Restoration of muscle function after injury requires the coordinate restoration of muscle fibers and microcirculation, as well as muscle and vascular innervation. Hypertension may have a significant effect on muscle regeneration, particularly on the regeneration of muscle blood vessels and the restoration of normal vascular control mechanisms. Applicants' preliminary studies, in which muscle injury was induced by tourniquet ischemia, Marcaine injection, or nerve-intact graft, indicate that experimental muscle injury in the SHR is associated with significantly slower and less complete regenerative recovery than occurs in the normotensive Wistar Kyoto rat (WKY). Moreover, the rate and extent of regenerative recovery in SHR is more severely limited when both muscle fibers and blood vessels are involved than when only the fibers are affected. In addition to being hypertensive, SHR is hyperinsulinemic, a state in which insulin receptors and IGF-I receptors are down-regulated. Down-regulation of receptors would impede the action of these growth factors during the repair process after injury. The investigators propose to determine: whether the impaired regenerative recovery of SHR muscle is linked to impaired regeneration of muscle blood vessels and lack of restoration of normal mechanisms controlling blood flow; whether the degree of vascular injury is related to the level and duration of hypertension; and whether the delayed recovery is related to decreased effectiveness of insulin and insulin-like growth factors, IGF-I and IGF-II. There are four AIMS to investigate various aspects of regeneration in extensor digitorum longus (EDL) and soleus (SOL) in hypertension, addressing: I) the effects of age and duration of hypertension on recovery; II) the effect of blood pressure, per se , on the recovery process, by studying muscle injury in SHR with pharmacologically normalized blood pressure (prazocin, propranolol and captopril), WKY with Golblatt hypertension, and cross-grafted EDL muscles between WKY and SHR; III) the functional state of the vessels in recovering muscle, by in vitro and in vivo assessments of arteriolar reactivity, capillary function, and blood flow; IV) the effect of the hyperinsulinemic state in SHR on effectiveness of IGF-I in promoting regenerative growth, by studying IGF-I receptor number and affinity, and concentration and binding characteristics of IGF-I plasma binding proteins. Hypertension and hyperinsulinemia are important risk factors in the progressive development of cardiovascular disease in humans, and these studies may elucidate mechanisms by which they interact, particularly with regard to regenerating vasculature in injured tissue.
