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We have tested the role of various protein kinases in noradrenaline-induced, alpha1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.

To investigate the concept of initiating therapy with low doses of a calcium antagonist and an ACE inhibitor, a fixed combination of isradipine 2.5 mg plus the ACE inhibitor spirapril 3 mg was compared with its components, with the full-dose monotherapies (isradipine 5 mg or spirapril 6 mg), and with placebo. After a 2-week wash out phase in pretreated patients and a subsequent 2-week placebo period, 405 patients with a diastolic blood pressure (DBP) between 100 and 114 mmHg were randomly allocated to 12-week once-daily double-blind treatment in one of the six treatment arms. In patients whose blood pressure was not normalized (defined as DBP≤90 mmHg) after 6 weeks of treatment, the dosage of either medication was doubled or, in the placebo group, was switched to the fixed combination. After week 6, the mean reductions from baseline in sitting systolic/diastolic blood pressure 24 hours after dosing (trough) for the fixed combination or the monotherapies isradipine 5 mg, isradipine 2.5 mg, spirapril 6 mg, spirapril 3 mg, and placebo were10.4/8.7, 10.0/9.4, 6.5/6.7, 10.0/8.3, 7.0/5.8, and 2.2/4.7 mmHg, respectively. The blood pressure changes obtained with the low-dose fixed combination were essentially identical to those observed with the full-dose monotherapies, thus showing an additive effect of low-dose isradipine and spirapril. In terms of tolerability, the lowest rate of any adverse events was found in the combination group. In this group, typical adverse events of calcium antagonists, such as headache, flushing, ankle edema, or palpitations, were observed only in 5%, 2%, 1%, and 0%, respectively, dry cough, considered typical for ACE inhibitors, was observed in only 1% of the combination group. In conclusion, the low-dose components isradipine 2.5 mg and spirapril 3 mg were shown to have an additive effect when combined, exerting a blood pressure–lowering effect comparable with the full doses and a trend to a better tolerability profile in comparison with the standard doses. Thus, low-dose combination therapy with these drugs appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.

Prospective epidemiological studies on the evolution of the cardiovascular risk-profile in young adulthood have not been published so far for Germany. In 1975 a sample of 5 924 adolescents aged 15–19 was examined at schools in the city of Cologne. After reexamination in 1976 und 1980, a long-term follow-up was carried out with those still living in the city and thus being easily available in 1990. For that purpose 613 former adolescents were identified and invited to the university hospital; 210 young adults (143 males (M) and 67 females (F)) now 30 – 34 years old were examined for main cardiovascular risk factors using the same methodology as in 1975. Whereas systolic and diastolic (phase 5) blood pressures (SBP and DBF) did not change very much, the means of total cholesterol (CHOL) and body-mass (BMI) increased considerably (CHOL from 158 mg/dl in 1975 to 195 in 1990 (M) and from 176 to 199 (F); BMI from 20.8 kg/sqm to 24.1 (M) and from 20.6 to 22.7 (F)). Pearson correlations increased especially between SBP and DBP (from .21 to .52 (M) and from .45 to .65 (F)) and between DBP and BMI (from .16 to .26 (M) and from .25 to .40 (F)). Autocorrelations remained quite high over the entire period (SBP .43, DBP .48, CHOL .42 and BMI.71 (M) and .51, .36, .49 and .81 (F)). Regression analysis shows that 51 % of the variance of SBP and of DBP in 1990 can be explained mainly by the foregoing measurements, but only 24 % of the variance of total cholesterol. Risk patterns in terms of aggregation of risk factors and risk habits worsened considerably during the 15 years of observation. Given the rarity of longitudinal risk factor observations in early adulthood, the Cologne data underline the considerable stability of cardiovascular risk factors also during this period of life and stress the importance of appropriate monitoring and intervention early in life.

The ability of progesterone to increase sodium excretion only in the presence of active mineralocorticoids has led to the suggestion that progesterone antagonizes mineralocorticoid action at the renal tubular level. We have examined the effects of progesterone and aldosterone on sodium and potassium excretion in adrenalectomized rats and have compared these results with the ability of progesterone to inhibit the binding of aldosterone to cytoplasmic and nuclear mineralocorticoid receptors. The administration of aldosterone to saline-loaded, adrenalectomized male rats resulted in a dose-dependent fall in the urinary sodium to potassium ratio with a near maximum effect produced by 1 μg aldosterone. Progesterone alone in doses of 10, 100, and 1000 μg had no significant effect on the sodium to potassium ratio, but when administered simultaneously with 1 μg aldosterone, the same concentrations of progesterone inhibited the effect of aldosterone in a dose-dependent manner; 1 mg progesterone completely blocked t...