Acta Anaesthesiol Scand 1993: 37, Supplementum 99: 33-37

Haemodynamics and tissue specificity with isradipine J. B. LESLIE Department of Cardiac Anaesthesia, Duke University Medical Center, Durham, North Carolina, USA

The significant effects of isradipine in producing arterial vasodilatation and mild negative chronotropic effects without significant negative inotropic effects suggests that this agent should provide excellent antihypertensive efficacy in the treatment of perioperative hypertension. Isradipine may prove to be a safe antihypertensive treatment in patients with impaired ventricular function (cardiac failure), impaired myocardial perfusion (ischaemia), and in cases of selected conduction abnormalities or arrhythmias. The demonstration that its effects are limited to vascular resistance rather than vascular capacitance is an important distinguishing feature of isradipine compared with other antihypertensive agents. Finally, the potential application of this dihydropyridine calcium antagonist for cytoprotection and its effects on atherosclerosis remain exciting therapeutic prospects.

K y words: Antihypertensive treatment; calcium antagonists; cardiovascular effects; isradipine; tissue-specific effects.

Isradipine is a dihydropyridine calcium antagonist with significant arterial vasodilatatory properties and antihypertensive effects. The drug binds to calcium channels with very high affinity and excellent speci- ficity. Isradipine has been shown to preferentially di- late specific vasculature, including the coronary, cer- ebral and skeletal arterial vessels, and blood pressure reductions are seen in all three parameters: systolic, diastolic and mean arterial pressure (MAP). Greater binding of the dihydropyridine occurs in the larger arteries, again suggesting greater selectivity of action. Thus, the antihypertensive effects of isradipine are di- rected at the resistance vessels and not the capacitance vessels, an important distinction from other calcium antagonists or antihypertensive agents. Finally, be- cause of the greater selectivity of isradipine for vascular smooth muscle than myocardium or specialized con- duction tissue, the compound has negligible negative chronotropic, dromotropic and inotropic actions.

OVERVIEW OF CALCIUM ANTAGONISTS Because of the fundamental role of calcium in in- numerable intracellular reactions and intracellular sig- nalling, the calcium antagonists have been shown to have a wide range of physiological activities and nu- merous potential indications (1) (Table 1). These agents have been divided into three different classes, based on their chemical structure. The classes include: the phenylalkylamines, typified by verapamil; the ben- zothiazepines, typified by diltiazem; and the dihydro-

pyridines, the largest group of calcium antagonists currently available for the treatment of hypertension.

Selectivity and speczjicity Calcium antagonists bind stereospecifically to a 165 kD polypeptide (alpha, subunit) of the calcium slow, voltage-operated, L channel (2) . While the L channel is present in cardiac and vascular smooth muscle, there are at least two other voltage-operated channels, the T and N, each with a different percentage of distri- bution in various tissues and organs. The binding sites for the three classes of calcium antagonists are also slightly different, which contributes to their differences in tissue selectivity (3). The dihydropyridines have a relatively greater effect on vascular smooth muscle with minimal effects on cardiac contractility. The phenylal- kylamines can produce alterations in cardiac conduc- tion which limit their use especially in combination with the beta-blockers.

Calcium antagonists currently available or under development Of the currently available calcium antagonists for oral antihypertensive therapy, at present none are ap-

Table 1 Potential theraneutic indications for calcium antaeonists.

Hypertension Myocardial ischaemia Cardiac arrhythmias Cerebral infarctions

34 J. B. LESLIE

proved and available in an intravenous preparation for the treatment of perioperative hypertension. How- ever, as several of these drugs are in the final stages of clinical trials, they may soon be available to the prac- tising physician for use as antihypertensives, anti- arrhythmia or any other clinician-determined prescri- bing indications. Therefore, it is important to provide comparisons between these agents wherever possible as, in addition to differences in selectivity and speci- ficity, calcium antagonists also exhibit significant dif- ferences in their pharmacokinetic properties.

ISRADIPINE SPECIFICITY The effects of isradipine on the myocardium include an increased coronary blood flow as a consequence of decreased coronary vascular resistance, and an in- creased peak left ventricular dP/dt. There is mild inhi- bition of sinus node function, but no effects on atriov- entricular conduction nor decreases in myocardial contractility. This is in contrast to other dihydropyri- dines that have varying degrees of negative inotropism (Table 2) (4).

Isradipine reduces myocardial oxygen consumption through its effects on afterload. There may be, how- ever, an increase in heart rate due to an overriding reflex sympathetic activation following the drug-in- duced reduction of blood pressure. This increase in heart rate is usually not statistically significant and, even more important, of no clinical significance. Dur- ing pacing in patients with coronary artery disease, the drug increases ejection fraction and minimizes the decrements in percent regional myocardial segment shortening. In these patients, a decrease in cumulative ST-segment depression with isradipine has been docu- mented, although its anti-anginal efficacy remains to

Table 2 Tissue selectivity of calcium antagonists.

Conducting and

Myo- Vascula- nodal Skeletal cardium ture tissue muscle

- Verapamil + + + Gallopamil (D600) + + + Diltiazem + + + Nifedipine + + + Ni trendipine + + + + Nisoldipine + + + + + - - Nimodipine + + + + + Felodipine + + + + + Amlodipine + + + + + - -

- -

- - - -

- -

- -

Isradiuine + + + + + - -

Modified from reference 4, with permission. + - + + + + =range of effect; - =no effect.

be proven. Chronic treatment may reduce left ven- tricular wall thickness and mass in association with its antihypertensive efficacy, and there is usually a reduction in pulmonary vascular resistance.

Cardiovascular effects The additional vascular effects of isradipine include not only a significant reduction in systemic vascular resistance (SVR), but also a reduction in systolic wall tension. Ventricular relaxation and diastolic filling are also improved.

There is a minimal effect on ventricular filling press- ures [left ventricular end-diastolic pressure (LVEDP) and central venous pressure (CVP)] with maintenance of the pulmonary wedge pressure (PCWP) and in- creases in cardiac performance (cardiac output, CO). These increases in CO, however, are not usually conse- quential solely to a significant increase in the heart rate. Perhaps as a consequence of this selectivity, the drug produces minimal orthostatic hypotension.

There is a marked decrease in total peripheral resist- ance (TPR) and blood pressure following isradipine, and either nil, or only slight, increases in heart rate (around 5%) which are normally of no clinical signifi- cance (5, 6).

Myocardial contractility. Isradipine appears to have less myocardial depressant effect than either nifedipine or diltiazem compared at similar levels of vasodilatation and antihypertensive effect (7 ,8) . The relative negative inotropic activity of several calcium antagonists has been investigated in electrically driven human papil- lary muscle strips and human atrial trabeculae. When ranking the potential negative inotropism on the basis of therapeutic plasma concentrations, investigators have shown the cardiodepressant risks to be verapam- il > nifedipine > diltiazem > isradipine (9). Due to its selectivity and specificity, isradipine has been safely used in patients with heart failure (10, 11).

Myocardial conduction. Most of the dihydropyridines have relatively minor effects on cardiac conduction; however, verapamil slows impulse conduction through the atrioventricular node and is useful in the treatment of supraventricular tachycardias. Isradipine, as with other dihydropyridines, is often used in combination with beta-blockers in the treatment of hypertension without significant adverse effects ( 12). In addition, isradipine has been used safely in patients with sick sinus syndrome ( 13).

Myocardial ischaemia. The calcium antagonists are simi- lar in efficacy to beta-blockers as antianginal agents, and have also been shown to prevent exercise-induced

ISRADIPINE TISSUE SPECIFICITY 35

coronary constriction of stenotic segments when in- jected directly into the coronary arteries (14, 15). Isradipine has been used safely and effectively in pa- tients with angina and hypertension ( 16).

Myocardial hypertrophy. Reversal of left ventricular hypertrophy (LVH) has been observed with some anti- hypertensives. Unlike some of the other calcium antag- onists which produce variable results, isradipine has been shown to reverse experimental LVH and to re- duce left ventricular mass (as determined by electro- cardiographic Romhilt-Estes scoring). The regression of LVH appears early in the course of clinical therapy, as soon as 45 days after initiation of therapy, and progresses with continued therapy, as measured at 90 days (17, 18). The failure of other calcium antagonists to reverse LVH is not well understood and may not be related to antihypertensive effectiveness alone.

Peripheral ischaemia. The vascular selectivity of isradi- pine also suggests potential effectiveness in patients with peripheral vasoconstriction. As expected, it has been demonstrated to have a favourable effect in Ray- naud’s phenomenon ( 19).

Cerebral effects Several of the dihydropyridines, including isradipine, have been shown to reduce cerebral damage and im- prove neurological outcome following embolic stroke in a rat model (20).

Isradipine increases cerebral blood flow and reduces cerebrovascular resistance (2 1 ) . I n addition, isradipine reduces the disappearance of high-energy phosphates [for example, adenosine triphosphatase (ATP)] from ischaemic brain tissue, thereby producing a potentially cytoprotective effect. This was shown by the reduced infarct size [as determined by magnetic resonance ima- ging (MRI) and histology] in animals following isch- aemic insults (22, 23).

Atherosclerosis Isradipine may have an effect on atherosclerosis and cholesterol accumulation in arterial vessel walls, with the potential to prevent or produce regression of the disease (24). Isradipine and other calcium antagonists have been shown to reduce the cholesterol level in cultured endothelial cells, although the dihydropyri- dines appear to have little or no clinical effects on lipid profiles (25-27). However, a 1-year study of elderly hypertensive patients treated with isradipine demon- strated a significant reduction in total cholesterol with an increase in the levels of the “protective” high-den- sity lipoprotein (HDL)-cholesterol (28). Furthermore, in another study, isradipine produced a significant

decrease in low-density lipoprotein (LDL)-cholesterol with an increase in the HDL:LDL ratio over a period of only 10 - 13 weeks (29).

A 3-year evaluation is currently underway using high-resolution B-mode ultrasonography to determine the effect of isradipine us a diuretic on the rate of progression of carotid artery atherosclerosis in hyper- tensive subjects (30, 31). This study, the Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS), is a randomized, double-blind, active-control trial comparing 2.5 or 5 mg of isradipine twice daily with 12.5 or 25 mg of hydrochlorothiazide twice daily in 883 patients with atherosclerotic plaques between 1.3 and 3.5 mm thick (intima plus media).

Coagulation Isradipine mildly inhibits platelet aggregation in vitro through various mechanisms [for example, collagen and adenosine diphosphate (ADP)] and enhances the production of prostacyclin, a highly potent endo- genous platelet anti-aggregant and arterial dilator. The drug may also increase fibrinolytic activity through increased tissue-plasminogen activator (t-PA) activity and euglobulin clot-lysis time (ECLT) in comparison to the untreated hypertensive patient (32). In addition, isradipine restores the impaired platelet response to serotonin and LDL in the hypertensive patient.

There is, as yet, no conclusive proof that some of these effects are not due to the antihypertensive actions of the drugper se rather than a direct effect of the drug on platelets and fibrinolytic activity. Other antihyper- tensives may reduce blood pressure, but they may also render platelets more aggregable or produce variable effects on fibrinolytic activity (33, 34). Further detailed studies are needed to determine the tissue-specific ef- fects of isradipine on platelets in hypertensive com- pared with normotensive patients.

Blood viscosity and rheology. In several studies, untreated hypertensive patients have been shown to have higher levels of fibrinogen and haematocrit, red blood cell deformities (assessed by filtration rate) and mean cor- puscular volume (MCV). Treatment with isradipine, in addition to reducing the blood pressure, has also been found to improve red blood cell filterability and blood rheology (35, 36).

Platelets. Low-density lipoprotein is involved in platelet aggregation in terms of platelet sensitivity to LDL, which may promote atherosclerotic progression, which is itself increased by elevated blood pressure and ciga- rette smoking (37). Treatment with isradipine can re- duce both the LDL-induced and serotonin-induced platelet aggregation, and may be another important

36 J. B. LESLIE

mechanism of selective thrombovascular protection provided by this calcium antagonist (38).

Although there are no effects on platelet numbers, isradipine does reduce platelet aggregation both at rest and during exercise in response to several other platelet aggregants, such as ADP, serum thromboxane B, (TXB,) and beta-thromboglobulin (beta-TG) (39, 40).

Renal effects Isradipine produces a mild diuresis and natriuresis on first-dosing that is usually maintained during long- term therapy (41-43). Renal blood flow is maintained while renal vascular resistance is reduced. In addition, there are increases in renal plasma flow, natriuresis and urine volume, while the glomerular filtration rate remains unchanged and the filtration fraction is de- creased. Plasma renin activity is variably affected. These specific natriuretic and diuretic effects of isradi- pine may help to explain why long-term therapy is usually not associated with undesirable fluid retention as is produced by other vasodilators.

It has been postulated that the ankle oedema oc- casionally noted with calcium antagonist therapy, for example with nifedipine, may be due to systemic vaso- dilatation, which increases the capillary pressures, thereby leading to an increased filtration of fluid into the tissues (44).

Other organ-specific effects Isradipine inhibits both spontaneous and oxytocin- induced uterine activity. It has been used safely and effectively in the treatment of pregnancy-induced hy- pertension and has been found to have no effects on uteroplacental or foetal blood flows (45, 46).

The drug also has no effect on fasting glucose levels, fasting insulin levels, glucose tolerance or insulin secre- tion, and can be used safely in diabetics who have hypertension requiring therapy (47,48). As with other calcium antagonists, isradipine inhibits cytochrome P- 450 liver microsomes in rats, but the clinical signifi- cance of this in humans has not been investigated except to demonstrate that there are no significant effects on digoxin pharmacokinetics.

CONCLUSIONS On the basis of the significant effects due to arterial vasodilatation accompanied by mild negative chrono- tropism and no significant negative inotropism, isradi- pine should provide excellent antihypertensive efficacy in the treatment of perioperative hypertension. This compound may prove to be a safe antihypertensive agent in patients who have impaired ventricular func-

tion (cardiac failure), impaired myocardial perfusion (ischaemia) , and selected conduction abnormalities or arrhythmias. The demonstration that the action of isra- dipine is on the resistance vessels and not the capaci- tance vessels is an important distinction from other antihypertensive agents. Finally, the potential appli- cation of this dihydropyridine for cytoprotection and its effects on atherosclerosis remain exciting therapeutic prospects.

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John B. Leslie MD Department of Cardiac Anesthesia Duke University Medical Center 3432 Duke University Hospital North P.O. Box 3094 Durham, North Carolina 27710 USA