The possible involvement of different kinases in the alpha(1)-adrenoreceptor (AR)-mediated positive inotropic effect (PIE) was investigated in rat papillary muscle and compared with beta-AR-, endothelin receptor- and phorbol ester-induced changes in contractility. The alpha(1)-AR-induced PIE was not reduced by the inhibitors of protein kinase C (PKC), MAPK (ERK and p38), phosphatidyl inositol 3-kinase, or calmodulin kinase II. However, PKC inhibition attenuated the effect of phorbol 12-myristate 13-acetate (PMA) on contractility. alpha(1)-AR-induced PIE was reduced by approximately 90% during inhibition of myosin light chain kinase (MLCK) by 1-(5-chloronaphthalene-1-sulfonyl)1H-hexahydro-1,4-diazepine (ML-9). Endothelin-induced PIE was also reduced by ML-9, but ML-9 had no effect on beta-AR-induced PIE. The Rho kinase inhibitor Y-27632 also reduced the alpha(1)-AR-induced PIE. The alpha(1)-AR-induced PIE in muscle strips from explanted failing human hearts was also sensitive to MLCK inhibition. alpha(1)-AR induced a modest increase in (32)P incorporation into myosin light chain in isolated rat cardiomyocytes. This effect was eliminated by ML-9. The PIE of alpha(1)-AR stimulation seems to be dependent on MLCK phosphorylation.

Increasing contractility through stimulation of alpha 1-adrenoceptors in situ by the endogenous agonist may be an alternative way of inotropic support during heart failure and even more so during beta-adrenoceptor blockade.

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The aim of the present study was 1) to characterize qualitatively the positive inotropic effect of the Ca-channel activator BAY K 8644 and to compare this response to response-types with known and different relationship to the cyclic AMP (cAMP) system (e.g. responses elicited through alpha- and beta-adrenergic receptor stimulation) and 2) to study the effect of simultaneous muscarinic cholinergic stimulation upon the BAY K 8644 response in order to further evaluate the role of the cAMP system in this response. The responses were evaluated in isolated, electrically paced, isometrically contracting papillary muscles from rat heart. Isometric tension (Tmax), rate of rise and decline of tension (first derivative = T') and rate of transition from tension rise to tension decline (negative part of second derivative = T") were recorded. In the presence of the alpha 1-adrenergic receptor blocker prazosin (10(-7) mol/l) and the beta-adrenergic receptor blocker timolol (10(-6) mol/l), the positive inotropic effect of 1.7 x 10(-6) mol/l BAY K 8644 developed rather slowly with a time to half maximal effect of about 4 minutes. Qualitatively the response was characterized by an almost proportional ("symmetrical") increase in all parts of the contraction-relaxation cycle with a small prolongation of time to peak tension and of the duration of the whole cycle. This response contrasted sharply with the cAMP-dependent response to beta-receptor stimulation (beta-type response with shortening of time to peak tension), but was very similar to the cAMP-independent response to alpha-receptor stimulation (alpha-type response).(ABSTRACT TRUNCATED AT 250 WORDS)

The metals, zinc (Zn2+) and copper (Cu2+) from inhaled particulate matter may reach the systemic circulation and the cardiac tissue. In the present study, the potential of Zn2+ and Cu2+ to induce interleukin (IL)-6 responses in cardiomyocytes (CMs) and cardiac fibroblasts (CFs), in mono- and cocultures, was examined. Both metals induced IL-6 release in a concentration (20-200 microM)-dependent manner. Zn2+ appeared more potent than Cu2+ in both mono- and cocultures of CMs and CFs. In the cocultures, the basal- and metal-induced IL-6 responses were synergistically increased compared to the monocultures. Exposure to Zn2+ increased phosphorylation of the MAP-kinases, ERK1/2 and p38, in monocultures of CMs and CFs. Cu2+ induced an increased phosphorylation of p38 in both cell types and of ERK1/2 in CFs, but at higher concentrations than Zn2+. Treatment with a p38 inhibitor (SB202190) reduced the IL-6 responses to Zn2+ and Cu2+ in both cell types. Pretreatment with PD98059 to inhibit ERK1/2 was without significant effect; however, insignificant reductions was observed in the in the CFs. In conclusion, Zn2+ and Cu2+ increased IL-6 release and MAP-kinase activation in primary cardiac cells, processes known to be involved in cardiac inflammation and hypertrophy.