Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation.

Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor-Gq/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB1R) in these effects. Expression of CB1R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10-9-10-7 M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10-7 M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB1R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB1R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB1R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction.

Opposing Roles of S1P3 Receptors in Myocardial Function.

Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator with diverse biological function mediated by S1P1-5 receptors. Whereas S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury, other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac effects of S1P during I/R and identify the signaling pathways involved. Wild type (WT), S1P2-KO and S1P3-KO Langendorff-perfused murine hearts were exposed to intravascular S1P, I/R, or both. S1P induced a 45% decrease of coronary flow (CF) in WT-hearts. The presence of S1P-chaperon albumin did not modify this effect. CF reduction diminished in S1P3-KO but not in S1P2-KO hearts, indicating that in our model S1P3 mediates coronary vasoconstriction. In I/R experiments, S1P3 deficiency had no influence on postischemic CF but diminished functional recovery and increased infarct size, indicating a cardioprotective effect of S1P3. Preischemic S1P exposure resulted in a substantial reduction of postischemic CF and cardiac performance and increased the infarcted area. Although S1P3 deficiency increased postischemic CF, this failed to improve cardiac performance. These results indicate a dual role of S1P3 involving a direct protective action on the myocardium and a cardiosuppressive effect due to coronary vasoconstriction. In acute coronary syndrome when S1P may be released abundantly, intravascular and myocardial S1P production might have competing influences on myocardial function via activation of S1P3 receptors.