F. Berti

Growth Hormone-Independent Cardioprotective Effects of Hexarelin in the Rat

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 μg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 μg/kg sc) produced similar results, whereas administration of EP 51389 (8...

Cardiac ischemia and impairment of vascular endothelium function in hearts from GH-deficient rats: Protection by hexarelin

The ability of hexarelin, an effective growth hormone (GH)-releasing hexapeptide, to reverse the worsening of cardiac dysfunction in GH-deficient animals was studied in young male rats passively immunized by administration of an anti-GH-releasing hormone (GHRH) serum. Heart preparations from anti-GHRH serum-treated rats, undergoing low-flow ischemia and reperfusion, showed: (1) a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion with a consistent decrease of the left ventricular-developed pressure; (2) a decreased rate of formation of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), a stable metabolite of prostacyclin, in perfusates from preischemic and reperfusion periods; (3) an increased vasopressor activity of angiotensin II. Hexarelin (80 microg/kg, bid, s.c.), administered for 15 days to anti-GHRH serum-treated rats, restored to normal the impaired somatotropic function and counteracted the ischemic damage, improving postischemic left ventricular developed pressure to values higher than those of controls. Furthermore, both the generation of 6-keto-PGF1alpha and the vasopressor activity of angiotensin II reverted to those of control preparations. Administration of hexarelin to control rats induced a considerable improvement of postischemic ventricular function of the perfused hearts which was similar to that present in preparations from anti-GHRH serum-treated rats given hexarelin. This protective activity was divorced from any further stimulation of somatotropic function. Collectively, these data indicate that, in GH-deficient rats, hexarelin is capable of restoring somatotropic function and has a beneficial effect in myocardial ischemia and reperfusion damage. In addition, the increased responsiveness of the coronary vasculature to angiotensin II and the decreased generation of prostacyclin in hearts from GH-deficient rats would indicate that for prevention of injury and dysfunction of the vascular endothelium a normal somatotropic function is mandatory.

Prostacyclin (PGI2) in pregnant human uterus

Prostacyclin lowers the tonus and reduces the spontaneous motility of isolated pregnant human myometrium. This effect seems to be related to coclic-AMP accumulation, since PGI2 increases the formation of this cyclic nucleotide in incubated minces of pregnant and non-pregnant uterus. The ability of this tissue to generate a labile substance which inhibits platelets aggregation, has been demonstrated and discussed.

The hydrogen sulphide-releasing derivative of diclofenac protects against ischaemia–reperfusion injury in the isolated rabbit heart

Hydrogen sulphide (H2S) is an endogenous gaseous mediator active in the multilevel regulation of pathophysiological functions in mammalian cardiovascular tissues.

Effects of chlomipramine and fluoxetine on subcutaneous carrageenin-induced inflammation in the rat.

We have previously shown that, after acute administration, antidepressant drugs exert anti-inflammatory actions in rats. In this study we evaluated the effects of 3 different doses of chlomipramine (10, 20, and 40 mg/kg i.p), and fluoxetine (5.0, 10, and 20 mg/kg i.p.) on subcutaneous carrageenin-induced inflammation. Both drugs dose-dependently reduced the inflammatory exudate, as well as the PGE2-like bio- and immuno-activity in the exudate. Chlomipramine dose-dependently reduced substance P concentrations in the exudate, whereas fluoxetine was effective only at the highest dose. Our results confirm that antidepressant drugs are able to reduce the development of inflammation in the rat and suggest that the inhibition of substance P production might play a role in mediating the anti-inflammatory effects of chlomipramine.

Bronchoconstriction by histamine and bradykinin in guinea pigs: Relationship to thromboxane A2 generation and the effect of aspirin

Histamine 2.5, 5, 10 or 20 microgram/kg i.v. induce a pronounced bronchospasm in guinea-pigs, accompanied by a dose-related increase of TXA2 in arterial blood, as revealed by contraction of rabbit isolated aorta and by radioimmunoassay. Aspirin 10 mg/kg prevented formation of TXA2-like material without significantly modifying the severity of the bronchospasm. Bradykinin 0.5, 1 or 2 microgram/kg i.v. acted similarly, except that pretreatment with aspirin blocked both the increased airway resistance and release of TXA2. Aspirin also blocked the increase in blood pressure and heart rate caused by histamine or bradykinin.

Antithrombotic activity of a polydeoxyribonucleotidic substance extracted from mammalian organs: A possible link with prostacyclin

Abstract The antithrombotic activity of Fraction P (FP), a polydeoxyribonucleotide extracted from mammalian organs, was studied in different models of experimental thrombosis. FP displays a remarkable protec ting activity against thrombosis induced by collagen (venous thrombosis), electrical stimulation (arterial thrombosis) and iontophoretic application of ADP (venular thrombosis). The activity of FP is long lasting and evident either by oral administration or intra venous injection. The antithrombotic activity of FP is partly due to its already reported fibrinolytic effect, but also other mechanisms which involve vascular reactivity and platelet function may come into play. The ability of FP to promote generation and release in the circulation of a deaggregating substance and to increase prostacyclin-like activity from incubated aortic tissue is discussed in order to explain the mode of action of FP in preventing thrombosis formation.

Pharmacological activity of PGI2 and its metabolite 6-OXO-PGF1α on human uterus and fallopian tubes

The actions of prostacyclin (PGI2) and its stable metabolite 6-OXO-PGF1alpha were investigated in strips of normal human uterus and in fallopian tubes. Both compounds were also compared with natural prostaglandins (PGE2, PGF2alpha and PGD2). PGI2 showed biphasic response both in uterus and fallopian tubes qualitatively and quantitatively similar to that induced by PGE2 and PGD2; prostacyclin was also able to inhibit the spasmus induced by PGF2alpha but not that induced by BaCl2 and vasopressin. 6-0XO-PGF1alpha on the other hand induced only small contractions on both tissues investigated. The authors discusse the possible implication of these findings in the physiology of the reproductive system.

Nitric Oxide and Prostacyclin Influence Coronary Vasomotor Tone in Perfused Rabbit Heart and Modulate Endothelin-1 Activity

Summary: Using isolated perfused rabbit heart electrically paced, we assessed the relevance of both nitric oxide (NO) and prostacyclin (PGI2) in regulation of resting coronary perfusion pressure (CPP). In preparations in which NO-synthase was inhibited by NG-monomethyl-L-arginine (L-NMMA, 10 μM), resting CPP increased significantly; this phenomenon was potentiated by indomethacin infusion (3 μM), prevented by L-arginine (100 μM) and significantly reduced by iloprost (55 nM) and defibrotide (200 μg/ml). Furthermore, the increase in resting CPP induced by graded doses of endothelin-1 (ET-1 0.6–160 pmol), was further augmented by blocking of prostaglandin biosynthesis with indomethacin (3 μM) and was substantially reduced when the rate of formation of PGI2 was enhanced by defibrotide (200 μg/ml). Moreover, the coronary vasoconstriction induced by ET-1 (2, 4, and 8 pmol) was increased in hearts in which NO-synthase was blocked by L-NMMA (10 μM) and this event was abolished in preparations in which PGI2 synthesis was stimulated by defibrotide (200 μg/ml). These results further emphasize that rabbit coronary vessels are continuously dilated by NO released from endothelial cells. They also indicate that PGI2 takes part in NO generation in the endothelial-derived relaxing mechanism. Inactivation of this mechanism, owing to decreased formation of NO and PGI2 in rabbit heart, induces hyperreactivity of coronary smooth muscles to ET-1. Finally, an increase in PGI2 production (such as that caused by defibrotide) may counterbalance impaired NO generation and attenuate hyperreactivity of the coronary vasculature.

Nonsteroidal antiinflammatory drugs aggravate acute myocardial ischemia in the perfused rabbit heart: a role for prostacyclin

Myocardial ischemia was induced in perfused paced isovolumic left heart preparation of the rabbit by reducing, for a period of 40 min, the flow rate from 20 ml/min to 0.2 ml/min (severe model) and to 1 ml/min (moderate model). The relationship between prostaglandin biosynthesis and cardiac ischemic damage was evaluated in the two experimental models. The results obtained indicate that the total amount of 6-keto-PGF1α generated increases with the severity of the ischemia, particularly during the 20 min of reperfusion (moderate model 81.8 ± 13.7 ng: severe model 375 ± 102 ng). The inhibition of the prostaglandin synthesis, prostaglandin-E2, and 6-keto-prostaglandin-F1α (PGE2 and 6-keto-PGF1α levels below the detection limits) by Aspirin (20 μg/ml) and Indomethacin (1 μg/ml) in moderate myocardial ischemia was correlated with greater increments in resting diastolic tension (nearly 100% and 40%, respectively). This phenomenon was also associated to a further decrease on cardiac contractility and increase on coronary perfusion pressure upon reperfusion. On the contrary drugs which stimulated prostaglandin generation in myocardial tissue, such as Defibrotide (400 μg/ml), completely protected the organ from ischemia. U-60257 (3 pig/ml) and FPL-55712 (2 μg/ml), compounds, which respectively inhibits biosynthesis and the effects of leukotrienes, displayed a beneficial activity on this moderate model of ischemia. The present data suggests that the deleterious effect of nonsteroidal antiinflammatory drugs in low flow myocardial ischemia and reperfusion damage may be associated with removal of PGI2 and PGE2 from ischemic myocardium.