The Status of Bradykinin System in Relation to Hypertension

    

    

    Figure 1: Shows the kinin formation and its inactivation.
    
    

Hypertension and Bradykinin system

Hypertension is a major risk factor in the development of cardiovascular diseases, such as coronary heart disease, congestive heart failure and peripheral vascular & renal diseases. There is ample evidence documenting the role of BK in the pathogenesis of hypertension [6,2]. The pharmacological actions of BK in regulation of systemic BP are vasodilation in most areas of circulation, reduction in total peripheral vascular resistance and regulation of sodium excretion from the kidney [7]. The role of KKS in hypertension was established by Margolius and co-investigators [8] with the observations that urinary kallikrein excretion is significantly reduced in hypertensive patients.

In addition, transgenic mice over-expressing renal tissue kallikrein were hypotensive and that administration of aprotinin, a tissue kallikrein inhibitor, restored the BP of the transgenic mice [9]. We have shown the suppression of hypotensive responses of ACEIs by aprotinin in SHR [10]. These findings highlight a role of tissue kallikrein in the regulation of BP. Recently; it has been proposed that tissue kallikrein gene delivery into various hypertensive models exhibits protection, such as reduction in high BP, attenuation of cardiac hypertrophy, inhibition of renal damage and stenosis [11-13]. This may indicate the future therapeutics prospect of kallikrein gene therapy for cardiovascular and renal pathology.

ACEIs are currently used in the treatment of both clinical and experimental hypertension [14,15]. Kininase II inhibitors could lower BP by inhibiting the biodegradation of kinin as well as blocking the formation of angiotensin II (AgII). Previous study has demonstrated that urinary kallikrein excretion was found to be diminished in family members at risk for hereditary hypertension and that urinary kallikrein may be one of the major genetic markers associated with family history of hypertension [16].

Left ventricular hypertrophy is regarded as an independent risk factor in hypertensive patients in inducing cardiac abnormalities. BK can counter the development of LVH in rats with hypertension produced by aortic banding [17,18]. This anti-hypertrophic effect of BK was abolished by the B₂ receptor antagonist treatment as well as by NO synthetase inhibitor. Thus, the BK has a role in protecting the heart against developing LVH by releasing NO in this model of hypertension induced by aortic banding. In this regard, we have for the first time demonstrated that the lack of the cardiac KKS could be responsible for the induction of LVH in SHR and SHR with diabetes [4]. It is suggested that the reduced cardiac tissue kallikrein and cardiac kininogen may be responsible for reduced BK generation in the heart. Therefore deficient components of the BK in the heart may be responsible for inducing excessive hypertrophy and myocardial dysfunction in cases of hypertension. It is highly desirable to develop stable compounds of BK to evaluate their efficacy and potency in cases of cardiac failure, cardiac ischemia and hypertension.

We have recently observed the reduction in plasma prekallikrein prekallikrein levels in Kuwaiti patients with hypertension those they did not receive the treatment. This might be serving as early marker in the development of renal and cardiovascular abnormalities [19,20] (Figure 2).

    

    

    Figure 2: Plasma prekallikrein levels in healthy subjects and hypertensive
patients. Data are presented as mean and SEM. There is a **(p<0.001)
significance between control and hypertensive. Number=4 (unpublished
observation by Sharma et al. 2017).