The Newly Synthesized Pyrazole Derivative 5-(1-(3 Fluorophenyl)-1H-Pyrazol-4-yl)-2H-Tetrazole Reduces Blood Pressure of Spontaneously Hypertensive Rats via NO/cGMO Pathway

Neidiane R Trindade,Paulo R Lopes,James O Fajemiroye,Ricardo Menegatti,Carlos H Castro,Luciano M Lião,Gustavo R Pedrino,Ana C S Rebelo,Pedro H Alves,Valdir A Braga,Nathalia O Amaral,Lara M Naves

doi:10.3389/fphys.2018.01073

Abstract

The search for new antihypertensive drugs has grown in recent years because of high rate of morbidity among hypertensive patients and several side effects that are associated with the first-line medications. The current study sought to investigate the antihypertensive effect of a newly synthesized pyrazole derivative known as 5-(1-(3 fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-21). Spontaneously hypertensive rats (SHR) were used to evaluate the effect of LQFM-21 on mean arterial pressure (MAP), heart rate (HR), renal vascular conductance (RVC), arterial vascular conductance (AVC), baroreflex sensitivity (BRS) index, and vascular reactivity. Acute intravenous (iv) administration of LQFM-21 (0.05, 0.1, 0.2, and 0.4 mg kg-1) reduced MAP and HR, and increased RVC and AVC. Chronic oral administration of LQFM-21 (15 mg kg-1) for 15 days reduced MAP without altering BRS. The blockade of muscarinic receptors and nitric oxide synthase by intravenous infusion of atropine and L-NAME, respectively, attenuated cardiovascular effects of LQFM-21. In addition, ex vivo experiments showed that LQFM-21 induced an endothelium-dependent relaxation in isolated aortic rings from SHR. This effect was blocked by guanylyl cyclase inhibitor (ODQ) and L-NAME. These findings suggest the involvement of muscarinic receptor and NO/cGMP pathway in the antihypertensive and vasodilator effects of LQFM-21.

Highlights

Blood pressure control is a complex process that involves variety of organ systems, such as cardiovascular system, central nervous system, adrenal glands, and kidneys (Coffman and Crowley, 2008)
Recent studies showed that pyrazole derivatives as neural and inducible nitric oxide synthase inhibitors (Carrión et al, 2008), 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles as N-type calcium channel inhibitors (Winters et al, 2014), vasorelaxant and phosphodiesterase inhibitor (Griebenow et al, 2013)
All experiments were conducted on adult male Spontaneously hypertensive rats (SHR) or Wistar normotensive rats (NTRs) (280–350 g)

Summary

Introduction

Blood pressure control is a complex process that involves variety of organ systems, such as cardiovascular system, central nervous system, adrenal glands, and kidneys (Coffman and Crowley, 2008). Several classes of drugs (beta and alpha blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, diuretics, etc.) are currently being used for the treatment of hypertensive. Pyrazole Derivative Reduce Blood Pressure patients in order to reduce cases of morbidity and mortality that are associated with cardiovascular diseases (Law et al, 2009). These classes of drugs are often used in combination for several reasons. Recent studies showed that pyrazole derivatives as neural and inducible nitric oxide synthase (nNOS and iNOS) inhibitors (Carrión et al, 2008), 2,4,5,6-tetrahydrocyclopenta[c]pyrazoles as N-type calcium channel inhibitors (Winters et al, 2014), vasorelaxant and phosphodiesterase inhibitor (Griebenow et al, 2013)

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Results

Conclusion