What is the role of the renin-angiotensin system (RAS) in blood pressure regulation and how is it targeted in the management of hypertension?

From the Guidelines

The renin-angiotensin system (RAS) plays a crucial role in blood pressure regulation and should be targeted in the management of hypertension using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as first-line treatment, as recommended by the most recent guidelines 1.

Role of RAS in Blood Pressure Regulation

The RAS is a complex system that regulates blood pressure by controlling fluid balance and vascular tone. When blood pressure drops, the kidneys release renin, which converts angiotensinogen to angiotensin I. Angiotensin-converting enzyme (ACE) then transforms angiotensin I to angiotensin II, a potent vasoconstrictor that also stimulates aldosterone release, leading to sodium and water retention. This cascade ultimately increases blood volume and blood pressure.

Targeting RAS in Hypertension Management

In hypertension management, several medication classes target different components of the RAS system. ACE inhibitors like lisinopril, enalapril, and ramipril block the conversion of angiotensin I to II, while ARBs such as losartan, valsartan, and olmesartan prevent angiotensin II from binding to its receptors. Direct renin inhibitors like aliskiren reduce renin activity, and aldosterone antagonists such as spironolactone block aldosterone's effects. These medications effectively lower blood pressure while offering additional benefits like renal protection and reduced cardiovascular events, particularly in patients with diabetes, heart failure, or chronic kidney disease.

Recommendations for RAS Inhibition

The most recent guidelines recommend the use of ACEIs or ARBs as first-line treatment for hypertension, particularly in patients with diabetes, heart failure, or chronic kidney disease 1. The combination of an ACEI and an ARB is not recommended due to the increased risk of adverse events such as hyperkalemia and acute kidney injury. Instead, dual therapy with a RAS blocker and a calcium channel blocker or diuretic is recommended as first-line treatment for patients with hypertension who require multiple medications to achieve blood pressure control 1.

Key Considerations

When targeting the RAS system in hypertension management, it is essential to consider the potential side effects of these medications, such as cough with ACE inhibitors, hyperkalemia, and potential fetal harm during pregnancy. Careful monitoring and appropriate patient selection are necessary to minimize the risk of adverse events. Additionally, patients with diabetes and hypertension should be encouraged to self-monitor their blood pressure and adjust their medication regimen as needed to achieve optimal blood pressure control 1.

From the FDA Drug Label

1. 1 Mechanism of Action Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)] is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

The renin-angiotensin system (RAS) plays a crucial role in blood pressure regulation by controlling vasoconstriction and aldosterone secretion.

• Angiotensin II is the primary vasoactive hormone of the RAS, causing vasoconstriction and stimulating aldosterone secretion.
• Losartan targets the RAS by selectively blocking the binding of angiotensin II to the AT1 receptor, thereby inhibiting its vasoconstrictor and aldosterone-secreting effects.
• The management of hypertension involves targeting the RAS with medications like losartan, which helps to regulate blood pressure by reducing the effects of angiotensin II 2.
• Additionally, it is essential to avoid dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren, as it may increase the risk of hypotension, syncope, hyperkalemia, and changes in renal function 2.

From the Research

Role of the Renin-Angiotensin System in Blood Pressure Regulation

• The renin-angiotensin system (RAS) plays a crucial role in the development of hypertension, heart failure, and nephropathy, particularly diabetic nephropathy 3.
• The RAS is involved in the regulation of blood pressure, water, and salt balance, and tissue growth control under physiologic conditions 4.
• Angiotensin II, the biologic effector of the RAS, prompts structural and functional abnormalities through the activation of cellular effects mediated via its binding with the AT(1) subtype receptors 4.

Targeting the Renin-Angiotensin System in the Management of Hypertension

• Blockade of the RAS plays a key role in the management of hypertension and other cardiovascular diseases 3.
• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are first-line anti-hypertension drug classes that are potent, effective, and largely safe 5.
• Direct renin inhibitors (DRIs), such as aliskiren, have shown similar blood pressure reduction but with more side effects 5.
• Aliskiren introduces a new concept into the management of hypertension by simultaneously reducing angiotensin I, angiotensin II, and plasma renin activity (PRA) 3.

Efficacy of Renin-Angiotensin System Inhibitors

• The efficacy of ACE inhibitors and ARBs extends beyond blood pressure reduction alone, providing cardiovascular, cerebrovascular, and renal protection 5, 6.
• However, closer scrutiny of outcome data shows little evidence that the efficacy of RAS blockers in hypertension extends beyond blood pressure reduction 5.
• Aliskiren has a dose-related systolic/diastolic blood pressure lowering effect as compared with placebo, with a magnitude of blood pressure lowering effect similar to that of ACE inhibitors and ARBs 7.

Safety Profile of Renin-Angiotensin System Inhibitors

• Mortality and non-fatal serious adverse events are not increased with aliskiren monotherapy 7.
• Diarrhea is increased in a dose-dependent manner with aliskiren, particularly with the 600 mg dose 7.
• The most frequent adverse events reported with aliskiren are headache, nasopharyngitis, diarrhea, dizziness, and fatigue 7.