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Hypertension and bradykinin: a dangerous affair?

Katsi, Vasilikia; Katsimichas, Themistoklisb; Pittaras, Andreasb; Grassos, Charalambosb; Katsimichas, Alexandrosa; Tousoulis, Dimitriosb; Stefanadis, Christodoulosb; Kallikazaros, Ioannisa

Cardiovascular Endocrinology & Metabolism: June 2012 - Volume 1 - Issue 2 - p 24–30
doi: 10.1097/XCE.0b013e328357a94c
Review article
Free

Hypertension is a disorder of the heart and vessels that affects almost a billion individuals worldwide and is considered the most important preventable factor for premature death. Overall, 95% of all cases are deemed as primary or essential hypertension, where no cause can be identified. Essential hypertension has a complex pathophysiology, involving derailment of endocrine and sympathetic mechanisms, still not completely understood. The kallikrein–kinin system comprises a collection of autacoid peptides such as bradykinin that exert multiple physiologic actions and are of strategic importance for the regulation of blood pressure. Scientific research suggests that its impairment contributes toward the development of hypertension and hypertension-induced end-organ damage.

aDepartment of Cardiology, Hippokration Hospital

bFirst University Department of Cardiology, Hippokration Hospital, University of Athens Medical School, Athens, Greece

Correspondence to Themistoklis Katsimichas, Hypertension Unit, First University Department of Cardiology, Hippokration Hospital, V. Sofias 108, 11527 Athens, Greece Tel: +30 697 967 5858; e-mail: arovant@gmail.com

Received April 9, 2012

Accepted May 27, 2012

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Introduction

It is probably safe to say that hypertension has been affecting man since well before the beginning of recorded history. It is one of the earliest recorded medical disorders, with documents dating back to around 2600 BC 1, and, currently, has been identified by the WHO as the leading cause of cardiovascular mortality.

Extensive research has implicated a multitude of molecules in the regulation of blood pressure and investigated their functional status in hypertension. Kinins are active, autacoid polypeptides involved in the regulation of blood pressure and the protection of the cardiovascular system. Considerable evidence has linked the kallikrein–kinin system and its impairment to the regulation of blood pressure and hypertensive states, respectively. In this short review, we discuss elements of this system and the relationship between bradykinin and hypertension, as bradykinin appears to be of utmost importance not only in preventing blood pressure from increasing markedly but also in protecting the cardiovascular system from hypertension-related complications, such as left ventricular hypertrophy (LVH).

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The kallikrein–kinin system

The first observation that led to the discovery of the kallikrein–kinin system was made in 1909, when Abelous and Bardier reported the hypotensive effect of injected human urine, now known to be caused by excreted renal kallikrein. As mentioned above, kinins are active, autacoid polypeptides involved, among various other actions, in the regulation of blood pressure. The kinin family includes several members in mammals, such as bradykinin, kallidin or lys-bradykinin, and methionyl-lysyl-bradykinin 2,3. Kallidin and methionyl-lysyl-bradykinin are converted into bradykinin by aminopeptidases present in plasma and urine 3. Kallikreins are serine proteases that cleave active kinins off their inactive precursors, kininogens (α2 globulins) 3. Kinins are subsequently rapidly inactivated (<15 s) by circulating kininases, so that their mode of action is essentially confined to their production site 3,4.

At the cellular level, kinins act through two transmembrane, G protein-coupled receptors, specifically, B1 and B2 3–5. Receptor B1 is rarely expressed in normal tissue, but is upregulated in pathological states of inflammation and injury 3. However, recent research indicates that it acts centrally to mediate nociception, which suggests its constitutive presence in the brain and perhaps the spinal cord 6. Kinins also act through receptor B2, present in a large number of organs and tissues, to exert many biological effects. There are also reports of an additional B3 receptor, present in the large airways, and a B4 receptor, present in the opossum esophagus 3,7.

The action of kinins is mediated by several signal transduction, second messenger systems, including the phospholipase A2 and phospholipase C pathways, and direct coupling of the receptors with ion transporters and adenylate cyclase 2,3. It involves changes in intracellular calcium and the production of vasoactive substances from endothelial cells that cause vasodilation, namely, nitric oxide (NO), prostacyclin, prostaglandins, and endothelium-derived hyperpolarizing factor 2. Apart from vasodilation, which leads to local hyperemia and a reduction in blood pressure, kinins also increase vascular permeability and cytokine release (hence their importance in inflammation) 2,3. Depending on tissue, kinins also exert many other actions, such as catecholamine release from sympathetic ganglia and the adrenal medulla, the contraction of smooth muscle cells, and the translocation of the GLUT4 glucose transporter 2. Figure 1 summarizes some major bradykinin actions.

Fig. 1

Fig. 1

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Bradykinin, hypertension, and the cardiovascular system

Bradykinin and hypertension

Plasma circulating kinins are inactivated rapidly, with plasma concentrations in the low picogram range. However, local kallikrein–kinin systems are known to exist in the kidney, the myocardium, and blood vessels, and their operation is of strategic importance for the regulation of blood flow, blood pressure, and cardiovascular protection from ischemia, LVH, and remodeling 2,3,7,8. The basic mechanism of bradykinin action in the regulation of systemic blood pressure is vasodilation in most areas of circulation, a reduction in total peripheral resistance, and regulation of sodium excretion from the kidney 3. The major role of the kallikrein–kinin system in the kidney may be the suppression of sodium reabsorption along the collecting ducts 9. Bradykinin acts directly to inhibit sodium chloride and water reabsorption by the distal nephron. The inhibitory actions of bradykinin on the distal nephron salt and water reabsorption, combined with its renal vasodilator effects, counteract the ‘hypertensinogenic’ actions of the renin–angiotensin system. A reduced activity of the kallikrein–kinin system thus contributes to an impaired ability of the kidneys to respond to increases in dietary salt intake with appropriate increases in salt and water excretion, and increases arteriolar sensitivity to vasoconstrictive substances, leading eventually to high blood pressure 9,10. It must be noted, however, that, although such an impaired activity of the kallikrein–kinin system has been shown to result in salt-sensitive hypertension under some conditions, it is not clear whether all forms of salt-sensitive hypertension are associated with a reduction in the activity of the kallikrein–kinin system 9.

In terms of receptors, it was long accepted that bradykinin acts mainly through B2 to exert its physiological action. However, growing evidence from gene overexpression and knockout studies, and the use of selective receptor agonists and antagonists, also suggest a protective role for receptor B1 in vascular disease states, such as hypertension or ischemic organ diseases (although B1 receptor function in the regulation of blood pressure still remains somewhat controversial). A study found that, when B2 is inhibited or absent, receptor B1 is upregulated and might develop some B2 hemodynamic properties, which indicates that they both play a role in the maintenance of normal vasoregulation or the development of hypertension 11. In a similar experiment, in normal (wild-type) mice, experimental manipulations to induce hypertension also resulted in a significant upregulation of B1 receptor gene expression in cardiac and renal tissues, even more pronounced than that in the B2 receptor gene knockout counterparts. These manipulations produced no change in B2 receptor gene expression. One could speculate that the induction of receptor B1 may be one of the mechanisms by which bradykinin exerts its tissue-protective effects under hypertensive conditions, whereas B2 receptor activity participates in regulating the balance between vasoconstrictors and vasodilators in the resting state 12. Furthermore, chronic administration of an angiotensin-converting enzyme (ACE) inhibitor to normotensive rats induced vascular and renal B1 receptor expression, and the hypotensive effect was attenuated by the administration of a B1 receptor antagonist, as well as by the administration of a B2 receptor antagonist 13. The expression and activation of the B1 receptor might play a role in a vascular self-defense mechanism against recurrent ischemic episodes, which can be improved by ACE inhibition and angiotensin II, AT-1 receptor blockade 11,14,15. Functional renal B1 receptors are also induced in spontaneously hypertensive, stroke prone rats, in accordance with the elevation in blood pressure, and the administration of a B1 receptor antagonist elevated systemic blood pressure 14. The vascular effects of B1 receptor activation may be a result of the release of endothelial NO, prostaglandins, and possibly endothelium-derived hyperpolarizing factors 16,17. However, natural B1 receptor ligands [the des-Arg(9)kinin metabolites, namely, des-Arg(9)bradykinin and lys-des-Arg(9)bradykinin, increased in inflammation] are rapidly inactivated by tissue and plasma peptidases, having limited stability and protective action 18. Therefore, it seems that there is a shift in the recent literature against a long-prevailing dogma that receptor B2 is mainly responsible for bradykinin-protective actions, and emerging evidence shows that both receptors participate in all actions of kinins, including those protective and favorable to the cardiovascular system.

Considerable evidence links the kinin system and its impairment to the regulation of blood pressure and hypertensive states. An injection of bradykinin into the renal artery has been shown to produce natriuresis and diuresis through a prostaglandin-mediated increase in renal blood flow 19. In addition, it has been shown in animal models that a continuous infusion of bradykinin prevents an increase in systemic and renal vascular resistance after the administration of angiotensin II 20. Also, human tissue kallikrein induces hypotension in transgenic mice 21. Through selective inbreeding, Dahl and colleagues developed two strains from Sprague–Dawley rats: Dahl salt-sensitive (DSS) hypertensive and Dahl salt-resistant normotensive rats. Urinary kallikrein activity is reduced in DSS hypertensive rats when compared with Dahl salt-resistant normotensive rats 22. It is known that kininogen levels and a kinin potentiating factor have been found to be reduced in essential and malignant hypertensive patients 23. Moreover, transgenic mice overexpressing renal tissue kallikrein are hypotensive and the administration of the tissue kallikrein inhibitor aprotinin restored blood pressure 24. Crossover kidney transplantation between normotensive and hypertensive rats showed that the resulting blood pressure levels were significantly linked to the origin of the transplanted kidney 25. Studies in B2 receptor knockout mice have shown these animals to be predisposed to salt-sensitive hypertension, a finding that has been linked to impaired NO release 26. Acute blockade of the B2 receptor substantially decreases renal blood flow and the natriuretic response, and chronic blockade increases susceptibility to angiotensin II-induced hypertension 27. A nonpeptide B2 receptor agonist has been shown to prevent the development of hypertension in young spontaneously hypertensive rats, when continuously infused in an early, critical phase, providing future avenues for hypertension prevention, rather than therapy 28. It is also known that ACE inhibitors could lower blood pressure not only by blocking the formation of angiotensin II but also by inhibiting the degradation of bradykinin by ACE, and possibly by directly interacting with the B2 receptor, for example by stabilizing it to a high-affinity state 8,29. The activation of the endogenous bradykinin system and the subsequent augmentation of NO and PGE2 synthesis are also critical for the beneficial effects induced by chronic angiotensin II type 1 receptor antagonist treatment in DSS rats, and these effects presumably occur through the activation of angiotensin II type 2 receptors 27. In models of renovascular hypertension, such as the two-kidney, one-clip mouse (2K1C), a clearly high renin model of hypertension where high blood pressure is sustained by the activation of the renin–angiotensin system, pharmacological blockade or genetic disruption of the B2 receptor has been shown to accelerate the development of renovascular hypertension, suggesting a role for kinins in counterbalancing high blood pressure angiotensin stimuli 30. However, recent studies investigating the role of the kallikrein–kinin system in the development of 2K1C hypertension in (a) mice rendered deficient in tissue kallikrein and kinins by tissue kallikrein gene inactivation and (b) their wild-type counterparts found that tissue kallikrein and kinins do not influence the trophicity of kidneys, the synthesis and secretion of renin, increases in blood pressure, and cardiac remodeling as a consequence of the activation of the renin–angiotensin system 31. In the field of genetics, the B1 and B2 receptor genes have been mapped to the human chromosomal region 14q32.1–q32.2 and polymorphisms have been documented. Cardiovascular risk associated with hypertension among middle-aged UK men was found to be influenced by a functional variation in these genes: in the presence of the B2R(+9) or B1R−699G alleles, markers of low-kinin activity, cardiovascular risk is increased as blood pressure increases, an effect not found among men homozygous for the B2R(−9) or B1R−699C alleles 32. Altered activity in the human coronary vascular kallikrein–kinin system may underlie these data.

Collectively, the above evidence suggests an important role of the kinin system in hypertension, which was first observed by Elliot and Nuzum 33 and then established by Margolius et al.34 through observations that urinary kallikrein excretion is significantly reduced in hypertensive patients and rats (although later research indicates that corrections for race and renal function must be made before drawing such conclusions in humans) 10,35. It is proposed that a deficient kallikrein–kinin system may be a significant factor in the pathophysiology of hypertension, at least in part through a decrease in sodium excretion and subsequent sodium accumulation, arterial vasoconstriction, and increased peripheral resistance.

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Bradykinin-mediated cardiovascular protection

Considerable data indicates that bradykinin exerts cardiovascular protective actions. Overall, components of the kallikrein–kinin system are known to exist in the heart and vessels, and their impairment, because of genetic abnormality, receptor downregulation, or other reasons, could account for pathologic states such as LVH and ischemia 36. Kinins are released during ischemia and affect the heart in a beneficial way; bradykinin antagonists have been shown to worsen ischemia-induced effects; bradykinin itself contributes to the effects of ischemic preconditioning and can, at a dose that has no effect on blood pressure, prevent LVH by releasing NO in rats with aortic banding-induced hypertension; it can also prevent cardiac remodeling in rats with chronic coronary ligation, and reduce the size of a cardiac infarct after preconditioning in rabbits, a phenomenon abolished by treatment with bradykinin antagonist Hoe 140 9,37. Last but not least, the cardioprotective effects of ACE inhibitors have been shown to be bradykinin mediated 8,28,38,39.

A complete analysis of all known kinin cardioprotective properties is beyond the scope of this short review. The focus will only be on LVH, a direct pathophysiological result of hypertension. LVH is an established pathophysiologic response to hypertension and a strong independent factor for cardiovascular disease, predisposing to arrhythmia, ischemia, and heart failure 8,29. In contrast to a physiologically hypertrophied heart (athlete’s heart), the rate of capillary growth in hypertension-induced LVH does not keep pace with the increase in myocardial mass, leading to diminished capillary supply and priming the heart for ischemia. As LVH progresses, myocyte loss and reactive proliferation of connective tissue occurs, which results in interstitial and perivascular fibrosis and further reduction in the myocardial energy supply 29. Bradykinin has the potential to decrease collagen formation and cardiomyocyte growth through the stimulation of endothelial NO and prostacyclin production 29. In the rat with aortic banding-induced hypertension, bradykinin counters the development of LVH, and this effect is abolished by treatment with a bradykinin B2 receptor antagonist and a NO synthetase inhibitor 39. A lack of the cardiac kallikrein–kinin system may also be responsible for the induction of LVH in spontaneously hypertensive rats and spontaneously hypertensive rats with diabetes 8. Reduced cardiac tissue kininogen and kallikrein may be responsible for reduced bradykinin formation in the heart. Cardiac hypertrophy and microvascular deficit have been described in kinin B2 receptor knockout mice 40. Myocardial hypertrophy was prevented by direct treatment with bradykinin in 2K1C rats 41. In particular, treatment clearly prevented cardiac fibrosis, and B2 receptor blockade or inhibition of NO synthetase reversed the cardioprotective action of bradykinin. Finally, it is known that ACE inhibitors have not only antihypertensive but also antihypertrophic actions. Enhancement of the kinin concentration in the heart induced by ACE inhibitor therapy suggests that, apart from inhibition of the potent growth factor angiotensin II, ACE inhibitors promote antihypertrophic effects by potentiating endogenous kinins 29,42. Any treatment of hypertension could lead to a partial regression of LVH by reducing afterload, but ACE inhibitors exert a particularly strong antihypertrophic effect, which has been confirmed in clinical trials involving β-blockers and diuretics 43–45. ACE inhibitors can also prevent hypertrophy, as has been shown in the rat model of suprarenal aortic coarctation using ramipril 29. This effect was abolished by concomitant treatment with the B2 receptor antagonist Hoe 140, again implicating the kinin system in ACE inhibitor antihypertrophic actions 46. Other animal models have suggested that bradykinin counters the development of LVH through B2 receptor stimulation, but it is not an essential factor involved in the regression of an already existing LVH by ACE inhibitor therapy 29. Furthermore, the effects of ACE inhibitors on LVH in low or normal renin animal models of hypertension, such as spontaneously hypertensive rats and stroke prone spontaneously hypertensive rats, have been shown to be not so clearly linked to the kinin system, as chronic B2 receptor blockade did not attenuate the antihypertrophic effect of ACE inhibitors in such animals 47. In such models, the effects of the ACE inhibitors on LVH are better explained by the reduction in afterload and the attenuation of the growth-promoting effects of angiotensin II. However, it has been shown that in rats with genetic hypertension, such as the spontaneously hypertensive rats, LVH is associated with reduced heart capillary density, and that ACE inhibition led to capillary proliferation, which could in part be attributed to vasodilation and augmentation of coronary blood flow by bradykinin, as the increase in capillary density was prevented by B2 receptor blockade 10. As a final note, discrepancies between the ACE inhibition mode of action between animal models of high and normal or low renin may be attributed to the different pathogenic mechanisms of hypertension in such models. Rats with renal hypertension respond to ACE inhibition more drastically than rats with genetic hypertension, as they are highly dependent on the renin–angiotensin system and a compensatory stimulation of the kinin system may be involved, although some studies contradict this 31. In contrast, genetic hypertension rats, such as spontaneously hypertensive rats, may be less dependent on both systems.

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Kallikrein gene therapy

Hypertension has a significant genetic pathogeny and it has been postulated that gene therapy for hypertension will result in longer lasting and more stable control of blood pressure than current control with antihypertensive medication 48. A number of studies have provided evidence that links low renal kallikrein levels with hypertension in animal models and humans. Moreover, transgenic mice overexpressing human tissue kallikrein are known to show a life-long reduction in blood pressure, and this effect has been shown to be mediated by the bradykinin B2 receptor. Transgenics overexpressing human bradykinin B2 receptors are also hypotensive for life. Experimental research on animal models has led to the development of human kallikrein gene delivery systems that have yielded excellent results, countering an increase in blood pressure in hypertensive animals 49–53.

Many factors should be taken into account when considering hypertension gene therapy, such as how to control the extent of reduction of blood pressure, the potential risk of hypotensive effects in hypertensive patients, and the duration of the antihypertensive effect. Therefore, the choice of appropriate vectors for gene delivery and the selection of the targeting gene are crucial factors of a successful strategy. The recombinant adeno-associated viral (rAAV) vector has been used for gene therapy protocols 54,55, as it can mediate stable transduction and long-term expression of target genes in vivo, without any known adverse effects. A single intravenous injection of the rAAV-mediated human kallikrein target gene countered an increase in blood pressure in adult Sprague–Dawley rats that were administered a high-salt diet for 8 weeks, without any effect on the basal blood pressure measured before inducing high-salt diet hypertension, or the normal blood pressure of rats fed a normal diet 56. These results indicate that human tissue kallikrein gene overexpression is a potentially safe method for the treatment of hypertension and, most importantly, prevention. Evidence suggests that intramuscular delivery of the human kallikrein gene also exerts a hypotensive action in spontaneously hypertensive rats and reproduces protective effects found with intravenous delivery, such as amelioration of LVH, renal injury, and collagen depositions 57. Research with models of renovascular hypertension has also led to excellent results. A single adenovirus-mediated delivery of the human tissue kallikrein gene produced a sustained delay in a blood pressure increase for more than 24 days in 2K1C Goldblatt hypertensive rats, along with attenuation of cardiac hypertrophy, and increased renal function. It may seem that kallikrein gene delivery produces a wide spectrum of beneficial effects, making it an excellent candidate for the treatment of renovascular hypertensive and cardiovascular diseases 58. Furthermore, rAAV-mediated human kallikrein gene delivery led to a long-term and stable reduction in blood pressure and protected against renal injury and cardiac remodeling in the spontaneously hypertensive rat model 59. Another study showed that a single intravenous injection of the human tissue kallikrein gene in an adenoviral vector not only attenuates cardiac hypertrophy and fibrosis but also promotes neovascularization in the heart of spontaneously hypertensive rats, even though the blood pressure-lowering effect did not last for more than 2 weeks in this animal model 60. Finally, it has been shown that cell apoptosis is increased in the heart, kidney, and aorta of hypertensive patients, resulting in heart failure, renal dysfunction, and vascular remodeling 61. rAAV-mediated human kallikrein gene therapy protects against hypertension target organ injuries by the inhibition of cell apoptosis in spontaneously hypertensive rats in vivo, and human embryonic kidney cells (HEK 293) in vitro, indicating that the kallikrein–kinin system protects against hypertension-induced end organ damage not just by lowering blood pressure but by inhibiting apoptosis as well 62.

It is clear that hypertension gene therapy could have a bright future and might soon challenge current trends in therapy, the kallikrein–kinin system holding a major role in such a treatment shift.

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Potentially harmful kinin effects

Although the kallikrein–kinin system has been proven to be highly valuable in the regulation of blood pressure and the mediation of the antihypertensive and antihypertrophic effects of ACE inhibitors, there still remain clinical states in which kinin effects might have a negative impact on health. An increase in bradykinin can produce adverse effects through B1 or even B2 receptor activation and their proinflammatory properties. Kinins participate in various acute or chronic immune responses linked to severe human diseases, such as Alzheimer’s disease, or diabetes mellitus. Receptor B2 is believed to play an important role in the acute phase of inflammation and somatic and visceral pain and, conversely, the B1 receptor plays a role in the chronic phase of such responses and probably plays an important role in disorders with a strong immune component, such as rheumatoid arthritis, multiple sclerosis, septic shock, and diabetes mellitus 6. It has also been reported that receptor B1 plays a dual role in some diseases, where it can exert either protective (multiple sclerosis and septic shock) or harmful (pain and inflammation) actions 63. It is known that bradykinin is activated in endotoxemia, and, in such a case, B receptor inhibition may be more useful to possibly reverse pathological sequelae 20. Receptor B2 is expressed in human and experimental murine tumors, thus implicating bradykinin in the induction of pathologic signal transduction in cancer growth, and NO production and vascular permeability augmentation in tumors, which also raises the possible utility of bradykinin antagonists 64. Finally, angioedema is a potentially life-threatening adverse effect of ACE inhibitor therapy, linked to the active bradykinin metabolite des-Arg9-bradykinin. There exist many potential B1 and B2 receptor agonists awaiting approval for cardiovascular and other trials, one of the main challenges being to determine whether there is a safe therapeutic window between cardioprotective and adverse effects, such as proinflammatory effects, following receptor agonism 27. It has also been reported that bradykinin can stimulate catecholamine release from the adrenal medulla or even the central nervous system, although these results were obtained by an exogenous administration of bradykinin at pharmacologic doses 30. A summary of protective and possibly harmful kinin effects is presented in Table 1.

Table 1

Table 1

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Conclusion

Almost a billion individuals worldwide suffer from hypertension, which is considered to be the most important preventable factor for premature death. Its pathophysiology is not clearly understood, but research has indicated the kallikrein–kinin system to be of key importance in the regulation of blood pressure and its impairment as crucial in the development of hypertension. Bradykinin exerts several antihypertensive and cardioprotective actions and constitutes a strategic weapon against hypertension and the risk of cardiovascular death. Several kinin receptor agonists have been developed and may soon be cleared for clinical trials. Caution should be exercised as such substances could exert kinin-related adverse effects, mainly proinflammatory actions. Nevertheless, the future of the hypertensionbradykinin affair seems quite promising.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

bradykinin; hypertension; kallikrein–kinin system

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