a mainstay treatment for cancer. While effective in preventing tumor growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin-1 (ET-1) upregulation. ET-1 via stimulation of the ET A receptor causes pro-hypertensive effects whereas stimulation of the ET B receptor can elicit both pro- or anti-hypertensive effects. In the present study, we hypothesized that selective ET A receptor blockade versus dual ET A /ET B blockade provides better cardiovascular protection from angiogenesis inhibitor-induced hypertension. Male WKY rats were treated with vehicle, sunitinib (VEGF inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ET A/B receptor antagonist; 30 mg/kg/day) or sitaxentan (ET A receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry at baseline and days 1-6 of treatment. Vasoreactivity to acetylcholine (ACh) and ET-1 was assessed in iliac vessels. Compared to vehicle treatment, sunitinib treatment caused a rapid and sustained increase in MAP (1±1 versus 23±2 mmHg on day 6 of treatment, respectively, P<0.001). Co-treatment with macitentan blunted the pressor response to sunitinib, such that on day 6 of treatment the increase in MAP was 7±4 mmHg (P<0.01 versus sunitinib-treated). Similar results were observed for co-treatment with 30 mg/kg/day of sitaxentan. Conversely, co-treatment with 100 mg/kg/day sitaxentan, which has been shown to induce a depressor response in normotensive Wistar rats, completely abolished sunitinib-induced hypertension, with MAP actually decreasing before returning to near baseline level (-1±1 mmHg on day 6 of treatment, P<0.001 versus sunitinib-treated). Compared to vehicle treatment, ET B receptor stimulation yielded a constrictor response after 8 days of sunitinib treatment, while the response to ACh was unaltered. Both macitentan and sitaxentan reversed the constrictor ET B receptor response. Our results support a key role for the ET-1 system in the development of sunitinib-induced hypertension and suggest that selective ET A receptor blockade is sufficient to block this effect.

Selective ETA vs. dual ETA/B receptor blockade for the prevention of sunitinib-induced hypertension and albuminuria in WKY rats

2019 ◽  
Vol 116 (10) ◽  
pp. 1779-1790 ◽  
Author(s):  
Katrina M Mirabito Colafella ◽  
Karla B Neves ◽  
Augusto C Montezano ◽  
Ingrid M Garrelds ◽  
Richard van Veghel ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Renal Injury ◽  
Angiogenesis Inhibitor ◽  
Receptor Blockade ◽  
Receptor Antagonism ◽  
Sunitinib Treatment ◽  
Wky Rats ◽  
Induced Hypertension ◽  
Eta Receptor ◽  
Stimulation Of

Abstract Aims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or anti-hypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria. Methods and results Male Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of ∼25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan. Conclusions Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury.

Abstract 05: Cyclooxygenase-2 Inhibition As A New Tool To Combat Angiogenesis Inhibitor-induced Hypertension And Renal Toxicity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daan C van Dorst ◽  
Katrina M Mirabito Colafella ◽  
Leni van Doorn ◽  
Richard van Veghel ◽  
Ingrid M Garrelds ◽  
...  
Keyword(s):  
Vascular Function ◽  
Renal Toxicity ◽  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
High Dose ◽  
Angiogenesis Inhibition ◽  
Dose Aspirin ◽  
Induced Hypertension ◽  
Cox 2 ◽  
Cox 1

Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI 2 ) and thromboxane (TXA 2 ). Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10mg/kg/day), a PGI 2 analogue (iloprost 100 μg/kg/day), or a dual TXA 2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n=7-8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. SU induced a rapid increase in MAP (16±2 vs. 3±1 mmHg after vehicle on day 6, P<0.001), which was blunted by celecoxib (10±2 mmHg on day 6, P=0.06 versus SU), temporarily attenuated by iloprost (on treatment days 1-2) and unaffected by picotamide. Wire myography demonstrated a trend towards increased vasoconstrictor response to endothelin-1 in iliac arteries after SU, which was prevented by celecoxib (P<0.001). SU increased albuminuria (0.6±0.1 vs. 0.3±0.1 mg/24h after vehicle; P<0.001), and this was prevented by celecoxib only (0.4±0.1 mg/24h, P=0.01 vs. SU). SU increased the PGI 2 /TXA 2 ratio in both plasma (2.7±1.2 vs. 0.6±0.2 after vehicle, P=0.05) and urine (22±2.2 vs. 0.9±0.2 after vehicle, P<0.001). In conclusion, selective COX-2 inhibition combats angiogenesis inhibitor-induced hypertension and renal toxicity. SU paradoxically increases the PGI 2 /TXA 2 ratio, particularly in the kidney. Although this upregulation might initially be protective, it could eventually contribute to renal toxicity, most likely because PGI 2 exerts deleterious effects in excessive concentrations. Targeting excessive renal PGI 2 production might be another promising strategy to prevent renal toxicity during angiogenesis inhibition.

Arterial baroreceptor and vagal inputs to sympathoexcitatory neurons in rat medulla

1987 ◽  
Vol 252 (4) ◽  
pp. R699-R709 ◽  
Author(s):  
M. K. Sun ◽  
P. G. Guyenet
Keyword(s):  
Receptor Antagonist ◽  
Pressor Response ◽  
Low Frequency ◽  
Single Pulse ◽  
Vagal Afferents ◽  
High Frequency Stimulation ◽  
Dependent Manner ◽  
Frequency Stimulation ◽  
Stimulation Of ◽  
Arterial Baroreceptor

Lumbar sympathetic nerve discharge and unit activity of reticulospinal sympathoexcitatory (SE) neurons located in nucleus paragigantocellularis lateralis (PGCL) were recorded in rats. The sympathoinhibition produced by low-frequency stimulation of vagal afferents was abolished by bilateral microinjections of 20 pmol of bicuculline methiodide (BIC, a GABA-receptor antagonist) into PGCL and was converted into a pressor response by injections of 100 pmol. These BIC injections also inhibited the arterial baroreflex in a dose-dependent manner. In contrast the sympathoexcitation produced by high-frequency stimulation of vagal afferents was selectively blocked by bilateral injections of kynurenic acid (KYN, a Glu-receptor antagonist) into PGCL. Convergence of vagal excitatory, vagal inhibitory, and arterial baroreceptor inputs was detected in all SE neurons recorded. Single-pulse stimulation of vagal afferents produced up to two peaks of excitation of SE neurons, both blocked by iontophoretic applications of KYN and at least one inhibitory period selectively blocked by iontophoresis of BIC. The results emphasize the importance of SE neurons and surrounding area in integrating the brain vasomotor output to spinal preganglionic neurons.

Role of central ANG II receptors in stress-induced cardiovascular and hyperthermic responses in rats

1997 ◽  
Vol 272 (1) ◽  
pp. R26-R33 ◽  
Author(s):  
Y. Saiki ◽  
T. Watanabe ◽  
N. Tan ◽  
M. Matsuzaki ◽  
S. Nakamura
Keyword(s):  
Receptor Antagonist ◽  
Immobilization Stress ◽  
Blood Pressure Response ◽  
Pressor Response ◽  
At1 Receptor ◽  
Plasma Norepinephrine ◽  
Receptor Blockade ◽  
Dependent Manner ◽  
Ang Ii ◽  
Dose Dependent

The present study was carried out using a biotelemetry system to investigate whether central angiotensin II (ANG II) is involved in stress-induced cardiovascular and body temperature responses in rats. Intracerebroventricular injections of the nonselective ANG II-receptor antagonist saralasin and of the ANG II AT1-receptor antagonist losartan attenuated both the heart rate and pressor responses to immobilization stress in a dose-dependent manner. The elevation of plasma norepinephrine and epinephrine induced by immobilization stress was also suppressed by central ANG II-receptor blockade, suggesting a general attenuation of stress-induced sympathetic nervous and adrenomedullary activity by central ANG II-receptor blockade. The hyperthermia induced by immobilization stress was attenuated by central ANG II AT1-receptor blockade in a dose-dependent manner. The effects of central saralasin on the blood pressure response induced by immobilization stress were greater in Wistar-Kyoto rats than in spontaneously hypertensive rats. The present results suggest that central ANG II AT1-receptors are involved in expression of the tachycardia and hyperthermia, as well as the pressor response, induced by immobilization stress.

CATECHOLAMINE ANTAGONISM TO OXYTOCIN-INDUCED MILK-EJECTION

1971 ◽  
Vol 68 (1_Suppla) ◽  
pp. S5-S38 ◽  
Author(s):  
Helmuth Vorherr
Keyword(s):  
Receptor Blockade ◽  
Milk Ejection ◽  
Beta Adrenergic ◽  
Beta Receptor ◽  
Beta Receptors ◽  
Alpha Receptors ◽  
Adrenergic Blockers ◽  
Beta Receptor Blockade ◽  
Second Pain ◽  
Stimulation Of

ABSTRACT In lactating rats and rabbits the mode of antagonism of sympathomimetics, angiotensin or pain toward oxytocin-induced milk-ejection was investigated. In rats intra-arterial (intrafemoral) doses of 0.01–0.02 μg or intravenous (iv) doses of 0.1–0.5 μg of either epinephrine, isoproterenol, norepinephrine, angiotensin or 10 μg of phenylephrine injected simultaneously with, or 30 seconds before an oxytocin dose (10 μU intrafemoral, 300 μU iv) greatly inhibited or suppressed the oxytocin response. A 15 second pain stimulus caused moderate inhibition. With alpha-receptor blockade pain, epinephrine, isoproterenol, norepinephrine, phenylephrine and angiotensin inhibition were, respectively, 70%, 75%, 100%, 40%, 0% and 100%. Under beta-receptor blockade the corresponding values were 14%, 40%, 0%, 70%, 100% and 100%; with simultaneous intrafemoral injections neither catecholamine was inhibitory toward oxytocin. In corresponding rabbit experiments approximately 10-fold higher iv drug dosages were applied and similar results were observed. In both species, combined alpha and beta-receptor blockade nearly eliminated the antagonistic actions of sympathomimetics toward oxytocin, whereas angiotensin inhibition persisted unchanged. The results indicate: 1) Mammary myoepithelial cells contain beta-adrenergic receptors but no alpha-receptors; 2) Inhibition of oxytocin-induced milk-ejection by isoproterenol and phenylephrine is meditated through stimulation of myoepithelial beta-receptors (myoepithelial relaxation) and vascular alpha-receptors (vasoconstriction), respectively; 3) Epinephrine and norepinephrine inhibition of milk-ejection is due to stimulation of vascular alpha-receptors and myoepithelial beta-receptors; 4) Angiotensin effects are unrelated to adrenergic receptor mechanisms; 5) Administration of both alpha and beta-adrenergic blockers is desirable for stabilizing the sensitivity of the oxytocin milk-ejection assay preparation against interference from endogenous or exogenous catecholamines; 6) Other than using adrenergic blockers, pharmacologic doses of oxytocin can correct nursing difficulties in animals and man with hyperfunction of the adrenal-sympathetic system.

Neurotransmission in the medulla mediating insular cortical and lateral hypothalamic sympathetic responses

1998 ◽  
Vol 76 (7-8) ◽  
pp. 737-746 ◽  
Author(s):  
Kenneth S Butcher ◽  
David F Cechetto
Keyword(s):  
Receptor Antagonist ◽  
Sympathetic Nerve ◽  
Pressor Response ◽  
Ventrolateral Medulla ◽  
Bipolar Electrode ◽  
Hypothalamic Area ◽  
Renal Nerve ◽  
Lateral Hypothalamic ◽  
Baseline Activity ◽  
Sympathetic Responses

Previous evidence has shown sympathetic nerve responses to insular cortical (IC) stimulation are mediated by synapses within the lateral hypothalamic area (LHA) and ventrolateral medulla (VLM). The present study was aimed at determining the neurotransmitter(s) and receptor(s) involved at the synapse in the VLM. Twenty male Wistar rats were instrumented for renal nerve, arterial pressure, and heart rate recording. The IC or the LHA was stimulated with a bipolar electrode (200-1000 µA; 2 ms; 0.8 Hz) to elicit sympathetic nerve responses. Antagonists were then pressure-injected into the VLM (300 nL). Bilateral and unilateral kynurenate (25 mM) resulted in 100% block of IC- and LHA-stimulated sympathetic nerve responses. Bilateral injection of the non-NMDA (N-methyl-D-aspartate) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 200 µM) also resulted in up to 100% block of IC and LHA sympathetic responses. In addition, unilateral injections of CNQX were made in two animals, resulting in 100 and 83% block of LHA sympathetic responses. Bilateral injection of the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5; 200µM) did not affect the response to IC or LHA stimulation. Kynurenate, CNQX, and AP5 all resulted in an elevation of baseline sympathetic nerve activity and a pressor response. Kynurenate resulted in a 263 ± 79% increase in baseline activity, while CNQX and AP5 resulted in 83 ± 19% and 91 ± 21% increases, respectively. Bilateral injections of antagonists for GABAA (bicuculline; 0.1 µM), acetylcholine (atropine; 0.1 µM) and catecholaminergic alpha and beta receptors (phentolamine and propranolol: 0.1 µM) had no effect on LHA sympathetic responses. Thus, sympathetic responses originating in the IC and LHA are mediated by a non-NMDA receptors in the VLM, which are likely AMPA receptors.Key words: insular cortex, ventrolateral medulla, glutamate, sympathetic activity.

Abstract 453: Angiogenesis Inhibition-Induced Hypertension and Nephrotoxicity: Not All Antihypertensives are the Same

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Stephanie Lankhorst ◽  
Mariëtte H Kappers ◽  
Joep H Van Esch ◽  
Frank M Smedts ◽  
Stefan Sleijfer ◽  
...  
Keyword(s):  
Ace Inhibitor ◽  
Ace Inhibition ◽  
Cell Swelling ◽  
Histological Evaluation ◽  
High Dose ◽  
Angiogenesis Inhibition ◽  
Vegf Inhibitor ◽  
Renal Histology ◽  
Anti Cancer ◽  
Induced Hypertension

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy inducing hypertension and nephrotoxicity. Here we compared the effects of the endothelin antagonist (ET-R) macitentan (30 mg/kg/day, p.o; n=8), the calcium channel blocker (CCB) amlodipine (3 mg/kg/day, p.o; n=9), or the ACE-inhibitor captopril (3 or 12 mg/kg/day, s.c.; n=9) vs. no treatment (n=14) in sunitinib (26.7 mg/kg/day, p.o)-exposed hypertensive WKY rats. Treatment lasted 8 days; mean arterial pressure (MAP) was monitored telemetrically. At the end of the treatment period, 24-hour urine samples for protein and endothelin-1 (ET-1) measurements, and blood samples and kidneys for histological evaluation were collected. With sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). Co-administration of macitentan (Δ12.3±1.5 mmHg, p<0.001) or amlodipine (Δ11.4±1.7 mmHg, p<0.001) attenuated the sunitinib-induced MAP rise, whereas low and high captopril doses did not (Δ28.1±2.0 and Δ27.2±1.1 mmHg). With sunitinib, serum creatinine increased from 8.0±2.7 to 29.9±4.6 μmol/l (p<0.01) and proteinuria from 7.5±1.3 to 33.3±4.8 mg/day, p<0.05. Although no agent could prevent the sunitinib-induced rise in creatinine, the induced proteinuria was attenuated by 62% (p<0.01) with macitentan and by 88% with low and 114% (p<0.001) with high dose of captopril, while proteinuria increased by 56% (p=NS) with amlodipine. With sunitinib, urinary ET-1 increased from 3.3±0.5 to 4.8±1.0 pg/day (p<0.05). Macitentan and captopril abolished this increase. Renal histology revealed extensive glomerular ischemia and endothelial cell swelling. Concomitant with the decrease in proteinuria, glomerular intra-epithelial protein deposition decreased with macitentan and captopril. In conclusion, ET-R antagonism and CCB effectively reduced the sunitinib-induced hypertension, whereas ACE-inhibition did not. Both ET-R antagonism and ACE inhibition diminished the sunitinib-induced proteinuria. Since ET-R antagonists are not yet available as anti-hypertensive agents, CCBs are preferred in angiogenesis inhibition-induced hypertension, while adding an ACE-inhibitor might be considered when proteinuria is also present.

Excitatory amino acid receptors within NTS mediate arterial chemoreceptor reflexes in rats

1993 ◽  
Vol 265 (2) ◽  
pp. H770-H773 ◽  
Author(s):  
W. Zhang ◽  
S. W. Mifflin
Keyword(s):  
Electrical Stimulation ◽  
Amino Acid ◽  
Receptor Antagonist ◽  
Carotid Body ◽  
Excitatory Amino Acid ◽  
Pressor Responses ◽  
Carotid Body Chemoreceptors ◽  
Arterial Chemoreceptor ◽  
Stimulation Of ◽  
Arterial Baroreceptor

The nucleus tractus solitarius (NTS) is the primary site of termination of arterial baroreceptor and chemoreceptor afferent fibers. Excitatory amino acid (EAA) receptors within NTS have been shown to play an important role in the mediation of arterial baroreceptor reflexes; however, the importance of EAA receptors within NTS in the mediation of arterial chemoreceptor reflexes remains controversial. Therefore, in chloralose-urethan-anesthetized, mechanically ventilated, paralyzed rats, 4 nmol of the broad-spectrum EAA receptor antagonist kynurenic acid (Kyn) was injected into the NTS to observe the effects of EAA receptor blockade on the pressor responses evoked by either activation of ipsilateral carotid body chemoreceptors (by close arterial injection of CO2-saturated bicarbonate) or electrical stimulation of ipsilateral carotid sinus nerve (CSN). Under control conditions, activation of carotid body chemoreceptors and CSN stimulation evoked increases in arterial pressure of 27 +/- 2 (n = 24 sites) and 28 +/- 3% (n = 8), respectively. Kyn microinjection into NTS significantly reduced the pressor responses evoked by activation of carotid body chemoreceptors and electrical stimulation of the CSN for 20 and 25 min, respectively. Attenuation of pressor responses evoked by chemoreceptor activation were maximal at 20 min post-Kyn injection (13 +/- 2%), whereas CSN-evoked pressor responses were maximally attenuated at 15 min (6 +/- 4%). Microinjection into NTS of 4 nmol of xanthurenic acid, a structural analogue of Kyn with no EAA receptor antagonist properties, had no effect on chemoreceptor reflexes. We conclude that EAA receptors within NTS play an important role in the mediation of arterial chemoreceptor reflexes.

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