How Do Antihypertensive Drugs Work? Insights from Studies of the Renal Regulation of Arterial Blood Pressure

Abstract

Though antihypertensive drugs have been in use for many decades, the mechanisms by which they act chronically to reduce blood pressure remain unclear. Over long periods, mean arterial blood pressure must match the perfusion pressure necessary for the kidney to achieve its role in eliminating the daily intake of salt and water. It follows that the kidney is the most likely target for the action of most effective antihypertensive agents used chronically in clinical practice today. Here we review the long-term renal actions of antihypertensive agents in human studies and find three different mechanisms of action for the drugs investigated. (i) Selective vasodilatation of the renal afferent arteriole (prazosin, indoramin, clonidine, moxonidine, α-methyldopa, some Ca(++)-channel blockers, angiotensin-receptor blockers, atenolol, metoprolol, bisoprolol, labetolol, hydrochlorothiazide, and furosemide). (ii) Inhibition of tubular solute reabsorption (propranolol, nadolol, oxprenolol, and indapamide). (iii) A combination of these first two mechanisms (amlodipine, nifedipine and ACE-inhibitors). These findings provide insights into the actions of antihypertensive drugs, and challenge misconceptions about the mechanisms underlying the therapeutic efficacy of many of the agents.

Keywords: antihypertensive drugs; diuretics; hypertension; renal circulation; vasodilator agents.

Figure 1

The profile of hydrostatic pressures along the renal vasculature, showing typical normal values. MAP, mean arterial pressure; Pglom, glomerular pressure; Ppc, peritubular capillary pressure. The large arrow labeled “Filtrate” is a cartoon representation of the flow of glomerular filtrate, most of which is reabsorbed from the tubule into the peritubular capillaries. The small fraction of the filtrate that is not reabsorbed is depicted by the arrow labeled “Urine.”

Figure 2

Pressure–natriuresis lines for eight hypertensive adult patients before (open circles) and after (closed circles) administration of a thiazide diuretic (mefruside 25 mg daily). Urinary sodium excretion rate was measured after several periods of 7 days of constant daily sodium intake of between 1 and 18 g NaCl and systemic mean arterial pressure plotted as a function of sodium excretion. Data from Saito and Kimura (1996). Note that the untreated hypertensive patients showed a marked dependence of mean arterial pressure (MAP) on sodium excretion, whilst thiazide administration reduced this dependence and also lowered MAP.

Figure 3

The actions on the hydrostatic pressure profile along the renal vasculature of drugs that primarily dilate the afferent arterioles and leave glomerular filtration rate, glomerular capillary pressure (P_glom), and pressures downstream of the glomerular capillaries unchanged. MAP, mean arterial pressure; P_pc, peritubular capillary pressure.

Figure 4

The actions on the hydrostatic pressure profile along the renal vasculature of drugs that primarily redistribute the peritubular capillary pressure (P_pc) component of the Starling forces across the tubular epithelium by inhibiting active solute uptake from the renal tubule. MAP, mean arterial pressure; P_glom, glomerular capillary pressure.

Figure 5

The actions on the hydrostatic pressure profile along the renal vasculature of drugs that both dilate afferent arterioles and redistribute the peritubular capillary pressure (P_pc) component of the Starling forces across the tubular epithelium. These actions lead to a raised glomerular capillary pressure (P_glom) and a greater pressure drop across the efferent arterioles, either due to efferent arteriolar constriction or an increased renal blood flow. MAP, mean arterial pressure.

Figure 6

Kimura's classification of antihypertensive drugs according to their effects of the pressure-natriuresis relationship. Adapted from Dorrington and Pandit (2009).

Figure 7

Depiction of the hypothesis that increasing vasodilatory action of diuretics inhibiting tubulo-arteriolar feedback can account for the decrease in gradient of the pressure-natriuresis line brought about by these drugs. A constant degree of afferent arteriolar dilatation leads to a parallel downward shift of the pressure-natriuresis line (as shown in Figure 6). The stack of pressure-natriuresis lines depicted here for diuretics arises because the degree of afferent arteriolar dilatation is hypothesized to depend upon inhibition tubulo-arteriolar feedback, which in turn depends upon the sodium excretion rate.