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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 less than 0.001); in 33 of 46 patients a diastolic pressure less than or equal to 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 less than or equal to 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 less than 0.001) and pretreatment mean blood pressure (r = 0.470; p less than 0.01) and inversely related to plasma renin activity (r = 0.558; p less than 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 less than 0.01), and nitrendipine and nifedipine (r = 0.953; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Active tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or membrane-diffusible synthetic diacylglycerols such as 1,2-dioctanoyl-sn-glycerol (DiC8), which specifically activate protein kinase C (PKC), inhibited the agonist-mediated rise in cytosolic calcium [(Ca2+)i] in a mast cell line (PB-3c) and human platelets. TPA inhibition of agonist-mediated calcium transient in platelets was readily reversed by the PKC inhibitor staurosporine. In contrast to DiCs, only active tumor promoters induced a time- and dose-dependent translocation of cytosolic PKC to membranes as determined both enzymatically or by immunoblotting. However, the concentration of TPA required to induce a half-maximal subcellular redistribution of immunodetectable PKC activity was an order of magnitude greater than the half-maximal dose required to inhibit the intracellular rise in (Ca2+)i. Thus, activation of PKC seems not to be exclusively coupled to its translocation to membranes, suggesting that translocation of PKC is mainly involved in the down-regulation of PKC. Down-regulation of immunoprecipitable PKC was studied in various human breast cancer cell lines that display differential growth inhibitory responses toward the tumor promoter. TPA induced translocation of [35S]methionine-prelabeled cytosolic 80 kDa PKC to membranes followed by complete degradation of the enzyme (t1/2 = 2 h) without affecting PKC synthesis. During prolonged TPA exposure, 20-80% of total 80 kDa PKC of control cells was still synthetized as a membrane-bound 74/80 kDa PKC doublet. Although both proteins lacked PKC activity and phorbol ester binding, they revealed structural similarity with the active 80 kDa PKC form of untreated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium antagonists induce vasodilation and a consequent fall in blood pressure that initially is associated with baroreflex-mediated stimulation of the sympathetic nervous and renin-angiotensin system, resulting in increased heart rate and cardiac output. During chronic treatment, baroreflex-mediated stimulatory effects subside, probably because of a resetting of baroreflexes or inhibition of neuronal noradrenaline release. Ultimately, the antihypertensive response is codetermined by the responsiveness of these counterregulatory systems in the individual patient. In older patients who have blunted baroreflex and beta-adrenoceptor-mediated functions, a greater fall in blood pressure results as compared with younger patients in whom counterregulatory reflexes are more vivid. Therefore, older patients respond particularly well to calcium antagonists, whereas younger patients respond better to beta-blockers. In patients with essential hypertension, free cytosolic calcium concentration in platelets is elevated and calcium influx-dependent vasoconstriction is enhanced. Antihypertensive treatment with calcium antagonists and beta-blockers results in a normalization of both calcium influx-dependent vasoconstriction as well as free calcium concentration in platelets. Free cytosolic calcium concentration in platelets may reflect free calcium concentration in vascular smooth muscle cells, its reduction leading to vasodilation and antihypertensive response.

In patients with essential hypertension, the vasodilator response in the forearm circulation to postjunctional alpha 1-adrenoceptor blockade with prazosin is enhanced. Besides the effects at classical postjunctional alpha 1-adrenoceptor, postjunctional alpha 2-adrenoceptor-mediated effects contribute to vascular tone, and these may be comparable in magnitude to those observed with prazosin. Owing to the extrajunctional localization of alpha 2-adrenoceptors, they may be preferential targets for circulating catecholamines and adrenaline in particular. No evidence of autoinhibitory noradrenaline feedback system via prejunctional alpha 2-adrenoceptors was found by measuring noradrenaline release from the forearm. Therefore increased sympathetic nerve activity, as demonstrated by increased plasma adrenaline concentrations, plays an important role in the pathophysiology of essential hypertension by contributing to increased vascular resistance. Central prejunctional alpha 2-adrenoceptor-stimulating drugs lower sympathetic nerve activity and thereby peripheral resistance and blood pressure, and this effect seems to override peripheral (pre-) and postjunctional alpha 2-adrenoceptor-stimulating effects.

In essential hypertension, calcium-influx-dependent vasoconstriction is enhanced, and free calcium concentration in platelets is elevated. To investigate calcium-influx-dependent vasoconstriction as related to platelet calcium concentration blood pressure, forearm blood flow (FAF) and free calcium concentration in platelets were measured in five patients with essential hypertension before and after a 6-week treatment with nitrendipine or acebutolol. Starting from comparable basal values, the increase in FAF (ml/min/100 ml tissue) to intraarterially infused nitrendipine (20 micrograms/100 ml tissue) was 40.7 +/- 6.1 before and 30.7 +/- 12.3 after chronic nitrendipine treatment (p less than 0.05) and 41.6 +/- 6.2 before and 34.6 +/- 14.9 after chronic acebutolol treatment. The "nonspecific" vasodilator response to intraarterial sodium nitroprusside or to postischaemic reperfusion were similar before and during treatment. Platelet-free calcium concentration fell on nitrendipine (p less than 0.05) and on acebutolol (p less than 0.01) treatment. Antihypertensive treatment with calcium entry as well as beta-adrenoceptor blockade resulted in a reduction of calcium-influx-dependent vasoconstriction and a fall in free calcium concentration in platelets. Thus, increased calcium platelets may reflect increased calcium in vascular smooth muscle cells and arteriolar tone.

The sympathetic nervous activity contributes to the pathophysiology of essential hypertension in an early phase and in younger patients mainly through increased beta-adrenoceptor-mediated functions and in a later phase and in older patients in whom beta-adrenoceptor-mediated functions are blunted, through increased alpha-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 alpha 1-and alpha 2-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 alpha 2-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.

More than 20 years ago calcium antagonists were shown to lower elevated blood pressure. Today's 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 patient's 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.

Distribution of intracellular free calcium concentration, (Ca2+)i, in living cells has been measured with submicron resolution in isolated, single vascular muscle cells from neonatal Wistar-Kyoto (WKY) rats. The experiments were carried out on cells loaded with fura-2 using a digital photon-counting camera (PMI VIM) with computer analysis of 16-bit images. Determination of the fluorescence intensity at 360 nm excitation allowed correction for a nonhomogenous intracellular fura-2 dye distribution and revealed areas with high calcium concentrations (hot spots, HS) associated with putative sarcoplasmic reticulum (SR), even in nonactivated cells. Investigation of the effects of caffeine and ryanodine revealed that caffeine activates both centrally and peripherally located SR to release calcium, while ryanodine preferentially acts on peripherally located SR, presumably to lock calcium channels of the SR in an open state. The interaction of calcium release and uptake mechanisms in excitation-contraction coupling is supported by intracellular calcium distributions during spontaneous contraction and relaxation, which suggest a pattern of calcium release from peripherally located SR followed by release from centrally located SR. Additional studies on the effects of neuropeptide Y and norepinephrine virtually rule out any potentiation of norepinephrine by neuropeptide Y via direct modulation of (Ca2+)i in vascular muscle cells.