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The place of the calcium antagonist verapamil in antihypertensive therapy.

The antihypertensive efficacy of the calcium antagonist verapamil was tested in 43 patients with essential hypertension, examining relationships between age and pretreatment renin and blood pressure and comparing intraindividually the responses with those obtained using beta-blockers (n = 29) and diuretic therapy (n = 18). Verapamil produced a decrease in mean blood pressure that was directly related to the patients age and pretreatment blood pressure but inversely to pretreatment renin. Although there was no difference in overall pressure response between verapamil, beta-blocker, and diuretic therapy, the pressure responses with diuretics paralleled those obtained with verapamil, whereas, in contrast, responses with beta-blockers correlated indirectly with the patients age and directly with pretreatment renin. These data provide the basis for a new antihypertensive treatment concept proposing a calcium antagonist as the first choice for the older and low renin patients in place of a diuretic agent and a beta-blocker as the first-line drug for the younger and high renin patients.

Age, race, blood pressure and renin: Predictors for antihypertensive treatment with calcium antagonists

Age, race, pretreatment blood pressure and plasma renin activity have been related to the antihypertensive response to calcium antagonists in studies that included 215 patients with mild to moderate essential hypertension. Adverse effects necessitated withdrawal from therapy in about 10% of the patients. All calcium antagonists lowered blood pressure significantly and comparably without weight gain or reflex tachycardia. In a multiple linear regression analysis of 138 white patients, age, pretreatment blood pressure and renin activity were of independent and significant predictive value for the antihypertensive response. Stratification of patients into 3 age groups disclosed a greater effect in patients older than 60 years compared with those between 40 and 60 years and those below 40 years, respectively (p less than 0.01). In 16 middle-aged black patients, antihypertensive therapy with a calcium antagonist proved highly efficacious. Monotherapy with a calcium antagonist may become a first-line treatment for essential hypertension, particularly in older patients who have low renin activity and possibly in black patients as well.

Position of calcium antagonists in antihypertensive therapy.

More than 20 years ago calcium antagonists were shown to lower elevated blood pressure. Todays worldwide recognition, at least in part, is due to rising research interest in cellular ion regulation abnormalities in essential hypertension. Using the human platelet as a model for the vascular smooth muscle cell, a direct relationship was observed between intracellular free calcium concentration and the height of blood pressure before as well as during different antihypertensive treatments. Calcium influx is an important determinant of vasoconstriction, and excess calcium influx-dependent vasoconstriction was shown with plethysmographical studies in patients with essential hypertension. Calcium antagonists acutely lower blood pressure by reducing intracellular calcium and peripheral vascular resistance. The degree of the attendant sympathetic nerve reflex activation and counterregulatory mechanisms codetermine the antihypertensive result of the individual. Chronic monotherapy with calcium antagonists results in an antihypertensive response that is related directly to the patients age and pretreatment blood pressure and indirectly to renin. These studies led to a new treatment concept: calcium antagonists can be used as alternatives to diuretic drugs primarily in the older and low-renin patients and beta-blockers or converting enzyme inhibitors can be used in the younger or high-renin patients with greater efficacy. With the appropriate choice, calcium antagonists alone or combined with any other antihypertensive drug provide good blood pressure control with little subjective and objective adverse effects.

Antihypertensive Therapy with the Long-acting Calcium Antagonist Nitrendipine

Summary The antihypertensive efficacy of the calcium entry blocker nitrendipine administered as monotherapy (20–80 mg; mean, 36/day) on the average for 144 days to 46 patients with essential hypertension (WHO I and II) was investigated in relation to age, pretreatment blood pressure, and plasma renin activity. In addition, we compared the blood pressure responses to verapamil (n = 11) and nifedipine (n= 15) with those to nitrendipine. Nitrendipine monotherapy reduced blood pressure from 168 ± 16/107 ± 7 mm Hg to 145 ± 13/91 ± 6 (both p < 0.001); in 33 of 46 patients a diastolic pressure ≤ 95 mm Hg was achieved. During long-term treatment, heart rate and body weight remained unchanged. Thirteen of 16 patients in whom blood pressure was measured 24 h after a single oral dose (20 to 40 mg) reached a diastolic pressure ≤ 95 mm Hg. Treatment with nitrendipine had to be discontinued because of severe headache in two and ankle oedema in one patient. The fall in mean blood pressure after nitrendipine was directly related to age (r = 0.553; p < 0.001) and pretreatment mean blood pressure (r = 0.470; p < 0.01) and inversely related to plasma renin activity (r = 0.558; p < 0.001). These correlations were also significant for systolic and diastolic blood pressure. There was comparable antihypertensive efficacy, as expressed by changes in mean blood pressure, between nitrendipine and verapamil (r = 0.869; p < 0.01), and nitrendipine and nifedipine (r = 0.953; p < 0.001). This study documents the antihypertensive effectiveness of nitrendipine monotherapy—often administered in a once-daily dose—and further supports our previous findings that the antihypertensive response of calcium entry blockers is greatest in older and low-renin patients.

ABNORMAL CELLULAR CALCIUM REGULATION IN ESSENTIAL-HYPERTENSION

The plasticity of cellular Ca2+ control and the events regulated by [Ca2+]i and other messengers make it difficult to assign causative or consequential roles to deranged platelet Ca2+-linked processes in the pathophysiology of essential hypertension. Our studies in human platelets support an underlying membrane pathology as being causative since observed derangements including partial membrane depolarization and enhanced calcium influx, enhanced hormone responsiveness and coupling to adenylate cyclase, increased phosphoinositide metabolism, as well as stimulated Ca2+-ATPase extrusion activity are membrane associated systems. Modification of phosphoinositide metabolism may be a key factor accounting for the multifaceted membrane abnormalities and eventually contribute to the elevated cytosolic [Ca2+]i concentration in essential hypertension. Whether these membrane abnormalities can also be found in human smooth muscle cells has yet to be determined.

Adrenoceptors, Calcium, and Vasoconstriction in Normal and Hypertensive Humans

The sympathetic nervous activity contributes to the pathophysiology of essential hypertension in an early phase and in younger patients mainly through increased β-adrenoceptor-mediated functions and in a later phase and in older patients in whom β-adrenoceptor-mediated functions are blunted, through increased α-adrenoceptor-mediated and calcium-influx-dependent vasoconstriction. Intracellular free calcium concentration is elevated in platelets of hypertensive patients and relates directly to the degree of their blood pressure, likely reflecting increased intracellular calcium concentration in vascular smooth muscle cells. A sympathetic factor is suggested further by the enhanced α1- and α2-adrenoceptor-mediated and calcium influx-dependent, vasoconstriction both of which are normalized by antihypertensive treatment in parallel with a normalization of intracellular free calcium and of the increased adrenaline sensitivity of platelets. The higher sensitivity to adrenaline for thrombin-induced calcium increases in platelets of hypertensive patients indicates potentiation of calcium influx (and mobilization from intracellular stores) by adrenaline, a mechanism that is mediated by α2-adrenoceptors. As this effect is more pronounced in younger patients, increased adenylate cyclase sensitivity may prevail in the early and alterations in calcium influx-dependent mechanisms in the later phase of essential hypertension. The transition into a hypertensive state with reduced-reflex cardiovascular counterregulation codetermines the antihypertensive effectiveness of calcium antagonists in these patients.

Cardiac and vascular beta-adrenoceptor-mediated responses before and during treatment with bisoprolol or atenolol.

&NA; The degree of cardiac and vascular &bgr;‐adrenoceptor blockade of bisoprolol and atenolol was determined by the chronotropic dose 25 (CD25) of isoproterenol (the dose of an intravenous isoproterenol bolus required to increase resting heart rate by 25 beats/min) and by the increase in forearm blood flow (venous occlusion plethysmography) to intrabrachial artery infusions of increasing doses of isoproterenol (0.12, 1.2, 4, 12, and 20 ng/min/100 ml forearm tissue). Measurements were taken following placebo and after one weeks treatment with atenolol or bisoprolol under double‐blind conditions using a within‐patient crossover design. Two patients received 10 mg bisoprolol and 50 mg atenolol daily, and three patients 20 and 100 mg daily, respectively. Both &bgr;‐blockers produced a similar fall in blood pressure, heart rate, and plasma renin activity. While CD25 of isoproterenol was comparable for both drugs, forearm blood flow to intra‐arterial infusion of isoproterenol increased to a greater extent following bisoprolol (20 mg) than during atenolol (100 mg) treatment. Equieffective cardiac &bgr;‐blockade with bisoprolol and atenolol was associated with a lesser degree of vascular &bgr;‐adrenoceptor blockade during treatment with the more cardioselective &bgr;‐blocker bisoprolol.

Hemodynamic and Counterregulatory Effects of Calcium Antagonists in Hypertension

Increased systemic vascular resistance in essential hypertension depends on increased calcium influx. Calcium antagonists lower cytosolic free calcium concentrations mainly through a reduction of transmembraneous calcium influx and are potent arterial vasodilators. Dihydropyridine calcium antagonists are pharmacologically more potent with respect to arterial vasodilatation than verapamil- or diltiazem-type calcium antagonists and have less or no clinically detectable negative inotropic effects, but this seems to be of importance only in patients with reduced cardiac function. All calcium antagonists lower high blood pressure through a reduction of elevated systemic vascular resistance without clinically relevant activation of sympathetic reflexes or the renin-angiotensin-aldosteron system. However, subtle changes of sympathetic nervous system activity may codetermine the acute and chronic blood pressure response. They do not lead to volume retention because of improved intrarenal hemodynamics and a diuretic effect. Interference with angiotensin and sympathetically mediated vasoconstrictor mechanisms probably also contributes to their antihypertensive effect. This hemodynamic profile is similar for all calcium antagonists but the degree of acute sympathetic stimulation seems to be greater for dihydropyridines. Their overall favorable hemodynamic and neurohumoral profile and their proven efficacy and lack of serious side effects have made calcium antagonists a valuable addition to the armanentarium available for monotherapy of hypertension.

The vasodilating effect of atrial natriuretic peptide in normotensive and hypertensive humans.

Summary: Atrial natriuretic peptide (ANP) infused intraarterially into the forearm results in a dose‐dependent vasodilator response of rapid onset. The maximal forearm vasodilator response to ANP amounts to about 60% of the maximal forearm vasodilator response to sodium nitroprusside and combined infusion of ANP and sodium nitroprusside has an additive vasodilator effect. ANP‐induced vasodilation is greater than that of postjunctional &agr;1‐ or &agr;2‐adrenoceptor blockade or of &bgr;2‐adrenoceptor stimulation but is smaller than due to calcium entry blockade. ANP‐induced vasodilation can easily be overcome by norepinephrine and to a lesser extent by angiotensin II (Ang II). The similarity of the dose‐response relationships for vasodilation and for natriuresis suggests that ANP may be equally effective on its renal and vascular targets. In patients with essential hypertension, intra‐arterial infusion of ANP produced a greater vasodilator response than in normotensives and this was inversely related to plasma renin activity, suggesting greater vasodilator responsiveness to ANP in lowrenin hypertension. ANP causes vasodilation in humans but this may become less apparent when ANP is infused into the systemic circulation because of cardiovascular sympathetic reflex mechanisms blunting ANP vasodilation. Although the role of ANP in circulatory disease states is unclear, it appears that it could serve a physiological function as an endogenous vasodilator (and natriuretic) principle for volume homeostasis in humans.

The Role of Catecholamines and Calcium in the Regulation of Blood Flow in Normotensive Subjects and in Patients with Essential Hypertension

The role of catecholamines and calcium in the regulation of blood flow was assessed by measuring their contributions to vascular tone by pharmacological intervention in the forearm arterial circulation. Postjunctional α1- and α2-adrenoceptor blockade with prazosin and yohimbine, respectively, produced a greater increase in forearm blood flow (FAF; venous occlusion plethysmography) in patients with essential hypertension than in normotensive subjects. This suggests that the sympathetic nervous system contributes to the elevated vascular resistance in essential hypertension via an enhanced α-adrenoceptor-mediated vasoconstrictor component. Adrenaline induced vasoconstriction through stimulation of postjunctional α2-adrenoceptors was demonstrated and this may be important in conditions associated with high concentrations of circulating adrenaline. Under resting conditions the β-adrenoceptor-mediated vasodilator force as measured by vascular β-adrenoceptor blockade was small compared to its vasodilator potential: intraarterial infusion of isoproterenol increased FAF about 3.5 times, the vasodilator response decreasing with older age. Enhanced calcium influx dependent vasoconstriction in patients with essential hypertension was demonstrated by the greater increase in FAF to calcium entry blockade. Together with the elevated intracellular free calcium concentration in platelets of hypertensive patients, this points to a derangement in the handling of calcium at the subcellular level in essential hypertension. A link between the elevated intracellular free calcium concentration and enhanced calcium influx dependent vasoconstriction is suggested by the normalization of both during antihypertensive treatment. Increased adrenergic activity in essential hypertension as reflected by supranormal plasma adrenaline concentrations in about one-third of patients may contribute to enhanced cellular calcium influx through receptor-operated calcium channels, and this is supported by the direct relationship between plasma adrenaline concentrations and the increases in FAF to α-adrenoceptor as well as to calcium entry blockade. Increased sympathetic activity and enhanced cellular calcium influx thus greatly contribute to the elevated vascular resistance in essential hypertension.