The ability to reverse, not only prevent, target organ damage of the heart and especially the kidney is the current focus of hypertension research. Hypertension, a complex, multifactorial disease, comprises a host of hormonal and humoral factors that interrelate, in addition to factors such as concomitant diseases and aging, to produce target organ involvement, specifically of the heart, kidney and brain.

The progressive increase in hospitalization rates and mortality from heart failure and end-stage renal disease (ESRD) is not well recognized, despite a decrease in stroke and coronary heart disease mortality rates. Heart disease constitutes the most common diagnosis in the United States for people aged 65 years and older and contributes to the increased incidence of heart failure in this population. Diabetes and hypertension play key roles in this increase in end-stage renal disease, with a close interrelationship between them, both of which are frequently present in most people with ESRD.

Left ventricular hypertrophy (LVH) typifies the changes seen in the heart in the setting of hypertension, namely, hypertrophy of the myocytes associated with ischemia. Oxygen demands are increased with increased levels of blood pressure and myocardial size, leading to greater demands in terms of ischemia and coronary flow reserve.

However, ischemia and reduction in coronary flow reserve are also caused by the co-existing epicardial occlusive arterial disease of the coronary circulation produced by atherosclerosis and by arteriolar disease of the coronary circulation, due to the vasoconstriction of hypertension itself.

Both LVH and epicardial disease lead to ischemia and both are associated with endothelial dysfunction. Endothelial dysfunction is present not only in the larger coronary artery, but also in the arterioles. The concept of collagen deposition and fibrosis intervention, little known a decade ago, adds to the clinical complexity. Collagen is present in the ventricular tissues in the extracellular matrix, whereas fibrosis is present perivascularly. Patients with hypertension and LVH subjected to treadmill testing who had electrocardiographically-defined ST-segment changes, had a reduction in coronary flow reserve, compared to patients who did not have significant ST-segment depression on treadmill testing.

Ventricular hypertrophy confers a greater risk than that by increased systolic or diastolic pressure. A reduction in hypertension or elevated cholesterol reduces the risk associated with these factors. In contrast, a reduction in myocardial mass does not confer a decrease in risk. However, this has been difficult to demonstrate because the drugs used to decrease myocardial size also reduce pressure. Other drugs given in this setting could prevent arrhythmias or increase flow to the myocardium. Thus, whether the improvement in risk is related to decreased myocardial size or decreased blood pressure is unclear. The hypertrophied muscle perhaps confers risk itself. Clearly, ischemia and fibrosis are also contributing to the increased risk.

The important role of coronary flow reserve in hypertensive patients with diminished resting coronary flow, maximum coronary flow, minimal coronary vascular resistance, and coronary flow reserve has been demonstrated by studies in Frohlich's laboratory. Coronary flow reserve is diminished slightly in hypertensive patients, despite a normal treadmill study. Yet, the decrease in coronary flow reserve was less than that seen in patients with hypertension without epicardial atherosclerotic disease with diminished coronary flow reserve in ST-wave segments on treadmill testing.

Endothelial dysfunction is present in addition to the ischemia from vasoconstriction and the demand of the ventricle, which is not satisfied by the physiological or pharmacological load. Endothelial dysfunction, the inability of the endothelium to increase nitric oxide production locally to increase myocardial blood flow, is caused by a range of diseases and naturally-occurring events, such as aging and menopause. Many of the causes of endothelial dysfunction can be addressed, such as the treatment of hypertension or diabetes, smoking cessation, the use of hormone replacement therapy, or, as Frohlich and colleagues recently demonstrated in hypertensive rats, by giving drugs to prevent or reverse the hypertensive problems seen with aging.

Laboratory studies have shown that hypertensive SHR rats cannot increase their coronary flow reserve, even if basal flow is normal, in response to maximal exercise or dipyridamole, in contrast to normotensive WKY rats. Interestingly, coronary flow reserve is increased to the same level as in normotensive rats with 12-weeks of treatment with an ACE inhibitor or an angiotensin receptor blocker (ARB) alone or in combination to achieve the same level of blood pressure reduction. The increase in coronary flow is greater with exercise or dipyridamole. This is due to the diminished conversion of angiotensin I to angiotensin II and the increased availability of kinins with the ACE inhibitor. The angiotensin type 1 (AT₁) blocker is able to capture more of the angiotensin and block its effects. Other contributing mechanisms include upregulation of angiotensin II receptors, increased local nitric oxide formation, reduced collagen deposition, reduced intravascular thrombosis, and reduced apoptotic changes. Notably, hypertensive heart disease is a dynamic, not static, disease process. Hence, correction of the associated problems through treatment is possible.

Hypertension continues to be the most common cause of heart failure in patients aged 50 years or more. However, diastolic dysfunction is now more predominant than systolic dysfunction. Diastolic dysfunction, impaired ventricular function in diastole that may precede systolic function, occurs primarily in elderly persons and in patients with ischemic heart disease. Shapiro and McKenna demonstrated that normotensive athletes, with the same degree of ventricular hypertrophy as hypertensive patients, based on three different indices of diastolic function, maintained normal diastolic function. In contrast, the hypertensive patients consistently had impaired diastolic function, particularly the older patients.

Aging contributes to diminished coronary flow reserve, even at baseline, in the left and right ventricles of hypertensive rats compared to normotensive rats. Notably, even normotensive rats without LVH have diminished coronary flow reserve in older age. Also, at every age in the non-hypertrophied hypertensive ventricle, there is a reduction in right ventricular coronary flow reserve, even though in the older age group there is diminished flow in the non-hypertrophied right ventricles. Further, hydroxyproline concentration increases and coronary flow reserve decreases in both the normotensive and hypertensive rats with aging. Hydroxyproline is the constitutive chemical responsible for collagen development. Clearly, both fibrosis and ischemia are associated with hypertension.

Coronary flow reserve in the right and left ventricle of study animals has been increased with ACE inhibitors and calcium antagonists. Both class of agents decreased the hydroxyproline concentration and content in the left ventricle. But, in the right ventricle the calcium antagonist increases hydroxyproline. Notably, no change in hydroxyproline concentration in the right ventricle was seen with an ACE inhibitor. Therapy in the animals was able to reduce the collagen content of the left and right ventricles, particularly with the ACE inhibitor, and even with a calcium antagonist.

The diminished coronary flow and coronary flow reserve associated with aging, hypertrophy, and non-hypertrophy can be increased with the current antihypertensive therapies. While fibrosis is diminished by all of the available therapeutic agents, the response is different in the left and right ventricles and in the hypertrophied or non-hypertrophied ventricle. Angiotensin type 2- (AT₂) receptor blockade increased coronary flow reserve in the right and left ventricles. AT₁- receptor blockade had no effect on the hemodynamics of the ventricle. Notably, when blocking both the type-2 and type-1 receptors the benefit seen with the hydroxyproline reduction is lost, because the type-2 receptor is mediating the fibrosis from angiotensin stimulation at the receptor sites.

Elucidation of this complex problem continues through animal and clinical studies. Various investigators have shown that 1) one year of treatment with an ACE inhibitor resulted in a marked reduction in the amount of collagen in the ventricle; 2) although an ACE inhibitor and a thiazide diuretic reduced blood pressure to the same degree, the ACE inhibitor decreased the levels of hydroxyproline and collagen, whereas the thiazide diuretic increased them (the ACE inhibitor inhibits and the thiazide diuretic stimulates local angiotensin synthesis); 3) there is a correlation between the amount of collagen in the heart and the degree of the circulating peptide; 4) collagen plays a role in the ventricular mass generated in hypertension and its reduction with antihypertensive therapy.

The effects of ischemia and fibrosis seen in the heart are also seen in the kidney. Aging increases the glomerular filtration rate and reduces the filtration fraction promoting hyperfiltration and the renovascular resistance, despite lowering of blood pressure to normal levels in hypertensive rats with an ACE inhibitor, as shown in studies in 72-week-old rats. Micropuncture studies to assess glomerular dynamics show an increase in the single nephron plasma flow in superficial nephrons with an ACE inhibitor. ACE inhibitor therapy is associated with increased glomerular filtration rate, slightly decreased filtration fraction, reduced glomerulus pressure to normal levels, and reduced resistance in the afferent and efferent arterials.

Pathological studies are continuing to measure the degree of glomerular and arteriolar injury. The ACE inhibitors have been shown to reduce the arteriolar injury, but more profoundly to reduce the glomerular injury based on the nephrosclerosis index. The improvement in the glomerular injury is primarily in the deeper juxtaglomerular, associated with markedly reduced urinary protein excretions in the study animals. Thus, the ACE inhibitors are a therapeutic class of agents that can reverse the hypertensive diseases produced by severe nephrosclerosis.

In laboratory studies, glomerular damage was caused by endothelial injury using L-NAME to arrest or inhibit nitric oxide production to further study the association between aging and hypertension, atherosclerosis and nephrosclerosis. Systemic hemodynamics were measured after three weeks of treatment with an ACE inhibitor or thiazide diuretic in 21-week-old rats. Both agents reduced blood pressure to the same degree, although the mean arterial pressures of about 190 mm Hg are elevated. L-NAME reduced cardiac output and increased vascular resistance, whereas the reverse occurs with the ACE inhibitor with increased cardiac output and decreased vascular resistance. In contrast, the thiazide diuretic further increases vascular resistance and cardiac output is not improved. The single nephron plasma flow, reduced with L-NAME, and glomerular filtration are increased and normalized with the ACE inhibitor, as shown by micropuncture studies. The filtration coefficients are markedly improved with the ACE inhibitor, but not with the thiazide diuretic alone.

ACE inhibitor therapy, in contrast to thiazide diuretics, is also associated in these studies with improvements in glomerular hydrostatic pressure, stop flow pressures, and afferent and efferent arteriolar resistances. Clearly, the renin angiotensin system (RAS) in the kidney is inhibited with an ACE inhibitor and stimulated with a thiazide diuretic, which have disparate effects on the renal hemodynamic and glomerular dynamic findings. Glomerular and arteriolar injury were improved with an ACE inhibitor, but were aggravated with a thiazide diuretic. The ACE inhibitor improved the total nephrosclerosis score and protein excretion, which were aggravated with a thiazide diuretic.

Studies with an ARB, an ACE inhibitor, and an ACE inhibitor with a bradykinin antagonist showed that each decreased plasma flow and improved the glomerular filtration rate and filtration fraction. In these studies, therapy was clearly able to reverse the injury produced in the animals. The intra-renal hemodynamics in these studies showed that the afferent, efferent, glomerular hydrostatic pressures and stop flow pressures were improved with therapy. Notably, the lack of a differential effect with the bradykinin antagonist demonstrates that the angiotensin, not the bradykinin, is responsible for the observed improvements. Glomerular and arteriolar injury were improved with the angiotensin-1 blocker and the ACE inhibitor, while there was little difference with bradykinin blockade.

Calcium antagonists (N-type, P-type, L-type) have been shown in animal studies in Frohlich's laboratory to improve renal plasma flow, glomerular filtration rate, and renovascular resistance. The micropuncture studies showed these agents improved single nephron flow, plasma flow, glomerular filtration rate, and filtration coefficients in the kidney. Further, the arteriolar resistance in the afferent and efferent arterioles, stop flow pressures, glomerular hydrostatic pressure, creatinine levels and glomerular and arteriolar injuries were improved and urinary protein levels decreased with the calcium antagonists.

Thus, it appears that the calcium antagonist reverses target organ damage in the kidney as well as ACE inhibitors and ARBs. The final common pathway may not be angiotensin itself, but rather the effect of angiotensin and calcium antagonists on intracellular calcium. In the kidney, the renal lesions are reversible in naturally-occurring or experimental hypertension where glomerular injury is induced in the endothelium with L-NAME. This reversal is not solely dependent on effects on blood pressure. Drugs that prevent the participation of the RAS or perhaps even the generation of calcium intracellularly can reverse lesions.