Clinical Potential of Combined Organic Nitrate and Phosphodiesterase Type 5 Inhibitor in Treatment-Resistant Hypertension

Abstract

Abstract-NO donor drugs (eg, isosorbide mononitrate; ISMN) and phosphodiesterase 5 inhibitors (eg, sildenafil) have antihypertensive properties, and the combination can markedly reduce blood pressure (BP). The objective of this "proof-of-concept" study was to investigate the effect on BP of a combination of single oral doses of sildenafil (50 mg) and ISMN (10 mg) in patients with treatment-resistant hypertension. Six subjects with treatment-resistant hypertension were included, and their usual antihypertensive medication was continued during the study. Sildenafil alone, ISMN alone, and the combination all reduced brachial and central aortic BPs compared with placebo. The combination of sildenafil and ISMN produced the largest fall in BP (maximum brachial BP reduction of 26/18 mm Hg compared with placebo), without producing significant adverse effects. ISMN, alone and in combination with sildenafil, also reduced arterial wave reflection and central BP. In summary, in patients with treatment-resistant hypertension maintained on their usual antihypertensive treatment, sildenafil given alone and ISMN given alone both acutely reduced BP. There was additional BP reduction when these drugs were given in combination. In this therapeutically challenging group of patients, the combination of an NO donor drug and a phosphodiesterase 5 inhibitor may represent an effective treatment.Longer studies in larger numbers of patients are now justified. (Hypertension. 2010;56:62-67.)Key Words: NO Ⅲ cGMP Ⅲ sildenafil Ⅲ isosorbide mononitrate Ⅲ treatment-resistant hypertension N O causes vasodilation by stimulating vascular smooth muscle soluble guanylate cyclase to convert GTP to cGMP, which, in turn, leads to a reduction in intracellular calcium concentration. 1 cGMP is degraded by cGMPspecific, cGMP-binding phosphodiesterase 5 (PDE5), and inhibition of this enzyme enhances vascular smooth muscle relaxation. By stimulating vasodilation within the corpora cavernosa during sexual stimulation, PDE5 inhibitors, such as sildenafil, facilitate penile erection and are useful treatments of male erectile dysfunction. 2 Inhibitors of PDE5 are also vasodilators in the systemic circulation. Indeed, we 3 and others 4 have demonstrated previously that PDE5 inhibitors constitute effective regular antihypertensive therapy in untreated and treated subjects with mild-to-moderate hypertension.The organic nitrates, such as isosorbide mononitrate (ISMN), are antianginal drugs that dilate arteries and veins through their action as NO donors. 5 The simultaneous provision of exogenous NO from organic nitrates and inhibition of cGMP breakdown with PDE5 inhibition can result in substantial blood pressure (BP) reduction, as we have shown previously. 6 -8 Although these combinations are currently contraindicated, there is the potential that the combination of an NO donor and a PDE5 inhibitor could be exploited clinically to achieve better BP control in patients with treatment-resistant hypertension (TRH).The aim of the present proof-of-concept study was to inv...

Potential Therapeutic Role of Phosphodiesterase Type 5 Inhibition in Hypertension and Chronic Kidney Disease

“…In a group of patients with treatment-resistant hypertension, sildenafil and isosorbide mononitrate, given alone, both acutely lowered BP. 66 However, the combination provided additional BP reduction and was well tolerated. The potential efficacy of this combination in treatment-resistant hypertension may be linked to the novel targeting of the NO-cGMP pathway, which is only exploited indirectly by the current gold standard antihypertensive treatments.…”

Case of Refractory Hypertension Controlled by Repeated Renal Denervation and Celiac Plexus Block

“…There was a small study published in Hypertension, which shows that combining nitrates with Viagra can have a significant reduction in blood pressure. 3 We tried it, and initially it worked. There was a huge drop in blood pressure, but it became refractory after several days.…”

Twenty-four-hour ambulatory blood pressure measurement in clinical practice and research: a critical review of a technique in need of implementation

“…We must question also why the bodies that regulate the approval of antihypertensive drugs have not made BP measurement over 24 h mandatory for studies of drug efficacy and why the pharmaceutical industry funds such studies. Although 24-h ABPM is being used increasingly in clinical trials, it is surprising, nonetheless, that many studies continue to rely on clinic BP measurement to assess drug efficacy [3,[78][79][80][81][82][83][84][85][86][87]. Whereas these studies may be well conducted and may indeed show that the BP-lowering effect at one point in the 24-h profile is superior or inferior to another drug (or combination of drugs), they cannot provide information on the duration of BP-lowering efficacy of the drug being evaluated nor its effect on nocturnal phenomena, such as nondipping and the morning surge.…”