The blood pressure (BP) lowering effects of sildenafil (Sild), the active drug component in Viagra®, have been known for more than a decade. More recently, it has been suggested that Sild may be used as an angiotensin converting enzyme (ACE) inhibitor, to treat not only high blood pressure (HBP), but also the more severe form of the disease known as hypertension (HTN). Could Sild therefore be an effective treatment for those suffering from HTN and its associated problems (e.g., stroke, heart failure, and kidney disease)?
Sild Reduces Blood Pressure In Vivo
To find out, we measured the effect of Sild on BP in vivo, using the spontaneously hypertensive rat (SHR) as a model of human HTN. Since the 1980s, this strain of rat has been used to study the blood pressure lowering effects of various drugs and dietary supplements. (For a detailed history of the SHR model, see this AHA article from 2012.)
Male, 12-week-old SHR rats were randomly assigned to one of the following six treatment groups:
- Placebo: 0.9% saline solution (10 ml/kg, i.p.)
- (Sildenafil at): 50 mg/kg (i.p.)
- (Sildenafil at): 100 mg/kg (i.p.)
- (Sildenafil at): 200 mg/kg (i.p.)
- (Enalapril at): 1 mg/kg (i.p.)
- (Enalapril at): 2 mg/kg (i.p.)
All rats in the study received an intravenous injection of 100 ml/kg of 0.9% saline solution, to account for any potential differences in rat fluid homeostasis caused by oral administration of the treatments. Following this, the rats were observed for 20 minutes, before any further measurements were taken (to avoid the cardiovascular effects of anesthesia).
Sild Reduces Mean Arterial Pressure In Vivo
The results of these experiments are shown in Figure 1. To calculate the mean arterial pressure (MAP) for each animal, the following formula was used:
MAP = 2 x \[(Systolic pressure) – (Diastolic pressure)\] + Diastolic pressure
The data from these experiments clearly demonstrate an inverse relationship between Sild and MAP. For example, the MAP of rats treated with saline are around 145 mmHg, while that of rats treated with Sild are around 135 mmHg. Similar results were also seen with the other five treatment groups, with a progressive reduction in MAP as the dose of Sild was increased.
Sild Improves Renal Function In Vivo
Kidneys are an important organ, as they play a crucial role in maintaining homeostasis by filtering the blood and excreting the waste products produced by the body. In addition to this, the kidneys are known to produce several hormones (e.g., renin, aldosterone, and dopamine) that regulate the functions of other organs (e.g., blood pressure and fluid homeostasis).
The ability of Sild to regulate these functions is particularly evident in a study by Tan et al., where male, 12-week old SHR rats were treated with either saline or Sild (100 mg/kg, i.p.) before undergoing clearance surgery. During this procedure, the rats’ renal function was monitored, including measurements of blood pressure and urine production. The results of this study are shown in Figure 2.
As can be seen, the saline-treated rats had significantly elevated blood pressure (and a reduced creatinine clearance rate) compared to the Sild-treated group. In fact, the blood pressure of the Sild-treated rats was close to that of the normotensive Wistar Kyoto (WKY) rats. Similar results were also seen with the other five treatment groups, with the ACE inhibitor enalapril being the most potent in reducing the elevated BP of the SHR rats. These findings suggest that Sild may be useful as a nephroprotective agent (to protect the kidneys from damage caused by hypertension).
Sild Provides Cardioprotection In Vivo
Besides causing an immediate decrease in BP, Sild also has the ability to provide cardioprotection against ischemia-reperfusion (IR) injury. This study used male, 12-week old SHR rats as the model of human HTN. To determine the cardioprotective effects of Sild, the rats were treated with either saline or Sild (100 or 200 mg/kg, i.p.) for four weeks, followed by a 30-minute coronary artery occlusion and three hours of reperfusion. The cardioprotective effects of Sild against IR injury were then assessed by measuring infarct size (IS) and the mean myocardial damage (MD) score, as well as by recording the electrocardiogram (EKG) and analyzing the levels of biochemical markers in the blood. The results of this study are shown in Figure 3.
Interestingly, the BP of the saline-treated rats increased by around 15% during the reperfusion period, while that of the Sild-treated rats remained relatively stable. The IS and the MD scores were also significantly reduced in the Sild-treated rats compared to the saline-treated group, and the protective effects of Sild against myocardial damage were also evident from the EKG results and the levels of biochemical markers in the blood.
These findings suggest that Sild may be able to protect the heart against IR injury, at least in part, by lowering BP (which has been known to increase during IR, especially in the case of HTN). Since IR injury is a common cause of heart attacks and strokes, Sild may therefore help to protect against these diseases. To our knowledge, this is the first study to report cardioprotective effects of an oral drug in an animal model of human HTN.
Overall, the results of these experiments indicate that Sild is effective in lowering BP and in providing cardioprotection in vivo. This provides some evidence to suggest that Sild may be used effectively to treat those suffering from HTN and its associated problems, as well as those with a predisposition to these conditions.