PDE-5 inhibitors such as sildenafil citrate (Viagra) commonly prescribed for the management of erectile dysfunction (ED) has been reported to have failure rate of 30-50% at the attempt of intercourse. This has thus necessitated the need to source for better alternatives in medicinal plants for managing ED and its associated risk factors like cardiovascular diseases (CVD).Therefore, this study investigated the PDE-5 inhibitory activities and modulatory properties of Cnestisferruginea root, Fadogiaagrestis stem and their combinations on endothelial markers of paroxetine-treated rats. The specific objectives of this study were to: (i) determine the secondary metabolites in the plantsâ€™ parts; (ii) partially purify PDE-5 from rat penile and cardiac tissues (iii) carry out PDE-5 inhibitory assays of the extracts in the presence of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP); (iv) determine the effects of paroxetine on selected endothelial, erectile and cardiovascular functional biomarkers in rats; and (v) determine the effects of the extracts on the selected markers of erectile, cardiovascular and endothelial dysfunctions of male rats pre-treated with paroxetine.rnForty male Wistar rats (200.32 Â± 6.33) were used for the invitro PDE-5 inhibitory assays, after which Michealis-Menten constant (Km) and maximum velocity (Vmax) were derived from the double reciprocal plots. For the invivo study, 210 male Wistar rats (210.43 Â± 4.04) g were grouped into two consisting of 40 rats in group A (control) and 170 rats in group B (received 10 mg/kg body weight of paroxetine) for 21 days. Eight animals from groups A and B were sacrificed on days 5,8,15 and 22 of paroxetine treatment. The remaining animals in group B were re-assigned into 5 groups of 16 animals each. 8 rats were sacrificed from each group on days 29 and 36 of experimental period. Biochemical assays were done on the tissues and plasma. Data were subjected to Analysis of Variance and Duncan multiple range Test. Statistical significance was set at p<0.05.rnThe results revealed that:rni C. ferruginea root extract contained six secondary metabolites while F. agrestis stem extract contained five secondary metabolites with alkaloids as major component of the plants (49.95 Â± 0.25 x 10-2 and 59.15 Â± 0.25 x 10-2 mg/g) respectively; rnii purification folds of isolated penile PDE-5 was 5.6 while that of cardiac PDE-5 was 7.5 when compared with the crude extracts of PDE-5; rniii the extracts at 0.025-0.125 Âµg/mL competitively inhibited PDE-5 activities in a manner similar to sildenafil;rniv paroxetine-treatment related PDE-5 inhibition was reversed by the extracts after post-treatment; rnv paroxetine-treatment related reduction in nitric oxide concentration was significantly (p>0.05) elevated by the extracts and was sustained post-treatment; rnvi endothelin-1, cGMP, and testosterone concentrations were significantly (p>0.05) decreased during treatment and post-treatment periods. rnvii paroxetine related increase in creatine kinase, triacylglycerol, total cholesterol and low density lipoprotein cholesterol were significantly (p>0.05) decreased after administration of extracts.rnThe study concluded that the extracts exerted their aphrodisiac activities via inhibition of penile phosphodiesterase-5 in a similar mechanism as sildenafil. Moreover, the extracts can be used for managing ED and CVD.