Cardiovascular disease (CVD) is known as the major cause of disability and early death in both developed and developing countries (WHO, 2007[20]). In this regard, coronary heart disease (CHD) makes up more than half of all cardiovascular events in American population < 75 years of age (Thom et al., 2001[18]). Diabetes is one of the nine major risk factors that are involved in pathogenesis of CHD (Greenland et al., 2003[4]; Yusuf et al., 2004[21]).

Previous studies demonstrated the beneficial effect of semelil, a formulated extract of Melilotus officinalis plant containing important compounds such as 7 hydroxy coumarin and flavonoids, as a new herbal drug in treatment of diabetic foot ulcers (Ebrahimi et al., 2009[3]; Heshmat et al., 2008[6]). Although exact anti-ulcer mechanism of semelil is not clear, this has been attributed to the antioxidant (Hirakawa et al., 2000[7]) and anti-inflammatory properties (Pleşca-Manea et al., 2002[16]) of its components. However, Hemmatabadi et al. (2009[5]) reported that non-antioxidant effects may be involved in the therapeutic action of semelil on diabetic foot ulcers. Improvement in blood flow has been suggested as another possible effect of this agent (Bahrami et al., 2008[2]). Recently, Asadi-Shekaari et al. (2010[1]) showed the neuroprotective role of semelil in rat with focal cerebral ischemia. Despite the clinical use of semelil in Iran, less attention has been paid to the consequences of its administration on the cardiovascular system.

Considering the possible role of this drug in improving blood flow and lack of adequate knowledge about its cardiovascular consequences, in the present study we investigated the pretreatment effect of semelil on cardiovascular performance of animals subjected to experimental myocardial injury based on hemodynamic, electrophysiological, biochemical and histopathological indices.

The present study was conducted to assess the effect of semelil on cardiovascular system in stressful conditions. High doses of isoproterenol, a non selective beta adrenergic agonist, by induction of cardiac stress cause myocardial injury and this method has been accepted as a standard experimental model to induce cardiac dysfunctions and to evaluate following interventions (Rona et al., 1959[17]; Wexler, 1978[19]; Joukar et al., 2010[10]). In agreement with previous investigations, the present study showed that injection of isoproterenol (50 mg/kg) for two successive days was associated with significant reduction in myocardial function observed by increase in LVEDP and decrease in LVSP and positive and negative dp/dt maxes (see Figure 1(Fig. 1) and Table 1(Tab. 1)). Increase in plasma cardiac troponin I, ECG disturbances and mild to moderate leukocyte infiltration and myodegeneration of the heart muscle was also seen. Blood pressure level was slightly decreased in animals with heart damage (ISO group), but higher doses of semelil was associated with less reduction in mean arterial pressure which may be due to improvement in heart perfusion. Previous studies have reported positive effect of semelil on tissue blood flow (Bahrami et al., 2008[2]). The present study showed that semelil at doses of 5 and 10 mg/kg improved left ventricular function of damaged heart by inducing positive inotropic effect (+dp/dt max, an important index of myocardial contractility) (Koeppen and Stanton, 2008[12]), and positive lusitropic effect (-dp/dt max, indicator of myocardial relaxation). It also reduced the ISO-induced increase in LVEDP (marker of heart failure), in a dose-dependent manner. To our best knowledge, no study in the literature has yet investigated the effects of semelil on the heart function. Increased calcium influx to cardiac cells and prevention of myocardial stunning during heart injury may be two possible reasons for positive inotropic effect of semelil in higher doses. However, confirmation of these possibilities needs future investigations.

Despite the positive effect of semelil on cardiac function, it was associated with more intense myocardial damage based on histology data (Figure 3(Fig. 3)). Although the improvement of myocardial contractility leads to more stroke volume, more cardiac output and consequently better blood pressure stability (Table 1(Tab. 1)), this could increase cardiac workload and oxygen demand leading to heart damage in ischemia conditions. In this regard, reduction of myocardial energy demands is one of the several approaches for declining infarct size in patients with myocardial injury (Zipes et al., 2005[22]). More extent and exacerbation of heart lesions in semelil experiments may be due to increased cardiac load and myocardial oxygen supply limitation resulted from increase in contractility that in turn could justify high mortality rate in animals that received the drug in dose of 20 mg/kg. Today, the role of inflammatory processes in the development of cardiovascular disease is well known (Little et al., 2011[13]). Exacerbation of inflammatory process followed by semelil injection may be the negative effect of this drug on heart tissue. The anti inflammatory effect of chronic semelil use has been shown in a previous study (Mousavi-Jazi et al., 2010[14]). In the present study we used semelil only for two consecutive days in each treated groups that can be a reason of difference between our results with others. In addition the heart tissue inflammatory response to semelil may be different from other tissues.

Surprisingly the lower dose of semelil exacerbated the effect of ISO on blood pressure and heart rate. It seems that semelil in this dose has directly suppressed pacemaker activity (S-A node) of the heart because despite the lowering effect on blood pressure (BP) heart rate (HR) was also reduced, while it is anticipated that reduction in BP causes an increase in HR through baro-receptor reflex (sympathetic stimulation). In fact reduction of BP may be the consequence of reduction in HR and hence cardiac output. However, in larger doses, semelil recovered BP through improving myocardial contractility. The evidence for this statement is increase in LVSP and reduction in LVEDP in groups that received larger doses of semelil (Table 1(Tab. 1)). Therefore semelil should have two different mechanisms of action in low and high doses and this hypothesis needs further investigations to prove.

From ECG point of view, semelil administration had no additional effect on ISO effect alone. This finding may mean that semelil does not affect current injury and conduction properties of the heart. However, the influence of semelil on incidence of cardiac arrhythmia needs complementary studies.

In conclusion the present study showed that semelil administration can help to maintain the heart contractility and hence blood pressure stability in myocardial injury conditions. However this beneficial effect may associate with further cardiac injury due to increased cardiac workload and activation of inflammatory process. In long term periods, this could lead to deterioration of the ischemic heart function. It is noteworthy that present study examined the acute effects of semelil and future studies are needed to elucidate the chronic effects of this drug on cardiovascular system.

The authors confirm that there is no conflict of interest in this study. We are grateful to ParsRoos Company and also Dr. Khorram Khorshid and Dr. Mohammad Doost for kindly dedication of semelil. This study was financially supported by Kerman University of Medical Sciences and Health Services of Iran.