ACE inhibitors and the renal regulation of blood pressure

An overriding trend in the medical profession is the movement toward increasingly patient-specific treatment protocols, or so called ‘personalized medicine’. In accordance with this transition away from generalized applications of medical knowledge, clinical and pharmacological research has taken a particular interest in evaluating the outcomes of patients with increasingly specific risk factors and co-morbidities.

Figure 1: The renin-angiotensin-aldosterone system and the site of ACE Inhibitor action

Angiotensin-converting enzyme (ACE) inhibitors are a first line pharmacological therapy in the management of hypertension (high blood pressure) and congestive heart failure. The primary mechanism by which these drugs achieve lower blood pressures in hypertensive patients is due to the reduction in activity of ACE and thus the inhibition of the conversion of angiotensin I to angiotensin II. In addition, ACE Inhibitors have been shown to inhibit the degradation of the vasodilating peptide, bradykinin, by ACE. Further details of this mechanism are shown in Figure 1.

Due to the multifactorial nature of the renin-angiotensin-aldosterone system (RAAS), several potential targets for pharmacological treatment are readily identified. Indeed, in addition to ACE Inhibitors, angiotensin receptor blockers (ARBs), as well as direct renin inhibitors are routinely used. Although all of these drugs are effective in the management of hypertension, each one does so by means of a different mechanism, oftentimes accompanied by unique secondary effects. The efficacies of each of these drugs are continually evaluated through clinical practice, and as new research and potential new applications come to light, treatment algorithms are regularly adjusted.

A $1999$‍ study, noting that a strong majority of hypertensive individuals also demonstrate insulin resistance and decreased peripheral glucose dispersal as well as hyperinsulinemia, examined the effects of ACE Inhibitors and ARBs on glucose transport in insulin resistant muscle. Obese rats were injected with water, Captopril (an ACE Inhibitor), bradykinin, or eprosartan (an ARB). After treatment, the rats were anesthetized, and both epitrochlearis muscles removed, and incubated in a solution of $8\text{mM}$‍ glucose, $32\text{mM}$‍ mannitol, and $0.1\mathrm{\%}$‍ bovine serum albumin (BSA). One muscle from each rat was incubated with the addition of a $2\text{mUnits/mL}$‍ insulin medium. After twenty minutes of incubation, the muscles were dissolved and used to determine glucose transport activity. The results of the experiment are shown in Figure 2.

Figure 2: Effects of acute treatment with Captopril, bradykinin, or Eprosartan on glucose transport activity. Controls (vehicle-treated) are demonstrated for each treatment group, and the glucose uptake in the absence (-) and presence (+) of insulin reported with the net increase above basal (∆) caused by insulin. A “*” denotes data that is statistically significant.

To further elucidate causal relationships and eliminate potential statistical confounding factors, the experiment is run again, this time including a treatment group which received a dose of “Drug X”. Drug X is a well documented agent that is known to produce significant anti-hypertensive effects in patients and experimental models. The mechanism by which this is achieved is through the direct inhibition of renin.

Passage adapted from: Henriksen, E. J., Jacob, S., Kinnick, T. R., Youngblood, E. B., Schmit, M. B., & Dietze, G. J. ACE inhibition and glucose transport in insulin resistant muscle: roles of bradykinin and nitric oxide. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 277.