IJCS | Volume 33, Nº4, July and August 2020

409 myocardial infarction or with heart failure) indicate that drugs belonging to these therapeutic classes, such as enalapril and lisinopril, would be able to increase the gene expression of ACE2 in the heart. Losartan, on the other hand, showed an increase in protein expression and enzyme activity in healthy hearts. 13,20 The literature also points that other therapeutic classes encompassing drugs such as spironolactone, ibuprofen, thiazolidinediones, atorvastatin, and fluvastatin also modulate positively the activity and / or protein expression of this enzyme in some tissues. 15,20 ACEI / ARB are therapeutic classes widely used by the hypertensive population, as well as indicated for patients with heart failure, and, according to the literature, their actions on ACE2 are indirect. The mechanism of action of ACE inhibitors, such as lisinopril, encompasses their ability to bind to ACE, inhibiting its activity and, therefore, the formation of Ang II. ARBs, like losartan, are AT1 receptor antagonists, binding to this pharmacological receptor and preventing its activation by Ang II. Thus, both classes are able to decrease vasoconstriction mediated by this active peptide and blood volume, justifying the antihypertensive effect, as well as reducing the cardiac remodeling observed in heart failure and apparently predisposing patients to infection with the new coronavirus, although the latter association is still uncertain (figure 2). 17 As Ibuprofen also increases the expression of ACE2, the WHO (World Health Organization) requested caution and the suspension, when possible, of the use of this non-steroidal anti- inflammatory as an analgesic and antipyretic for the treatment of disease symptoms. However, it should be noted that there is greater evidence of RAAS and Ang II activity, to the detriment of Ang 1-7, in patients infected with the new coronavirus due to ACE2 endocytosis, which is then correlated to viral load and pulmonary damage. From this perspective, intervention with ARB and ACE inhibitors in patients with COVID-19 and CVD could then be positive, due to the fact that the decrease in overactivation of RAAS and the favoring of the ACE2 pathway, with higher production of Ang 1-7, have the additional potential to mitigate lung injury. 20 Thus, there is a duality associated with the negative modulation of RAAS and the consequent increase in the expression of ACE2 in the course of COVID-19: the possible facilitation of host infection by the new coronavirus versus the attenuation of the deleterious effects of the disease by increasing the availability of Ang 1-7. Therefore, the use of camostat, a protease inhibitor approved for the treatment of chronic pancreatitis, can increase the safety of drugs that increase ACE2 expression. This substance seems to inhibit the TMPRSS2 transmembrane protease present in the host cell membrane that favors the access of the viral genome to the cellular machinery for replication via S protein - ACE2 interaction. A randomized, placebo-controlled study is being conducted to verify the effects of this agent in COVID-19. 11 Figure 2 illustrates the RAAS, in the absence or in the presence of pharmacological interventions covering ACEI and ARB, as well as its point of intersection with the infection by the new coronavirus. Other Cardiovascular Drugs  The review by Solaimanzadeh, published on March 20, 2020, points to the benefit of using other drugs with action on the cardiovascular system such as nifedipine, a calcium channel blocker used as an antihypertensive and anti-anginal agent, acetazolamide, an example of a diuretic inhibitor of carbonic anhydrase, used in acute mountain sickness, in edematous conditions and in glaucoma, as well as phosphodiesterase inhibitors commonly prescribed for erectile dysfunction, such as sildenafil and tadalafil, in patients with COVID-19. This is because all these drugs are useful in the treatment of high-altitude pulmonary edema (HAPE). Both conditions exhibit a reduced proportion of partial arterial oxygen pressure to fractional inspired oxygen, with concomitant hypoxia and tachypnea, reduced levels of carbon dioxide and the presence of irregular infiltrates in the lung fields. Likewise, elevated levels of fibrinogen in both conditions are likely to be an epiphenomenon of edema formation rather than activation of clotting. Thus, both COVID-19 and HAPE converge to ARDS. Acetazolamide is then useful as it potently reduces hypoxic pulmonary vasoconstriction, improves minute ventilation, and expired vital capacity, as does nifedipine and phosphodiesterase inhibitors, which are also drugs that reduce pulmonary pressure. 21 Table 1 shows the dosage of cardiovascular drugs that may be useful for patients with ARDS in the course of COVID-19. Pedro et al. Cardiovascular pharmacotherapy and covid-19 Int J Cardiovasc Sci. 2020; 33(4):404-411 Viewpoint