Cardiovascular pharmacology of vasodilating drugs in the pig : a study on dihydropyridine calcium-channel blockers, pyridazinone-derivatives and nicorandil

In this thesis the cardiovascular pharmacological actions of a number of vasodilating drugs have been studied and compared in pigs. Firstly, we compared the vasodilator profile of the dihydropyridine-derivatives nisoldipine, nimodipine and nifedipine and also studied the claimed preference of nisoldipine for the coronary circulation (Kazda et al., 1980; Serruys et al., 1985; Drexler et al., 1986b) and of nimodipine for the cerebral circulation (Kazda et al., 1982) (chapters 2-5). Secondly, since the perfusion of organs and tissues may be compromised in several pathological disorders for which vasodilating drugs might be employed (ischemic heart disease, heart failure, hypertension), we compared the vasodilator profiles of the dihydropyridinederivatives nisoldipine and nimodipine with those of pimobendan, UD-CG 212 CL and nicorandil after intravenous administration in anesthetized pigs (chapters 6-9). Thirdly, in view of the potentially useful combination of vasodilators and 13-adrenoceptor antagonists to reduce h;,rpotension -induced baroreceptor reflex-mediated tachycardia, we compared the systemic hemodynamic actions of the different vasodilating drugs in conscious pigs in the absence or presence of 13-adrenoceptor blockade (chapters 9-11). Finally, the long-held view that vasodilation in ischemic myocardium is maximal (see Berne and Rubio, 1979) and, therefore, vasodilators may induce coronary "steal" (Weintraub et al., 1981; Gross and Warltier, 1981; Gewirtz et al., 1984), may not hold true. Recently, vasodilator therapy has been shown to induce an improvement of perfusion and function of ischemic myocardial areas by recruiting vasodilator reserve (Gorman. et al., 1984; Heusch and Deussen, 1984; Aversano and Becker, 1985; Canty and Klocke, 1985; Pantely et al., 1985). In view of these new findings, lending support to the possible usefulness of vasodilator drugs in myocardial ischemia, we investigated the effects of nisoldipine on perfusion of myocardium distal to a fixed concentric coronary artery stenosis in conscious pigs (chapter 12). In. addition, the possible anti-ischemic action of this drug was studied during myocardial ischemiainduced in animals subjected to treadmill-exercise (chapter 13)

Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise

A pivotal role for adenosine in the regulation of coronary blood flow is still controversial. Consequently, we investigated its role in the regulation of coronary vasomotor tone in swine at rest and during graded treadmill exercise. During exercise, myocardial O2 consumption increased from 167 +/- 18 micromol/min at rest to 399 +/- 27 micromol/min at 5 km/h (P </= 0.05), which was paralleled by an increase in O2 delivery, so that myocardial O2 extraction (76 +/- 1 and 78 +/- 1% at rest and 5 km/h, respectively) and coronary venous PO2 (24.5 +/- 1.0 and 22.8 +/- 0.3 mmHg at rest and 5 km/h, respectively) remained unchanged. After adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg iv), the relation between myocardial O2 consumption and coronary vascular resistance was shifted toward higher resistance, whereas myocardial O2 extraction rose to 81 +/- 1 and 83 +/- 1% at rest and 5 km/h and coronary venous PO2 fell to 19.2 +/- 0.8 and 18.9 +/- 0.8 mmHg at rest and 5 km/h, respectively (all P </= 0.05). Thus, although adenosine is not mandatory for the exercise-induced coronary vasodilation, it exerts a vasodilator influence on the coronary resistance vessels in swine at rest and during exercise

Animal models of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) constitutes a clinical syndrome in which the diagnostic criteria of heart failure are not accompanied by gross disturbances of systolic function, as assessed by ejection fraction. In turn, under most circumstances, diastolic function is impaired. Although it now represents over 50% of all patients with heart failure, the mechanisms of HFpEF remain understood, precluding effective therapy. Understanding the pathophysiology of HFpEF has been restricted by both limited access to human myocardial biopsies and by the lack of animal models that fully mimic human pathology. Animal models are valuable research tools to clarify subcellular and molecular mechanisms under conditions where the comorbidities and other confounding factors can be precisely controlled. Although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfil all the features present in human disease. In this review we will provide an overview of the currently available models to study HFpEF from rodents to large animals as well as present advantages and disadvantages of these models

Sex differences in pulmonary vascular control: focus on the nitric oxide pathway

Although the incidence of pulmonary hypertension is higher in females, the severity and prognosis of pulmonary vascular disease in both neonates and adults have been shown to be worse in male subjects. Studies of sex differences in pulmonary hypertension have mainly focused on the role of sex hormones. However, the contribution of sex differences in terms of vascular signaling pathways regulating pulmonary vascular function remains incompletely understood. Consequently, we investigated pulmonary vascular function of male and female swine in vivo, both at rest and during exercise, and in isolated small pulmonary arteries in vitro, with a particular focus on the NO-cGMP-PDE5 pathway. Pulmonary hemodynamics at rest and during exercise were virtually identical in male and female swine. Moreover, NO synthase inhibition resulted in a similar degree of pulmonary vasoconstriction in male and female swine. However, NO synthase inhibition blunted bradykinin-induced vasodilation in pulmonary small arteries to a greater extent in male than in female swine. PDE5 inhibition resulted in a similar degree of vasodilation in male and female swine at rest, while during exercise there was a trend towards a larger effect in male swine. In small pulmonary arteries, PDE5 inhibition failed to augment bradykinin-induced vasodilation in either sex. Finally, in the presence of NO synthase inhibition, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in female swine both in vivo and in vitro. In conclusion, the present study demonstrated significant sex differences in the regulation of pulmonary vascular tone, which may contribute to understanding sex differences in incidence, treatment response, and prognosis of pulmonary vascular disease

Role of K(ATP)(+) channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine

The role of ATP-sensitive K(+) (K(ATP)(+)) channels in vasomotor tone regulation during metabolic stimulation is incompletely understood. Consequently, we studied the contribution of K(ATP)(+) channels to vasomotor tone regulation in the systemic, pulmonary, and coronary vascular bed in nine treadmill-exercising swine. Exercise up to 85% of maximum heart rat