New and developing pharmacotherapies for hypertension.

INTRODUCTION: Despite the significant contribution of hypertension to the global burden of disease, disease control remains poor worldwide. Considering this unmet clinical need, several new antihypertensive drugs with novel mechanisms of action are under development. AREAS COVERED: The present review summarizes the recent advances in the development of emerging pharmacological agents for the management of hypertension. The latest technological innovations in the design of optimized formulations of available antihypertensive drugs and the potential role of the modification of intestinal microbiota to improve blood pressure (BP) control are also covered. EXPERT OPINION: Significant efforts have been made to develop new antihypertensive agents with novel actions that target the main mechanisms involved in resistant hypertension. Sacubitril/valsartan may emerge as a potential first-line drug due to its superiority over renin angiotensin system inhibitors, and SGLT2 inhibitors can reduce BP in difficult-to-control hypertensive patients with type 2 diabetes. In addition, firibastat and aprocitentan may expand the therapeutic options for resistant hypertension by novel mechanism of actions. Since gut dysbiosis not only leads to hypertension but also causes direct target organ damage, prebiotics and probiotics could represent a potential strategy to prevent or reduce the development of hypertension and to contribute to BP control.

Enantioselective pharmacokinetics and cardiovascular effects of nebivolol in L-NAME hypertensive rats.

The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg(-1) i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): -16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: -1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that ß-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.

Acute effects of third generation ß-blockers on short-term and beat-to-beat blood pressure variability in sinoaortic-denervated rats.

An increase in blood pressure variability (BPV) contributes to the development of target organ damage associated with hypertension. Treatment with conventional ß-blockers, such as atenolol, has been associated with an increase in BPV; however, the extrapolation of these results to third generation ß-blockers with pleiotropic effects seems to be inappropriate. The cardiovascular effects of third generation ß-blockers, carvedilol and nebivolol, were assessed in sinoaortic-denervated rats (SAD) and compared with the second generation ß-blocker atenolol and the calcium channel blocker verapamil, with a special focus on short-term BPV. Male SAD rats were acutely treated with carvedilol, nebivolol, atenolol or verapamil at two different doses, and the effects on blood pressure and BPV were recorded. Short-term BPV was assessed by the s.d. of BP recordings. Beat-to-beat BPV was studied using spectral analysis to assess the vascular sympatholytic activity of carvedilol and nebivolol by estimating the effects of these drugs on the ratio of low frequency (LF) to high frequency (HF) BPV (LF/HF ratio). Nebivolol, carvedilol and the calcium channel blocker verapamil significantly attenuated short-term BPV at both doses in SAD animals, and there were no differences between the drugs. Conversely, atenolol did not modify baseline s.d. values at either dose. Carvedilol and nebivolol significantly reduced the LF/HF ratio in SAD rats compared with the effects of atenolol and verapamil, suggesting the ability of the third generation ß-blockers to reduce vascular sympathetic activity. In conclusion, third generation ß-blockers induce a marked reduction in short-term BPV in SAD rats compared to atenolol. Moreover, the ability of carvedilol and nebivolol to reduce short-term BPV in SAD rats is equivalent to that of verapamil, suggesting that these ß-blockers may have an additional beneficial effect through their control of short-term variability to a similar extent to calcium channel blockers.

Effect of nebivolol on beat-to-beat and short-term blood pressure variability in spontaneously hypertensive rats.

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats.

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic-pharmacodynamic (PK-PD) modeling. Male Sprague-Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability.

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg(-1) (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic-pharmacodynamic (PK-PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg(-1) compared with WKY rats. PK-PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.

Angiotensin-(1-7) blocks the angiotensin II-stimulated superoxide production.

Angiotensin (Ang)-(1-7), a bioactive compound of the renin-angiotensin system, exerts effects leading to blood pressure reduction which counterbalance Ang II pressor actions. The present study was conducted to examine Ang-(1-7) and Ang II effects on superoxide anion production in rat aorta using the lucigenin chemiluminescence method. Ang II dose-dependently increased superoxide anion formation when compared to control levels; a maximal increase (2.5-fold) was observed with 1 x 10(-10)M peptide concentration. The Ang II-stimulated superoxide formation was blocked by 1 x 10(-10)M losartan, the specific AT(1) receptor antagonist, but not by 1 x 10(-10)M PD 123319, the AT(2) receptor antagonist, suggesting that the increased superoxide levels caused by Ang II are mediated through AT(1) receptors activation. The Ang II-stimulated superoxide production was not modified by 2 x 10(-8)M allopurinol or 1 x 10(-7)M indomethacin, but was completely abolished by NAD(P)H oxidase inhibitors: 1 x 10(-8)M diphenylene iodonium, or 2 x 10(-8)M apocynin, demonstrating that NAD(P)H oxidase participates in such response. In contrast to Ang II, Ang-(1-7) concentrations ranging 1 x 10(-12) to 1 x 10(-6)M did not modify superoxide anion levels, but prevented the Ang II-enhanced superoxide production. In conclusion, we demonstrated that Ang-(1-7) blocks the pro-oxidant effects of Ang II, thus reducing the superoxide anion production and delaying the hypertension development.

Aortic coarctation induces oxidative stress in rat tissues.

The purpose of this study was to evaluate the induction of oxidative stress in heart and erythrocytes from rats with abdominal aorta coarctation (Coa) compared with sham-operated normotensive controls (Sham). The group of Coa animals developed myocardial hypertrophy, showing heart homogenates markedly increased levels of reduced glutathione (48%), lipid peroxidation (148%) and activation of superoxide dismutase and glutathione peroxidase (189% and 37%, respectively), compared with controls. Other oxidative stress indicators were also altered in erythrocytes from Coa rats: increased protein carbonyl content (141%) and total glutathione level (349%) were determined. Inactivation of the antioxidant enzymes catalase (27%), superoxide dismutase (58%) and glutathione peroxidase (25%) was observed in erythrocytes from the Coa group. Taken jointly our results provide strong evidence for the production of oxidative stress in heart and erythrocytes from aortic coarcted rats.

Effects of angiotensin II type 1 receptor blockade on the oxidative stress in spontaneously hypertensive rat tissues.

The aim of this work was to investigate the production of oxidative damage in homogenized kidney, liver and brain of spontaneously hypertensive rats (SHR), as well as the involvement of angiotensin (Ang) II in this process. Groups of 12-week-old SHR and Wistar Kyoto rats (WKY) were given 10 mg/kg/day losartan in the drinking water during 14 days. Other groups of WKY and SHR without treatment were used as controls. The production of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were determined. No significant difference in TBARS was observed between untreated SHR or WKY rats; GSH content was lower in the liver but higher in the brain of SHR compared to WKY rats. In tissues from the SHR group, SOD and Gpx activities were reduced, whereas CAT activity was slightly increased in kidney. TBARS levels did not change in WKY rats after losartan administration, but were reduced in SHR liver and brain. Losartan treatment decreased GSH content in WKY kidney, but increased GSH in SHR liver. The activity of the antioxidant enzymes was not modified by losartan in WKY rats; however, their activities increased in tissues from treated SHR. The lower activity of antioxidant enzymes in tissues from hypertensive rats compared to those detected in normotensive controls, indicates oxidative stress production. Ang II seems to play no role in this process in normotensive animals, although AT1 receptor blockade in SHR enhances the enzymatic activity indicating that Ang II is implicated in oxidative stress generation in the hypertensive animals.