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PubMed2001

The effect of topically applied vasoactive agents and testosterone versus testosterone in the treatment of erectile dysfunction in aged men with low sexual interest.

The objective was to evaluate the efficacy and safety of topically applied cream containing testosterone, isosorbide dinitrate and co-dergocrine mesylate compared to testosterone cream in the treatment of erectile dysfunction in aged men with low sexual interest. A randomised double-blind crossover trial was performed over two months. The subjects were 42 men with erectile dysfunction and low normal or slightly depressed testosterone level randomly allocated to two equal groups. Polypharmacy cream containing testosterone 0.8%, isosorbide dinitrate 0.5% and co-dergocrine mesylate 0.06% was applied for one month, and testosterone 0.8% cream for another month. The serum level of total testosterone was measured before and after each phase of treatment. Response to each therapy was assessed by a sexual questionnaire, measurement of tumescence and repeat penile duplex ultrasonography. Twenty-eight patients reported full erection and satisfactory intercourse with the polypharmacy cream. Thirteen men reported full erection and satisfactory intercourse with either cream. Polypharmacy cream increased penile arterial flow (P<0.001) and induced tumescence in 34 patients in lab. No patient in either phase of the study has tumescence or a significant increase in cavernous arterial peak systolic velocities after the application of testosterone cream. Serum level of total testosterone increased in all patients (P<0.05). Sexual desire was improved in 85% and 62% of patients during the treatment with polypharmacy cream and testosterone cream, respectively. No marked side effects were reported after either of them. Topical treatment with cream containing testosterone and vasoactive agents may represent a new effective treatment for erectile dysfunction associating with aging.

Administration, Topical↗
PubMed1997

Effect of continuous regional vasoactive agent infusion on liver metastasis blood flow.

Regionally administered vasopressors might increase tumour chemotherapy uptake by differentially constricting normal and tumour blood vessels, leading to a selective increase in blood flow to the tumour. In this study, we compared the effects of the vasopressors angiotensin II, vasopressin and endothelin I and the vasodilator calcitonin gene-related peptide (CGRP) by continuously measuring liver parenchymal and tumour blood flow during a 30-min regional vasoactive infusion in a rat HSN liver metastasis model. Vasopressin and angiotensin II produced a vasoconstriction that decreased despite continued infusion, while endothelin I infusion led to prolonged vasoconstriction with a more gradual onset. CGRP infusion resulted in increased vessel conductance but a reduction in blood flow due to systemic hypotension. The tumour to normal flow ratio (TNR) was transiently increased during infusion of all pressors, but only endothelin I produced sufficient change to result in a rise in average TNR throughout pressor infusion. Continuous liver and tumour blood flow measurement throughout vasoactive infusion demonstrated that the extent and the duration of blood flow change varied with the agents assessed. No vasoactive agent increased tumour blood flow, but endothelin I had the most suitable vasoactive properties for enhancing tumour uptake of continuously infused chemotherapy.

Angiotensin II↗
PubMed2001

Metabolic effects of vasoactive agents.

After adequate volume resuscitation, the mainstay of therapy in critically ill patients with shock is treatment with vasoactive substances to restore haemodynamics or to improve regional perfusion. These agents include adrenoceptor agonists with inotropic combined with either vasoconstricting or vasodilating effects, and predominantly vasodilating drugs such as prostacyclin and related compounds. However, vasoactive agents not only affect the cardiovascular system, but also have profound metabolic effects. The interdependence of vasoactive drugs with metabolism may be relevant regarding adequate oxygen and substrate delivery to cover actual organ needs. Therefore, the profiles of these metabolic effects have to be considered during their therapeutic administration.

Journal Article↗
PubMed1987

Intraocular microendoscopy of the ciliary-process vasculature in albino rabbits: effects of vasoactive agents.

The reactions of the ciliary-process microvasculature following administration of various vasoactive substances were studied in the albino rabbit using a new method of intraocular microendoscopy. This technique allows an in vivo observation of arterioles, capillaries and venules of the ciliary body and iris. As long as these tissues are not traumatized, the newly described method of intraocular microendoscopy produces no reactive changes in the vasculature. The video images of microendoscopy were also evaluated quantitatively. Administration of substance P caused a short-term ischemic phase in the ciliary-process vasculature which preceded a long-term hyperaemia. After topical administration of epinephrine as well as intra-arterial administration of epinephrine, phenylephrine and isoproterenol, rapid and intense vasoconstrictory or vasodilatory reactions were seen in the terminal arterioles of the vascular territories in the ciliary processes. The terminal arterioles of the iridial ciliary processes responded faster and more intensely than those of the major ciliary processes. It is concluded that the terminal arterioles play an important role in blood-flow regulation of the ciliary processes and function as special afferent vessel segments which control the circulation within the ciliary-process capillaries.

Animals↗
PubMed1986

Effect of vasoactive agents on prostanoid synthesis in isolated rat glomeruli.

We studied the influence of vasoactive substances (angiotensin II, epinephrine, norepinephrine and acetylcholine) on the synthesis of prostanoids in isolated rat glomeruli. A significant increase of prostaglandin E2, and of thromboxane B2, but not of prostaglandin F2 alpha synthesis was observed after the administration of angiotensin II at physiological doses. Neither catecholamines nor acetylcholine influenced prostaglandin synthesis. The stimulation of vasoactive prostaglandins by angiotensin II, may modify the hemodynamic status of the glomerulus.

Acetylcholine↗
PubMed1999

[Contraindicated medical references and vasoactive agents in arterial pathology of the lower limbs].

INTRODUCTION: Treatment of arteriopathy of the lower limbs (ALL) with vasoactive drugs must follow French health laws recently introduced in regard to the prescription of unuseful drugs and treatments and the frequency at which some patients resort to specific drugs and treatments. Prescription of vasoactive drugs in ALL requires the existence of functional discomfort. Prescription of only one vasoactive drug is sufficient. CURRENT KNOWLEDGE AND KEY POINTS: Results of published clinical trials demonstrate the efficacy of vasoactive drugs for the relief of claudication related to arteriopathy. To conform to the rules of the European Drug Agency, treatment with vasoactive drugs which improve the walking distance is recommended as "symptomatic treatment of arterial claudication in ALL". Iloprost is only used in the treatment of permanent ischemia. Prescription of vasoactive drugs is part of a scheme of therapeutic indications that are well known and rigorous. Rules of hygiene and reduction of risk factors are the essential preliminary elements. In the case of arterial claudication due to femoral or distal obliteration, chemical medication is suggested, whereas in the case of iliac lesion, angioplasty should be considered. FUTURE PROSPECTS AND PROJECTS: Walking is recommended in all the cases; however, usually less than a quarter of all patients will conform to this recommendation. Vasoactive drugs thus find their place in the therapeutic scheme. Evaluation of the efficiency of vasoactive drugs rises above simple measures of the walking distance, rather integrating quality of life and usefulness of the treatment.

Angioplasty↗
PubMed1985

A microcirculatory technique for evaluating intravascular and topical administration of vasoactive agents: response to AVP in the SHR.

A "closed bath" cremaster muscle preparation is described which permits the administration of vasoactive materials to the microvasculature via intraarterial injection and topical suffusion. The technique is evaluated in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats by comparing arteriolar responses to intraarterial and topically suffused arginine vasopressin. The preparation utilizes a thermostatically heated brass suffusion chamber overlying the cremaster. The chamber is closed with a glass coverslip. Experimental materials are presented to the microvessels via intraarterial injection or suffusion through the chamber. The coverglass permits high optical resolution with both routes of administration. Following vasopressin administration, changes in arteriolar diameter were continuously monitored by image-shearing techniques or variable-resistance calipers. The responses were analyzed by comparing both the peak 5-sec vasoconstriction and a 60-sec integrated response. Intraarterial and topical suffusion of vasopressin (1.25 X 10(-10)-3.75 X 10(-7) M) caused dose-dependent vasoconstriction among 23-microns arterioles. Compared to the WKY, vasoconstriction was greater in the SHR when vasopressin was administered intraarterially. A similar strain difference was not observed with topical suffusion. The dose-response curves with intraarterial vasopressin were shifted approximately 100-fold in concentration to the right relative to those with topically suffused vasopressin. The "closed bath" cremaster muscle preparation described has several distinct advantages: (1) it permits introduction of different vasoactive materials in the most physiological manner in the same animal, and (2) it maintains high optical resolution and clarity for critical observation of the smallest vessels, even with suffusion.

Administration, Topical↗
PubMed1998

Responsiveness of human infant cerebral arteries to sympathetic nerve stimulation and vasoactive agents.

Responses of segments of basilar and middle cerebral arteries of eight human infants to activation of perivascular nerves and to vasoactive drugs were studied using a resistance artery myograph. The infants ages ranged from 23 wk of gestation to 34 postnatal days. Neurogenic vasoconstriction occurred in all segments and at 8 Hz was 12.7 +/- 3.5% (11%) of tissue maximum and was blocked by phentolamine (10(-6) M). There was no evidence of a neurogenic dilator response. Catecholamine histofluorescence was seen in nerves in the adventitia at all ages studied. Norepinephrine ED50 was 7.6 +/- 1.8 x 10(-7) M, and its maximum effect was 43.1 +/- 5.7% of tissue maximum. Both neural and norepinephrine responses were greater than those of the proximal parts of adult human middle cerebral arteries obtained postmortem and surgically removed adult human pial arteries. Electron microscopy demonstrated that neural density at the adventitiomedial junction in the infant vessels was greater than in the pial arteries. Constrictor responses to serotonin and prostaglandin F2 alpha were minimal in the two infants of 23 and 24 wk of gestation but were clearly present in the older infants. Histamine and acetylcholine were potent vasodilators. Indomethacin potentiated agonist-induced contraction. In a limited number of trials angiotensin II, neuropeptide Y, caused contraction and bradykinin, relaxation. It is concluded that there is a quantitative similarity between the studied responses of infant cerebral artery segments and human pial arteries of similar diameter. However, sympathetic nerves may potentially play a more important role in the regulation of cerebrovascular tone in the infant compared with the adult, and during the gestational period examined these vessels possess an indomethacin-sensitive system that buffers agonist tone.

Acetylcholine↗
PubMed1994

Combining bioreductive drugs (SR 4233 or SN 23862) with the vasoactive agents flavone acetic acid or 5,6-dimethylxanthenone acetic acid.

PURPOSE: To determine whether 5,6-dimethylxanthenone acetic acid (DMXAA), a potent analogue of flavone acetic acid (FAA) inhibits blood flow in mouse mammary tumors, and to assess whether DMXAA enhances the antitumor effects of Tirapazamine (SR 4233) and the novel bioreductive drug SN 23862 (a dinitrobenbenzene mustard). METHODS AND MATERIALS: MDAH-MCa-4 mouse mammary tumors were grown i.m. in the leg of C3H/HeN mice. Tumor blood flow was assessed by the pertechnetate clearance method and subsequent growth delay was determined in the same tumors. RESULTS: Administration of DMXAA (65-70 mumol/kg) resulted in inhibition of tumor blood flow to approximately 25% of control values, with no recovery observed up to 36 h post-treatment. Combination of DMXAA with SR 4233 provided a significant increase in tumor growth inhibition relative to either drug alone. In this effect, DMXAA was qualitatively similar to FAA, but was approximately 10 x more potent. The interaction between DMXAA (65 mumol/kg) and SR 4233 (200 mumol/kg) was maximal with SR 4233 given between 15 min before and 60 min after DMXAA. For SN 23862, a similar enhanced growth delay was observed in combination with DMXAA, with no obvious time dependence between 15 min before and 4 h after DMXAA. When mean values for groups treated with SR 4233 (200 mumole/kg) alone and in combination with DMXAA (65-90 mumole/kg) were compared, a correlation was observed between tumor blood flow inhibition and subsequent growth delay. CONCLUSION: DMXAA is a potent inhibitor of blood flow in MDAH-MCa-4 tumors. Combination of this vasoactive drug with bioreductive agents leads to an enhanced antitumor effect. For SR 4233 and DMXAA, this enhanced effect may be predictable by measurement of tumor blood flow inhibition shortly after drug administration.

Aniline Mustard↗
PubMed2002

[Investigation of vasoactive agents with indole skeletons at Richter Ltd].

Investigation of agents with indol skeleton was started in Richter Ltd. 50 years ago. This paper presents the results obtained by Richter's scientists. At first, a vasoactive alcaloid, vincamine was extracted from the leaves of Vinca minor in industrial quantity in 1955. This agent selectively improves the cerebral blood supply. Vincamine (Devincan) is used for the treatment of cerebrovascular disorders from 1959. Vinpocetine (Cavinton), the most powerful vasoactive compound was produced by transforming the chemical structure of vincamine. Cavinton is a cis(3S,16S)-derivate of vincamine having antianoxic, antiischaemic and neuroprotective properties. Therefore, it is frequently used in the therapy of cerebral disorders of vascular origin. Cavinton was introduced into clinical practice in 1978. At present, Cavinton tablets are approved in 47 countries. The third compound, vintoperol is a trans(3S,16R)-derivate of vincamine. Vintoperol proved to be a powerful enhancer of blood flow in the lower extremities. Because of its toxic side effects the agent is not used in clinical practice.

Animals↗
PubMed1975

Treatment of circulatory shock. Use of sympathomimetic and related vasoactive agents.

Reduction of effective blood flow represents the primary disturbance accounting for circulatory shock. Four categories of circulatory shock are identified: cardiogenic, hypovolemic, distributive, and obstructive. The pharmacology and clinical implications for treatment of shock with vasoactive drugs are reviewed in this context. Except for epinephrine, when it is used for treatment of anaphylactic shock, there is no specific indication for the routine use of alpha- or beta-adrenergic receptor agonists. These agents may increase blood pressure or cardiac output, but nutritive flow is not necessarily improved. Comparable limitations are observed with alpha-adrenergic receptor blocking agents. However, selective effects on the myocardium and on the resistance, exchange, and capacitance vessels may be advantageous as an interim and complementary measure. Since vasoactive drugs frequently intensify the fundamental defect accounting for perfusion failure, their selective rather than routine employment is mandatory.

Adrenergic alpha-Agonists↗
PubMed1998

[Evaluation of 452 patients with erectile dysfunction treated by combinations of vasoactive agents by penile injection].

In the past 15 years there has been continuous increase in the use of injections into the corpora cavernosa of different vasoactive drugs for treatment of erectile dysfunction (ED). However, some of these drugs are very expensive, are not available everywhere, and have side effects. We therefore compared the success rate of the most widely used compounds, papaverine and regitine, in 452 patients (age range 26-85) with different types of ED. Each patient received in the clinic injections of papaverine, 6-25 mg, and regitine, 0.05-1.5 mg. When maximal rigidity of the penis (MRP) was > 80%, we instructed the patient to self-inject the drug at home, 5-30 minutes before coitus. If after 3 injections MRP was not > 80%, prostaglandin E1 (PGE1) in an average dose of 10-25 mcg was added. If there was no response, papaverin + regitine + PGE1 were given in higher dosage, and atropine sulfate, 0.02 + 0.06 mg, was added if necessary. Of 452 patients, 305 (67.4%) had MRP > 80% after 3 injections of papaverine plus regitine. The other patients received PGE1 in addition. This was helpful in 61 patients (41.5%), while 55 (63.9%) required papaverine + regitine + prostin in higher doses. Of these, only 31 received papaverine + regitine + PGE1 + atropine sulfate. Of these, 20 (64.5%) reached MRP > 80%, and 11 (2.4%) MRP < 60. For these 11 patients, we recommended a penile prosthesis. Thus in 67.4% of the 452 patients, papaverine + regitine injections were effective; in 41.5%, PGE1; in 63.9%, papaverine + regitine + prostin + atropine sulfate. Only 11 (2.4%) did not react to intracorporeal injection. This progressive method of treatment enabled us to select the optimal dosage and combinations of compounds in 441/452 patients (97.5%) according to the severity of their dysfunction. During follow-up of 6 months, spontaneous erections without injection were achieved in 115 (26.0%).

Adult↗
PubMed1996

Release of vasoactive agents during cordocentesis: differences between normally grown and growth-restricted fetuses.

OBJECTIVE: The purpose of this study was to evaluate whether cordocentesis is associated with the release of vasoactive substances and whether there are differences between normally grown and growth-restricted fetuses. STUDY DESIGN: 6-Keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin), endothelin-1, and cyclic guanosine monophosphate were measured in fetal blood at the beginning and closing of cordocentesis in 30 normally grown fetuses and 25 growth-restricted fetuses. This latter group was characterized by abnormal Doppler index values in umbilical artery and middle cerebral artery, suggestive of chronic hypoxemia as the causative factor of the impaired growth. In six growth-restricted fetuses bradycardia occurred at the end of the procedure. Umbilical artery pulsatility index was measured by Doppler ultrasonography immediately before and after the procedure. RESULTS: The median interval between the two blood samples obtained by cordocentesis was 90 seconds (range 60 to 320 seconds). During this interval a significant rise of 6-keto-prostaglandin F1 alpha (p < or = 0.0001) and endothelin-1 (p = 0.03) was evidenced in normally grown fetuses. The increase in 6-keto-prostaglandin F1 alpha was significantly related (r = 0.52, p = 0.002) to the fall of umbilical artery pulsatility index occurring after the procedure. In growth-restricted fetuses cordocentesis induced a marked increase of endothelin-1 (p = 0.0002), which was significantly related to the severity of acidosis (r = 0.52, p = 0.018), whereas no modifications were evidenced for the other agents tested. The increase of endothelin-1 was higher in those growth-restricted fetuses showing bradycardia at the end of the procedure than in growth-restricted fetuses that did not (p = 0.04). The variations of the vasoactive substances assayed were not significantly related to the type of procedure (transamniotic or transplacental), the amount of blood aspirated during the procedure, the interval elapsing between the first and second samples, the gestational age at which the procedure was performed, and the degree of fetal smallness. CONCLUSION: Cordocentesis induces the rapid release of vasoactive substances and the effect differs between normally grown and growth-restricted fetuses. This may explain the different hemodynamic response and the higher rate of complications occurring in the latter group after cordocentesis.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Release of vasoactive agents from the isolated perfused human ovary.

OBJECTIVE: To investigate local vascular control in the isolated perfused premenopausal human ovary by measuring flow-induced release of vasoactive substances. DESIGN: Release of adenosine 5' triphosphate (ATP), substance P (SP), endothelin (ET), and vasopressin (AVP) from the ovarian vascular endothelium was estimated in perfusate under basal conditions and during two periods of increased flow. MAIN OUTCOME MEASURES: Vascular resistance; ATP, SP, ET and AVP release. RESULTS: The mean ratio (pressure/flow during increased flow):(pressure/flow at basal flow) was 1.27 +/- 0.04 for the first, and 1.15 +/- 0.05 for the second period of increased flow (n = 10), indicating significant vasoconstriction (P < 0.01 and 0.05, respectively), present to a greater extent during the first period of increased flow compared to the second (P < 0.05). ATP release was seen in response to increased flow (n = 8, P < 0.05). From 12 ovarian bed preparations, five released ET and SP and three of these released AVP. Four of the five perfused ovaries that released peptides contained either a developing follicle or a corpus luteum while all those that showed no peptide release were inactive. CONCLUSIONS: ATP release may play a role in the local control of the human premenopausal ovarian vasculature independent of ovulatory status. Peptides may also contribute to local vascular control in the ovary and their release from predominantly active ovaries suggests a relationship between ovulation and vascular endothelial function.

Adenosine Triphosphate↗
PubMedDate not supplied

Alterations in vascular sensitivity to vasoactive agents after discontinuation of propranolol in SHR.

Spontaneously hypertensive rats (SHR) were treated with propranolol (P) (70 mg/kg) daily for 2 or 4 weeks and then the effects of vasoactive substances on blood pressure were studied 10 or 36 hours after the last dose of P. At 10 hours after the last dose of P, vascular hyperresponsiveness to norepinephrine (NE) and angiotensin II (AII) had largely disappeared, but the hypotensive action of isoproterenol and prostacyclin was still blocked in P-treated SHR. An increase of cyclic AMP (cAMP) in response to isoproterenol was blocked in the thoracic aorta. Similarly, an increase of circulating cAMP and blood glucose in response to epinephrine (E) was depressed. At 36 hours after the last dose of P, an elevation of blood pressure in response to NE and AII was significantly reduced in P-treated SHR. Although basal blood pressure with or without anesthesia was the same in P-treated SHR and control SHR, a decrease of blood pressure in response to isoproterenol and prostacyclin was augmented significantly in P-treated SHR. This was also true in normal rats similarly treated. In addition, an increase of cAMP in the thoracic aorta in response to isoproterenol and prostacyclin was augmented significantly in P-treated SHR. An increase in blood glucose in response to E was not blocked, but an increase of circulating cAMP in response to E was blocked. These data suggest that cAMP synthesis in the vessels is somehow related to the production of peculiar vascular responses during escape from P action.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1999

Development of human and rabbit vaginal smooth muscle cell cultures: effects of vasoactive agents on intracellular levels of cyclic nucleotides.

In this study, we subcultured and characterized human and rabbit vaginal smooth muscle cells and investigated the synthesis of second messenger cyclic nucleotides in response to vasodilators and determined the activity and kinetics of phosphodiesterase (PDE) type 5 (EC 3.1.4.35 3',5'-cyclic GMP phosphodiesterase). Cultured vaginal cells exhibited growth characteristics typical of smooth muscle cells and immunostained with antibodies against alpha smooth muscle actin. The cells retained functional prostaglandin E and beta-adrenergic receptors as demonstrated by increased intracellular cAMP synthesis in response to PGE1, or isoproterenol. The response to these vasoactive substances was augmented with forskolin, suggesting stabilization of G-protein-activated adenylyl cyclases. Treatment with the nitric oxide donor, sodium nitroprusside, in the presence of sildenafil, a PDE type 5 inhibitor, enhanced intracellular cGMP synthesis and accumulation. Incubation of rabbit vaginal tissue with sildenafil, sodium nitroprusside, and PGE1 or forskolin produced a marked increase in intracellular cGMP. These observations were similar to findings with cultured cells and suggest that subcultured cells retain functional characteristics exhibited in intact tissue. The cells retained phosphodiesterase type 5 expression as shown by specific cGMP hydrolytic activity. Sildenafil and zaprinast inhibited cGMP hydrolysis competitively and bound with high affinity (Ki = 7 and 250 nM, respectively). These observations suggest that cultured human and rabbit vaginal smooth muscle cells retained their metabolic functional integrity and this experimental system should prove useful in investigating the pathway of nitric oxide and PDE type 5 inhibitors in modulating vaginal smooth muscle tone.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Total ischemic burden: effect of vasoactive agents.

Treatment of the total ischemic burden is dependent on adequate documentation of both painful and painless episodes of myocardial ischemia, an understanding of the pathophysiologic mechanisms involved, and knowledge of prognosis for affected patients. Because a vasoconstrictive component appears to be an important element in the genesis of many episodes of myocardial ischemia, those vasoactive drugs that produce increased flow in the coronary circulation should be clinically useful. Nitrates and calcium blockers--especially nifedipine--have been found to be particularly valuable in this regard in both experimental and clinical trials.

Animals↗
PubMed1994

Differential contractile response of cultured microvascular pericytes to vasoactive agents.

OBJECTIVE: Microvascular pericytes may contract in two different ways: In the first, a circumferential or radial mechanical force applied at right angles to the long axis of the vessel may constrict the underlying vessel affecting blood flow and transmural pressure. Retraction and elongation of pericyte processes may also occur tangentially and at right angles to the vessel axis and alter microvessel permeability by changing the amount of ablumenal surface covered or the openness of interendothelial junctions. In this study, cultured pericytes were utilized as a model experimental system to determine if vasoactive stimulation changes their shape in a manner consistent with this hypothesis. METHODS: Pericytes cultured from isolated rate capillaries were subjected to angiotensin II and histamine. Their response was monitored by measuring the area of non-yielding substrate covered by the pericytes and the manner in which their shape changed. Shape changes were quantified by calculating the surface area: perimeter perimeter ratios. RESULTS: Histamine significantly reduced surface area covered and the surface area:perimeter ratio. The pericyte processes retracted, resulting in elongated, spindle-shaped cells. These effects were nullified by the H1 blocker diphenhydramine suggesting a receptor-specific response. Angiotensin II also elicited contraction and reduced surface area, but the cells contracted laterally and longitudinally. The surface area: perimeter ratios also decreased. CONCLUSIONS: These results indicate that pericytes are capable of two types of contractile responses in culture, depending on the specific vasoactive stimulus.

Angiotensin II↗