Basic Pharmacology of Bradykinin Receptor Agonists

  

    
studies
    
applicatio
    
Ligands
  
  

    
- Rabbit
      
- rodent 
    
  - Metabolically stable
      
- High affinity and selectivity
      
- Hypertension
      
- Stimulation of vascular formation following    ischemia 
    
Agonists 
      
R-838(Sar-[D-Phe8]des-Arg9-BK)
  
  

    
- Rat
      
- Mice
    
- Pain
      
- Ischemic vascular disease
    
Antagonists 
      
  [Leu8]des-Arg9-BK
  
  

    
- Human B1 receptor antagonist
    
- Optimal B1 receptor antagonist
    
Lys-[Leu8]des-Arg9-Bk
  
  

    
- Rabbit
    
- Metabolically stable (not very potent compared with the affinity of    reference compound Lys-[Lue8]des-Arg9-BK
    
Ac-Lys-[MeAla6,Leu8]des-Arg9-BK
  
  

    
- Human and rabbit B1 receptor
      
- Mice
    
- High affinity
      
- Allergic lung inflammation
    
R-715(Ac-Lys-[�D-Nal7,Ile8]des-Arg9-BK
  
  

    
- Human and rabbit B1 receptor
    
- Fairly high selectivity for B1 receptor due to Lys
      
- Metabolically stable residue
    
B9858(Lys-Lys-[Hyp3,Igl5,D-Igl7,Oic8]des-Arg9-BK)
  
  

    
- Rabbit jugular vein, guinea pig ileum,    rabbit aorta
    
- Residual antagonistic effects on B2 receptor
      
- Moderate affinity
    
Des-Arg10-HOE 140
  
  

    
- Demonstration of compatibility of B1 and B2 receptors structure by the accommodation of a single    pharmacophore
    
- Mixed B1 and B2 receptor antagonist even if desArg9 fragment has substantial    selectivity for B1 receptor
    
B9430 (D-Arg-[Hyp3,Igl5,D-Igl7,Oic8]-BK)
  
  

    
- Mice
      
- Rat model
    
- Allergic lung inflammation
      
- Air way allergy
    
R-954(Ac-Orn-[Oic2,a-MePhe5,D-�Nal7,Ile8]des-Arg9-BK)
  
  

    
- Human receptor (no in vivo data)
    
- Potent and competitive B1 receptor antagonist
      
- High affinity
    
PS020990
  
  

    
- Human and rat B1 receptor in vitro
      
- Rat and dog
      
- Rabbit aortic preparation, rabbit jugular    vein
      
- Mice and rat
    
- Selective antagonist 
      
  - Powerful and selective antagonist
      
- Hyperalgesia
      
- Speculative on pain, inflammation and sepsis
      
- Inflammation and hyperalgesia
    
-Compound 12 (benzodiazepine based structure) 
      
Benzo-sulfonylamide compounds
      
- Compound 12
      
- Compound 11
      
- SSR240612
  
  

    
- In    vivo rodent models
      
- Human: phase II studies on glioma
    
- Vascular permeability (blood brain barrier):    adjuvant to chemotherapy of brain tumors
    
Agonists
      
Labradimil ([Hyp3, Thi5, 4-MeTyr8    ψ(CH2-NH)Arg9]-BK)
  
  

    
- Rat
    
- Hypertension
    
FR190997
  
  

    
- Rat uterus, guinea pig ileum
      
- Rat uterus, guinea pig ileum
    
- low potency, antagonist/ partial agonist activity
      
- Potent antagonist, no agonist activity
    
Antagonists 
      
First generation
      
[D-Phe7]-BK
      
[Thi5,8, D-Phe7]-BK
  
  

    
- Animal model (high affinity for the human,    rabbit and guinea pig B2 receptor)
      
- Human, nasal treatment
      
- Human
      
- Rat
    
- High affinity, long lasting, competitive    activity
      
- No residual agonist effect
      
- Resistance to peptidases
      
- Acute rhinitis
      
- Asthma
      
- Early stage of inflammation
      
- Persistent inflammatory pain
    
Second generation 
      
HOE 140 (Icatibant; D-Arg-[Hyp3, Thi5, D-Tic7,    Oic8]-BK)
      
 
      
 
      
 
      
 
      
 
  
  

    
- On human tissue
      
- For guinea pig B2 receptor
    
- In active 
      
  - Limited affinity
    
 
      
Third generation
      
Phosphonium family:
      
WIN64338
  
  

    
- Identification of the absolute requirement    for B2 receptor binding affinity: presence of two positive charges at a    distance about 10 A� separated by a lipophilic residue, playing the role of    the Phe8 side chain in the native ligand
    
-Micromolar binding affinity to human B2    receptor
    
WIN62318
  
  

    
- Oral activity at doses ranging between 1 and    30 mg/kg in different tests and species.
    
- High B2 receptor affinity and selectivity    versus B1 receptor
    
Quinoline and imidazole    [1,2-a]pyridine family:
  
  

    
- Rat and mice
    
- Oral activity on hyperalgesia and    inflammation
    
FR165649, 
      
FR173657,
      
FR184280
  
  

    
- Guinea pig ileum, human A-431 cells 
      
  - Guinea pigs (oral    activity) designed as clinical candidate to treat inflammatory disease
    
- Selective and high potent binding activity 
      
  - bronchoconstriction
    
FR167344
  
  

    
- Human B2 receptor
    
- High affinity
    
Compound 38
  
  

    
- Human B2 receptor
    
- High affinity
      
- Modeled on CP0597 by replacing �-turn    conformation of the peptide by a rigid 1,4 piperazine ring
    
CP2522
  
  

    
- Human B2 receptor
    
- B2 receptor antagonist at the nanomolar    range
    
Substituted 1,4-dihydropyridines
  
  

    
- Rodent
    
- Hypertension, inflammation
    
Bradyzide
  
  

    
- Alkakoid isolated from    the South American tropical plant Martinella iquitosensis
    
- Affinity for both B1 and B2 receptors at the    micromolar range but not selective
    
Nnatural compound
      
Pyrroloquinoline alkaloid: Martinelline
  
  

    
- Complex metabolite isolated from a culture    of the mould Microsphaeropsis sp.
      
- No future pharmacological data
    
- Inhibition of bradykinin binding to cloned    human B2 receptor at micromolar range
    
L-755807
  

Table 1:  Agonists and antagonists of B2 receptors Ligands application studies.

Bradykinin B₂ receptor agonists

By stimulation of BK B₂ receptors, kinins exert a wide variety of diverse biological actions [6]. In various humans and animals studies, it has been demonstrated that the stimulation of BK B₂ receptors is implicated in cardioprotective mechanism [6,12]. The best-characterized peptide BK B₂ receptor agonists are JMV-1116 and RMP-7 [13]. The key feature of these two potent and selective agonists is their improved resistance to enzymatic degradation by kininases, rendering them valuable pharmacological tools for studying the effects of BK B₂ receptor stimulation without the accompanying rapid breakdown of BK [6]. In vitro study of JMV- 1116 exhibited a high affinity towards the human cloned B₂ receptor in a radioligand-binding assay [13]. Moreover, JMV-1116 behaved as a full BK B₂ receptor agonist on human umbilical vein and rat uterus preparation with the same efficacy as BK [13]. Preliminary clinical trials in oncology indications confirmed that RMP-7 permeabilised the blood-brain tumour barrier to increase the delivery of agents such as carboplatin to tumors [14]. Moreover, RMP-7 enhances drug delivery to solid peripheral tumors [14,15]. The first potent, selective non-peptide BK B₂ receptor agonists FR-190997 and FR- 191413 were discovered in 1997 [6,12,16]. FR-190997 is described as 4-(2-pyridyl-methoxy)-quinolone and FR-191413 is described as 3-(2-pyridylmethoxy)-benzimidazole [6,12]. The structures of both these two BK B₂ receptor agonists are closely related to those of non-peptide BK B₂ antagonists such as quinolone FR-167344 and benzimidazole FR-173657 [12]. The key difference between BK B₂ receptor antagonist and agonist is the substitution of the quinolone moiety in position 4 with an additional 2-pyridylmethoxy group in the case of FR-190997 and the substitution of the benzimidazole moiety in position 3 with an additional 2-pyridylmethoxy group in the case of FR-191413 [6,12].

The 4-(2-pyridylmethoxy)-quinolone is a very potent nonpeptide BK B₂ receptor agonist [6,12]. FR-190997 was reported to stimulate IP3 hydrolysis in Chinese Hamster Ovary (CHO) cells transfected with the human BK B₂ receptor and to increase PGE2 production in human fibroblast [6,12]. However, detailed in vitro evaluations on human, rabbits and pig vascular BK B₂ receptors have revealed that this agonist shows different intrinsic activity depending on the tissue preparations [16]. FR-190997 acts as a partial agonist in the human umbilical vein and especially in the rabbit jugular vein, but as a pure antagonist in the pig coronary artery [16]. From this study it was suggested that the addition of a 2-pyridylmethoxy group to the basic structure of the antagonist FR-173657 might not be completely sufficient to change the pharmacological spectrum of a pure antagonist to that of a full agonist [16]. FR-190997 induced hypotensive response in anaesthetized spontaneously hypertensive rats after continuous infusion into the abdominal aorta [17]. Moreover, FR-190997 induced natriuresis and diuresis without any influence on urinary potassium excretion in anaesthetized rabbits [18].

FR-191413 is a second promising series of non-peptide BK B₂ receptor agonists. The pharmacological properties of FR-191413 have been less intensively evaluated than those of FR-190997 [6]. FR-191413 was reported to have similar effects to those obtained for FR-190997 on membranes CHO cells tranfected with the human BK B₂ receptor. This indicates that FR-191413 is almost equipotent to FR-190997 in vitro [12]. Potent non-peptide BK B₂ agonists have been discovered recently, but the oral efficacy of these agonists is very limited due to their inadequate pharmacokinetic properties [6]. This excludes their development as potential therapeutic agents for the treatment of all cardiovascular indications [6].

The Kinin System in Cardiovascular Disorders

Hypertension

Hypertension is a major risk factor for the development of cardiovascular diseases, for example, coronary heart disease, congestive heart failure, and peripheral vascular and renal diseases [1,2,5]. Kinins have potent diuretic and natriuretic effects that regulate sodium excretion from the kidney [6]. Moreover, kinins have a vasodilator action on peripheral blood vessels [1,2,5,6]. The deficiency of KKS may participate in the genesis of hypertension [2]. The involvement of kinins in blood pressure regulation has been confirmed in transgenic mouse models overexpressing human BK B₂ receptor [19]. In a transgenic mouse model, over-expression of BK B₂ receptor caused the development of sustained lifetime hypotension. Administration of aprotinin, a tissue kallikrein inhibitor, or icatibant, a specific B₂ receptor antagonist, to the transgenic mouse restored their blood pressure to normal levels [19]. The suppression of the hypotensive response of ACE inhibitors by aprotinin in spontaneously hypertensive rats has been documented [20]. Research on the systemic changes in the KKS has provided further insight regarding various hypertensive conditions [1,5]. In essential and malignant hypertension, it is known that kininogen levels and kininpotentiating factor are reduced [1,2,5]. It may be possible that the deficiency in plasma HMWK is due to decreases in liver synthesis in individuals who develop hypertension after mild exercise [1,2]. It seems possible that deficient kallikrein-kininogens-kinin formation might be a significant factor in pathophysiology of hypertension. Renal KKS may cause excretion of excessive sodium in the urine [1,2,5,6]. Studies on the role of the renal KKS using congenitally kininogen-deficient Brown-Norway Katholiek rat and also BK B₂ receptor knockout mice revealed that this system induces natriuresis and diuresis in the presence of high sodium in the body that might be due to excess sodium intake or excessive aldosterone release [21]. Thus, it can be hypothesized that the renal KKS works as a safety valve for sodium accumulation [21]. This may help in development of a compound having renal kallikrein-like activity to excrete the excess amount of sodium [1,5]. Recently, it has been proposed that tissue kallikrein gene delivery into various hypertensive models exhibit protection, for example, a reduction in high blood pressure, attenuation of cardiac hypertrophy, inhibition of renal damage and fibrosis and enhances capillary growth in spontaneously hypertensive rats [22]. These findings may indicate the prospect of this kallikrein gene therapy for cardiovascular and renal pathology [1,5]. Kininase II (ACE) inhibitors like captopril and enalapril are currently used in treatment of hypertension [1,2,5]. Kininase II inhibitors lower blood pressure by blocking the conversion of Ang I to Ang II, and increase levels of BK [2]. Abnormality in the urinary kallikrein excretion has been corrected after nifedipine, a calcium channel blocker, treatment of patients with essential hypertension [1,2]. It is a generally accepted view that the BK-induced blood pressure lowering effect is mediated by the B₂ receptor, but the B₁ receptor may also be involved under special situation [1]. It has been demonstrated that B₂ receptor antagonist FR-173657 significantly abolished the hypotensive action of captopril [2]. Hence, it would be reasonable to suggest that the hypotensive response of ACE inhibitors is mediated mainly via B₂ receptors activation [1,2]. The accumulation of BK after administration of ACE inhibitors with subsequent release of endothelium derived relaxing factor NO, PGE₂ and PGI₂ could be additional mediators released in the process of anti-hypertensive effects of captopril like drugs [1,2,5]. However, the use of BK antagonists can abolish the effectiveness of anti-hypertensive drugs, therefore these drugs must be contraindicated in patients with hypertension [1,5].

Cardiac Failure and Ischaemia

Cardiac failure and ischaemia are characterized by narrowed or blocked arteries, which impair the supply of blood and starve tissues of necessary nutrients and oxygen [4]. Cardiac failure and ischaemia are the leading cause of death in the developing and developed countries [1,4,5]. Kinins increase coronary perfusion and reduce preload, afterload and oxidative stress via stimulation of the release of NO and PGs mainly from the coronary cardiac endothelium, which protects the heart from acute ischaemic damage [1,5,6]. But the possible effects of kinins in the heart have been neglected for a long time [1,4,5]. ACE not only acts as a kinin-degrading enzyme but also contributes to Ang II generation [4]. Preventing the formation of Ang II could limit ventricular dilation, delay the progression of clinical symptoms, and improve mortality rate [1,5]. The ability of ACE inhibitors to prevent kinin-degrading enzyme represents a relevant mechanism contributing to cardioprotection [1,4,5]. This concept fuelled many studies and evidence demonstrating the presence of a local KKS in the heart [1,4]. Kinins released from the vascular endothelium activate BK B₁ and B₂ receptors on endothelial and vascular smooth muscle cells [4,5]. Binding to B₁ and B₂ receptors conjointly promotes the formation of PGs and NO, which increases intracellular cAMP and cGMP concentration [4]. Thus, exerting vasodilator, anti-ischaemic and anti-proliferative effects, and preserving myocardial stores of energy-rich phosphate and glycogen [4,5]. Circumstantial evidence also suggests that a dysfunctional KKS may contribute to the pathogenesis of heart failure [1,4,5]. In fact, reduced kinin outflow from the heart and blunted NO formation have been reported in microvessels of failing human heart [1,5]. Icatibant (HOE 140) is the most potent, stable and long lasting specific B₂ kinin receptor antagonist [3]. It represents a second generation of kinin antagonists, and has been a useful tool to evaluate the role of kinins in cardiac ischaemia [3]. In isolated rat hearts, perfusion with HOE 140 caused reversal of the beneficial BK cardioprotective effects and facilitated the development of cardiac failure [3]. Kinins act as a cardioprotective agent in perfusion and participate in the process of ischaemic preconditioning. Preconditioning is a protective adaptive mechanism produced by short periods of ischaemic stress; this protection includes reduction in ischaemic cellular damage and in life-threatening ventricular arrhythmias [3]. BK infused into the coronary artery of anesthetized dogs reduces significantly, the severity of ischaemiainduced arrhythmia [3,5]. Rats, dogs and human studies revealed that kinins are released under the conditions of ischaemia and myocardial infarction [3]. This will help in determining the role of kinin in protecting the heart under myocardial infarction. After myocardial infarction, increased plasma levels of kallikrein, kininogen and BK were found, and the increase in plasma kallikrein levels was positively correlated with early survival rate of post-myocardial infarction patients [23,24]. It has been shown that kinins are released directly from the myocardium during myocardial infarction and contribute to the impact of ischaemic damage [23,24]. Moreover, the influence of the BK B₂ receptor on the infarct size in rats with permanently ligated coronary arteries has already been confirmed using a nonpeptide BK B₂ receptor antagonist and agonist, respectively. In this model, the infarct size was reduced by a continuous infusion of the BK B₂ receptor agonist FR-190997, whereas it was increased upon oral administration of the BK B₂ receptor antagonist FR-173657 [25]. The effect of locally administered BK on the limitation of infarct size has been investigated. In anesthetized dogs, the left descending coronary artery was ligated for 6 hours. One group received saline into the main stem of the left coronary artery. The second group received BK in a subhypotensive dose of 1ng. Kg ^–1. min ^–1. The intracoronary route and the very low dose of BK were chosen to obtain a local cardiac effect with no or minimal effects on systemic hemodynamics. Within 6 hours of coronary occlusion, infusion of BK had no significant effect on systemic blood pressure [3]. This study showed that BK limited infarct size and provided evidence for the involvement of kinins in ischaemic events [3]. In conclusion, kinins may act as mediators of endogenous cardioprotective agents. Kinins are generated and released during ischaemia, with subsequent formation of PGs and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profiles resemble those of ACE inhibitors. However, more investigations are needed on the molecular biology and gene mapping of KKS in the heart during health and cardiovascular disorders, which may provide the answers to many questions about the role of KKS in cardiovascular pathophysiology [1,5].

Myocardial hypertrophy

Left Ventricular Hypertrophy (LVH) has been shown to be an independent predictor for increased morbidity and mortality from cardiac diseases [1,5,6]. The antihypertrophic efficacy of BK is due to B₂ receptor mediated release of the endothelial cardioprotective NO and PGs [5,6]. However, B₂ receptor antagonists and NO synthetase inhibitors can counter this effect [1,5]. In this regard, in hypertensive and diabetic rats, the lack of cardiac kinin forming components in the development of LVH has been documented [26]. Therefore, reduced cardiac tissue kallikrein and cardiac kininogen may be responsible for reduced BK generation in the heart that will lead to LVH [1,5]. In more recent study, in adult rat isolated cardiomyocytes and in Langendorff-perfused rat hearts, it was shown that BK exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cGMP may be an important anti-hypertrophic mechanism caused by BK in the heart [27]. In another recent study in hypertensive rats, blood pressure reduction and regression of LVH with captopril treatment might be due to enhanced renal tissue kallikrein activity [28]. This may further support the view that tissue kallikrein may act as a cardioprotective agent [1,5].

The most conclusive evidence suggests that BK 2 receptor activation limits the infarct size and lowers the threshold for myocardial preconditioning of angiotensin converting enzyme inhibitor treatment in the isolated rat heart [29]. This observation supports the view that BK 2 receptor agonists may have future prospect of treating cardiovascular disorders. Also, BK is able to induce mitochondrial reactive oxygen, cGMP, protein kinase G and mitochondrial ATPsensitive K+ channel opening to cause cardioprotection in the rabbit cardiomyocytes [30].

It is of interest to learn that BK inhibits development of myocardial infarction through BK2 receptor signalling by increment of regional blood flow around the ischaemic lesion in the rats [31]. Furthermore, BK at reperfusion reduces infarction in rabbit hearts through PI3K, ERK and NO [32]. It has been indicated that the mechanical load caused by pressure-overload produces a down-regulation of BK 2 receptor expression during the initial stage of LVH [33].

Thus, these recent findings may highlight the significance of the BK is the protection of heart in the various disorders. Most recently, a discovery of the first non-peptide full agonist for human BK 2 receptor development in Japan [34] may provide us with the greater prospects of the application of this agonist in experimental and clinical values in cardiology.

The unwanted effects of kinin agonists

Kinin agonist displayed very pronounced and long-lasting pro-inflammatory properties in vivo [6,12]. It increased vascular permeability upon intradermal injection into dorsal skin of rats in a dose-dependant, long-lasting manner; markedly induced paw swelling upon subcutaneous injection into the hind paw of mice; enhanced frequency of writhing reactions in mice upon intraperitoneal injection in mice; and increased angiogenesis as well as granulation upon topical application in mice sponge implants [17]. BK B₂ receptor-mediated activation of cyclooxygenase COX- 1 or COX-2 and synergism with PGI2 are suggested as underlying mechanisms of the described events [6]. Interestingly, FR-190997 proved to be a significant less active bronchoconstrictor than BK [17]. These observations indicate that pain induction or edema formation should be considered as one of the peripheral side effects of stable kinin receptor agonists when they have developed therapeutic usefulness [6,12]. Therefore, further studies are required to demonstrate that there is a sufficient therapeutic window between the pathophysiological and beneficial kinin receptor-mediate effects, which would allow the treatment of inflammatory disorders and chronic pain with BK B₂ receptor antagonists without diminution of the beneficial systemic and cardiovascular effects of endogenous kinins and, vice versa, the treatment of cardiovascular and metabolic diseases with BK B₂receptor agonists without concomitant proinflammatory side effects, especially upon chronic administration [6,12].

Conclusion

Recent studies indicate that the KKS has a role in the various pathophysiological process of the cardiovascular system, such as in hypertension, cardiac failure and ischaemia and myocardial hypertrophy. It seems that the activity of the KKS in the pathological conditions of hypertension, cardiac failure and the development of myocardial hypertrophy is deficient. These pathological states may be due to genetic abnormality of the KKS or to down regulation of BK receptors. These diseases may be treated by the application of BK B₂ receptor agonists. However, these hypothesis can only be confirmed when the defined roles of KKS have been fully established after more preclinical therapeutic investigations on human.

Recent studies indicate that BK B₂ receptor agonists may offer therapeutically valuable novel opportunities for the treatment and even prevention of cardiovascular diseases. However, BK B₂ receptor agonists have to demonstrate efficacy in cardiovascular diseases without potential concomitant proinflammatory side effects, especially upon chronic administration. In conclusion, BK B₂ receptor agonist represents a promising but challenging pharmacological target for the treatment of a wide spectrum of cardiovascular diseases.

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